Brad C. Dickerson

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.

<b>Objective: </b> To use fMRI to investigate whether hippocampal and entorhinal activation during learning is altered in the earliest phase of mild cognitive impairment (MCI). <b>Methods: </b> Three groups of older individuals were studied: 10 cognitively intact controls, 9 individuals at the mild end of the spectrum of MCI, and 10 patients with probable Alzheimer disease (AD). Subjects performed a face-name associative encoding task during fMRI scanning, and were tested for recognition of stimuli afterward. Data were analyzed using a functional-anatomic method in which medial temporal lobe (MTL) regions of interest were identified from each individual9s structural MRI, and fMRI activation was quantified within each region. <b>Results: </b> Significantly greater hippocampal activation was present in the MCI group compared to controls; there were no differences between these two groups in hippocampal or entorhinal volumes. In contrast, the AD group showed hippocampal and entorhinal hypoactivation and atrophy in comparison to controls. The subjects with MCI performed similarly to controls on the fMRI recognition memory task; patients with AD exhibited poorer performance. Across all 29 subjects, greater mean entorhinal activation was found in the subgroup of 13 carriers of the <i>APOE</i> ε4 allele than in the 16 noncarriers. <b>Conclusions: </b> The authors hypothesize that there is a phase of increased medial temporal lobe activation early in the course of prodromal Alzheimer disease followed by a subsequent decrease as the disease progresses.

We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease.Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations, and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests.44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008) and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers.Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease.Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.

With high resolution, quantitative magnetic resonance imaging (MRI) techniques, it is now possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer’s disease (AD). In this study, we compared MRI-derived entorhinal and hippocampal volume in healthy elderly controls, patients who presented at the clinic with cognitive complaints, but did not meet criteria for dementia (non-demented), and patients with very mild AD. The two patient groups differed significantly from controls in entorhinal volume, but not from each other; in contrast, they differed from each other, as well as from controls, in hippocampal volume, with the mild AD cases showing the greatest atrophy. Follow-up clinical evaluations available on 23/28 non-demented patients indicated that 12/23 had converted to AD within 12–77 months from the baseline MRI examination. Converters could be best differentiated from non-converters on the basis of entorhinal, but not hippocampal volume. These data suggest that although both the EC and hippocampal formation degenerate before the onset of overt dementia, EC volume is a better predictor of conversion.

Previous cross-sectional fMRI studies in subjects with prodromal Alzheimer disease (AD) have reported variable results, ranging from hypoactivation, similar to patients with AD, to paradoxically increased activation or hyperactivation compared to cognitively normal older individuals. We have hypothesized that subjects in early phases of prodromal AD may experience a period of hippocampal hyperactivation, followed by loss of hippocampal activation as the disease progresses.We studied 51 older individuals without dementia (Clinical Dementia Rating [CDR] at baseline of 0, n = 21, and 0.5, n = 30) with longitudinal clinical and neuropsychological assessments, as well as fMRI during a face-name associative memory paradigm. Whole brain and region-of-interest analyses were applied to the longitudinal fMRI data.Subjects classified as CDR 0 at baseline showed no difference in fMRI activity over 2 years, whereas those who were CDR 0.5 at baseline demonstrated a decrease in fMRI activity in the right hippocampus (p < 0.001). Dividing the subjects on the basis of their clinical and neuropsychological change over the 2 years, we found that subjects with more rapid decline demonstrated both the highest hippocampal activation at baseline, and the greatest loss of hippocampal activation. These findings remained significant after accounting for age, hippocampal volume, and APOE epsilon4 carrier status.Clinical decline is associated with loss of hippocampal activation in older subjects. Longitudinal fMRI provides a reliable indicator of brain activation over time, and may prove useful in identifying functional brain changes associated with cognitive decline on the trajectory toward clinical Alzheimer disease.

Alzheimer's disease (AD) is associated with functional and structural alterations in a distributed network of brain regions supporting memory and other cognitive domains. Functional abnormalities are present in mild cognitive impairment (MCI) with evidence of early hyperactivity in medial temporal lobe regions, followed by failure of hippocampal activation as dementia develops. Atrophy in a consistent set of cortical regions, the "cortical signature of AD," has been reported at the stage of dementia, MCI, and even in clinically normal (CN) older individuals predicted to develop AD. Despite multiple lines of evidence for each of these findings, the relationship between this structural marker of AD-related neurodegeneration and this functional marker of the integrity of the episodic memory system has not yet been elucidated. We investigated this relationship in 34 nondemented older humans (CN, N = 18; MCI, N = 16). Consistent with previous studies, we found evidence of hippocampal hyperactivation in MCI compared with CN. Additionally, within this MCI group, increased hippocampal activation correlated with cortical thinning in AD-signature regions. Even within the CN group, increased hippocampal activity was negatively correlated with cortical thinning in a subset of regions, including the superior parietal lobule (r = -0.66; p < 0.01). These findings, across a continuum of nondemented and mildly impaired older adults, support the hypothesis that paradoxically increased hippocampal activity may be an early indicator of AD-related neurodegeneration in a distributed network.

<h3>Objective:</h3> To use functional MRI (fMRI) to investigate whether hippocampal activation during a memory task can predict cognitive decline in individuals with mild cognitive impairment (MCI). <h3>Methods:</h3> 25 older individuals with MCI performed a visual scene encoding task during fMRI scanning, and were followed clinically for at least 4 years after scanning. A hypothesis driven analysis of fMRI data was performed. First, fMRI data were analysed at the group level to identify the regions of the hippocampal formation that were engaged by this memory task. Parameter estimates of each subject’s memory related hippocampal activation (% signal change) were extracted and were analysed with a linear regression model to determine whether hippocampal activation predicted the degree or rate of cognitive decline, as measured by change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB). <h3>Results:</h3> Over 5.9 (1.2) years of follow-up after scanning, subjects varied widely in degree and rate of cognitive decline (change in CDR-SB ranged from 0 to 6, and the rate ranged from 0 to 1 CDR-SB unit/year). Greater hippocampal activation predicted greater degree and rate of subsequent cognitive decline (p&lt;0.05). This finding was present even after controlling for baseline degree of impairment (CDR-SB), age, education and hippocampal volume, as well as gender and apolipoprotein E status. In addition, an exploratory whole brain analysis produced convergent results, demonstrating that the hippocampal formation was the only brain region where activation predicted cognitive decline. <h3>Conclusions:</h3> In individuals with MCI, greater memory task related hippocampal activation is predictive of a greater degree and rate of cognitive decline subsequent to scanning. fMRI may provide a physiological imaging biomarker useful for identifying the subgroup of MCI individuals at highest risk of cognitive decline for potential inclusion in disease modifying clinical trials.

Introversion/extraversion and neuroticism are 2 important and frequently studied dimensions of human personality. These dimensions describe individual differences in emotional responding across a range of situations and may contribute to a predisposition for psychiatric disorders. Recent neuroimaging research has begun to provide evidence that neuroticism and introversion/extraversion have specific functional and structural neural correlates. Previous studies in healthy adults have reported an association between neuroticism, introversion/extraversion, and the activity of the prefrontal cortex and amygdala. Studies of individuals with psychopathological states have also indicated that anatomic variations in these brain areas may relate to extraversion and neuroticism. The purpose of the present study was to examine selected structural correlates of neuroticism and extraversion in healthy subjects (n = 28) using neuroanatomic measures of the cerebral cortex and amygdala. We observed that the thickness of specific prefrontal cortex regions correlates with measures of extraversion and neuroticism. In contrast, no such correlations were observed for the volume of the amygdala. The results suggest that specific aspects of regional prefrontal anatomy are associated with specific personality traits.

Many neuroscience studies have demonstrated that the human amygdala is a central element in the neural workspace that computes affective value. Emerging evidence suggests that novelty is an affective dimension that engages the amygdala independently of other affective properties. This current study is the first in which novelty, valence, and arousal were systematically examined for their relative contributions to amygdala activation during affective processing. Healthy young adults viewed International Affective Picture System (IAPS) images that varied along the dimensions of valence (positive, negative, neutral), arousal (high, mid, low), and novelty (novel, familiar). The results demonstrate that, in comparison to negative (vs. positive) and high (vs. low) arousal stimuli, the amygdala has higher peak responses and a selectively longer time course of activation to novel (vs. familiar) stimuli. In addition, novelty differentially engaged other affective brain areas including those involved in controlling and regulating amygdala responses (e.g., orbitofrontal cortex), as well as those transmitting sensory signals that the amygdala modulates (e.g., occipitotemporal visual cortex). Taken together with other findings, these results support the idea that an essential amygdala function is signaling stimulus importance or salience. The results also suggest that novelty is a critical stimulus dimension for amygdala engagement (in addition to valence and arousal).

Noninvasive brain stimulation techniques (NiBS) have gathered substantial interest in the study of dementia, considered their possible role in help defining diagnostic biomarkers of altered neural activity for early disease detection and monitoring of its pathophysiological course, as well as for their therapeutic potential of boosting residual cognitive functions. Nevertheless, current approaches suffer from some limitations. In this study, we review and discuss experimental NiBS applications that might help improve the efficacy of future NiBS uses in Alzheimer's Disease (AD), including perturbation-based biomarkers for early diagnosis and disease tracking, solutions to enhance synchronization of oscillatory electroencephalographic activity across brain networks, enhancement of sleep-related memory consolidation, image-guided stimulation for connectome control, protocols targeting interneuron pathology and protein clearance, and finally hybrid-brain models for in-silico modeling of AD pathology and personalized target selection. The present work aims to stress the importance of multidisciplinary, translational, model-driven interventions for precision medicine approaches in AD.

Atrophy of the hippocampal formation, a region important for the acquisition of new declarative knowledge, has been well-documented in Alzheimer's disease (AD), although the relation of such atrophy to the extent of memory dysfunction in these patients has been less clear. In the present study, 18 patients with a clinical diagnosis of probable AD were studied with a high-resolution, quantitative magnetic resonance imaging (MRI) protocol, as well as the verbal and spatial versions of the Buschke controlled learning task. The volumes of the hippocampal formation and, as a control for generalized atrophy, parahippocampal gyrus and temporal neocortex were computed from gapless coronal slices taken perpendicular to the long axis of the hippocampus. To correct for individual differences in brain size, volumes of regions of interest were divided by total intracranial volume. Separate stepwise regression analyses (with age, right and left hippocampal, parahippocampal gyrus, and temporal lobe volumes as the independent variables) showed that left hippocampal volume was the best predictor of free recall and delayed free recall of verbal information (P = 0.0042 and P < 0.0001, respectively). Recall and delayed recall of the spatial location of verbal items were best predicted by right hippocampal volume (P = 0.0054 and P = 0.0118, respectively). Memory scores did not correlate either with parahippocampal gyrus or temporal lobe volume. Furthermore, the relation between hippocampal volume and memory function observed in cases with AD did not hold for healthy aged control subjects.

The application of advances in biomedical computing to medical imaging research is enabling scientists to conduct quantitative clinical imaging studies using data collected across multiple sites to test new hypotheses on larger cohorts, increasing the power to detect subtle effects. Given that many research groups have valuable existing (legacy) data, one goal of the Morphometry Biomedical Informatics Research Network (BIRN) Testbed is to assess the feasibility of pooled analyses of legacy structural neuroimaging data in normal aging and Alzheimer’s disease. The present study examined whether such data could be meaningfully reanalyzed as a larger combined data set by using rigorous data curation, image analysis, and statistical modeling methods; in this case, to test the hypothesis that hippocampal volume decreases with age and to investigate findings of hippocampal asymmetry. This report describes our work with legacy T1-weighted magnetic resonance (MR) and demographic data related to normal aging that have been shared through the BIRN by three research sites. Results suggest that, in the present application, legacy MR data from multiple sites can be pooled to investigate questions of scientific interest. In particular, statistical analyses suggested that a mixed-effects model employing site as a random effect best fits the data, accounting for site-specific effects while taking advantage of expected comparability of age-related effects. In the combined sample from three sites, significant age-related decline of hippocampal volume and right-dominant hippocampal asymmetry were detected in healthy elderly controls. These expected findings support the feasibility of combining legacy data to investigate novel scientific questions.

Prevalence of affective disorder points at a prominent sex-specific component. Specifically, women are diagnosed with affective disorder approximately twice as frequently as men are. Women experience more frequent affective symptoms during the luteal phase of the menstrual cycle, when progesterone levels are high. During the luteal phase, connectivity between the default mode and salience networks of the brain, endocrine stress responses, and memory for affective experience all increase. Similar increases in these areas are observed in comparisons between individuals with affective disorder and healthy controls. We propose that sex differences in affective disorder can be explained by a midluteal window of vulnerability in women, in which increased connectivity, stress reactivity, and affective memory make negative experiences more potent and memorable, promoting negative affect. We argue that examining sexually dimorphic aspects of brain structure and function at singular time points can be misleading, and that such differences should be conceptualized as part of a dynamic process unfolding over time. This may help explain discrepancies in studies of sex differences in brain function. The rate of affective disorder is substantially higher in women than in men, and considerable evidence points to the actions of ovarian hormones in mediating this disparity. In this Opinion, we discuss the hypothesis that cyclic changes in ovarian hormone levels produce cyclic alterations in connectivity between the intrinsic networks of the brain. These alterations produce specific temporal windows within the menstrual cycle when internetwork connectivity is increased, associated with increased stress reactivity and better memory for unpleasant, arousing events, leading to increased negative mood and susceptibility to affective disorder. Our windows of vulnerability model offers insights for both treatment of affective disorder and research on sex differences in the brain. The rate of affective disorder is substantially higher in women than in men, and considerable evidence points to the actions of ovarian hormones in mediating this disparity. In this Opinion, we discuss the hypothesis that cyclic changes in ovarian hormone levels produce cyclic alterations in connectivity between the intrinsic networks of the brain. These alterations produce specific temporal windows within the menstrual cycle when internetwork connectivity is increased, associated with increased stress reactivity and better memory for unpleasant, arousing events, leading to increased negative mood and susceptibility to affective disorder. Our windows of vulnerability model offers insights for both treatment of affective disorder and research on sex differences in the brain.

Abstract The ability to spontaneously recall recently learned information is a fundamental mnemonic activity of daily life, but has received little study using functional neuroimaging. We developed a functional MRI (fMRI) paradigm to study regional brain activity during encoding that predicts free recall. In this event‐related fMRI study, ten lists of fourteen pictures of common objects were shown to healthy young individuals and regional brain activity during encoding was analyzed based on subsequent free recall performance. Free recall of items was predicted by activity during encoding in hippocampal, fusiform, and inferior prefrontal cortical regions. Within‐subject variance in free recall performance for the ten lists was predicted by a linear combination of condition‐specific inferior prefrontal, hippocampal, and fusiform activity. Recall performance was better for lists in which prefrontal activity was greater for all items of the list and hippocampal and fusiform activity were greater specifically for items that were recalled from the list. Thus, the activity of medial temporal, fusiform, and prefrontal brain regions during the learning of new information is important for the subsequent free recall of this information. These fronto‐temporal brain regions act together as a large‐scale memory‐related network, the components of which make distinct yet interacting contributions during encoding that predict subsequent successful free recall performance. © 2007 Wiley‐Liss, Inc.

Patients with frontotemporal dementia (FTD) often exhibit prominent, early and progressive impairments in social behaviour. We developed the Social Impairment Rating Scale (SIRS), rated by a clinician after a structured interview, which grades the types and severity of social behavioural symptoms in seven domains. In 20 FTD patients, we used the SIRS to study the anatomic basis of social impairments. In support of hypotheses generated from a prior study of healthy adults, we found that the relative magnitude of brain atrophy in three partially dissociable corticolimbic networks anchored in the amygdala predicted the severity of distinct social impairments measured using the SIRS. Patients with the greatest atrophy in a mesolimbic, reward-related (affiliation) network exhibited the most severe socioemotional detachment, whereas patients with the greatest atrophy in an interoceptive, pain-related (aversion) network exhibited the most severe lack of social apprehension. Patients with the greatest atrophy in a perceptual network exhibited the most severe lack of awareness or understanding of others’ social and emotional behaviour. Our findings underscore observations that FTD is associated with heterogeneous social symptoms that can be understood in a refined manner by measuring impairments in component processes subserved by dissociable neural networks. Furthermore, these findings support the validity of the SIRS as an instrument to measure the social symptoms of patients with FTD. Ultimately, we hope it will be useful as a longitudinal outcome measure in natural history studies and in clinical trials of putative interventions to improve social functioning.

A new protocol for measuring the volume of the entorhinal cortex (EC) from magnetic resonance images (MRI) was developed specifically to measure the EC from oblique coronal sections used in hippocampal volumetric studies. The relative positions of the anatomic landmarks demarcating EC boundaries were transposed from standard coronal sections to oblique ones. The lateral EC border, which is the most controversial among anatomists, was defined in a standard and conservative manner at the medial edge of the collateral sulcus. Two raters measured the EC twice for 78 subjects (healthy aged individuals, very mild AD patients, and elderly patients who did not meet criteria for dementia) to study intra- and inter-rater reproducibility and reliability of measurements. The level of accuracy achieved (coefficients of reproducibility of 1.40-3.86%) and reliability of measurements (intraclass correlation coefficients of 0.959-0.997) indicated that this method provides a feasible tool for measuring the volume of the EC in vivo.

Financial planning decisionss are fundamentally affective in nature; they are decisions related to money, longevity and quality of life. Over the next several decades people will be increasingly responsible for managing their own assets and investments, and they will be subject to the affective influences on active, personal decision-making. Many of these crucial decisions are made and revised across the lifespan, including when to buy or sell a home, how to save for childrens' education, how to manage healthcare costs, when to retire, how much to save for retirement and how to allocate retirement funds. As average life expectancy increases, many retirees will be faced with inadequate savings to live comfortably until the end of their lives. In the current article, we examine the problems of and potential solutions to inadequate financial planning through the lens of affective science, with an emphasis on how brain-based changes in affective processing with age might contribute to the challenge of financial planning.

Abstract We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. ( n =6) or placebo ( n =2), the second cohort 40 mg b.i.d. ( n =6) or placebo ( n =2), and the third cohort 40 mg t.i.d. ( n =6) or placebo ( n =2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4–20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions—Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort.

Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Abstract Introduction Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. Methods A total of 135 sporadic (s‐bvFTD; mean age 63.3 years; 34% female) and 99 familial (f‐bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f‐bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 ( C9orf72 ) gene expansions, 28 with known or presumed microtubule‐associated protein tau (MAPT) mutations, 14 with known progranulin ( GRN ) mutations, and 14 with a strong family history of FTD but no identified mutation. Results Participants with f‐bvFTD were younger and had earlier age at onset. s‐bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores due to more frequent endorsement of depression and irritability. Discussion f‐bvFTD and s‐bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy-Richardson and variant progressive supranuclear palsy syndromes). Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy-Richardson, 52 with a progressive supranuclear palsy-cortical variant (progressive supranuclear palsy-frontal, progressive supranuclear palsy-speech/language, or progressive supranuclear palsy-corticobasal), and 17 with a progressive supranuclear palsy-subcortical variant (progressive supranuclear palsy-parkinsonism or progressive supranuclear palsy-progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation. The data supported two subtypes, each with a distinct progression of atrophy: a 'subcortical' subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a 'cortical' subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy-subcortical cases and 81% of progressive supranuclear palsy-Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy-cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the 'subcortical' subtype was associated with worse clinical severity scores compared to the 'cortical subtype' (progressive supranuclear palsy rating scale and Unified Parkinson's Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up. In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression.

SUMMARY Non-invasive G amma EN trainment U sing S ensory stimuli (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study ( NCT04042922 ) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS ( NCT04055376 ) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimer’s disease.

<b>Background: </b> Functional MRI (fMRI) has shown promise as a tool to characterize altered brain function in Alzheimer disease (AD) and for use in proof of concept clinical trials. FMRI studies of subjects with AD have demonstrated altered hippocampal and neocortical activation while encoding novel stimuli compared to older controls. However, the relationship between fMRI activation and performance on standardized clinical trial memory measures has not been fully investigated. <b>Objective: </b> To determine whether patterns of activation during an associative-memory fMRI paradigm correlate with performance on memory measures used in AD clinical trials. <b>Methods: </b> Twenty-nine subjects with AD underwent neuropsychological testing, including the AD Assessment Scale (ADAS-Cog), and an associative-encoding fMRI paradigm. Scores were entered as regressors in SPM2 analyses of the differential fMRI activation to novel-vs-repeated (NvR) stimuli. To account for cerebral atrophy, native-space structure-function analyses were performed with subjects’ high-resolution structural images. <b>Results: </b> Performance on the ADAS-Cog verbal memory component, and the ADAS-Cog total score, correlated with NvR activation in left superior temporal (<i>p</i> = 0.0003; <i>r</i> = −0.51) and left prefrontal (<i>p</i> = 0.00001; <i>r</i> = −0.63) cortices. In a subgroup with more extensive neuropsychological testing (n = 14), performance on the Free and Cued Selective Reminding Test was correlated with activation in these same regions. fMRI activation remained correlated with performance even when accounting for atrophy. <b>Conclusions: </b> The relationship between functional MRI (fMRI) activation and standardized memory measures supports the potential use of fMRI to investigate regional mechanisms of treatment response in clinical trials of novel therapies for Alzheimer disease. <b>GLOSSARY: </b><b>AD</b> = Alzheimer disease; <b>ADAS-Cog</b> = AD Assessment Scale; <b>EPI</b> = echoplanar imaging sequence; <b>FA</b> = flip angle; <b>FCSRT</b> = Free and Cued Selective Reminding Test; <b>FLAME</b> = FMRIB’s Local Analysis of Mixed Effects; <b>fMRI</b> = Functional MRI; <b>FOV</b> = field of view; <b>GLM</b> = general linear model; <b>HRF</b> = hemodynamic response function; <b>LFG</b> = left fusiform gyrus; <b>LPFC</b> = left prefrontal cortex; <b>LSTG</b> = left superior temporal gyrus; <b>MMSE</b> = Mini-Mental State Examination; <b>MTL</b> = medial temporal lobe; <b>NvR</b> = novel-vs-repeated; <b>ROI</b> = region of interest; <b>TE</b> = echo time; <b>TR</b> = repetition time.

Importance Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)–associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology. Objective To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. Design, Setting, and Participants This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort. Main Outcome and Measures Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling. Results Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P &amp;amp;lt; .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P &amp;amp;lt; .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005). Conclusions and Relevance In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Tau PET has enabled the visualization of paired helical filaments of 3 or 4 C-terminal repeat tau in Alzheimer disease (AD), but its ability to detect aggregated tau in frontotemporal lobar degeneration (FTLD) spectrum disorders is uncertain. We investigated 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5c']dipyridine ([18F]PI-2620), a newer tracer with ex vivo evidence for binding to FTLD tau, in a convenience sample of patients with suspected FTLD and AD using a static acquisition protocol and parametric SUV ratio (SUVr) images. Methods: We analyzed [18F]PI-2620 PET data from 65 patients with clinical diagnoses associated with AD or FTLD neuropathology; most (60/65) also had amyloid-β (Aβ) PET. Scans were acquired 30-60 min after injection; SUVr maps (reference, inferior cerebellar cortex) were created for the full acquisition and for 10-min truncated sliding windows (30-40, 35-45,…50-60 min). Age- and sex-adjusted z score maps were computed for each patient, relative to 23 Aβ-negative cognitively healthy controls (HC). Mean SUVr in the globus pallidus, substantia nigra, subthalamic nuclei, dentate nuclei, white matter, and temporal gray matter was extracted for the full and truncated windows. Results: Patients with suspected AD neuropathology (Aβ-positive patients with mild cognitive impairment or AD dementia) showed high-intensity temporoparietal cortex-predominant [18F]PI-2620 binding. At the group level, patients with clinical diagnoses associated with FTLD (progressive supranuclear palsy with Richardson syndrome [PSP Richardson syndrome], corticobasal syndrome, and nonfluent-variant primary progressive aphasia) exhibited higher globus pallidus SUVr than did HCs; pallidal retention was highest in the PSP Richardson syndrome group, in whom SUVr was correlated with symptom severity (ρ = 0.53, P = 0.05). At the individual level, only half of PSP Richardson syndrome, corticobasal syndrome, and nonfluent-variant primary progressive aphasia patients had a pallidal SUVr above that of HCs. Temporal SUVr discriminated AD patients from HCs with high accuracy (area under the receiver operating characteristic curve, 0.94 [95% CI, 0.83-1.00]) for all time windows, whereas discrimination between patients with PSP Richardson syndrome and HCs using pallidal SUVr was fair regardless of time window (area under the receiver operating characteristic curve, 0.77 [95% CI, 0.61-0.92] at 30-40 min vs. 0.81 [95% CI, 0.66-0.96] at 50-60 min; P = 0.67). Conclusion: [18F]PI-2620 SUVr shows an intense and consistent signal in AD but lower-intensity, heterogeneous, and rapidly decreasing binding in patients with suspected FTLD. Further work is needed to delineate the substrate of [18F]PI-2620 binding and the usefulness of [18F]PI2620 SUVr quantification outside the AD continuum.

Suspected non-Alzheimer's pathophysiology (SNAP) is a biomarker driven designation that represents a heterogeneous group in terms of etiology and prognosis. SNAP has only been identified by cross-sectional neurodegeneration measures, whereas longitudinal measures might better reflect "active" neurodegeneration and might be more tightly linked to prognosis. We compare neurodegeneration defined by cross-sectional 'hippocampal volume' only (SNAP/L−) versus both cross-sectional and longitudinal 'hippocampal atrophy rate' (SNAP/L+) and investigate how these definitions impact prevalence and the clinical and biomarker profile of SNAP in Mild Cognitive Impairment (MCI). 276 MCI patients from ADNI-GO/2 were designated amyloid "positive" (A+) or "negative" (A−) based on their florbetapir scan and neurodegeneration 'positive' or 'negative' based on cross-sectional hippocampal volume and longitudinal hippocampal atrophy rate. 74.1% of all SNAP participants defined by the cross-sectional definition of neurodegeneration also met the longitudinal definition of neurodegeneration, whereas 25.9% did not. SNAP/L+ displayed larger white matter hyperintensity volume, a higher conversion rate to dementia over 5 years and a steeper decline on cognitive tasks compared to SNAP/L− and the A- CN group. SNAP/L− had more abnormal values on neuroimaging markers and worse performance on cognitive tasks than the A- CN group, but did not show a difference in dementia conversion rate or longitudinal cognition. Using a longitudinal definition of neurodegeneration in addition to a cross-sectional one identifies SNAP participants with significant cognitive decline and a worse clinical prognosis for which cerebrovascular disease may be an important driver.

Abstract INTRODUCTION We compared white matter hyperintensities (WMHs) in early‐onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups in the Longitudinal Early‐Onset Alzheimer's Disease Study. METHODS We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t ‐tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. Highlights This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups across all brain regions.

Abstract Background Much of the genetic etiology of sporadic early onset Alzheimer’s disease and frontotemporal dementia is largely unknown. Genetic investigation using whole exome sequencing (WES) data in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) aims to address this gap, with the hypothesis that some individuals with early onset cognitive impairment may carry pathogenic, potentially causative variants in Parkinson’s disease (PD) genes. Methods Whole exome sequencing data for cognitively impaired LEADS participants (N = 301) was processed using the GATK best practices pipeline with Sentieon software; joint‐called VCFs were annotated with Annovar, and the results were filtered to prioritize amino acid code‐altering variants with minor allele frequencies &lt;1% that have not been reported as benign or likely benign in ClinVar. Variants in the acid beta‐glucocerebrosidase (GBA), leucine‐rich repeat kinase 2 (LRRK2), Parkin RBR E3 ubiquitin protein ligase (PRKN), PTEN‐induced putative kinase 1 (PINK1), protein kinase, interferon‐inducible double‐stranded rna‐dependent activator (PRKRA), and Parkinson disease 7, autosomal recessive early‐onset (PARK7) were reviewed. Heterozygous or homozygous carriers of variants meeting these criteria in GBA and LRRK2, as well as homozygous or potentially compound heterozygous variant carriers in the other genes, were reviewed for the presence of PD‐related symptoms documented with the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) collected at baseline (N = 283). Results There were no variants meeting inclusion criteria for PINK1, PARK7, PRKN, or PRKRA. However, we observed 21 individuals with predicted or reported functional variant(s) in GBA or LRRK2. The mean screening visit age for these carriers was 59 (range 53‐64), and all but two were amyloid positive. While only one case was documented with motor symptoms, several participants had peripheral nervous symptoms such as neuropathy. 17 carriers had amnestic‐type dementia, with similar frequency to non‐carriers. Conclusions While there are a small subset of individuals carrying functional variants in PD genes, they do not appear to substantially influence the phenotype of most cases at baseline. Future planned research efforts include assessing alpha synuclein pathology via alpha synuclein seeding assays, which will help clarify the potential role of mixed genetic etiology and pathology in risk for non‐familial early onset dementia.

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Abstract Background Non‐invasive gamma frequency light and sound stimulation at 40Hz reduced Alzheimer’s disease (AD) pathology and improved performance during behavioral testing in mouse models of AD (Iaccarino et al., Nature , 2016; Martorell et al., Cell , 2019; Adaikkan et al., Neuron , 2019). Sensory stimulation inducing 40Hz entrainment reduced amyloid and hyperphosphorylated tau burden and prevented brain atrophy in different mouse models of AD. Performance on tasks testing short‐term memory and spatial learning improved after 6 weeks of daily 40Hz stimulation. We therefore hypothesized that translation of gamma entrainment with light and sound can be used as a disease‐modifying therapeutic for AD. Methods We conducted a placebo‐controlled, randomized control trial (n = 15) in volunteers with probable mild AD to use our light and sound device at home for one hour daily (NCT 04042922). Control devices delivered constant light and white noise while devices with the active setting produced patterned and synchronized light and sound at 40Hz. Electroencephalogram (EEG) was used to evaluate for safety and entrainment when using the 40Hz stimulation. Weekly phone questionnaires were used to assess safety. Magnetic resonance imaging was used to evaluate brain structure and actigraphy was used to record sleep. Face‐name association delayed recall was done to assess changes in cognition. Results We report interim results after 3 months of daily 40Hz stimulation. Mild AD patients were highly compliant with usage in both the control and active groups. EEG data show that our novel light and sound device safely and effectively induced 40Hz entrainment in subjects with mild AD. After 3 months of daily stimulation, 40Hz entrainment prevents both hippocampal atrophy and ventricular enlargement and the extent of ventricular change differs between groups (p = 0.034, p = 0.024, p = 0.043, respectively). Circadian rhythmicity also improved with 40Hz stimulation (p = 0.03). Performance on the face‐name association delayed recall test improved in accuracy (p = 0.004). Conclusions Gamma frequency light and sound stimulation can be used safely daily for 3 months and prevents AD‐related degeneration. Induced entrainment using sensory stimulation at 40Hz shows promise as a novel disease modifying therapeutic for Alzheimer’s dementia.

A critical unmet need for FTLD research, especially therapeutic trials, is the development of biomarkers to distinguish FTLD-tau from FTLD-TDP and other non-tau FTLD pathologies. We are using [18F] T807, a novel PET ligand, to scan a series of patients with FTLD, to date including one MAPT P301L mutation carrier with moderate severity FTD dementia, an asymptomatic carrier of the same mutation, three patients with sporadic mild primary progressive aphasia, and three patients with progressive supranuclear palsy. We analyzed SUVR (cerebellum reference) data to localize and quantify [18F] T807 signal. We also co-registered analyzed [18F] T807 images to MRI images for visualization and calculation of % atrophy relative to controls. [18F] T807 signal was elevated in frontal, insular, and anterior temporal cortex in the MAPT carrier with dementia, and colocalized with atrophy. In two non-fluent aphasic patients, [18F] T807 signal was highest in inferior frontal and middle temporal gyri and temporal pole with marked asymmetry, most prominent in the dominant hemisphere, and localized remarkably well with atrophy. The asymptomatic carrier had mildly elevated signal in frontal, insular, and anterior temporal cortex as well as white matter. PSP patients showed elevated brainstem, basal ganglia, thalamic/subthalamic, cerebellar, and frontal signal. T807 is a promising new PET ligand for imaging tau pathology in vivo in patients with FTLD.

Early detection, accurate diagnosis, and appropriate management of neurodegenerative Cognitive Behavioral Syndromes (CBS), Alzheimer's disease (AD) and dementias represent a public health imperative. Despite more than two decades of advances in diagnostics; delineation of syndromic and disease criteria; and management, cognitive behavioral symptoms due to AD and related neurodegenerative dementias too often go unrecognized or are misattributed, causing delays in appropriate diagnoses and care that are both harmful and costly. In the United States, contributing to high variability, inefficiency, and suboptimal rates of timely diagnosis, is a lack of multidisciplinary clinical guidelines to inform evaluation practices for clinicians in primary and specialty settings who encounter and care for affected individuals and care partners (patient-care partner dyads). To address this gap, in early 2017 The Alzheimer's Association convened a Best Clinical Practices Guidelines (CPG) Workgroup consisting of multidisciplinary clinician experts in dementia care and research. The CPG workgroup was charged to evaluate relevant literature, delineate gaps, and integrate evidence and clinical experience to provide consensus recommendations for the clinical evaluation of CBS and AD dementia clinical spectrums. The CPG workgroup aimed to delineate best practice points and provide practical and specific U.S. guidelines that were multitiered in approach and relevant to both primary and specialty settings. Systematic evidence reviews and literature searches; and a modified Delphi method to develop and grade recommendations. 20 consensus best CPG recommendations for primary and specialty care settings were developed and graded for the evaluation of CBS, and AD dementia clinical spectrums. The recommendations delineate utilization of tiers of assessments and tests based on individual presentation, risk factors and profile to first establish the presence and characteristics of a CBS; second, to investigate possible causes and contributing factors to arrive at an etiologic diagnosis based on established disease criteria; and third, to appropriately educate, communicate findings, and disclose the syndromic and etiologic diagnosis(es), and ensure ongoing management, care and support. This poster will present details of the CPG workgroup aims, process, rationale, and recommendations.

Frontotemporal dementia (FTD) is a neurodegenerative disorder for which there is no effective pharmacological treatment. Recently, interneuron activity responsible for fast oscillatory brain activity has been found to be impaired in a mouse model of FTD with consequent cognitive and behavioral alterations. In this study, we aim to investigate the safety, tolerability, and efficacy of a novel promising therapeutic intervention for FTD based on 40 Hz transcranial alternating current stimulation (tACS), a form of non-invasive brain stimulation thought to engage neural activity in a frequency-specific manner and thus suited to restore altered brain oscillatory patterns.This is a multi-site, randomized, double-blind, placebo-controlled trial on 50 patients with a diagnosis of behavioral variant FTD (bvFTD). Participants will be randomized to undergo either 30 days of 1-hour daily tACS or Sham (placebo) tACS. The outcomes will be assessed at baseline, right after the intervention and at a 3- to 6-months follow-up. The primary outcome measures are represented by the safety and feasibility of tACS administration, which will be assessed considering the nature, frequency, and severity of adverse events as well as attrition rate, respectively. To assess secondary outcomes, participants will undergo extensive neuropsychological and behavioral assessments and fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans to evaluate changes in brain metabolism, functional and structural magnetic resonance imaging (MRI), resting and evoked electroencephalography, as well as blood biomarkers to measure changes in neurodegenerative and neuroinflammatory markers.The trial started in October 2020 and will end in October 2023. Study protocols have been approved by the local institutional review board (IRB) at each data-collection site.This study will evaluate the safety and tolerability of 40 Hz tACS in bvFTD patients and its efficacy on gamma oscillatory activity, cognitive function, and brain glucose hypometabolism.

A critical unmet need for FTLD research, especially therapeutic trials, is the development of biomarkers to distinguish FTLD-tau from FTLD-TDP and other non-tau FTLD pathologies. We are using [18F] T807, a novel PET ligand, to scan a series of patients with FTLD, to date including one MAPT P301L mutation carrier with moderate severity FTD dementia, an asymptomatic carrier of the same mutation, three patients with sporadic mild primary progressive aphasia, and three patients with progressive supranuclear palsy. We analyzed SUVR (cerebellum reference) data to localize and quantify [18F] T807 signal. We also co-registered analyzed [18F] T807 images to MRI images for visualization and calculation of % atrophy relative to controls. [18F] T807 signal was elevated in frontal, insular, and anterior temporal cortex in the MAPT carrier with dementia, and colocalized with atrophy. In two non-fluent aphasic patients, [18F] T807 signal was highest in inferior frontal and middle temporal gyri and temporal pole with marked asymmetry, most prominent in the dominant hemisphere, and localized remarkably well with atrophy. The asymptomatic carrier had mildly elevated signal in frontal, insular, and anterior temporal cortex as well as white matter. PSP patients showed elevated brainstem, basal ganglia, thalamic/subthalamic, cerebellar, and frontal signal. T807 is a promising new PET ligand for imaging tau pathology in vivo in patients with FTLD.

Symptomatic Alzheimer's disease (AD) has been associated with a cortical signature of thinning in specific limbic and association regions (Bakkour et al 2009, Dickerson et al 2009) measured with MRI. In this study we investigated whether the cortical signature of AD-related thinning is present in Presenilin 1 (PS1) E280A mutation carriers, an average of 7 years before clinical onset (mean age of 45). Thirty-nine volunteers from a Colombian population with familial AD were included. Eighteen presymptomatic subjects were positive for the Alzheimer's-associated PS1 mutation (carriers) whereas 21 were non-carriers. Subject groups were matched for age, sex, education, and performance on the CERAD cognitive battery. T1-weighted volumetric MRI images were acquired using a Philips 1.5 T MRI scanner. Cortical thickness was measured in a fully automated fashion using FreeSurfer. A priori regions of interest (ROIs) were used to obtain thickness from “AD-signature regions”, identified previously in mild AD dementia patients. ANOVA was used to compare the groups using the entire summary measure as well as individual regions. The presymptomatic PS1 mutation carriers and non-carriers did not differ significantly in their age (37±6 years), gender (78% female), educational level (11±2 years), or MMSE scores (29±0.8). Compared to noncarriers, presymptomatic PS1 carriers showed cortical thinning in the AD-signature summary measure (p < 0.008). Analyses of individual signature ROIs demonstrated thinning in right angular gyrus, right precuneus and left superior parietal lobule in carriers compared to non-carriers (p<0.05, uncorrected for multiple comparisons). Cognitively normal individuals at genetic risk for early-onset AD have subtle cortical thinning in brain regions known to be affected by typical late-onset sporadic AD. Further research is needed to determine whether this method could be used to characterize the age-dependent trajectory of atrophy in these and other brain regions in presymptomatic PS1 carriers and support their use in the evaluation of presymptomatic AD treatments.

Abstract Background Identifying factors that confer resilience to developing delirium is critical given the negative impact of delirium on clinical care and risk for mortality. Here, we investigated a cohort of cognitively normal older adults undergoing elective surgery and examined the role of pre‐operative memory function and cortical thickness in the incidence and severity of post‐operative delirium (POD). We hypothesized that 1) those older adults with episodic memory function comparable to that of young adults (“SuperAgers" or SA) would show reduced incidence of POD compared with typically‐aging older adults (TOA) and 2) cortical thickness in the anterior mid‐cingulate cortex (aMCC), the integrity of which has been consistently associated with SuperAging, would predict reduced incidence and severity of POD. Method 19 SA and 74 TOA (mean age 75.8 +/‐ 4.1; 57F/36M) completed neuropsychological testing and underwent structural brain MRI pre‐operatively as part of the Successful AGing after Elective Surgery (SAGES) Study. SA were identified based on neuropsychological criteria defined in previous studies. Delirium incidence and severity were assessed using the Confusion Assessment Method (CAM) daily throughout hospitalization. A general linear model analysis was performed to identify regions of the cerebral cortex whose thickness was associated with CAM scores. Results No differences were found in age or education between SA and TOA. Remarkably, no SA developed POD; POD occurred only in the TOA group (D‐TOA = 15). Severity of POD was negatively associated with cortical thickness of bilateral aMCC. A one‐way ANOVA comparing mean aMCC thickness across subgroups revealed a significant effect (F(2,89) = 3.09, p ≤ .05), with thickness greatest in SA compared with D‐TOA (t(31) = 2.47, p ≤ .019, Cohen’s d = 0.89), but comparable compared to thickness seen in non‐delirious (ND) TOA (t(76) = 0.72, p ≤ .72, d = 0.10). Greater aMCC thickness was also observed for ND‐TOAs compared with D‐TOAs (t(71) = 2.26, p ≤ .03 d = 0.72). Conclusion These findings suggest that superior memory function and greater structural integrity of the aMCC may be important indices of resilience to delirium in older adults that can serve as a target of preventive or therapeutic interventions.

Abstract Background Only a small percentage of early‐onset Alzheimer’s disease (EOAD) participants are known to carry autosomal dominant pathogenic variants in the amyloid beta precursor protein (APP) gene or in presenilin 1 or 2 (PSEN1/2); more research is needed to identify additional causative genetic variants. This study presents results of the initial genetic analyses in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) and planned next steps. Methods Whole exome sequencing (WES) is being performed for all cognitively impaired participants, including individuals with EOAD or frontotemporal dementia. Sequencing data is processed using GATK best practices and all variants for APP , PSEN1/2 , progranulin (GRN), and microtubule associated protein tau (MAPT) are reviewed for previously reported pathogenic variants. C9ORF72 is also assessed for pathogenic repeat expansions. WES was analyzed with CANOES and CoNIFER for copy number variants (CNVs). WES data has been reviewed for reported pathogenic variants in other neurodegenerative disease‐associated genes. Gene burden testing is being done for the LEADS cases and age‐matched controls from the Parkinson’s Progression Markers Initiative for rare variants in these genes. Results To date, WES has been generated for 301 cases, and GWAS for 384 participants (290 cases, 89 controls). Reported pathogenic variants or repeat expansions in C9ORF72 , PSEN1 , GRN , and MAPT were identified in 2% of cases for the six screened genes. No CNVs were detected in APP, PSEN1/2 , GRN , or MAPT . Review also identified individuals with pathogenic variants or CNVs in genes linked with diseases including Parkinson’s disease and Niemann‐Pick disease, including reported or predicted pathogenic variants in GBA , LRRK2 , and SMPD1 . Surprisingly, results do not show enrichment of functional TREM2 variants compared to population frequency. Conclusions Initial results indicate that LEADS is strongly enriched for novel genetic risk and/or causative factors, as only 2% have a reported pathogenic variant or repeat expansion in APP , PSEN1/2 , GRN , MAPT , or C9ORF72 . Review of reported pathogenic variants in other neurodegenerative disease‐associated genes indicates that while a small portion of disease etiology may be explained by these variants, more research is needed to identify additional causative and risk factors contributing to EOAD.

Abstract Background In EOAD, the localization of neurodegeneration is often more prominent in posterior lateral temporal, lateral and medial parietal, frontal, or occipital cortex relative to the medial and ventral temporal cortical localization of typical LOAD. Convergently, neuropathological investigations have identified a “hippocampal‐sparing” form of AD that is often present in younger patients. For these reasons, imaging biomarkers of neurodegeneration in EOAD, such as Magnetic Resonance Imaging (MRI) measures of atrophy, likely need to be different than those of neurodegeneration in typical LOAD. Although prior neuroimaging work has advanced our understanding of anatomical abnormalities in EOAD, these studies have included small samples, most composed of amnestic EOAD dementia and none focused on developing an MRI biomarker specific to EOAD. Such a disease‐signature MRI biomarker has been established and validated in LOAD dementia and has proven to be powerful in predicting progressive decline in people with MCI or who were cognitively unimpaired and in predicting molecular biomarker status. An a priori‐defined regional atrophy signature may also be helpful in constraining the analysis of MRI data in studies of putative disease‐modifying therapies. Method LEADS is an observational study which includes annual MRI. In this analysis, we used FreeSurfer to define the sporadic EOAD atrophy signature in a small sample of MGH EOAD patients, and investigated its reproducibility in LEADS, as well as the magnitude of atrophy and its relationship to clinical measures. Result The EOAD signature is robustly reproducible across the two independent patient cohorts, with prominent atrophy in caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortex, with relative sparing of medial temporal lobe structures. Comparing patients to controls, Cohen’s d effect sizes within various regions ranged from 0.99 to 1.98. Conclusion This study demonstrates the specific cortical regions with most prominent atrophy in patients with sporadic EOAD; this signature of regional atrophy will be used to examine longitudinal change.

Abstract Background We aimed to describe amyloid‐ and tau‐PET in patients with sporadic Early Onset AD (sEOAD) from the Longitudinal Early‐onset Alzheimer’s Disease Study. We focused on amyloid‐tau relationships and on the association between i) age, sex, and ii) cross‐sectional and longitudinal PET measures. Methods In December 2022, we selected patients who fulfilled the following criteria: 1) clinical diagnosis of MCI or mild dementia, 2) available amyloid‐PET (18F‐florbetaben), tau‐PET (18F‐fortaucipir), and structural MRI, 3) positive amyloid‐PET based on a process including visual read and quantification. Image acquisition, quality control, and processing followed ADNI procedures. Florbetaben‐PET Centiloids and mean cortical Flortaucipir‐SUVR were extracted in native space using FreeSurfer. Cross‐sectional analyses were performed using general linear models; longitudinal analyses (up to 4 scans/patient) were performed using linear mixed effect models with random intercepts. Results Out of the 372 cognitively impaired patients included in LEADS, 280 (75.3%) were amyloid‐positive patients with sEOAD (Table 1 for demographics and clinical characteristics). Cross‐sectionally, Centiloids and cortical Flortaucipir‐SUVR were correlated (r = 0.29, p&lt;.001; Fig 1a). Patient’s age was associated with cortical tau‐PET (older patients showing lower Flortaucipir‐SUVR, r = ‐0.47, p&lt;0.001, Fig 1b) but not amyloid‐PET (r = ‐0.02, p = 0.68). Females showed greater amyloid (d = 0.43, p&lt;0.001, Fig 1c) and tau‐PET burden (d = 0.35, p = 0.004), in the absence of sex differences in MMSE or CDR‐SB (d’s&lt;0.16, p’s&gt;0.37). Sex differences in tau‐PET remained significant (p = 0.04) when controlling for age and Centiloids. Both Centiloids and Flortaucipir‐SUVR increased longitudinally (p&lt;0.001, Figure 3a‐b). The rate of Centiloid change was not modulated by age (time*age, p = 0.79) or sex (time*sex, p = 0.91). Changes in tau‐PET were independent of sex (time*sex, p = 0.15), but younger patients tended to show greater FTP‐SUVR progression (time*age, p = 0.07). In a subsample of 123 patients with at least 2 timepoints for both amyloid and tau‐PET (Fig 3c), rates of amyloid and tau changes were correlated (r = 0.22, p = 0.013). Conclusion In patients with sEOAD, amyloid‐ and tau‐PET are modestly correlated at baseline and continue to increase together over time. In EOAD, younger age is associated with higher tau‐PET burden, independent of amyloid. Females show greater amyloid and tau burden than males despite similar clinical severity measures.

Abstract Background The Rey Auditory Verbal Learning Test (RAVLT) is a neuropsychological test used for assessing episodic memory impairment. The sequence of the RAVLT consists of five learning trials, an intrusion list recall, a subsequent recall (short delay), and a delayed recall (approximately thirty minutes after the short delay recall). The RAVLT has been studied extensively in various presentations of dementia, but there is limited research for early‐onset Alzheimer’s disease (EOAD). We analyze the influence of amyloid and diagnostic syndrome on traditional and novel RAVLT scores in EOAD. Method We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). Subjects were group by amyloid status (control/EOnonAD vs EOAD) and syndrome: posterior cortical atrophy (PCA), primary progressive aphasia (PPA), amnestic, and non‐amnestic presentations. The traditional method of scoring the RAVLT is to count the total number of correct words recalled for each task (i.e., raw score). Two other count‐based scores were calculated by examining serial position effects (SPEs). SPEs describe the tendencies to remember words in the beginning (primacy) or end (recency) of the list. A relational SPE score, known as J‐curve, is examined here and is defined as primacy minus recency. Three timing‐based scores were analyzed: duration, stopping time, and speed. The seven scores were entered separately into linear mixed effects models as dependent variables. Amyloid status, syndrome, and nuisance variables (age, sex, education) were entered as independent variables. Result Compared with amyloid‐negative subjects, amyloid‐positive subjects showed negative effects on raw score, primacy and recency. The presence of amyloid increased stopping time by 5%. Duration and speed were not found to be associated with amyloid. Significant differences among clinical syndromes were observed with recency, duration, and stopping time. Conclusion RAVLT measures are sensitive to the effects of amyloid and syndrome in early‐onset dementia. Stopping time is a novel score that may complement existing measures for describing amyloid‐positive individuals. Further work is needed to quantify the predictive value of these scores.

Abstract Background Fewer than 5% of patients with Alzheimer’s disease are diagnosed between 40‐64 years old, making “early‐onset Alzheimer’s disease” (EOAD) an uncommon phenomenon (Zu et al., 2015). To date, only basic knowledge on EOAD is known, no uniform criteria for EOAD have been implemented, and sample sizes in research have been small. The Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS) aims to provide a comprehensive understanding of EOAD symptomology, with the current project profiling baseline clinical, cognitive, and basic genetic characteristics of the cohort nearing the data‐collection mid‐point. Method Data from 371 participants undergoing the LEADS protocol were compared based on diagnostic group classification (cognitively normal [CN], amyloid‐positive EOAD, and amyloid‐negative Early‐Onset non‐Alzheimer’s disease [EOnonAD]). Because LEADS focuses on sporadic early‐onset dementia, impaired individuals with genetic mutations in Amyloid Precursor Protein (APP), Presenilin‐1 (PSEN1) or Presenilin‐2 ( PSEN2 ), Microtubule Associated Protein Tau ( MAPT ), Chromosome 9 Open Reading Frame 72 ( C9ORF72 ), or Granulin Precursor aka Progranulin ( GRN ) were excluded. Result Demographic characteristics for each group are shown in Table 1 . After adjusting for age, education, and sex, EOAD performed worse than CN for all domains ( ps &lt;.001, η 2 s = 0.05‐0.66), and worse than EOnonAD for all domains except language ( ps &lt;.001, η 2 s = 0.06‐0.29). As shown in Table 2 , EOAD showed worse performance on Episodic Memory ( z = ‐2.38), followed by Speed Attention ( z = ‐1.93) and Executive domains ( z = ‐1.43) relative to CN. An amnestic presentation was common among impaired participants, with several clinical phenotypes present. The EOAD group possessed a significantly greater proportion of apolipoprotein ε4 homozygous participants than the EOnonAD group ( p = .01, Cohen’s w = 0.15), and a trend of greater proportions of ε4 heterozygous participants than both CN and EOnonAD ( ps = .05‐.07, Cohen’s ws = 0.11; Table 3 ). Finally, LEADS participants generally consented at high rates to optional trial procedures like lumbar puncture (60%) and genetic disclosure (89%). Conclusion This work represents the best baseline characterization of sporadic EOAD in the U.S. to date. Early‐onset dementia presents with widespread cognitive impairment, characterized by several known clinical phenotypes. Apolipoprotein ε4 allele carrier status appears to remain important in EOAD. Future investigation will explore many potential associations between EOAD and cognition, neuropsychiatric symptoms, genetics, and imaging.

Abstract Background The Rey Auditory Verbal Learning Test (RAVLT) is a common neuropsychological test for characterizing episodic memory deficits. Performance of the RAVLT has been described in numerous presentations of cognitive impairment. However, there is limited research for analyzing the predictive value of RAVLT scores. We examine the ability of the RAVLT to classify individuals with early‐onset cognitive impairment in terms of amyloid positivity. Method We transcribed RAVLT recordings from 214 cognitively impaired subjects in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). Each RAVLT test consists of eight tasks: five learning trials, an interference list, short delay free recall, and long delay free recall. Subjects were stratified by amyloid positivity (EOAD vs . EOnonAD). We calculated traditional and novel scores based on counts (raw score, primacy, recency) and timings (stopping time and speed). To split the data into training and test sets, we selected subjects such that Cohen’s D was below 0.05 between nuisance covariates (age and education) and included similar proportions of each sex. Due to the imbalance of classes in the data set, we generated 1,000 equal‐sized bootstrap samples of cases and controls (n = 200) and fit a random forest classifier for each sample. Subjects in the test set were classified by majority vote. This classification process was applied to three different sets of RAVLT variables for comparing performance. Result With raw scores and demographics alone, we achieved AUC of 0.839. We obtained an AUC of 0.841 using variables with possible utility identified in previous work. The best model used only speed scores and demographic variables, with an AUC of 0.858. Conclusion We marginally improved the classification accuracy of amyloid‐positive subjects over raw scores alone. Further work is needed to determine the utility of novel scores in predicting biomarker positivity.

Abstract Background Approximately 10‐25% of amnestic early‐onset dementia are negative for amyloid (Early‐onset non‐Alzheimer’s Disease, EOnonAD). EOnonAD is a heterogenous group with various etiologies. In order to better understand the traits of EOnonAD, we clustered amnestic EOnonAD individuals according to cognitive patterns. Method Cognitive data of 62 EOnonAD individuals from the Longitudinal Early‐onset AD study (LEADS) were Z‐normalized to 91 intact individuals after adjusting for age, sex, and education. This led to domain‐averaged composite Z‐scores for memory, language, speed/attention, visuospatial, and executive function. Cluster analysis using the Ward method on the residuals for the five composites was performed. We used Scree plot using the pseudo T‐squared to determine the optimal number of clusters. We compared demographics, imaging biomarkers (amyloid and tau PET SUVR, hippocampal volume), plasma (pTau231, Aß40, Aß42, glial fibrillary acidic protein, and neurofilament light chain (NfL)), and cerebrospinal fluid (CSF) biomarkers (Aß42/40, NfL, Neurogranin, Visinin‐like protein, YKL‐40, and Synaptosome Associated Protein 25) across the clusters after adjusting for age, sex, and education. We compared gray matter density of each EOnonAD cluster to controls (n = 84) using voxel‐wise multiple linear regressions in SPM12, adjusting for age, sex, education, and intracranial volume. Result Scree plot using the pseudo‐T‐squared suggested three clusters. Cluster 1 (38/62, 61.3%) was characterized by having the mildest cognitive impairment in all domains. Cluster 2 (19/62, 30.6%) was characterized by more severe memory and language impairment. Cluster 3 (5/62, 8.1%) was characterized by more severe impairment in speed/attention, visuospatial, and executive function (Table 1). Cluster 3 showed significantly higher NfL for both plasma (Cluster 1 vs 3, p&lt;0.001; Cluster 2 vs 3, p &lt; 0.004) and CSF (Cluster 1 vs 3, p = 0.001). Other biomarkers did not show significant difference (Table 1). Only Cluster 3 showed significant atrophy in the bilateral fronto‐parietal areas at p&lt;0.01, uncorrected (Figure 1). Conclusion We identified heterogeneity in cognitive patterns among amnestic EOnonAD individuals. Cluster 1 had mildest cognitive impairment; Cluster 2 had predominant impairment in memory and language; and Cluster 3 had predominant impairment in speed/attention, visuospatial, and executive function, with significant fronto‐parietal atrophy and high NfL indicating active neurodegeneration.

Abstract Background We examined neuropsychiatric symptoms (NPS) and psychotropic medication use at the midway point of data collection of the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS). We compared amyloid‐positive early‐onset Alzheimer’s disease (EOAD) participants and amyloid‐negative early‐onset non‐Alzheimer’s disease [EOnonAD]) participants across NPS domains and psychotropic medication categories. Method 282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD ( n = 212) and amyloid‐negative EOnonAD ( n = 70). All participants were between ages 40 and 64 at baseline. NPS were measured with the Neuropsychiatric Inventory – Questionnaire (NPI‐Q) and Geriatric Depression Scale – Short Form (GDS‐SF). Medications were categorized into psychotropic category ( e.g ., antidepressants, antipsychotics, benzodiazepines). Groups were compared on NPI‐Q using binary logistic regression adjusting for sex and disease severity, on GDS‐SF using linear regression adjusting for sex and disease severity, and on psychotropic medication use using Chi square or Fisher’s exact test . Result Demographic data are presented in Table 1 . Average total NPI‐Q score was higher in EOnonAD than EOAD ( p = .002, ŋ p 2 = .03). Regardless of diagnostic group, informants endorsed Affective behaviors most frequently (76.2%). EOAD informants endorsed fewer Distress‐Tension behaviors ( p = .02, OR = .498) and Impulse Control behaviors ( p = .01, OR = .438). EOAD informants also endorsed apathy ( p &lt; .001, OR = .316), irritability ( p = .02, OR = .498), and disinhibition ( p = .04, OR = .476) at lower frequency than EOnonAD. GDS‐SF showed that the EOnonAD participants self‐reported more symptoms of depression than the EOAD group ( p = .002, ŋ p 2 = .03). ( Table 2A ). A minority of participants, regardless of diagnostic group, reported psychotropic medication use (35%). There was higher use in EOnonAD (38%) than EOAD (24%) ( p = .03, Cohen W = .14) ( Table 2B ). Conclusion NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants, despite EOnonAD being less severely impaired. LEADS continues to collect data. Future studies will examine etiologies that may be larger drivers of NPS than AD neuropathology, mediators ( e.g ., race, ethnicity) in the association between NPS and diagnostic group classication, compare NPS in EOAD vs. LOAD, and examine longitudinal changes in neuropsychiatric profiles.

Abstract Background Age‐related cognitive declines are well‐documented in cognitively normal adults (van der Willik et al., 2021), as are greater cognitive impairments with advancing age in traditional‐ (or “late‐”) onset Alzheimer’s disease (LOAD; Davis et al., 2018). Early‐onset Alzheimer’s disease (EOAD; diagnosis ≤65 years old) possesses a unique disease course and underlying pathology relative to LOAD (Mendez, 2012), consequently it is unknown if the association between age and cognitive severity is similar. The objective of the current study is to examine the relationship between cognition and age‐at‐baseline in participants enrolled in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS; Apostolova et al., 2019). Method Cross‐sectional cognitive data from 371 participants (aged 40‐64) enrolled in the LEADS protocol were analyzed, using composites for the domains of Episodic Memory, Speed/Attention, Visuospatial skills, Language, and Executive skills. Relationships between age‐at‐baseline and cognition were examined using linear regression based on diagnostic group classification (cognitively normal [CN], amyloid‐positive EOAD, and amyloid‐negative Early‐Onset non‐Alzheimer’s disease [EOnonAD]), controlling for the effects of age and education years. Result Demographic characteristics for each group are shown in Table 1 . Across cognitive domains, the CN group displayed either non‐significant or negative relationships (Executive skills; r = ‐0.30, p = .006) between age‐at‐baseline and cognitive performance ( Figure 1 and Table 2 ). Conversely, the EOAD group showed consistent positive relationships for domains of Speed/Attention ( r = 0.23, p &lt;.001), Visuospatial Skills ( r = 0.19, p = .01), and Episodic Memory ( r = 0.16, p = .02). A similar non‐significant trend was observed for the EOnonAD group for Speed/Attention ( r = 0.17, p = .19). When considering those with amnestic‐variant early‐onset dementia across diagnostic groups, positive relationships between age‐at‐baseline and cognition were observed for Speed/Attention ( r = 0.19, p = .006) and Visuospatial skills (non‐significant trend; r = 0.14, p = .05), but not for Episodic Memory ( r = ‐0.06, p = .35). Conclusion Worse cognitive severity was associated with younger age‐at‐baseline for EOAD participants in LEADS. Similar trends were observed for EOnonAD participants, though to a lesser magnitude. These results were counter to those observed for CN participants, and to what is known about cognitive trajectories in normal aging or LOAD. These findings further support previous suggestions that EOAD appears to be a distinct entity relative to LOAD.

Abstract Background Primary progressive aphasia (PPA) refers to a group of neurodegenerative disorders characterized by early language impairments. Neuroimaging evidence suggests that language networks anchored in prefrontal, temporal and parietal cortices are selectively affected in these syndromes. Focal neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), are able to change resting‐state functional connectivity in a network‐specific manner. Method Here, we characterized the language network of a patient with logopenic PPA and targeted this network in an individualized manner with high frequency (20Hz) rTMS and with sham rTMS. We used detailed language testing and resting‐state functional connectivity MRI as outcome measures. Result The patient’s language performance improved following active but not sham rTMS. This was accompanied by increased functional connectivity in the patient’s individually characterized language network after active but not sham rTMS. Conclusion This case report supports further controlled clinical trials of individually‐targeted rTMS in PPA.

Abstract Background Identifying individuals with symptomatic Alzheimer’s disease (AD) at greater risk of steeper cognitive decline would allow professionals and loved‐ones to make better‐informed medical, support, and life‐planning decisions. In typical AD, the magnitude of cerebral tau accumulation in vivo predicts clinical deterioration. Despite its promise, the utility of tau PET in predicting cognitive decline in individuals with atypical clinical presentations of AD remains unclear. We examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline across atypical AD syndromes. Method Fifty‐seven A/T/N‐positive patients (mean age = 64.13 ± 7.72; 24M/33F) with atypical syndromes of AD (19 Posterior Cortical Atrophy, 16 logopenic variant of Primary Progressive Aphasia, 16 dysexecutive AD, five early‐onset AD with single‐domain impairment, and one Corticobasal Syndrome) and 24 amyloid‐negative control participants were included in this study. All participants underwent 18 F‐Flortaucipir (FTP) PET, amyloid PET, and structural MRI scans at baseline. The rate of clinical decline was quantified as the annualized change in Clinical Dementia Rating Sum‐of‐Boxes scores (CDR‐SB) at baseline and follow‐up visits (mean time interval = 1.24 ± 0.34 years). General linear model analyses were performed to examine the pattern of baseline cortical tau deposition in atypical AD patients and its relationship with the rate of clinical decline. Result Compared with amyloid‐negative controls, atypical AD patients showed prominent FTP uptake in posterior cortical regions at baseline, including bilateral posterior cingulate cortex/precuneus and lateral temporo‐parietal cortices, which canonically constitute the posterior default mode network (DMN). A brain‐behavior regression analysis revealed widespread regions within the DMN where the magnitude of baseline FTP uptake predicted the rate of change in CDR‐SB, with anterior DMN regions (medial prefrontal and anterior temporal cortices) most strongly predicting clinical decline. Conclusion Greater baseline tau accumulation in the anterior DMN, possibly suggesting more extensive tau spread in this network, predicts faster clinical decline in atypical AD. This may serve as an imaging biomarker to guide prognostication for patients with atypical AD and their families and to inform the design of clinical trials, including potentially recruiting multiple clinical phenotypes of AD into a single trial.

Abstract Background Increased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this population. We aimed to demonstrate the effect of each biomarker on EOAD pathology by investigating their associations with amyloid burden, tau burden, and gray matter density (GMD). Method 183 EOAD participants from the Longitudinal EOAD study with available baseline plasma GFAP, NfL, p‐tau231, MRI, amyloid PET, and tau PET data were included (mean age = 58.7, 55.2% female, 54.1% APOE‐ε4 carrier, mean MMSE = 21.9). Voxel‐wise multiple linear regression models of amyloid PET, tau PET, and T1‐weighted MRI images yielded statistical maps with GFAP, NfL, or p‐tau231 as predictors. Covariates were hierarchically added: Model 1: age, sex; Model 2: age, sex and APOE‐ε4 ; Model 3: age, sex, APOE‐ε4 and MMSE. All models are displayed at a family‐wise error adjustment of p&lt;.05. Result Higher levels of GFAP, NfL, and p‐tau231 were significantly associated with greater amyloid burden and tau burden. Higher levels of GFAP and NfL were also significantly associated with lower GMD. No significant associations were found for p‐tau231 and GMD (Figures 1, 2 &amp; 3). When controlling for APOE‐ε4 carrier status, the effect of GFAP on amyloid burden was no longer significant (Figure 1). After additionally controlling for MMSE, the effects of NfL and p‐tau231 on amyloid burden were no longer significant, while the effects of all three biomarkers on tau burden were reduced but remained significant. In terms in of GMD, the effect of NfL survived correction for dementia severity, while the effect of GFAP did not. Conclusion These results suggest that all three plasma biomarkers show stronger associations with neurodegeneration (cortical atrophy and/or tau burden) than with amyloid burden. Furthermore, this study highlights the importance of plasma biomarkers for AD diagnosis and monitoring. Future work should investigate longitudinal associations and the mediational role of APOE‐ε4 and dementia severity.

Abstract Background Historically, Alzheimer’s disease (AD) biomarkers have been used to identify the presence of pathology and have been shown to change well ahead of symptom onset. While previous research has evaluated plasma pTau231 and its associations with cognition, little to none of this research has focused on early‐onset AD (EOAD) populations. Here we investigate how select plasma biomarkers are associated with global cognitive measures in early‐onset cognitive impairment. Method The current sample included 367 Longitudinal Early‐Onset AD Study (LEADS) participants (aged 41 to 65) categorized as amyloid PET‐positive EOAD, amyloid PET‐negative EOnonAD, or cognitively normal (CN). Each participant had baseline global cognitive (Mini‐Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA], Clinical Dementia Rating Scale sum of boxes [CDR‐SB], and ADAS‐Cog13) and plasma biomarker assessments (Simoa‐HDx N4PE kit: Aβ42/40, phosphorylated Tau [pTau231], Neurofilament light protein [NfL], and glial fibrillary acidic protein [GFAP]). Partial correlations were used to check for associations with cognitive performance controlling for age, sex, and years of education. Fisher r‐to‐z transformations were conducted to compare the performance across diagnostic groups. Result Partial correlations in the pooled sample showed moderate associations between cognition and plasma pTau231, GFAP and NfL ( r = .42‐.50, p &lt;.001) and weaker associations with Aβ42/40 ( r = .25‐.33, p &lt;.001). When split into diagnostic groups, the NfL and GFAP correlations were significant in both EOAD and EOnonAD, but not CN. The pTau231 correlations were significant only in EOAD. Aβ42/40 correlations were non‐significant within specific diagnostic groups. No differences were observed in the magnitude of the cognitive and biomarker associations between EOAD and EOnonAD samples (ps&gt;.05). Conclusion As expected, the neurodegenerative biomarkers pTau231 and NfL showed stronger association with cognition compared to the marker for brain amyloidosis (Aβ42/40). The nonspecific markers for neurodegeneration (NfL) and brain astrogliosis (GFAP) showed associations in both EOAD and EOnonAD while the markers specific to AD were only significant in EOAD. Plasma biomarkers show great promise for AD diagnosis and monitoring.

Abstract Background The longitudinal progression of tau pathology in sporadic early‐onset Alzheimer’s disease (EOAD, age‐at‐onset&lt;65) has not been well established and may be key to its understanding and treatment. We utilized in vivo PET imaging to characterize regional patterns of pathological tau accumulation in the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS), an ongoing, large‐sample, multi‐site cohort. Method [18F]Flortaucipir tau‐PET was acquired 75‐105min post‐injection in 277 amyloid‐PET‐positive patients with sporadic EOAD and 90 healthy controls (Table 1). Patients had mild cognitive impairment (CDR‐SB = 0.5‐4, n = 206) or mild dementia (CDR‐SB = 4.5‐8, n = 71) at baseline. Longitudinal tau‐PET was collected in 126 patients (2‐4 scans/subject, 1.3 ± 0.4 years apart). Tau‐PET SUVRs were calculated in 72 FreeSurfer‐defined regions referenced against inferior cerebellar gray matter, and SUVRs were W‐scored within‐region to adjust for age and sex associations in controls (control W‐score mean = 0, SD = 1). Baseline tau‐PET W‐score differences between patients and controls were assessed using linear regression. Linear mixed‐effects models were used to calculate tau‐PET W‐score change rates among EOAD patients. Result Tau‐PET was significantly elevated in EOAD patients at baseline in every region examined ( p &lt;0.05, FDR‐corrected), with highest tau‐PET signal in lateral prefrontal, parietal, and posterior cingulate cortices bilaterally, and relative sparing of primary cortices ( Figure 1a ). In longitudinal analyses, tau‐PET increased significantly in 69/72 regions ( p &lt;0.05, FDR‐corrected; Figure 1b ), and regions with higher tau‐PET at baseline had faster prospective accumulation rates on average ( r = 0.47, p &lt;0.0001; Figure 2 ). Exceptions were noted in posterior cingulate and parietal association regions, which had high tau‐PET at baseline but comparatively slow accumulation; and in anterior prefrontal and occipital regions with low‐to‐moderate tau‐PET at baseline yet rapid accumulation. Conclusion Tau pathology is present throughout cortex by the mild dementia stage in EOAD and is still accumulating globally, especially in anterior prefrontal and occipital cortices. Parietal association regions have high baseline tau but slower‐than‐expected prospective accumulation, suggesting these regions are early pathological foci that plateau early in the clinical disease stage.

Abstract Background Aβ deposition is thought to start decades prior to symptom onset. Previous studies have shown that mathematical modeling enables reconstruction of Aβ‐PET trajectory and age estimation at Aβ‐PET positivity in Aβ‐positive patients. We aimed to apply this approach to determine Aβ duration and estimate age at Aβ‐PET positivity in sporadic early‐ (&lt;65yo) and late‐ (≥65yo) onset AD (EOAD/LOAD). Method We combined PET data from the Longitudinal Early‐Onset AD Study (LEADS, n = 288) and ADNeuroimaging Initiative (ADNI, n = 915). First, we selected Aβ+ (baseline Centiloids ≥24) cognitively impaired patients with ≥2 Florbetaben‐PET scans to compare baseline and longitudinal amyloid‐PET in EOAD versus LOAD using linear mixed effects regression (Figure 1). Then, we used ADNI participants with ≥2 Florbetapir‐PET scans to assess the relationship between Aβ‐PET Centiloids and time (Figure 2). We estimated the Aβ temporal trajectory by integrating a reciprocal of the spline model from the accumulation rate and Centiloidmid‐point. Finally, we used the resulting Aβ trajectory to estimate Aβ duration and age at Aβ‐PET positivity onset for patients with EOAD and LOAD (Figure 3). Result EOAD patients had higher baseline Aβ burden than LOAD patients. Amyloid‐PET increased at similar rates in the two groups (Figure 1), allowing us to operate under the assumption that EOAD and LOAD follow the same Aβ trajectory, with a temporal shift. Aβ trajectory was estimated in ADNI Florbetapir‐PET, showing an almost linear dependency between Centiloids and Aβ duration (Figure 2). The model suggests that Aβ‐PET positivity (CL = 24) is reached after 7 years, and an additional 26 years are needed to reach 100 CL. When applied to the Florbetaben sample, we determined that 75yo LOAD patients became Aβ‐PET positive around 52yo, while 60yo patients with EOAD dementia were Aβ‐PET positive around age 31 (Figure 3). Conclusion Based on available data, the dynamic of Aβ accumulation seems similar in EOAD and LOAD, with a temporal shift indicating that EOAD patients might transition to Aβ‐PET‐positive in their early 30s. Prospective studies on early phases of Aβ accumulation in EOAD patients will be important for validation of these findings since existing data is limited.

Abstract Background Female sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐e4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐e4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aß 42/40, and pTau231. CSF markers included: Aß 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1). Method We included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐e4 genotype. Demographics (age, education, APOE‐e4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers. Result Compared to men, EOAD women showed greater levels of plasma NfL (p = .03), and GFAP (p&lt;.001) while Aß 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05). APOE‐e4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex. Conclusion As highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD. This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐e4 genotype‐based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.

Abstract Background Alzheimer’s disease (AD) is characterized neuropathologically by ß‐amyloid (Aß) plaques, hyperphosphorylated tau neurofibrillary tangles, and neurodegeneration which leads to a phenotypically heterogeneous cognitive‐behavioral dementia syndrome. Our understanding of how these neuropathological and neurodegeneration biomarkers relate to each other is still evolving. A relatively new approach to measuring structural brain change, gray matter to white matter signal intensity ratio (GWR), quantifies the signal contrast between these tissue compartments, and has emerged as a promising marker of AD‐related neurodegeneration. We sought to validate GWR as a novel MRI biomarker of neurodegeneration. Method Twenty‐nine amyloid‐, tau‐, and neurodegeneration positive patients with atypical syndromes of AD (16 Posterior Cortical Atrophy, 10 logopenic variant of Primary Progressive Aphasia, and 3 Amnestic Dysexecutive phenotype) and 24 amyloid‐negative control participants underwent structural MRI, 11C‐Pittsburgh Compound B (PiB) PET, and 18F‐flortaucipir (FTP) PET scans. Whole‐cortex vertex‐wise general linear models (GLM) were created to identify areas of the cerebral cortex where AD patients showed abnormal signal in each modality, and Pearson’s correlation coefficients were computed to examine the strength of bivariate associations between each pair of modalities at the group level. We then constructed linear mixed‐effects models to test the relative contribution of each non‐FTP modality to explaining the variance in regional FTP uptake. Result We found that GWR was associated with cortical thickness, tau PET, and amyloid PET, with GWR showing a larger magnitude of abnormality than cortical thickness. We also found that combining GWR, cortical thickness, and amyloid PET better explained observed tau PET signal than using these modalities alone, suggesting that the three imaging biomarkers contribute independently and synergistically to explaining the variance in the distribution of tau pathology. Conclusion We conclude that GWR is a uniquely sensitive in vivo marker of neurodegenerative change that reflects pathological mechanisms which may occur prior to cortical atrophy. By using all of these imaging biomarkers of AD together, we may be better able to capture, and possibly predict, AD neuropathologic changes in vivo, which we hope will ultimately contribute to better endpoints to evaluate the efficacy of therapeutic interventions as we move toward an era of disease‐modifying treatments for this devastating disease.

Abstract Background Identifying individuals with symptomatic Alzheimer’s disease (AD) at greater risk of steeper cognitive decline would allow professionals and loved‐ones to make better‐informed medical, support, and life‐planning decisions. In typical AD, the magnitude of cerebral tau accumulation in vivo predicts clinical deterioration. Despite its promise, the utility of tau PET in predicting cognitive decline in individuals with atypical clinical presentations of AD remains unclear. We examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline across atypical AD syndromes. Method Fifty‐seven A/T/N‐positive patients (mean age = 64.13 ± 7.72; 24M/33F) with atypical syndromes of AD (19 Posterior Cortical Atrophy, 16 logopenic variant of Primary Progressive Aphasia, 16 dysexecutive AD, five early‐onset AD with single‐domain impairment, and one Corticobasal Syndrome) and 24 amyloid‐negative control participants were included in this study. All participants underwent 18F‐Flortaucipir (FTP) PET, amyloid PET, and structural MRI scans at baseline. The rate of clinical decline was quantified as the annualized change in Clinical Dementia Rating Sum‐of‐Boxes scores (CDR‐SB) at baseline and follow‐up visits (mean time interval = 1.24 ± 0.34 years). General linear model analyses were performed to examine the pattern of baseline cortical tau deposition in atypical AD patients and its relationship with the rate of clinical decline. Result Compared with amyloid‐negative controls, atypical AD patients showed prominent FTP uptake in posterior cortical regions at baseline, including bilateral posterior cingulate cortex/precuneus and lateral temporo‐parietal cortices, which canonically constitute the posterior default mode network (DMN). A brain‐behavior regression analysis revealed widespread regions within the DMN where the magnitude of baseline FTP uptake predicted the rate of change in CDR‐SB, with anterior DMN regions (medial prefrontal and anterior temporal cortices) most strongly predicting clinical decline. Conclusion Greater baseline tau accumulation in the anterior DMN, possibly suggesting more extensive tau spread in this network, predicts faster clinical decline in atypical AD. This may serve as an imaging biomarker to guide prognostication for patients with atypical AD and their families and to inform the design of clinical trials, including potentially recruiting multiple clinical phenotypes of AD into a single trial.

Abstract Background Negative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, &lt;65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET. Method We identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols. Result Compared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR&gt;2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B). Conclusion Amyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes. ”

Abstract Background Aß deposition is thought to start decades prior to symptom onset. Previous studies have shown that mathematical modeling enables reconstruction of Aß‐PET trajectory and age estimation at Aß‐PET positivity in Aß‐positive patients. We aimed to apply this approach to determine Aß duration and estimate age at Aß‐PET positivity in sporadic early‐ (&lt;65yo) and late‐ ( = 65yo) onset AD (EOAD/LOAD). Method We combined PET data from the Longitudinal Early‐Onset AD Study (LEADS, n = 288) and ADNeuroimaging Initiative (ADNI, n = 915). First, we selected Aß+ (baseline Centiloids = 24) cognitively impaired patients with = 2 Florbetaben‐PET scans to compare baseline and longitudinal amyloid‐PET in EOAD versus LOAD using linear mixed effects regression (Figure 1). Then, we used ADNI participants with = 2 Florbetapir‐PET scans to assess the relationship between Aß‐PET Centiloids and time (Figure 2). We estimated the Aß temporal trajectory by integrating a reciprocal of the spline model from the accumulation rate and Centiloidmid‐point. Finally, we used the resulting Aß trajectory to estimate Aß duration and age at Aß‐PET positivity onset for patients with EOAD and LOAD (Figure 3). Result EOAD patients had higher baseline Aß burden than LOAD patients. Amyloid‐PET increased at similar rates in the two groups (Figure 1), allowing us to operate under the assumption that EOAD and LOAD follow the same Aß trajectory, with a temporal shift. Aß trajectory was estimated in ADNI Florbetapir‐PET, showing an almost linear dependency between Centiloids and Aß duration (Figure 2). The model suggests that Aß‐PET positivity (CL = 24) is reached after 7 years, and an additional 26 years are needed to reach 100 CL. When applied to the Florbetaben sample, we determined that 75yo LOAD patients became Aß‐PET positive around 52yo, while 60yo patients with EOAD dementia were Aß‐PET positive around age 31 (Figure 3). Conclusion Based on available data, the dynamic of Aß accumulation seems similar in EOAD and LOAD, with a temporal shift indicating that EOAD patients might transition to Aß‐PET‐positive in their early 30s. Prospective studies on early phases of Aß accumulation in EOAD patients will be important for validation of these findings since existing data is limited.

Abstract Background Prosopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus. Method A 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. VT values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry. Result Atrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients. Conclusion Although prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.

Abstract Background Increased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this population. We aimed to demonstrate the effect of each biomarker on EOAD pathology by investigating their associations with amyloid burden, tau burden, and gray matter density (GMD). Method 183 EOAD participants from the Longitudinal EOAD study with available baseline plasma GFAP, NfL, p‐tau231, MRI, amyloid PET, and tau PET data were included (mean age = 58.7, 55.2% female, 54.1% APOE‐e4 carrier, mean MMSE = 21.9). Voxel‐wise multiple linear regression models of amyloid PET, tau PET, and T1‐weighted MRI images yielded statistical maps with GFAP, NfL, or p‐tau231 as predictors. Covariates were hierarchically added: Model 1: age, sex; Model 2: age, sex and APOE‐e4; Model 3: age, sex, APOE‐e4 and MMSE. All models are displayed at a family‐wise error adjustment of p&lt;.05. Result Higher levels of GFAP, NfL, and p‐tau231 were significantly associated with greater amyloid burden and tau burden. Higher levels of GFAP and NfL were also significantly associated with lower GMD. No significant associations were found for p‐tau231 and GMD (Figures 1, 2 &amp; 3). When controlling for APOE‐e4 carrier status, the effect of GFAP on amyloid burden was no longer significant (Figure 1). After additionally controlling for MMSE, the effects of NfL and p‐tau231 on amyloid burden were no longer significant, while the effects of all three biomarkers on tau burden were reduced but remained significant. In terms in of GMD, the effect of NfL survived correction for dementia severity, while the effect of GFAP did not. Conclusion These results suggest that all three plasma biomarkers show stronger associations with neurodegeneration (cortical atrophy and/or tau burden) than with amyloid burden. Furthermore, this study highlights the importance of plasma biomarkers for AD diagnosis and monitoring. Future work should investigate longitudinal associations and the mediational role of APOE‐e4 and dementia severity.

Abstract Background Behavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous neurodegenerative disorder with variable rates of disease progression. Predictors of disease progression in bvFTD are significantly lacking, limiting the ability of clinical care planning. We recently showed that cortical atrophy in the frontoparietal control network (FPN) at baseline predicts the conversion to dementia in patients with Primary Progressive Aphasia (PPA). Leveraging this methodology, we hypothesized that FPN atrophy would predict progression of dementia in patients diagnosed with bvFTD. Method We analyzed data from 48 bvFTD patients (mean age 59.9 years, 20 Female) with very mild or mild dementia from our Frontotemporal Disorders Unit cohort and the Frontotemporal Lobar Degeneration Neuroimaging Initiative. Our primary outcome measure was change in the Clinical Dementia Rating‐FTLD Sum‐of‐Boxes (SoB) at baseline and at least one year later. Each participant underwent baseline MRI scanning for cortical thickness estimates. We ran a Pearson correlation analysis between the annualized change of CDR‐FTLD SoB from baseline to last observation, and baseline cortical network atrophy (quantified as network‐wise W scores). Vertex‐wise GLM analyses and network‐wise bivariate correlation analyses were also used to assess the relationship between network cortical atrophy and annualized CDR changes. Result Of the 7 networks investigated, only FPN atrophy predicted annualized change in CDR‐FTLD SoB scores ( r = ‐0.31, p = 0.03). That is, in bvFTD patients at the very mild/mild dementia stage, the greater the baseline FPN atrophy, the more rapid the clinical decline. Vertex‐wise GLM maps did not show that atrophy across the entire FPN predicted clinical decline. Rather, baseline atrophy in the dorsal precuneus and supramarginal gyrus nodes of the FPN was most predictive of clinical disease progression. Conclusion Cortical atrophy in the FPN, and particularly in posterior regions of this network, is predictive of the rate of clinical decline in bvFTD patients, possibly due to the critical roles this network serves in executive function and affective regulation. This work could promote the use of structural imaging biomarkers to guide prognostication for bvFTD patients and their families, and to inform the design of clinical trials.

Abstract Background Alzheimer’s disease (AD) is associated with increased cortical excitability, including an elevated risk of seizures. Transcranial magnetic stimulation with electromyography (TMS‐EMG‐EEG) can be used to index intracortical excitability. Prior work has shown that TMS‐based excitability measures are altered in AD and are related to disease severity. However, it is not yet known how TMS‐EMG measures are related to neurodegeneration within brain regions affected by AD. Method TMS‐EMG was applied to left motor cortex (M1) in 22 participants with biomarker‐confirmed mild cognitive impairment due to AD (early AD, aged 70.5±8.4, 11 females). Single pulse TMS was preformed to measure resting motor threshold (RMT) and motor evoked potential amplitude (MEP Amplitude). Paired‐pulse TMS was preformed to measure short interval intracortical inhibition (SICI, GABA‐ergic) and intracortical facilitation (ICF, glutamatergic). In 5 participants, TMS‐evoked responses on EEG were also obtained during single‐pulse stimulation to M1 and the inferior parietal lobe (IPL), and the local mean field amplitude (LMFA) was computed from 15 to 40 msec after the TMS pulse. Structural MRI scans for each participant were processed using Freesurfer to obtain cortical thickness measurements within the distributed Alzheimer‐signature brain regions (AD‐signature atrophy). The primary analyses tested the relationship between each TMS measure and AD‐signature atrophy using separate linear models, controlling for age. For TMS‐EEG analysis, effect sizes were reported in lieu of p‐values given the small sample sizes. Result In early AD, SICI was related to AD‐signature atrophy (R 2 adj = 0.40, B = ‐0.13, p = 0.018; Fig1), with less intracortical inhibition related to greater atrophy. RMT, MEP Amplitude, and ICF were not related to AD‐signature atrophy ( p ‐values&gt;0.105). There was a large effect size of IPL LMFA on AD‐signature atrophy (R 2 adj = 0.70), while the effect size of M1 was small (R 2 adj = ‐0.19). Conclusion Decreased intracortical inhibition is related to increased AD‐signature atrophy in early AD. Decreased function of GABA‐A circuitry related to cortical atrophy may play a role in the development of cortical hyperexcitability in AD. Our preliminary results further suggests that TEPs from stimulation of IPL, a node of the default mode network and an area commonly showing AD pathology, may also be related to AD‐signature atrophy.

Abstract Background Female sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐ε4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐ε4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aβ 42/40, and pTau231. CSF markers included: Aβ 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1). Method We included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐ε4 genotype. Demographics (age, education, APOE‐ε4 , MMSE ) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers. Result Compared to men, EOAD women showed greater levels of plasma NfL ( p = .03), and GFAP (p&lt;.001) while Aβ 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05). APOE‐ε4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex. Conclusion As highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD. This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐ε4 genotype ‐ based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.

Abstract Background Prosopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus. Method A 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11 C‐PBR28, an inflammation tracer, and 18 F‐flortaucipir. V T values for 11 C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18 F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry. Result Atrophy and 18 F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11 C‐PBR28 signal was however more extensive than atrophy or 18 F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients. Conclusion Although prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.

Abstract Background Negative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, &lt;65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET. Methods We identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols. Results Compared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR&gt;2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B). Conclusions Amyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes.

Abstract Background Previous studies have reported that age modifies the distribution and burden of tau (and, to a lesser extent, amyloid) pathology in sporadic Alzheimer’s disease (AD). Here we present preliminary baseline amyloid and tau PET results from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS), a multi‐site longitudinal study of sporadic early‐onset AD. Method 135 patients meeting clinical criteria for MCI or probable AD and 50 cognitively normal controls (all age&lt;65 at enrollment) were enrolled at 12 US centers between August 2018 and December 2019 (Table 1). 18 F‐Florbetaben amyloid‐PET (FBB) was used to assign patients to EOAD (amyloid‐positive) or EOnonAD (amyloid‐negative) subgroups based on visual rating and semi‐quantification. 130 patients and all controls had 18 F‐Flortaucipir tau‐PET (FTP). Regional Standardized Uptake Value Ratios (SUVR) for FBB (whole cerebellum reference) and FTP (inferior cerebellar gray reference) were extracted using co‐registered 3T‐MRI. Result 98 patients (72.6%) were amyloid PET‐positive (EOAD) and 37 (27.4%) were amyloid PET‐negative (EOnonAD). Compared to EOAD, EOnonAD patients had higher MMSE, MOCA and CDR sum‐of‐boxes (CDR‐SB) and were more frequently male (Table 1). Patients with EOAD showed elevated FBB and FTP SUVR in temporoparietal and frontal cortex compared to CN and EOnonAD (Figures 1‐2). In EOAD, MMSE, MOCA and CDR‐SB were significantly correlated with FTP SUVR (Figure 3), while no significant correlations were found with FBB SUVR. EOnonAD patients showed variable FTP binding ranging from negative to mildly elevated binding in anterior temporal and frontal cortex and underlying white matter. Two EOnonAD cases showed intense FTP binding comparable to typical EOAD cases, despite visually and quantitatively negative FBB scans. Conclusion Patients with clinically mild, sporadic EOAD typically show an extensive distribution and burden of tau pathology in the setting of positive amyloid PET. Global clinical measures correlate with tau but not amyloid PET. Over 25% of patients meeting clinical criteria for early‐onset MCI/probable AD have negative amyloid PET, suggesting alternative etiologies for cognitive decline. These findings will inform future design of drug trials in this important and under‐studied population.

Abstract Background Previous research has suggested that, compared to males, females are at greater risk for and have greater pathology burden in late onset. However, sex differences in early onset AD (EOAD) have not yet been studied. Method We included 167 participants [28 cognitively normal (CN, 68% females), 98 early onset AD (EOAD, 55% females), and 41 cognitively impaired amyloid‐negative (EOnonAD, 31% females] subjects from the Longitudinal Early‐Onset AD Study (LEADS) with available Flortaucipir PET, Florbetaben PET, and MRI data. Multiple linear regression (MLR) models including age and MMSE as covariates were used in the pooled sample to examine the effects of sex on hippocampal and white matter hyperintensity volume, mean cortical thickness, mean tau distribution by Braak regions and mean cortical amyloid SUVR. We also ran voxelwise MLR with sex as the predictor and cortical thickness, amyloid SUVR normalized to whole cerebellum, tau SUVR normalized to cerebellar crus, respectively, as the outcome measures while controlling for age, MMSE, and total intracranial volume (MRI only). Results are displayed at a cluster‐level FWE correction of p&lt;0.05. Result There were no significant demographic differences between males and females in any diagnostic group. Across the pooled sample females showed significantly greater atrophy of the hippocampus (p=0.0001), greater tau SUVR in Braak regions 3&amp;4 (p=0.05) and 5&amp;6 (p=0.04) and trend for greater global amyloid uptake (p=0.074) (Table 2). The analyses in imaging space confirmed these findings and showed that the effects are driven by the EOAD group. Females showed greater amyloid deposition globally and greater tau deposition in the frontal, inferior parietal and temporal lobes (Figure 3). Conclusion Female sex is associated with greater pathology burden in EOAD. Longitudinal studies will be needed to establish whether such difference translates in faster rates of progression in women relative to men.

While cognitive assessment by videoconference has become possible over the past decade, the COVID-19 pandemic underscores the critical need for expansion and examination of these methods, their appropriateness for various patient populations, and their benefits and limitations. Validity and reliability studies of tele-neuropsychological testing have been conducted in MCI or mild AD dementia patients (e.g., MMSE=25+); few studies have assessed the feasibility of neurologic examination by video, and none in atypical dementias, assuming that patients with some types (e.g., language, comportment) or greater severity of cognitive-behavioral impairment would be unable to participate. Here we report the feasibility of telehealth services for a multi-disciplinary dementia subspecialty clinic that include cognitive-behavioral and neurologic assessment with patients with atypical neurodegenerative syndromes.104 patient-carepartner (P-C) dyads met with providers in the MGH FTD Unit by videoconference (March-December, 2020) for routine clinical care. P-Cs completed validated questionnaires assessing cognition-mood/behavior/function on REDCap prior to video clinical interview and cognitive assessment, including the MoCA and Boston Cognitive Exam (BCE2.0), a newly revised brief cognitive assessment battery adapted for telehealth. P-Cs met with a neurologist for a basic neurologic examination (including eye-movement examination), review of assessment results, and discussion of care plan. P-Cs completed a satisfaction survey.The 104 P-Cs included a range of atypical neurodegenerative disorders (bvFTD, PCA, PPA, CBS, PSP, eoAD, Multidomain syndrome) mild-to-severe impairment (CDR range: 0-3). 76% completed the MoCA (25% had CDR=2). 36% also completed the BCEv2. Comparison of remote assessment data to previous in-person testing is ongoing. Of P-Cs who completed a satisfaction survey, all reported being "very satisfied" with the appointment, with 93% open to participating in a remote visit again. 87% found the telehealth visit comparable to an in-person visit. 66% preferred a future combination of remote and in-person visits.Multi-disciplinary telehealth visits appear to be feasible with patients with atypical cognitive-behavioral syndromes of across the severity spectrum. P-Cs report a high degree of satisfaction with the telehealth visit and an openness to ongoing telehealth visits. Results have implications for increasing accessibility of multidisciplinary medical services for patients and families living with complex forms of dementia.

Abstract Background Caregivers of individuals living with dementia frequently make medical decisions and develop care plans for future needs of care recipients, often without a clear understanding of those needs. For many, the COVID19 pandemic has exacerbated these challenges. Educational tools are needed to guide caregivers about when and how to raise the topic of advance care planning (ACP). Method As part of a larger study about the utility of video decision aids for ACP in dementia, caregivers of individuals living with dementia completed online surveys and watched educational videos about COVID19 and ACP. One day, one week and one month following watching the videos, we assessed ACP‐related knowledge, thoughts, readiness, plans, conversations, and actions in quantitative (validated ACP Engagement Survey) and through qualitative open‐ended questions. Forty‐six caregivers participated. For this analysis, we examined the subset of participants who were not at the most engaged level on the ACP engagement survey. We coded and conducted a content analysis of the open‐ended qualitative questions at one month follow up. Result From pre‐post intervention, about 1/3 of participants increased their scores about ACP knowledge, thoughts, plans, and readiness to be a substitute decision‐maker or to make decisions for their loved one if they became very sick (possibly due to Covid). In particular, on one question (how ready are you to discuss with your loved one’s doctor whether or not there are certain health situations that would make your loved one’s life not worth living?), 74% of participants increased their engagement score pre‐ to post‐intervention. In qualitative analyses, 57% reported they engaged in ACP conversations after the intervention. Conclusion Immediately after the ACP video intervention, a substantial proportion of caregivers of individuals with dementia increased ratings of knowledge, confidence, and readiness to participate in ACP plans, conversations, and actions for their loved one. One month after the intervention, more than half engaged in ACP conversations. In future research, we will examine participant’s characteristics (e.g., dementia stage of loved one) in relationship to ACP Engagement responses. We plan to evaluate whether exposure to ACP video educational tools increases caregiver confidence in planning for healthcare decisions.

Atrophy of the hippocampal formation, a region important for the acquisition of new declarative knowledge, has been well-documented in Alzheimer's disease (AD), although the relation of such atrophy to the extent of memory dysfunction in these patients has been less clear. In the present study, 18 patients with a clinical diagnosis of probable AD were studied with a high-resolution, quantitative magnetic resonance imaging (MRI) protocol, as well as the verbal and spatial versions of the Buschke controlled learning task. The volumes of the hippocampal formation and, as a control for generalized atrophy, parahippocampal gyrus and temporal neocortex were computed from gapless coronal slices taken perpendicular to the long axis of the hippocampus. To correct for individual differences in brain size, volumes of regions of interest were divided by total intracranial volume. Separate stepwise regression analyses (with age, right and left hippocampal, parahippocampal gyrus, and temporal lobe volumes as the independent variables) showed that left hippocampal volume was the best predictor of free recall and delayed free recall of verbal information (P = 0.0042 and P < 0.0001, respectively). Recall and delayed recall of the spatial location of verbal items were best predicted by right hippocampal volume (P = 0.0054 and P = 0.0118, respectively). Memory scores did not correlate either with parahippocampal gyrus or temporal lobe volume. Furthermore, the relation between hippocampal volume and memory function observed in cases with AD did not hold for healthy aged control subjects. Hippocampus 2:136–142, 2000 © 2000 Wiley-Liss, Inc.

18F-T807 PET has demonstrated promise as biomarker of tau pathology in vivo, but longitudinal studies are needed to establish its reliability and value as a marker of disease progression and neurodegeneration. Case presentation of a man who developed progressive impairment in fluency in speech and writing at age 61. Evaluations included detailed history and examination, neuropsychological testing, analysis of cortical thickness at baseline and 1 year using high resolution T1 MRI, analysis of CSF β-amyloid and tau levels, estimate of fibrillar β-amyloid pathology utilizing 11C-Pittsburgh Compound B (PiB) PET and estimates of hyperphosphorylated tau burden at baseline and 1 year using 18F-T807 PET. We compared the distribution of T807 uptake and cortical atrophy to a map of the language network derived from resting state functional connectivity MRI utilizing a sample of 72 healthy adults. Initial evaluation revealed disruptions in grammar and word-retrieval, with prominent circumlocutions and semantic paraphasias for verbs and nouns, without apraxia of speech. Cerebrospinal fluid (CSF) and PiB PET results were not suggestive of underlying Alzheimer disease pathology. 18F-T807 PET demonstrated prominent asymmetrical left>right hemisphere uptake in regions corresponding to key nodes of the language network including posterior inferior frontal gyrus, temporoparietal cortex, posterior superior temporal gyrus/sulcus, posterior middle temporal gyrus/inferior temporal sulcus, and anterior middle temporal gyrus. This distribution corresponded well to the distribution of cortical atrophy, extending slightly beyond it as a penumbra. 18F-T807 PET signal magnitude within ROIs at 1 year demonstrated excellent reliability (r>0.9) and its distribution suggested extension of tau pathology in a more contiguous manner throughout the language network. The distribution of 18F-T807 uptake in this patient with primary progressive aphasia due to suspected frontotemporal lobar degeneration corresponded to the distribution of neurodegeneration determined by cortical atrophy. Reliability at 1 year was excellent, with extension of uptake suggesting that the technique is sensitive to progression of neurodegenerative pathology over 1 year. Correspondence between the pattern of neurodegeneration and the functional anatomy of the language network provides additional support for the network degeneration hypothesis, as well as a useful framework for analyzing the specific features of this patient's aphasia.

The objective was to prepare for clinical trials of disease-modifying agents for frontotemporal lobar degeneration (FTLD) by building a network of investigators, recruitment tools, biomarker measurements, and training opportunities throughout North America. New treatments that target specific molecules (and genes) underlying FTLD including tau (MAPT), progranulin (GRN), TDP-43 (TARBP) and chromosome 9 open reading frame 72 (C9ORF72) are rapidly entering human clinical trials. Only a few randomized placebo controlled trials have ever been completed in FTLD, and little infrastructure exists to support new studies, especially trials defined based on molecular pathology as compared to clinical syndrome. Investigators at 14 centers pooled preliminary data regarding patient populations, potential enrollment, and barriers to clinical trial participation. We developed strategies for evaluating subjects using clinical measures and novel neuropsychological batteries, including the new FTLD module from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and tests from a NINDS funded executive function battery (EXAMINER). We identified a need for funding investigator training and pilot projects focused on biomarker development. Two research projects funded through the NINDS and the National Center for Advancing Clinical and Translational Science (NCATS) Rare Disease Research Consortium Network. ARTFL is a partnership between academic investigators and patient advocacy groups including the AFTD, Cure PSP, Bluefield Project, Tau Consortium, CBD Solutions, and ADDF. One project will develop an online research registry and evaluates patients with sporadic FTLD syndromes with predictable underlying pathologies (progressive supranuclear palsy, semantic variant primary progressive aphasia, and frontotemporal dementia with amyotrophic lateral sclerosis) in order to identify clinical and biomarker measures to facilitate clinical trials. Novel neuropsychological batteries, genotyping, and clinical assessments will be performed in 650 participants. The second project focuses on longitudinal evaluation of both symptomatic and asymptomatic familial FTLD cases, using the same assessments and neuroimaging in 910 participants. The first pilot project focuses on AV1451 tau PET imaging in FTLD. Sites have IRB approval and will begin enrollment in spring 2015. Data will be publicly available to interested investigators. The data, recruitment tools, biomarkers, and training opportunities developed by ARTFL will facilitate new clinical trials in FTLD.

Although many investigators believe that the majority of neurodegenerative dementias have an initial symptomatic phase consistent with mild cognitive impairment (MCI), there has been relatively little study of non-Alzheimer forms of MCI. We set out to investigate the frequency and characteristics of a recognizable clinical phase of MCI in patients with a diagnosis of Frontotemporal Lobar Degeneration (FLTD) and to investigate the clinical, psychometric, and structural MRI predictors of conversion to dementia in this population. A consecutive series of patients with a clinical diagnosis of FTLD were evaluated comprehensively, including functional assessment, to determine whether their overall clinical status was best defined as MCI or dementia. Cortical thickness analysis was employed to measure regional atrophy. Of the 124 patients in our FTLD cohort, 43 were classified as having a clinical status of MCI at initial presentation; the remainder (81) were classified as having a clinical status of dementia. Nearly half (20) of the patients who presented with MCI have since converted to dementia. The majority of patients (34) with MCI clinical status had one of the primary progressive aphasia phenotypes, with the remainder (9) having a behavioral variant FTLD (bvFTLD) phenotype. All but 1 of the bvFTLD patients converted to dementia. All MCI-FTLD patients demonstrated atrophy detectable on quantitative MRI, with distinct “signature” imaging findings for each phenotypic subtype. Analysis to date of our FTLD cohort suggests that it is relatively more common for aphasic than behavioral variant FTLD to present in a prodromal clinical phase consistent with MCI. MCI of the FTLD type usually has specific recognizable syndromic clinical characteristics and structural MRI changes that are often distinct from MCI due to Alzheimer's disease. Additional analyses are in progress to identify the best predictors of conversion to dementia.

Neurodegenerative Disease ManagementVol. 2, No. 4 News & ViewsFree AccessJournal Watch: Our experts highlight the most important research articles across the spectrum of topics relevant to the field of neurodegenerative disease managementSusan H Fox, Philippe Huot, Brad Dickerson, Dag Aarsland, Niklas Mattsson & Theresa A ZesiewiczSusan H FoxMovement Disorder Clinic, Toronto Western Hospital, and Division of Neurology, University of Toronto, ON, CanadaSearch for more papers by this author, Philippe HuotMovement Disorder Clinic, Toronto Western Hospital, and Division of Neurology, University of Toronto, ON, CanadaSearch for more papers by this author, Brad DickersonMassachusetts General Hospital and Harvard Medical School, MA, USASearch for more papers by this author, Dag AarslandAlzheimer’s Disease Research Center, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this author, Niklas MattssonInstitute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SwedenSearch for more papers by this author & Theresa A ZesiewiczUniversity of South Florida, Tampa, FL, USASearch for more papers by this authorPublished Online:23 Aug 2012https://doi.org/10.2217/nmt.12.38AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Richard IH, McDermott MP, Kurlan R et al. A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology 78(16), 1229–1236 (2012).Non-motor symptoms, such as depression, are being increasingly recognized as important manifestations of Parkinson’s disease (PD). Depression, for instance, may affect over 50% of PD patients with long-standing disease [1]. While there are several agents used to treat depression in the non-PD population, surprisingly few trials with antidepressants have been performed in the PD population. Those that have been performed have used small numbers of subjects, often with equivocal results. In particular, the comparative benefits of different types of antidepressants in PD are unknown. The Study of Antidepressants in PD (SAD-PD) is the first large randomized controlled trial to investigate the comparative effects of a selective serotonin reuptake inhibitor (SSRI) versus a mixed serotonin and noradrenaline reuptake inhibitor (SNRI) on PD depression. The study was a 12-week, randomized, placebo-controlled, double-blind, ‘double-dummy’ Phase III study, which enrolled 115 PD patients with depression. Participants received either the SSRI, paroxetine (maximum of 40 mg daily, mean dosage 24 ± 11 mg at the end of the study), the SNRI, venlafaxine extended release (XR; maximum of 225 mg daily, mean dosage 121 ± 75 mg at the end of the study) or placebo. In comparison with placebo, both paroxetine and venlafaxine XR reduced depression severity, as assessed with the Hamilton Rating Scale for Depression (decrease of 6.2 points with paroxetine and 4.2 points with venlafaxine XR). Both paroxetine and venlafaxine XR had beneficial effects on secondary depression outcome variables (Montgomery–Asberg Depression Rating Scale, Beck Depression Inventory II and Geriatric Depression Scale) relative to placebo. Perhaps surprisingly, neither paroxetine nor venlafaxine XR had any effect on quality of life (Parkinson’s Disease Questionnaire-39). Neither paroxetine nor venlafaxine XR had a detrimental effect on motor function (Unified Parkinson’s Disease Rating Scale part III), and both treatments improved bulbar function relative to placebo. Paroxetine, but not venlafaxine XR, had a favorable effect on insomnia, when compared with placebo. Sitting blood pressure was significantly higher in the venlafaxine XR group at the end of the study when compared with the initial visit.The SAD-PD study aimed to recruit 228 patients, but stopped after 115 subjects were enrolled, due to difficulty in recruitment. Nevertheless, this study is the largest randomized, placebo-controlled trial to date in PD patients with depression and provides Class I evidence that both paroxetine and venlafaxine XR are effective in treating depression in PD. The study was also insightful in suggesting that improving depression may not necessarily be associated with an improvement in overall quality of life, as several factors, such as motor symptoms, are also likely to impair quality of life. Although there was no apparent superiority between the drugs, the results suggest that paroxetine may be more suited for depressed PD patients experiencing insomnia, whereas venlafaxine XR may be of additional value in the treatment of depressed PD patients with hypotension, although further studies are needed to validate these hypotheses. Lastly and importantly, none of the two active treatments had a deleterious effect on motor function. Further studies are still needed to compare other antidepressant classes such as tricyclic antidepressants with SNRIs and SSRIs to determine comparative benefit versus side-effect profiles in PD subjects with depression.– Written by Philippe Huot & Susan H FoxBoeve BF, Boylan KB, Graff-Radford NR et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135(Pt 3), 765–783 (2012).In late 2011, two collaborative groups reported the identification of a novel genetic mutation in families, known as the C9ORF72 expansion, in which individuals developed frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) or, in some cases, both clinical syndromes. This paper reports details of the demographic, clinical, neuropsychological and imaging chararacteristics of patients with this mutation; some cases with neuropathology were also described. The authors refer to these patients as having c9FTD/ALS. Most cases had at least one relative with ALS or dementia, although a small number of apparently sporadic onset cases were reported.Of the 63 symptomatic individuals with the mutation, age of symptom onset was quite variable, ranging from 33 to 72 years (median 52 years); survival was also notably variable, ranging from 1 to 17 years (most died within 7 years of symptom onset). Behavioral variant FTD was the most common clinical phenotype (nearly 50%), followed by ALS (∼30%), and finally FTD/ALS (∼20%). Notably, no individual exhibited a primary progressive aphasia syndrome. Parkinsonism was common, with an akinetic-rigid phenotype (without tremor) in 35% of examined subjects. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction and impairment in rapid word retrieval. Approximately a third of subjects did not exhibit impairment on initial neuropsychological testing. Half of the patients had prominent psychosis (delusions or hallucinations), and all exhibited appetite or eating behavioral abnormalities.Neuroimaging studies showed bilateral frontal abnormalities, with more variable degrees of parietal with or without temporal changes; in contrast to cases with genetic mutations in progranulin, no case of c9FTD/ALS had strikingly focal or asymmetric findings. In the 14 patients with autopsy material available, TDP43 pathology was present. Motor neuron degeneration was detected in nine patients, including five without signs of motor neuron disease during life. In summary, while this genetic form of FTD/ALS exhibits variability, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings. This set of findings represents a major step forward in the fields of FTD and ALS, and underscores the value of the establishment of an infrastructure for the systematic collection of clinical and pathological data in patients with these disorders so that when new genetic mutations are identified, the clinical and pathological phenotypes of patients with the genotype can be rapidly reported.– Written by Brad DickersonSchrijvers EM, Verhaaren BF, Koudstaal PJ, Hofman A, Ikram MA, Breteler MM. Is dementia incidence declining? Neurology 78(19), 1456–1463 (2012).The prevalence of dementia has been estimated to double every 20 years due to demographic changes. However, this prediction assumes no change in incidence. With changing lifestyles and preventive measures, dementia incidence may, however, change. For example, stroke incidence has been shown to decrease [1]. In the Rotterdam Study, one of the world’s most important epidemiological dementia studies, the 10-year incidence of dementia was compared in two dementia-free cohorts aged 60–90 years from 1990 (n = 5277) and from 2000 (n = 1769). Patients were prospectively examined according to a standardized protocol every 3–4 years.Screen-positive cases (i.e., those with an Mini Mental State Examination score <26 or Geriatric Mental State organic level score >0 at follow-up) underwent cognitive examination or, if needed, neuropsychological examination. Although not all comparisons were statistically significant, the findings consistently suggested a reduction in age-adjusted dementia incidence of 25% across age-groups in the 2000 cohort compared with the 1990 cohort. This finding was paralleled by larger brain volumes and smaller white-matter lesion volumes and lower frequencies of cortical or lacunar infarcts on MRI. Similarly, the 2000 cohort was better educated, and the use of preventive treatments such as lipid-lowering and anti-thrombotic agents was higher. Whereas mortality was lower, the frequency of diabetes and hypertension was higher in the 2000 cohort compared with the 1990 cohort. These findings, consistent with some previous reports, support the hypothesis that dementia incidence is declining, possibly due to lifestyle changes and drug strategies to reduce vascular and other risk factors for dementia.– Written by Dag AarslandFavilla CG, Ullman D, Shukla AW, Foote KD, Jacobson CE, Okun MS. Worsening essential tremor following deep brain stimulation: disease progression versus tolerance. Brain 135, 1455–1462 (2012).Essential tremor (ET) is one of the most common movement disorders in the world, but treatment of the disorder can be challenging. It is estimated that 30–50% of ET patients do not respond to medical management. Deep-brain stimulation (DBS) of the ventral intermedius nucleus (VIM) of the thalamus is a therapeutic modality that has become increasingly utilized to treat ET patients with severe tremor. One concern about VIM–DBS treatment is the apparent loss of surgical efficacy in a minority of patients over time. It is unclear whether this phenomenon can be attributed to tolerance to the procedure, disease progression or suboptimal lead placement.Favilla et al. sought to determine whether tolerance or disease progression was responsible for the apparent loss of surgical efficacy in 28 patients who received VIM–DBS and 21 control subjects in this retrospective study. In both groups, the rate of tremor progression was found to be consistent with natural disease progression. Seven of the 28 patients in the VIM–DBS group were isolated from the treatment cohort due to evidence of secondary progression of tremor, defined as an increase in the ‘off’ tremor rating scale motor score between 6 and 36 months following surgery. Six of the seven subjects continued to experience a sustained benefit of stimulation at the study end point, suggesting potential disease progression rather than tolerance; one patient was found to have slightly suboptimal lead placement. The authors conclude that DBS tolerance may be over-reported in the literature, and that tolerance attributed to VIM–DBS must be separated from disease progression by more careful focus on lead location, trends in off-stimulation scores, clinical benefits and side effects that occur during programming.– Written by Theresa A ZesiewiczWahlqvist ML, Lee MS, Hsu CC, Chuang SY, Lee JT, Tsai HN. Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson’s disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat. Disord. 18(6), 753–758 (2012).Parkinson’s disease (PD) is a common neurodegenerative disease with a complex pathogenesis. The role of diabetes as an antecedent cause of PD has been controversial, with both positive and negative studies appearing in scientific literature. Wahlqvist and his colleagues sought to evaluate whether Type 2 diabetes mellitus (T2DM) and commonly used oral antihyperglycemic agents (OAAs) were associated with the development of PD in the Taiwanese population. Using data from a representative cohort of 800,000 people that was obtained between 1 January 1996 and 31 December 2007 from the Taiwan National Health Insurance database, the authors identified the presence or absence of T2DM and the use of OAAs. Patients with T2DM were matched with diabetes mellitus-free patients to determine PD incidence. Information about the presence or absence of OAAs in T2DM patients who did not have PD was also obtained.The study found that incident PD increased 2.2-fold in T2DM patients in the Taiwanese population. Sulfonylureas further increased the risk by 57%, which was avoided by combination use with metformin. Metformin (Glucophage® [Bristol-Myers Squibb], a member of the biguanides) appeared to provide protection against PD when sulfonylureas were used in both genders. Study limitations include the use of diagnostic codes for disease identification, the absence of information concerning T2DM severity, and whether OAA use could have been a surrogate for other risk factors. Nonetheless, the study provides important information about a possible risk factor for PD.– Written by Theresa A ZesiewiczToledo JB, Brettschneider J, Grossman M et al. CSF biomarkers cutoffs: the importance of coincident neuropathological diseases. Acta Neuropathol. 124(1), 23–35 (2012).With the development of potentially disease-modifying drugs for Alzheimer’s disease (AD), there is a boom in the interest of methods for early and accurate AD diagnosis, in order to optimize clinical patient management and facilitate selection or stratification of study participants in trials. The cerebrospinal fluid (CSF) biomarkers β-amyloid42, total-tau and phosphorylated tau reflect pathological processes in the CNS and are strong candidates for AD diagnostic methods. However, the use of these measurements is complicated by the fact that a large proportion of patients with neurodegenerative diseases show signs of combined pathologies with, for example, AD and coincident frontotemporal lobar degeneration, which may contribute to heterogeneity both in clinical presentation and in responsiveness to therapy. Since the clinical diagnosis of mixed pathologies is prone to error, neuropathological studies are needed to validate the performance of diagnostic biomarkers in these patients. Doing precisely this, the study by Toledo et al. is a valuable contribution to the literature. In 142 neuropathologically diagnosed patients (81% overall agreement with clinical diagnosis), CSF β-amyloid42, total-tau and phosphorylated tau had high diagnostic accuracy for AD, but lower diagnostic accuracy for frontotemporal lobar degeneration. Most patients with AD and a coincident other pathology (27% of the subjects) were classified as having AD by biomarker tests, which underscores the need for novel biomarkers to pin-point non-AD pathology in dementia patients. Finally, the use of clinical instead of neuropathological diagnosis underestimated the performance of CSF biomarkers, reminding us of the importance to use neuropathological confirmation in studies whenever possible.– Written by Niklas MattssonPottier C, Hannequin D, Coutant S et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset alzheimer disease. Mol. Psychiatry doi:10.1038/mp.2012.15 (2012) (Epub ahead of print).Although analysis of the genes PSEN1, PSEN2 and APP identifies a disease-causing mutation or duplication in most patients with early onset Alzheimer’s disease (AD), some patients with autosomal dominant forms of AD have no changes in these genes, indicating that additional AD-causing genes remain to be discovered. The development of novel genetic technology is now advancing this field forward. Using exome sequencing in 29 unrelated patients with a history of autosomal dominant early onset AD without mutations in PSEN1, PSEN2 or APP, Pottier et al. identified (different) mutations in the SORL1 gene in seven patients. This provides a strong case for SORL1 mutations as a direct cause of rare cases of AD. The finding is particularly interesting since SORL1 has previously been linked to β-amyloid trafficking and cholesterol metabolism, which are biological pathways important for AD. The importance of SORL1 for the large majority of AD patients having sporadic AD may be interesting to explore further.– Written by Niklas MattssonFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.FiguresReferencesRelatedDetailsCited ByInterview: Unraveling the neuropsychiatric symptoms of Parkinson’s and Alzheimer’s disease: current and future progressDag Aarsland19 November 2012 | Neurodegenerative Disease Management, Vol. 2, No. 5 Vol. 2, No. 4 Follow us on social media for the latest updates Metrics Downloaded 235 times History Published online 23 August 2012 Published in print August 2012 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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Atrophy in neurodegenerative disorders appears to occur and spread within functionally connected brain networks. Possible mechanisms for this observation include: (1) trans-neuronal spread of abnormal proteins between structurally connected regions, or (2) that network dysfunction leads to structural changes in connected brain regions, making them more vulnerable to neuropathology (diaschisis). These brain networks are intrinsically anti-correlated (negatively correlated) with other brain networks that share no direct structural connections. We hypothesized that patients with Alzheimer's disease would have paradoxically increased cortical thickness in these anti-correlated networks, supporting the functional diaschisis model. In 184 patients with Alzheimer's disease, we determined each patient's individual regions of decreased and increased cortical thickness vs. age matched normal controls (n=228) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Next, we determined if regions of decreased cortical thickness (atrophy) were functionally connected to regions of increased cortical thickness using a large (n=1000), publically available normative connectome. We compared these results to the correlation between atrophied areas and random regions. Finally, we assessed whether increased thickness in anti-correlated regions relates to hallucinations (n=20), which are hypothesized to be release phenomenon due to dysregulation of visual areas. Patients with AD had paradoxical increased cortical thickness. This growth occurred in regions anti-correlated to regions of atrophy (r = -0.08, p < 0.0001). Patients with hallucinations had increased cortical thickness in the visual cortex compared to AD patients without neuropsychiatric symptoms (p<0.0001), and compared to age-match controls (p<0.0001). This increased cortical thickness was explained by the strength of anti-correlation with atrophied areas (r = -0.23, p < 0.05). Patients with AD had paradoxical increased cortical thickness that occurred specifically in regions anti-correlated to regions of atrophy. This was associated with hallucinations, which are hypothesized to be release phenomena. Our results support the hypothesis that network dysfunction leads to structural changes in neurodegenerative disorders via functional diaschisis, providing potential insight into the mechanism of disease progression in dementia.

An important step in determining patients with possible dementia based on cognitive scores, is to estimate the distribution of scores in cognitively normal subjects; extreme scores relative to this control distribution may indicate dementia. To date, approaches have focused on determining the distribution of z-scores for a set of normal controls, and then compared the z-scores of new subjects with that distribution. The z-score approach was extended by Shirk et al. [1] to consider linear correction for age, sex, and education. Here this approach is further extended to consider non-linear relationships between predictors and cognitive score, as well as accounting for differing standard deviation of the cognitive scores with age. The same NACC database of normal controls was used as in [1] (data were used from 29 ADCs and considered UDS visits between September 2015 and May 2017). Nonlinear shape-constrained generalized additive models (SCAMs) [2] were fit to the data separately for each cognitive outcome. SCAM fits were generated with nonlinear corrections for age and education (constrained to be monotonic), and an additive term for sex. Another SCAM was then fitted to estimate change in the standard deviation of residuals with respect to age. A lookup table was generated based on these two SCAM fits. For each value of age, education level, and sex, an adjusted z-score (n-score) was generated, using the fitted mean and standard deviation for that age, education level, and sex. The figures display an example SCAM model fit for TRAIL B. There was a clear non-linear relationship between age and TRAIL B (Figure 1). The estimated relationship between education level and TRAIL B was linear (Figure 2). Increasing standard deviation was seen with age (Figure 3). Consistent improvements were seen across different neurocognitive outcomes by allowing for such non-linear adjustment.

Parkinsonism, motor neuron disease (MND), apraxia, etc. often occur in frontotemporal lobar degeneration (FTLD) syndromes. Previous instruments developed to capture the key clinical and salient aspects of patients with dementia (standard CDR and FTLD-CDR) did not include these relevant motor features. Additionally these instruments fail to capture sensitive information from a variety of sources like the individual him/herself, the informant and data from neuropsychological testing. The 12-item Multidomain Impairment Rating (MIR) scale was developed to encompass all key manifestations of the FTLD spectrum disorders for use in natural history studies and clinical trials. The MIR encompasses elements of the FTLD-CDR plus a visuospatial domain as well as domains for parkinsonism, MND and other non-cognitive/non-behavioral aspects of FTLD. The ratings of 0, 0.5, 1, 2 or 3 for each domain are based on three data sources – the subject, informant, and neuropsychological testing. Consensus summary ratings include the MIR Neuropsychology score, the global (MIR), and summed score (MIR SS). A reliability exercise was completed using baseline clinical and neuropsychological data in subjects participating in the ARTFL/LEFFTDS Consortium. Twenty subjects each from 2 sites were rated (blinded to the other site's ratings), and the data of the 40 subjects were analyzed. The cases were selected a priori to represent clinically normal (CN), MCI, and more severe degrees of cognitive, behavioral and motor impairment (e.g., bvFTD, PPA, FTD with parkinsonism, and FTD with MND). Weighted kappa statistic measured agreement. The analyses showed very good agreement for the global MIR ratings [κ=0.86 (95% CI 0.74-0.97)], the MIR SS ratings [κ=0.82 (95% CI 0.72-0.92)], and complete concordance on the MIR Neuropsychology ratings [κ=1.0]. These findings suggest good reliability for the global MIR, MIR SS and MIR Neuropsychology ratings. The MIR may provide added utility to the FTLD-CDR, and could be used in natural history studies and clinical trials to more optimally capture the spectrum of features in FTLD.

Abstract Background Clinical trials for tauopathies require novel biomarkers for disease detection and monitoring. One previous study found functional connectivity (FC) alterations in presymptomatic (preSx) MAPT mutation carriers (Whitwell et al ., 2011), yet studies have not examined FC networks along the MAPT disease continuum. We hypothesized that both symptomatic (Sx) and preSx MAPT mutation carriers would show FC alterations compared to healthy controls (HC). Method Leveraging task‐free fMRI data from the UCSF Memory and Aging Center and the ARTFL/LEFFTDS Consortia (Boeve et al., 2019), we compared 14 Sx and 33 preSx to 80 HC to characterize their FC profiles. Using a seed‐based approach, we studied FC within networks associated with different MAPT clinical syndromes (i.e., salience network [SN] for behavioral variant frontotemporal dementia, default mode network [DMN] for Alzheimer’s‐like amnestic syndrome, corticobasal syndrome [CBS] and progressive supranuclear palsy [PSP] networks). Complementing the seed‐based approach, we next calculated whole‐brain intra‐/inter‐network FC matrices for 14 networks (Brown et al., 2019), and applied K‐means clustering to assess whether preSx displayed heterogeneous connectivity profiles. ComBat was applied to harmonize multi‐site imaging data (Fortin et al., 2017, 2018). Thresholding was set at a joint height and extent threshold of p&lt;0.05 (uncorrected) with age, sex, education and handedness as nuisance covariates. Result Compared to HC, Sx featured disrupted FC within key hubs of all four networks, and regions of cerebellar and pontine hyperconnectivity within CBS and PSP networks. As seen in Sx vs. HC, preSx had similar anatomical patterns of SN/CBS network hypoconnectivity and CBS/PSP network hyperconnectivity vs. HC. In contrast to Sx, who had DMN disruption, preSx showed DMN hyperconnectivity vs. HC. Whole‐brain analyses revealed that Sx had disrupted intra‐/inter‐network FC in networks involving the insula/anterior temporal lobe. Clustering analysis identified two preSx subgroups. Compared to HC, preSx1 principally had disrupted FC across networks including those disrupted in Sx, whereas preSx2 mainly demonstrated hyperconnectivity. Conclusion Sx and preSx both demonstrated robust FC alterations. Future studies will investigate whether the preSx subgroup whose whole‐brain FC was similar to Sx in that it showed principally FC disruption may be at greater risk for imminent symptom conversion and/or neurodegeneration.

Abstract Background Patients with Primary Progressive Aphasia (PPA) are usually subtyped into one of the three canonical subtypes (nfvPPA, svPPA, lvPPA) based on a neurological and cognitive assessment including their language characteristics typically measured from a battery of confrontational tests. While widely used, this classification system has been criticized, and also the approach makes assumptions about the features of language that are important to measure. Here we use methods from Artificial Intelligence to measure features of speech from naturalistic connected speech samples with the goal of determining how well this data‐driven approach matches independent clinical subtypes and how its results relate to neuroanatomical abnormalities measured from MRI. Method Language data was obtained from 78 PPA patients (28 nfvPPA, 26 lvPPA, 24 svPPA) describing the WAB Picnic Scene. A transformer model, RoBERTa, was used to measure similarities in language features, IVIS to perform dimensionality reduction, and nested k‐means to cluster language samples. We then examined the cortical atrophy patterns of these clusters of PPA patients versus healthy controls (N=25). Result Seven PPA clusters were identified with 88% agreement with the classic classification system. Individuals in Clusters 1 and 2 (mainly nfvPPA) exhibited speech dysfluency and reduced clausal complexity with atrophy in the left pars opercularis, superior and caudal middle frontal gyri. Those in Clusters 3 and 4 (predominantly lvPPA) exhibited difficulties in subject‐verb agreement, demonstratives and tense and shared atrophy in the superior and middle temporal and inferior parietal gyri. Individuals in Clusters 5‐7 (mainly svPPA) exhibited deficits in nouns/verbs access with atrophy in the left temporal pole and inferior and middle temporal gyri. Conclusion Data‐driven Artificial Intelligence methods applied to naturalistic speech samples from PPA patients identify clusters of patients that match well to clinical subtypes, and that exhibit cortical atrophy patterns typical of those subtypes. This suggests that PPA subtypes are natural kinds and that computational analysis of simple speech samples can be used to identify them.

Abstract Background Accumulating evidence supports the relevance of the localization of tau pathology, as measured with 18 F‐flortaucipir (FTP) PET imaging, for characterizing clinical phenotypes of Alzheimer’s disease (AD), including posterior cortical atrophy (PCA). The present study investigated the degree to which the cortical distribution of elevated FTP uptake varies across individual patients with PCA, with the goal to identify regions of heightened vulnerability to tau pathology in this population. Based on available PET imaging evidence and using a systems neuroscience approach, we hypothesized that the majority of PCA patients would exhibit elevated FTP uptake in the visual and dorsal attention networks of the brain, consistent with impairments in basic and higher‐order visual processing characteristic of this syndrome. Method 15 patients with PCA underwent FTP PET imaging. Individual FTP standardized uptake value ratio (SUVR) maps were partial volume corrected and projected to template cortical surface space. These individual SUVR maps were converted to Z‐score maps using data obtained from 24 age‐matched healthy control subjects, then binarized at Z &gt; 1.5. Percent overlap maps were created based on the individual binarized Z‐score maps. A parcellation of the cerebral cortex into seven canonical intrinsic functional networks was used to characterize the spatial topography of elevated FTP uptake. Result 100% of PCA patients showed elevated FTP uptake in brain regions including bilateral superior parietal lobule, area MT, and importantly, bilateral frontal eye fields, which are key nodes of the dorsal attention network. In more than 80% of patients, elevated signal was also observed bilaterally in the occipital, parietal, and temporal areas that are nodes of the visual, frontoparietal, and default mode networks, with more circumscribed and variable involvement of prefrontal cortex. Conclusion The results support the hypothesis that tau pathology in PCA universally affects the key nodes of the dorsal attention network consistent with visuospatial and visuomotor deficits commonly observed in PCA, including oculomotor apraxia (impaired voluntary control of eye movements). In addition to the nearly universal involvement of visual association networks, key nodes of default mode and frontoparietal control networks likely subserve other cognitive deficits that are common but more variable in PCA.

We have been working with the AD-signature MRI biomarker to determine its utility in early diagnosis and prognosis, but have not yet examined its relationship to CSF markers. To begin to assess the specificity of the refined AD-signature index measure we analyzed the relationships between CSF biomarkers and the raw AD-signature measure (in millimeters) and the adjusted AD-signature index measure (adjusted for thickness of the Aging-signature regions (Bakkour et al., 2013)). We calculated an “AD-sign ature index” measure by performing a linear regression with the Aging-signature as the independent variable and the AD-signature as the independent variable. The residuals of this regression analysis were then saved as the “AD-signature index.” Thus. an individual with a lower AD-signature index value has cortical thickness within the AD-signature ROIs that is disproportionately smaller than the thickness of the Aging-signature ROIs, likely reflecting more specific AD-related neurodegeneration. Alternatively, an individual with a higher AD-signature index value has cortical thickness within the AD-signature ROIs that is of similar relative magnitude to Aging-signature ROIs, indicating possibly reflecting more diffuse effects. The adjusted AD-signature index exhibited substantially stronger correlations with all CSF biomarkers relative to the raw AD-signature, suggesting that this adjustment for “brain age” improves the specificity of this MRI biomarker for AD-related neurodegeneration. The adjusted AD-signature MRI biomarker reflects molecular markers of AD neuropathology.

Neuropathological studies have suggested that, on average at least 10% of people diagnosed with probable Alzheimer disease (pr AD) by clinical criteria do not meet pathological criteria for AD. The objective of this study was to investigate the demographic, neuropsychological, and cerebrospinal fluid (CSF) biomarker characteristics of amyloid-negative dementia subjects in the Alzheimer 's Disease Neuroimaging Initiative (ADNI) study. We categorized 416 subjects with prAD as amyloid-positive (Aβ+) or amyloid-negative (Aβ-) based on threshold criteria for cerebrospinal fluid Aβ42 levels and/or average cortical florbetapir or Pittsburgh Compound B (PiB) uptake.Dementia groups were compared to each other and to group of 209 amyloid-negative control subjects without cognitive impairment on measures of delayed recognition memory (RAVLT d '), divided attention (TMT-B), confrontation naming (BNT), and semantic fluency (animal fluency), along with apolipoprotein ε 4 (APOE4) frequency and CSF total (t-tau) and phosphorylated tau (p-tau181) levels. Aβ- prAD was characterized by an older mean age of onset and a much lower APOE4 frequency than Aβ+ prAD. Controlling for dementia severity, the Aβ- prAD group performed worse than controls and better than the Aβ+ group on measures of recognition memory and semantic fluency, and comparable to controls and better than the Aβ+ group on measures of divided attention and confrontation naming. The Aβ- prAD group had a mean CSF t - tau level intermediate between the control group and the Aβ+ group, whereas the mean CSF p-tau 181 level in the Aβ- group was comparable to that in the control group and lower than that in the Aβ+ group. These preliminary findings suggest that individuals with Aβ- amnestic dementia are likely to have an older age of onset and less impairment on neuropsychological measures of recognition memory, divided attention, semantic fluency and confrontation naming at a given level of functional impairment than individuals with Aβ+ dementia. Individuals with Aβ- dementia are much less likely to carry an APOE4 allele, and may have elevated levels of CSF t-tau but not p-tau181.

Hereditary frontotemporal dementia associated with mutations in the microtubule-associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms.

Although post-mortem studies of AD, FTLD, and other tauopathies have shown strong relationships between the density of tau pathology and cell loss and other markers of neurodegeneration, and in vivo CSF markers of hyperphosphorylated tau correlate with the magnitude of atrophy in AD, we have not had an imaging tool to investigate relationships between the regional localization and magnitude of tau pathology in vivo and regional atrophy. We are using [18F] T807, a novel PET ligand, to scan patients with FTLD, AD, and other tauopathies. We analyzed SUVR (cerebellum reference) data to localize and quantify [18F] T807 signal. We also co-registered analyzed [18F] T807 images to MRI images for visualization and calculation of % atrophy relative to controls. In AD and FTLD, [18F] T807 signal was elevated in areas expected based on clinical syndromes, and strongly colocalized with atrophy. Within single cases, the magnitude of [F18] T807 signal within cortical regions of interest (ROI) correlated strongly with the magnitude of atrophy within the same ROIs. In patients with AD and FTLD, [F18] T807 signal, a presumed in vivo marker of tau pathology, co-localizes with atrophy and its magnitude correlates with the magnitude of atrophy, supporting its value as an in vivo marker of neurodegeneration. Further work is ongoing to address technical issues including partial volume effects.

Future clinical trials involving putative disease-modifying therapies in familial frontotemporal lobar degeneration (f-FTLD) will require natural history data on the clinical, neuropsychological, neuroimaging and biofluid findings in presymptomatic (presym) and symptomatic (symp) mutation carriers. As part of the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) protocol (U01 AG045390), investigators at 8 centers in North America pooled data and developed strategies for evaluating subjects in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes. There are 306 known kindreds with 835 total subjects (including >295 mutation carriers) already identified, and the median (±SD) age of onset across all genetic groups is 55±11 years. Characteristics for each genetic group are as follows: MAPT – 45 kindreds, 223 subjects (including 50 symp and >36 asymp mutation carriers), median age 49±10 years; GRN – 81 kindreds, 335 subjects (including 55 symp and >27 asymp mutation carriers), median age 61±12 years; and C9orf72– 180 kindreds, 277 subjects (including 99 symp and >28 asymp mutation carriers), median age 55±11 years. The protocol involves periodic comprehensive clinical and neuropsychological assessments from 2015 to 2019 in 300 subjects, as well as brain MRI and biofluid sampling (eg, DNA, plasma, mRNA and CSF), to address several key aims: 1) to model the rates of decline in traditional measures of clinical (neuropsychological and behavioral composites) function and cortical volume on structural MRI in the symptomatic phase, 2) to model the rates of decline is the same measures in the asymptomatic phase, 3) to assess the value of novel imaging and clinical measures for characterizing asymptomatic f-FTLD subjects, and identify factors predicting clinical rates of progression in each group, and 4) to identify genetic and biofluid factors that modify rates of clinical and neuroimaging decline in the asymptomatic and symptomatic phases of f-FTLD. The clinical, neuropsychological and biomarker data, which will be available to interested investigators worldwide, should facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

A critical unmet need for FTLD research, especially therapeutic trials, is the development of biomarkers to identify and localize FTLD-tau in living patients. We are using [18F] T807, a novel PET ligand, to scan a series of patients with FTLD, to date including three symptomatic and two asymptomatic MAPT mutation carriers. We have also scanned FTD patients with C9ORF72 and GRN mutations, as well as 10 patients with sporadic mild primary progressive aphasia. We analyzed SUVR (cerebellum reference) data to localize and quantify [18F] T807 signal. We also co-registered analyzed [18F] T807 images to MRI images for visualization and calculation of % atrophy relative to controls. [18F] T807 signal was elevated in frontal, insular, and anterior temporal cortex in symptomatic MAPT carriers, and colocalized with atrophy. Signal was elevated above that of controls in asymptomatic MAPT carriers. In non-fluent aphasic patients, [18F] T807 signal was highest in frontal cortex with marked asymmetry, most prominent in the dominant hemisphere, and localized remarkably well with atrophy. Semantic variant PPA patients showed elevated anterior temporal signal. [F18] T807 is a promising new PET ligand for imaging tau pathology in vivo in patients with FTLD.

Abstract not available.

Despite a wealth of neuroimaging research that has associated Semantic Variant Primary Progressive Aphasia (svPPA, also known as Semantic Dementia) with a distributed pattern of cortical atrophy that is most prominent in the left anterior temporal cortex, there is little consensus regarding which specific region within the anterior temporal cortex is most prominently damaged, which may indicate the putative origin of neurodegeneration. In this study, we localized the most prominent and consistent region of atrophy in svPPA using cortical thickness analysis and surface-based inter-subject registration in two independent patient samples. Across both samples the point of maximal cortical atrophy was located in same region of the left dorsolateral temporal pole. Individual subject analyses localized the point of maximal atrophy for 100% of patients in both svPPA samples to the same temporopolar region (likely in cytoarchitectural area TG). Using resting state functional connectivity (rs-fcMRI) in healthy young adults, we showed that the seed region derived from the svPPA analysis anchored a large-scale network in healthy young adults that closely resembled the distributed atrophy pattern in svPPA. In both patient samples, the magnitude of atrophy within a brain region was predicted by that region’s strength of functional connectivity to the temporopolar seed region in healthy adults. These findings suggest that cortical atrophy in svPPA may follow connectional pathways within a large-scale network that converges on the temporal pole.

The Primary Progressive Aphasias (PPA) are neurodegenerative syndromes that target language networks. While neuropsychiatric symptoms often accompany language impairment in PPA, factors predicting emergence and progression of these symptoms remain elusive. We identify clinical and imaging predictors of neuropsychiatric symptoms in PPA across the three major variants. The sample included 60 PPA patients: 23 agrammatic/nonfluent (PPA-G), 16 semantic (PPA-S), 16 logopenic (PPA-L), and 5 other (PPA-O) variants. Baseline cortical thickness measures were available in 48 patients. All patients had serial Neuropsychiatric Inventory Questionnaires (NPI-Q) completed by informants over a 5-year period of follow-up. Mean baseline NPI-Q scores were highest for PPA-S patients (7.5) compared to PPA-G (3.2), PPA-L (2.3) and PPA-O (3.7). Higher baseline NPI-Q scores predicted greater increase in NPI-Q scores over time (p<0.038). Greater baseline cortical atrophy in bvFTD-vulnerable regions predicted greater increase in NPI-Q scores over time (p<0.003). In our cohort of PPA patients, more prominent baseline neuropsychiatric symptoms and greater cortical atrophy in bvfTD-vulnerable regions were predictors of a worse neuropsychiatric prognosis.

In Preclinical Alzheimer's disease (AD), AD neuropathology is present in cognitively normal (CN) individuals. It is not yet clear how long this phase of the disease may be present prior to symptoms. The “AD signature” MRI biomarker, a measure of cortical thinning in specific limbic and association regions, is detectable in CN individuals nearly a decade prior to dementia. Here we characterize the age-associated trajectory of the AD-signature thickness in a large Colombian kindred with the E280A presenilin 1 (PSEN1) mutation, one goal of which is to assess the potential duration of neurodegeneration prior to symptoms. 56 pre-symptomatic carriers (age = 22.9 ± 9.3 years), 11 symptomatic carriers (MCI or dementia; MMSE 23.1 ± 3.5; 47.5 ± 5 years), and 57 CN non-carriers (23.8 ± 9.4 years) from the Colombian kindred were evaluated. T1-weighted volumetric MRI images were acquired using a Siemens 1.5T scanner. Cortical thickness was measured in a fully automated fashion using FreeSurfer. A priori regions of interest (ROIs) were used to obtain thickness from “AD-signature regions”. ANOVA was used to compare the groups using the entire summary measure as well as individual regions. Regression curves for the trajectory of the AD-cortical signature associated with age were estimated and compared. As a whole, the presymptomatic PSEN1 carrier group did not show cortical thinning compared to non-carriers. However, symptomatic carriers demonstrated cortical thinning in the AD-signature summary measure and in all individual nine ROIs (P <0.001). Compared to non-carriers, preliminary regression curve analysis suggested that PSEN1 mutation carriers had a greater slope in which advancing age was associated with thinner cortex in the AD-signature measure (P <0.05). It is critical to begin using opportunities afforded by this and other large early-onset familial AD cohorts to investigate the potential duration of preclinical AD. Further analyses of this quantitative MRI biomarker are ongoing.

Patients with Frontotemporal Dementia (FTD) often exhibit progressive impairments in social behavior. Although there are a growing number of performance-based tests of social behavior, there are no existing instruments for clinicians to grade social symptoms in FTD. We set out to develop a new scale measuring the types and severity of social symptoms in FTD; and to test the hypothesis that atrophy in specific brain networks correlates with symptom severity. We developed the Social Impairment Rating Scale (SIRS), rated by a clinician after a structured interview. In a sample of 20 FTD patients, we used the SIRS to study the anatomic basis of social impairments in FTD. In support of hypotheses generated from a prior study of healthy adults, we found that the relative magnitude of brain atrophy in three partially dissociable corticolimbic networks anchored in the amygdala predicted the severity of distinct social impairments measured using the SIRS. Specifically, patients with the greatest atrophy in a mesolimbic, reward-related (affiliation) network exhibited the most severe socioemotional detachment, whereas patients with the greatest atrophy in an interoceptive, pain-related (aversion) network exhibited the most severe lack of social apprehension. Patients with the greatest atrophy in a perceptual network exhibited the most severe lack of awareness or understanding of others' socioemotional behavior. Our findings support the validity of the SIRS as an instrument to measure the social symptoms in FTD. Ultimately, we hope it will be useful as a longitudinal outcome measure in clinical trials of putative interventions to improve social functioning.

Subcortical ischemic disease, which is thought to lead to vascular cognitive impairment, and Alzheimer's disease (AD) are viewed as competing causes of mild cognitive impairment (MCI). The presence of white matter hyperintensities (WMH) on MR images is a marker of subcortical ischemic disease. We enrolled 71 study participants who had a CDR of 0.5 from our Alzheimer's Disease Research Center. All subjects were above the age of 60, non-demented, and had hypertension (plus in some cases other vascular risk factors). Each study participant underwent neuropsychological testing and MR imaging procedures. FreeSurfer's General Linear Model algorithm was used to generate a whole-cortex map of the correlation between log-transformed WMH and cortical thickness. In addition, the AD-signature summary measure was derived as previously published in order to test the hypothesis that WMH relate to cortical thickness in these AD-vulnerable regions. Analysis of the T1-MPRAGE revealed that WMH volume correlatedwith cortical thinning in the ventrolateral prefrontal cortex (R=-0.31, p=0.01; not corrected for multiple testing), a region not typically associated with AD. Cortical regions previously associated with Alzheimer's disease dementia (the so-called AD-signature regions) showed no relationship with WMH volume (R=-0.16, p=0.4). We conclude that subcortical ischemic disease may be associated with regionally specific cortical atrophy distinct from that seen in AD and potentially involved in executive function.

The relationship between AD and the DMN has been well documented. Not only does amyloid pathology accumulate in the distribution of this network in AD, there is evidence from resting state fMRI studies of disrupted functional connectivity within this network, evidence from structural MRI morphometric studies of atrophy in network regions, and evidence that integrity of the network is crucial for functions such as episodic memory that are lost early in the course of the illness. But should AD be viewed strictly as a disorder of the DMN, or are other large-scale functional networks implicated in the illness? We addressed this question by examining the topographic overlap between cortical regions that are consistently atrophic in AD patients and large-scale functional-anatomic networks defined by meta-analysis of the functional neuroimaging literature and covariance of BOLD signal in resting state fMRI data (Smith et al., PNAS, 2009). As expected, there was overlap between regions of cortical thinning in AD and nodes of the DMN. In addition, cortical thinning was observed in nodes of resting-state networks thought to subserve executive control, visual attention, and language. The findings suggest that Alzheimer disease should best be considered a multi-network disease, as implied by the clinical diagnostic criteria.

Since AD neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related a trophy in preclinical AD. Here we hypothesized that the “disease signature” of AD-related cortical thinning, previously identified in mild AD dementia patients, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up. We studied two independent samples of adults who were CN when scanned. In sample #1, 8 individuals developing AD dementia (CN-AD Converters) after an average of 11.1 years were compared to 25 individuals whore mained CN (CN-Stable). In sample #2, 7 CN-AD Converters (average follow-up 7.1 years) were compared to 25 CN-Stable individuals. AD-signature cortical thinning in CN-AD Converters in both samples was remarkably similar, about 0.2mm (p < 0.05). Despite this small absolute difference, Cohen's d effect sizes for these differences were very large ( > 1). Of the 11 CN individuals with baseline Low AD-signature Thickness (≥ 1 standard deviation(S.D.) below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 High AD-signature Thickness individuals (≥ 1S.D. above mean) developed dementia. This marker predicted time to diagnosis of dementia (H.R. = 3.4, p < 0.0005); one S.D. of thinning increased dementia risk by 3.4. By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia,making this measure a potentially important imaging biomarker of early neurodegeneration.

Neuropathological studies have suggested a weaker association between amnesic dementia and Alzheimer disease (AD)-type pathology in the very old (onset of symptoms ≥80 years) when compared to younger-old individuals (onset of symptoms between ages 65–79). Non-AD dementias including dementia due to Frontotemporal lobar degeneration pathologies are more common in younger individuals (onset of symptoms <65), and AD pathology appears to present more frequently with a non-amnesic phenotype in this early-onset dementia (EOD) group. The objective of this study was to investigate the prevalence of amyloid-positivity in groups of subjects with EOD, late-onset dementia (LOD), and very-late onset dementia (VLOD) due to probable AD (prAD), and to further characterize amyloid-positive subjects in each age group by Apolipoprotein E ε4 (APOE4) status and selected neuropsychological measures. We categorized 131 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with prAD as amyloid-positive or amyloid-negative based on threshold criteria for cerebrospinal fluid Aβ42 levels and/or average cortical florbetapir uptake. Subjects were divided into groups of EOD, LOD, and VLOD based on estimated age at onset of symptoms. The frequency of APOE4 alleles and neuropsychological variables pertaining to delayed recognition memory (RAVLT), divided attention (TMT-B), confrontation naming (BNT), semantic fluency (animal fluency), and visual construction (cube copying) were assessed for each age group. 32/32 (100%) subjects with EOD due to prAD were amyloid-positive, compared to 64/72 (89%) of LOD subjects and 19/27 (70%) of VLOD subjects (p<0.05). APOE4 frequency was comparable in the amyloid-positive EOD and LOD groups (56% and 52%, respectively), and greater in these groups than in the amyloid-positive VLOD group (31%, p<0.05). The EOD group performed significantly worse on divided attention and semantic fluency than the amyloid-positive LOD and VLOD groups (p<0.05), whereas the VLOD group performed significantly worse on confrontation naming than the other two groups (p<0.05). These preliminary findings suggest a higher frequency of amyloid-negative status in demented individuals with a later onset of symptoms. A “probable AD” phenotype in EOD is highly associated with amyloid pathology and frequently with prominent early deficits in divided attention and semantic fluency.

The logopenic variant of Primary Progressive Aphasia, also known as Logopenic Progressive Aphasia (LPA), is often an atypical clinical presentation of Alzheimer's disease (AD). With the anticipated emergence of novel therapeutics aimed at the earliest stages of AD pathobiology, the ability to identify individuals with an incipient progressive aphasia due to underlying AD pathology is increasingly urgent. We set out to identify the earliest clinical, psychometric, and imaging characteristics of LPA, and to characterize longitudinal clinical outcome. 9 patients were identified as meeting criteria for LPA, based on consensus between two neurologists and a speech pathologist. Clinical and psychometric characteristics were assessed at baseline and longitudinally. Quantitative MRI analysis was performed to measure regional cortical atrophy. Molecular markers of AD (CSF or PiB-PET) were assessed when available. All patients were identified in early stage LPA (global CDR 0.5), with average follow up of 3.8 years. Quantitative speech and language assessment with our Progressive Aphasia Severity Scale (PASS) demonstrated a distinct initial profile, preserved over longitudinal assessment. Cortical thickness analysis demonstrated focal atrophy in the dominant temporoparietal junction, detectable at an individual level on quantitative MRI. 5 out of 7 subjects had molecular markers consistent with AD. All subjects are still alive, and thus pathologic confirmation is not yet available. It is possible to identify patients with the prototypical clinical phenotype of LPA at the clinical stage of mild cognitive impairment or very mild dementia. Initial disease progression is characterized by worsening language dysfunction, out of proportion to other cognitive domains, and with a profile distinct from other progressive aphasias. There is a signature cortical atrophy pattern in the dominant temporoparietal junction, also identifiable at the earliest clinical stages. These findings provide further support for the consistency of this clinico-anatomic phenotype and potential biomarkers for use in clinical trials.

Primary Progressive Aphasia (PPA) is a heterogeneous clinical syndrome characterized by deterioration of speech/language abilities. Efficacious treatments are lacking, partly due to the need for standardized methods to monitor symptom progression. To address this, we developed the Progressive Aphasia Severity Scale (PASS) to rate presence and severity of impairment in ten domains of language. In addition, sensitive and specific imaging biomarkers will likely be crucial as inclusion/exclusion criteria and for measuring the potential effects of putative disease-modifying interventions. We are working on both types of measures to determine their utility for longitudinal studies. “MsoNormal” > Patients with PPA were rated at baseline and longitudinal follow-up using the PASS and underwent performance-based language testing and MRI scans that were processed for cortical thickness measures. We demonstrated a linear relationship between change in PASS Sum-of-Boxes and overall PPA-signature rate of atrophy (r = 0.3), with some patients progressing much more rapidly than others. Correlations were present between PASS fluency and WAB fluency (r = −0.92) and BDAE grammar (r = −0.94), PASS syntax/grammar and WAB fluency (r = −0.81) and BDAE grammar (r = −0.82), and PASS word comprehension and CSB word-picture matching (r = −0.87). The NACC UDS Global Language measure correlated with WAB fluency (r = −0.59) and BDAE grammar (r = −0.66) but not CSB. Inter-rater reliability (between neurologist and speech pathologist) of PASS ratings was high with ICC > 0.9 for fluency (0.99), grammar/syntax (0.99), word comprehension (0.91), and global CDR language (1.0). The PASS Sum-of-Boxes measure was more sensitive to the degree of clinical change than was the NACC UDS Global Language measure. These preliminary findings suggest that these novel clinical and imaging measures will likely cross-validate each other and demonstrate potential utility for clinical trials. The degree of impairment reflected by PASS scores was closely related to specific performance deficits, supporting the validity of the scale. The PASS Sum-of-Boxes measure was a more sensitive measure of clinical impairment and change over time than the existing global measure, supporting its value. Further work is in progress to assess the relationships between longitudinal change in PASS and longitudinal change in language test performance measures.

New diagnostic criteria have been developed for the detection of preclinical AD using biomarkers in cognitively normal (CN) older adults. We implemented these criteria using an MRI biomarker previously demonstrated to be associated with Alzheimer's disease (AD) dementia to test the hypothesis that individuals classified as preclinical AD using this markerwould be at elevated risk for cognitive decline consistent with symptoms of early AD. The ADNI dataset was interrogated for CN individuals. MRI data were processed to obtain cortical thickness measures using a previously published set of a priori regions of interest to derive a single composite measure known as the “AD-signature” (ADsig). Each individualwas then classified as ADsig-Low consistent with Preclinical AD (≥ 1S.D. below the mean), ADsig-Average (within 1 S.D. of the mean), or ADsig-High(≥ 1 S.D. above the mean). A three-year Cognitive Decline outcome was defined a priori using change in CDR Sum-of-Boxes and selected neuropsychological measures. We hypothesized that preclinical AD individuals would be at elevated risk of Cognitive Decline. Of the 125 individuals who were CN at baseline, the 19 classified as Preclinical AD using the MRI biomarker were at markedly increased risk of Cognitive Decline, which developed in 21% of them compared with 7% of ADsig-Average and 0% of ADsig-High groups (p = 0.03). A logistic regression model demonstrated that every 1 S.D. of cortical thinning was associated with a nearly tripled risk of cognitive decline (p = 0.02). In addition, of those for whom baseline cerebrospinal fluid (CSF) data were available, 60% of the preclinical AD group had CSF characteristics consistent with AD while 36% of the AD sig Average and 19% of the AD sig High groups had such CSF characteristics (p = 0.1). The present data supports our hypothesis that this approach to the detection of preclinical AD-identified in single NC individuals using this quantitative AD-signature MRI biomarker-may provide investigators with a population enriched for AD pathobiology and at relatively high risk for imminent cognitive decline consistent with prodromal AD.

Semantic memory deficits in early AD are typically subtle, and overshadowed by other cognitive impairments such as problems with episodic memory. FTD, in contrast, can sometimes cause early, prominent semantic impairment. Ongoing debate regarding the localization of semantic memory has focused on whether there is a distributed set of brain regions with convergence zones in association cortices, or whether the anterior temporal lobes form a “hub” for centralizing conceptual processing. We performed a series of analyses to address this issue. First, we examined ADNI data to determine the correlation between regional cortical atrophy and degree of semantic impairment in early AD. Our group has previously demonstrated that AD affects a “signature set” of cortical regions, overlapping with the default mode network. We hypothesized that, if semantic memory is subserved primarily by a distributed set of brain regions, the degree of semantic impairment in AD would correlate with the degree of atrophy distributed throughout this large-scale network. In contrast, if access to semantic memory requires a temporal pole hub, patients with greater semantic impairment would have greater atrophy in a pattern more consistent with a temporopolar network. Second, we analyzed FTD patients to identify brain regions associated with prominent semantic impairment. We extracted Boston Naming Test data from mild AD patients in ADNI. Cortical thickness analysis was performed, identifying areas in which cortical thinning was correlated with naming impairment, controlling for age, sex, education, and MMSE score. We performed a similar analysis of FTD patients (all subtypes). We then compared the thinning maps associated with semantic impairment between the two diseases. Naming impairment correlated strongly with left-lateralized anterior and lateral temporal cortical thinning, and not with thinning in the overall AD signature. This pattern was very similar in FTD. The basis for naming deficits in early AD appears to be neurodegeneration of temporal regions associated with lexico-semantic abilities. Semantic impairment in FTD follows a similar pattern: atrophy prominently affecting the ventral language network, with relative dorsal sparing. These findings provide further support that neurodegenerative diseases may target specific cognitive-behavioral brain networks, but demonstrate that distinct diseases may affect a single network.

New diagnostic criteria for MCI have been developed using biomarkers aiming to establish whether the clinical syndrome is likely due to underlying AD. We compared the utility of MRI versus CSF based biomarkers in predicting conversion from MCI to AD with the hypothesis that these markers would provide different prognostic information over different time intervals. Additionally, we were particularly interested in the predictive role of markers of neurodegeneration for outcome in “amyloid-negative” MCI. Data was obtained from ADNI and included cognitively normal (CN) individuals and MCI patients who had baseline MRI and CSF data available. Cortical thickness measures were determined in a standard manner and analyses were performed using an a priori set of regions to derive a measure previously demonstrated sensitive to prodromal AD, the “AD-signature.” We performed stepwise logistic regression analyses to identify the best baseline biomarker predictors, including standard structural and CSF measures, of progression to dementia over different intervals of follow-up. This analysis was also performed in patients designated “amyloid-negative” based on CSF A-beta. The AD-signature biomarker performed better than other MRI biomarkers. Although CSF tau was better than CSF abetafor predicting dementia within 1–2 years, the AD signature performed better than all CSF measures over this relatively short-term interval, but not at longer term intervals (≥3 years). Remarkably, amyloid-negative MCI patients displayed significant AD-signature cortical thinning relative to CN. The degree of this thinning correlated with tau levels and was predictive of conversion to dementia. Short-term (1–2 year) prognosis for progression to dementia relates strongly to baseline markers of neurodegeneration, with the AD-signature MRI biomarker of cortical thickness performing the best among MRI and CSF markers studied here. However, longer-term (≥3 years) prognosis may be better predicted by measures of cerebral amyloidosis. Amyloid-negative MCI patients may display atrophy in AD-specific regions, which also predicts the likelihood of future dementia conversion. While the underlying etiology of cognitive impairment is uncertain in these patients, the above findings suggest that tau-mediated neuropathology may be a contributor. Taken together, these results demonstrate the complementary nature of AD biomarkers and provide additional insight to emerging models of AD pathophysiology.