Helena C. Chui

This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury-not solely stroke-ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

The Mini-Mental State (MMS) examination is a widely used screening test for dementia. The Modified Mini-Mental State (3MS) incorporates four added test items, more graded scoring, and some other minor changes. These modifications are designed to sample a broader variety of cognitive functions, cover a wider range of difficulty levels, and enhance the reliability and the validity of the scores. The 3MS retains the brevity, ease of administration, and objective scoring of the MMS but broadens the range of scores from 0-30 to 0-100. Greater sensitivities of the 3MS over the MMS are demonstrated with the pentagon item drawn by 249 patients. A summary form for administration and scoring that can generate both the MMS and the 3MS scores is provided so that the examiner can maintain continuity with existing data and can obtain a more informative assessment.

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.

<b><i>Objective: </i></b> To update the 1994 practice parameter for the diagnosis of dementia in the elderly. <b><i>Background:</i></b> The AAN previously published a practice parameter on dementia in 1994. New research and clinical developments warrant an update of some aspects of diagnosis. <b><i>Methods:</i></b> Studies published in English from 1985 through 1999 were identified that addressed four questions: 1) Are the current criteria for the diagnosis of dementia reliable? 2) Are the current diagnostic criteria able to establish a diagnosis for the prevalent dementias in the elderly? 3) Do laboratory tests improve the accuracy of the clinical diagnosis of dementing illness? 4) What comorbidities should be evaluated in elderly patients undergoing an initial assessment for dementia? <b><i>Recommendations:</i></b> Based on evidence in the literature, the following recommendations are made. 1) The DSM-III-R definition of dementia is reliable and should be used (Guideline). 2) The National Institute of Neurologic, Communicative Disorders and Stroke–AD and Related Disorders Association (NINCDS-ADRDA) or the <i>Diagnostic and Statistical Manual</i>, 3rd edition, revised (DSM-IIIR) diagnostic criteria for AD and clinical criteria for Creutzfeldt–Jakob disease (CJD) have sufficient reliability and validity and should be used (Guideline). Diagnostic criteria for vascular dementia, dementia with Lewy bodies, and frontotemporal dementia may be of use in clinical practice (Option) but have imperfect reliability and validity. 3) Structural neuroimaging with either a noncontrast CT or MR scan in the initial evaluation of patients with dementia is appropriate. Because of insufficient data on validity, no other imaging procedure is recommended (Guideline). There are currently no genetic markers recommended for routine diagnostic purposes (Guideline). The CSF 14-3-3 protein is useful for confirming or rejecting the diagnosis of CJD (Guideline). 4) Screening for depression, B₁₂ deficiency, and hypothyroidism should be performed (Guideline). Screening for syphilis in patients with dementia is not justified unless clinical suspicion for neurosyphilis is present (Guideline). <b><i>Conclusions:</i></b> Diagnostic criteria for dementia have improved since the 1994 practice parameter. Further research is needed to improve clinical definitions of dementia and its subtypes, as well as to determine the utility of various instruments of neuroimaging, biomarkers, and genetic testing in increasing diagnostic accuracy.

Accurate diagnosis of vascular dementia is important for the recognition of underlying pathophysiology and the institution of appropriate therapy. It is also important for the determination of the incidence and prevalence of not only vascular dementia but also Alzheimer9s disease (AD), since differentiating between these two entities is often problematic. The State of California Alzheimer9s Disease Diagnostic and Treatment Centers (ADDTC) herein propose criteria for the diagnosis of ischemic vascular dementia (IVD). These criteria broaden the conceptualization of vascular dementia, include the results of neuroimaging studies, emphasize the importance of neuropathologic confirmation, refine nosology, and identify areas that require further research. Parallel use of the proposed definitions of “possible” and “mixed” categories in the diagnosis of both AD and IVD would ensure compatibility between the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria for AD and the ADDTC criteria for IVD. Uniform classification of subtypes of IVD will improve the generalizability of individual studies and aid in multicenter collaborations.

Vascular contributions to cognitive impairment are increasingly recognized1–5 as shown by neuropathological6,7, neuroimaging4,8–11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer’s disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood–brain barrier (BBB) breakdown14–16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8–10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8–10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer’s Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau. Neuroimaging and cerebrospinal fluid analyses in humans reveal that loss of blood–brain barrier integrity and brain capillary pericyte damage are early biomarkers of cognitive impairment that occur independently of changes in amyloid-β and tau.

Vascular dementia is the second most common type of dementia. The subcortical ischaemic form (SIVD) frequently causes cognitive impairment and dementia in elderly people. SIVD results from small-vessel disease, which produces either arteriolar occlusion and lacunes or widespread incomplete infarction of white matter due to critical stenosis of medullary arterioles and hypoperfusion (Binswanger's disease). Symptoms include motor and cognitive dysexecutive slowing, forgetfulness, dysarthria, mood changes, urinary symptoms, and short-stepped gait. These manifestations probably result from ischaemic interruption of parallel circuits from the prefrontal cortex to the basal ganglia and corresponding thalamocortical connections. Brain imaging (computed tomography and magnetic resonance imaging) is essential for correct diagnosis. The main risk factors are advanced age, hypertension, diabetes, smoking, hyperhomocysteinaemia, hyperfibrinogenaemia, and other conditions that can cause brain hypoperfusion such as obstructive sleep apnoea, congestive heart failure, cardiac arrhythmias, and orthostatic hypotension. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)and some forms of cerebral amyloid angiopathy have a genetic basis. Treatment is symptomatic and prevention requires control of treatable risk factors.

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

Alzheimer disease (AD) and Parkinson disease (PD) are associated with neuronal degeneration in major subcortical nuclei, but few studies have examined the neuronal degeneration in these nuclei concurrently.To identify clinical and pathological correlates of neuronal loss in the nucleus basalis (NB), locus coeruleus (LC), and substantia nigra pars compacta (SN) in AD and PD.The study sample comprised 86 cases with pathologically confirmed AD, 19 cases with PD, and 13 healthy elderly control subjects. The number of nucleolated neurons was counted in representative sections of the NB, LC, and SN. Effect sizes (ES) were computed to determine the standardized difference in cell counts relative to healthy controls.Cases of AD showed the greatest neuronal loss in the LC (ES = 3.16) followed by the NB (ES = 1.10), but variable loss in the SN (ES = 0.16). Cases of PD also showed the greatest neuronal loss in the LC (ES = 6.47), followed by the SN (ES = 2.58) and the NB (ES = 0.85). Significant correlations were found between the number of neurons in the NB and LC in PD (r = 0.54, P<.05), as well as AD (r = 0.24, P<.05). The duration of illness correlated with greater neuronal loss in the LC and NB in AD, and greater neuronal loss in the SN in PD.For both AD and PD the greatest neuronal loss was found in the LC. In AD, neuronal loss was most severe and best correlated with the duration of illness in the LC, rather than in NB as traditionally expected. Correlations between neuronal loss in the LC and NB (but not SN) in both PD and AD suggest that the former 2 nuclei may share common pathogenetic susceptibilities. Given the prominent loss of neurons in the LC, detection and treatment of noradrenergic deficiencies warrant attention in both AD and PD.

A Clinical Task Force, composed of clinical leaders from Alzheimer's Disease Centers (ADC), was convened by the National Institute on Aging to develop a uniform set of assessment procedures to characterize individuals with mild Alzheimer disease and mild cognitive impairment in comparison with nondemented aging. The resulting Uniform Data Set (UDS) defines a common set of clinical observations to be collected longitudinally on ADC participants in accordance with standard methods. The UDS was implemented at all ADCs on September 1, 2005. Data obtained with the UDS are submitted to the National Alzheimer's Coordinating Center and represent a unique and valuable source of data to support and stimulate collaborative research.

Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized1–6. Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer’s disease5,8–10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer’s disease11–14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15–19, which maintain BBB integrity20–22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers. Breakdown of the blood–brain barrier in individuals carrying the ε4 allele of the APOE gene, but not the ε3 allele, increases with and predicts cognitive impairment and is independent of amyloid β or tau pathology.

The neuropsychologic test battery from the Uniform Data Set (UDS) of the Alzheimer's Disease Centers (ADC) program of the National Institute on Aging consists of brief measures of attention, processing speed, executive function, episodic memory, and language. This paper describes development of the battery and preliminary data from the initial UDS evaluation of 3268 clinically cognitively normal men and women collected over the first 24 months of utilization. The subjects represent a sample of community-dwelling, individuals who volunteer for studies of cognitive aging. Subjects were considered “clinically cognitively normal” based on clinical assessment, including the Clinical Dementia Rating scale and the Functional Assessment Questionnaire. The results demonstrate performance on tests sensitive to cognitive aging and to the early stages of Alzheimer disease in a relatively well-educated sample. Regression models investigating the impact of age, education, and sex on test scores indicate that these variables will need to be incorporated in subsequent normative studies. Future plans include: (1) determining the psychometric properties of the battery; (2) establishing normative data, including norms for different ethnic minority groups; and (3) conducting longitudinal studies on cognitively normal subjects, individuals with mild cognitive impairment, and individuals with Alzheimer disease and other forms of dementia.

To prospectively determine if pulsed arterial spin-labeling perfusion magnetic resonance (MR) imaging depicts regional cerebral hypoperfusion in subjects with Alzheimer disease (AD) and mild cognitive impairment (MCI), compared with perfusion in cognitively normal (CN) subjects, that is consistent with results of fluorodeoxyglucose (FDG) positron emission tomography (PET) and hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) studies of similar populations.Institutional review board approval and informed consent were obtained. Twenty subjects with AD (13 men, seven women; mean age, 72.9 years), 18 with MCI (nine men, nine women; mean age, 73.3 years), and 23 CN subjects (10 men, 13 women; mean age, 72.9 years) underwent arterial spin-labeling and volumetric T1-weighted structural MR imaging. Perfusion images were coregistered to structural images, corrected for partial volume effects (PVEs) with information from the structural image to determine tissue content of perfusion voxels, and normalized to a study-specific template. Analyses of perfusion differences between groups, with and without corrections for PVEs, were performed on a voxel-by-voxel basis with a one-tailed fixed-effects analysis of covariance model adjusted for age. In addition, tests were performed with and without accounting for global perfusion.The AD group showed significant regional hypoperfusion, compared with the CN group, in the right inferior parietal cortex extending into the bilateral posterior cingulate gyri (P <.001), bilateral superior and middle frontal gyri (P <.001), and left inferior parietal lobe (P=.007). When PVEs from underlying cortical gray matter atrophy were accounted for, the AD group still showed hypoperfusion in the right inferior parietal lobe extending into the bilateral posterior cingulate gyri (P <.001) and left (P=.003) and right (P=.012) middle frontal gyri. With a more liberal voxel-level threshold of P <.01, the MCI group showed significant regional hypoperfusion relative to the CN group in the inferior right parietal lobe (P=.046), similar to the region of greatest significance in the AD group.Arterial spin-labeling MR imaging showed regional hypoperfusion with AD, in brain regions similar to those seen in FDG PET and HMPAO SPECT studies of similar populations; this hypoperfusion persists after accounting for underlying cortical gray matter atrophy.

Several sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination.Participants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the fifth revision of Diagnostic and Statistical Manual (DSM-5) Task Force.Cognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent cooccurrence of Alzheimer disease pathology emphasized.The proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Neuroimaging in mild cognitive impairment (MCI) and Alzheimer disease (AD) generally shows medial temporal lobe atrophy and diminished glucose metabolism and cerebral blood flow in the posterior cingulate gyrus. However, it is unclear whether these abnormalities also impact the cingulum fibers, which connect the medial temporal lobe and the posterior cingulate regions.To use diffusion tensor imaging (DTI), by measuring fractional anisotropy (FA), to test 1) if MCI and AD are associated with DTI abnormalities in the parahippocampal and posterior cingulate regions of the cingulum fibers; 2) if white matter abnormalities extend to the neocortical fiber connections in the corpus callosum (CC); 3) if DTI improves accuracy to separate AD and MCI from healthy aging vs structural MRI.DTI and structural MRI were preformed on 17 patients with AD, 17 with MCI, and 18 cognitively normal (CN) subjects.FA of the cingulum fibers was significantly reduced in MCI, and even more in AD. FA was also significantly reduced in the splenium of the CC in AD, but not in MCI. Adding DTI to hippocampal volume significantly improved the accuracy to separate MCI and AD from CN.Assessment of the cingulum fibers using diffusion tensor imaging may aid early diagnosis of Alzheimer disease.

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

<b><i>Objective:</i></b> To analyze the effect of white matter lesions in different brain regions on regional cortical glucose metabolism, regional cortical atrophy, and cognitive function in a sample with a broad range of cerebrovascular disease and cognitive function. <b><i>Methods:</i></b> Subjects (n = 78) were recruited for a study of subcortical ischemic vascular disease (SIVD) and Alzheimer disease (AD) contributions to dementia. A new method was developed to define volumes of interest from high-resolution three-dimensional T1-weighted MR images. Volumetric measures of MRI segmented white matter signal hyperintensities (WMH) in five different brain regions were related to regional PET glucose metabolism (rCMRglc) in cerebral cortex, MRI measures of regional cortical atrophy, and neuropsychological assessment of executive and memory function. <b><i>Results:</i></b> WMH was significantly higher in the prefrontal region compared to the other brain regions. In all subjects, higher frontal and parietal WMH were associated with reduced frontal rCMRglc, whereas occipitotemporal WMH was only marginally associated with frontal rCMRglc. These associations were stronger and more widely distributed in nondemented subjects where reduced frontal rCMRglc was correlated with WMH for all regions measured. In contrast, there was no relationship between WMH in any brain region and rCMRglc in either parietal or occipitotemporal regions. WMHs in all brain regions were associated with low executive scores in nondemented subjects. <b><i>Conclusions:</i></b> The frontal lobes are most severely affected by SIVD. WMHs are more abundant in the frontal region. Regardless of where in the brain these WMHs are located, they are associated with frontal hypometabolism and executive dysfunction.

Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.

Vascular dementia (VaD) incorporate different vascular mechanisms and changes in the brain, and have different causes and clinical manifestations. Variation in defining the cognitive syndrome, in vascular etiologies, and allowable brain changes in current clinical definitions of VaD have resulted in variable estimates of prevalence, of groups of subjects, and of the types and distribution of putative causal brain lesions. Thus current criteria for VaD select an etiologically and clinically heterogeneous group. This definitional heterogeneity may have been a factor in "negative" clinical trials. An alternative for clinical drug trials is to focus on a more homogeneous group, such as those with subcortical (ischemic) VaD. This designation incorporates two small vessel clinical entities "Binswanger's disease" and "the lacunar state". It comprises small vessel disease as the primary vascular etiology, lacunar infarct(s) and ischaemic white matter lesions as the primary type of brain lesions, and subcortical location as the primary location of lesions. The subcortical clinical syndrome is the primary clinical manifestation, a definition which still requires additional empirical data. We expect that subcortical VaD show a more predictable clinical picture, natural history, outcome, and treatment responses. We propose a modification of the NINDS-AIREN criteria as a new research criteria for subcortical VaD.

Winstein CJ, Rose DK, Tan SM, Lewthwaite R, Chui HC, Azen SP. A randomized controlled comparison of upper-extremity rehabilitation strategies in acute stroke: a pilot study of immediate and long-term outcomes. Arch Phys Med Rehabil 2004;85:620–8. Objective To evaluate the immediate and long-term effects of 2 upper-extremity rehabilitation approaches for stroke compared with standard care in participants stratified by stroke severity. Design Nonblinded, randomized controlled trial (baseline, postintervention, 9mo) design. Setting Inpatient rehabilitation hospital and outpatient clinic. Participants Sixty-four patients with recent stroke admitted for inpatient rehabilitation were randomized within severity strata (Orpington Prognostic Scale) into 1 of 3 intervention groups. Forty-four patients completed the 9-month follow-up. Interventions Standard care (SC), functional task practice (FT), and strength training (ST). The FT and ST groups received 20 additional hours of upper-extremity therapy beyond standard care distributed over a 4- to 6-week period. Main outcome measures Performance measures of impairment (Fugl-Meyer Assessment), strength (isometric torque), and function (Functional Test of the Hemiparetic Upper Extremity [FTHUE]). Results Compared with SC participants, those in the FT and ST groups had significantly greater increases in Fugl-Meyer motor scores (P=.04) and isometric torque (P=.02) posttreatment. Treatment benefit was primarily in the less severe participants, where improvement in FT and ST group Fugl-Meyer motor scores more than doubled that of the SC group. Similar results were found for the FTHEU and isometric torque. During the long term, at 9 months, the less severe FT group continued to make gains in isometric muscle torque, significantly exceeding those of the ST group (P<.05). Conclusions Task specificity and stroke severity are important factors for rehabilitation of arm use in acute stroke. Twenty hours of upper extremity-specific therapy over 4 to 6 weeks significantly affected functional outcomes. The immediate benefits of a functional task approach were similar to those of a resistance-strength approach, however, the former was more beneficial in the long-term.

Abstract Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer’s disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women’s Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice ( 5xFAD +/− /human APOE ɛ 3 or ɛ 4 +/+ ) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral β-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aβ deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aβ oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aβ production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.

Though neglect is often thought to be a sign of parietal lobe damage, particularly of the non-dominant hemisphere, there is evidence that lesions in the frontal lobes and in the basal ganglia can produce neglect also. We present five patients, with lesions in both the mesial and dorsolateral aspects of the frontal lobe, and in the basal ganglia, as examples of "non-parietal" neglect. It is possible that all of these structures belong to an anatomically inter-connected system subserving selective attention and that lesions in each of the components are capable of producing neglect although with slightly different characteristics. Bien qu'on attribue souvent la négligence aux atteintes du lobe pariétal, particulièrement de l'hémisphère droit, il existe des preuves que les lésions frontales et les lésions des ganglions de la base peuvent aussi produire la négligence. Nous présentons comme exemple de négligence "non pariétale" 5 malades avec lésions frontales internes et dorsolatérales et des ganglions de la base. Il est possible que toutes ces structures appartiennent à un système anatomiquement interconnecté sous tendant l'attention sélective. Il est possible aussi que les lésions de chacune de ces composantes soient capables de produire la négligence bien qu'avec des caractéres légèrement différents. Neglekt wird oft für ein Symptom der Schädigung des Parietallappens, besonders der nicht dominanten Hemisphäre gehalten. Es gibt jedoch Beobachtungen die zeigen, daß auch Läsionen im Frontallappen und in den Stammaganglien zu Neglekt führen können. Wir beschreiben 5 Patienten mit Läsionen des medialen und dorso-lateralen Frontallappens und in den Stammganglien als Beispiel für "nicht parietalen" Neglekt. Es ist möglich, daß alle diese Strukturen zu einem anatomisch verbundenen System gehören, welches selektive Aufmerksamkeit vermittelt. Es könnte sein, daß Läsionen in jedem Anteil dieses Systems Neglekt hervorrufen, wenn auch mit geringfügig unterschiedlichen Charakteristika.

Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls.We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs.We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.

Clinical subtypes of dementia of the Alzheimer type were evaluated by comparing age at onset, aphasia, family history, and motor disorder in 146 individuals with progressive dementia. Early onset was significantly associated with more prevalent and more severe language disorder. Forty-five percent of all probands had familial history of dementia, but we could not differentiate relative familial risk based on age at onset or aphasia. Independent of duration of illness, myoclonus and noniatrogenic extrapyramidal disorder were associated with greater severity of dementia.

Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present.This report includes 93 subjects from a longitudinally followed cohort recruited for the study of Alzheimer's disease (AD) and subcortical cerebrovascular disease (CVD). MR images were analyzed to quantify cortical gray matter volume, hippocampal volume, white matter hyperintensities, and lacunes. Neuropathological examination quantified CVD parenchymal pathology, AD pathology (defined as Consortium to Establish a Registry for Alzheimer's Disease scores and Braak and Braak stage), and hippocampal sclerosis. Subjects were pathologically classified as 12 healthy control subjects, 46 AD, 14 CVD, 9 mixed AD/CVD, and 12 cognitively impaired patients without significant AD/CVD pathology. Multivariate models tested associations between magnetic resonance and pathological findings across the entire sample.Pathological correlates of cortical gray matter volume were AD, subcortical vascular pathology, and arteriosclerosis. Hippocampal volume was related to AD pathology and hippocampal sclerosis, and the effects of hippocampal sclerosis were greater for subjects with low levels of AD pathology. White matter hyperintensities were related to age and to white matter pathology. Number of MRI lacunes was related to subcortical vascular pathology.In this clinical setting, the presence of lacunes and white matter changes provide a good signal for vascular disease. The neuropathological basis of MR defined cerebral cortical and hippocampal atrophy in aging and dementia is complex, with several pathological processes converging on similar brain structures that mediate cognitive decline.

Introduction: In 2015, the US Alzheimer’s Disease Centers (ADC) implemented Version 3 of the Uniform Data Set (UDS). This paper describes the history of Version 3 development and the UDS data that are freely available to researchers. Methods: UDS Version 3 was developed after years of coordination between the National Institute on Aging-appointed Clinical Task Force (CTF), clinicians from ∼30 ADCs, and the National Alzheimer’s Coordinating Center (NACC). The CTF recognized the need for updates to align with the state of the science in dementia research, while being flexible to the diverse needs and diseases studied at the ADCs. Version 3 also developed a nonproprietary neuropsychological battery. Results: This paper focuses on the substantial Version 3 changes to the UDS forms related to clinical diagnosis and characterization of clinical symptoms to match updated consensus-based diagnostic criteria. Between March 2015 and March 2018, 4820 participants were enrolled using UDS Version 3. Longitudinal data were available for 25,337 of the 37,568 total participants using all UDS versions. Discussion: The results from utilization of the UDS highlight the possibility for numerous research institutions to successfully collaborate, produce, and use standardized data collection instruments for over a decade.

Impaired everyday function is a diagnostic criterion for dementia, and a determinant of healthcare utilization and caregiver burden. Although many previous studies have demonstrated a cross-sectional relationship between cognition (particularly executive functions and memory) and everyday function in older adults, very little is known about longitudinal relationships between these domains. This study examined the association between longitudinal change in episodic memory (MEM) and executive functioning (EXEC) and change in everyday function. Participants were a cognitively heterogeneous group of 100 elderly persons including those with normal cognition, as well as those with mild cognitive impairment and dementia. They were followed for an average of 5 years. Random effects modeling showed that change in both MEM and EXEC were independently associated with rate of change in informant-rated instrumental activities of daily living (IADLs), even after controlling for age, education, and gender. Findings indicate that declines in MEM and EXEC over time make unique and independent contributions to declines in older adults’ ability to function in daily life.

Because deposition of cerebral β-amyloid (Aβ) seems to be a key initiating event in Alzheimer disease (AD), factors associated with increased deposition are of great interest. Whether elevated serum cholesterol levels act as such a factor is unknown.To investigate the association between serum cholesterol levels and cerebral Aβ during life early in the AD process.A multisite, university medical center-based, cross-sectional analysis of potential associations between contemporaneously assayed total serum cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and cerebral Aβ, measured with carbon C11-labeled Pittsburgh Compound B (PIB) positron emission tomography. Seventy-four persons (mean age, 78 years) were recruited via direct outreach in stroke clinics and community senior facilities following a protocol designed to obtain a cohort enriched for cerebrovascular disease and elevated vascular risk. Three patients had mild dementia. All others were clinically normal (n = 33) or had mild cognitive impairment (n = 38).Cerebral Aβ was quantified using a Global PIB Index, which averages PIB retention in cortical areas prone to amyloidosis. Statistical models that controlled for age and the apolipoprotein E ε4 allele revealed independent associations among the levels of LDL-C, HDL-C, and PIB index. Higher LDL-C and lower HDL-C levels were both associated with a higher PIB index. No association was found between the total cholesterol level and PIB index. No association was found between statin use and PIB index, and controlling for cholesterol treatment in the statistical models did not alter the basic findings.Elevated cerebral Aβ level was associated with cholesterol fractions in a pattern analogous to that found in coronary artery disease. This finding, in living humans, is consistent with prior autopsy reports, epidemiologic findings, and animal and in vitro work, suggesting an important role for cholesterol in Aβ processing. Because cholesterol levels are modifiable, understanding their link to Aβ deposition could potentially and eventually have an effect on retarding the pathologic cascade of AD. These findings suggest that understanding the mechanisms through which serum lipids modulate Aβ could offer new approaches to slowing Aβ deposition and thus to reducing the incidence of AD.

Objective The aim of this study was to examine the putative adverse effects of ambient fine particulate matter (PM 2.5 : PM with aerodynamic diameters &lt;2.5μm) on brain volumes in older women. Methods We conducted a prospective study of 1,403 community‐dwelling older women without dementia enrolled in the Women's Health Initiative Memory Study, 1996–1998. Structural brain magnetic resonance imaging scans were performed at the age of 71–89 years in 2005–2006 to obtain volumetric measures of gray matter (GM) and normal‐appearing white matter (WM). Given residential histories and air monitoring data, we used a spatiotemporal model to estimate cumulative PM 2.5 exposure in 1999–2006. Multiple linear regression was employed to evaluate the associations between PM 2.5 and brain volumes, adjusting for intracranial volumes and potential confounders. Results Older women with greater PM 2.5 exposures had significantly smaller WM, but not GM, volumes, independent of geographical region, demographics, socioeconomic status, lifestyles, and clinical characteristics, including cardiovascular risk factors. For each interquartile increment (3.49μg/m 3 ) of cumulative PM 2.5 exposure, the average WM volume (WMV; 95% confidence interval) was 6.23cm 3 (3.72–8.74) smaller in the total brain and 4.47cm 3 (2.27–6.67) lower in the association areas, equivalent to 1 to 2 years of brain aging. The adverse PM 2.5 effects on smaller WMVs were present in frontal and temporal lobes and corpus callosum (all p values &lt;0.01). Hippocampal volumes did not differ by PM 2.5 exposure. Interpretation PM 2.5 exposure may contribute to WM loss in older women. Future studies are needed to determine whether exposures result in myelination disturbance, disruption of axonal integrity, damages to oligodendrocytes, or other WM neuropathologies. Ann Neurol 2015;78:466–476

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.

Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.

Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium.The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria.Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242).We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger's disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. Binswanger's disease patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts, and inflammation that act synergistically to disrupt the blood-brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid, neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathologic changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.

Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10-8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10-6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10-6).Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Abstract Evidence suggests exposure to particulate matter with aerodynamic diameter &amp;lt;2.5 μm (PM2.5) may increase the risk for Alzheimer’s disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer’s disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer’s disease associated with exposure. Participants included older females (n = 998; aged 73–87) enrolled in both the Women’s Health Initiative Study of Cognitive Aging and the Women’s Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999–2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1–3; List B) and delayed free recall (short- and long-delay), and up to two brain scans (MRI-1: 2005–06; MRI-2: 2009–10). Subjects were assigned Alzheimer’s disease pattern similarity scores (a brain-MRI measured neuroanatomical risk for Alzheimer’s disease), developed by supervised machine learning and validated with data from the Alzheimer’s Disease Neuroimaging Initiative. Based on residential histories and environmental data on air monitoring and simulated atmospheric chemistry, we used a spatiotemporal model to estimate 3-year average PM2.5 exposure preceding MRI-1. In multilevel structural equation models, PM2.5 was associated with greater declines in immediate recall and new learning, but no association was found with decline in delayed-recall or composite scores. For each interquartile increment (2.81 μg/m3) of PM2.5, the annual decline rate was significantly accelerated by 19.3% [95% confidence interval (CI) = 1.9% to 36.2%] for Trials 1–3 and 14.8% (4.4% to 24.9%) for List B performance, adjusting for multiple potential confounders. Long-term PM2.5 exposure was associated with increased Alzheimer’s disease pattern similarity scores, which accounted for 22.6% (95% CI: 1% to 68.9%) and 10.7% (95% CI: 1.0% to 30.3%) of the total adverse PM2.5 effects on Trials 1–3 and List B, respectively. The observed associations remained after excluding incident cases of dementia and stroke during the follow-up, or further adjusting for small-vessel ischaemic disease volumes. Our findings illustrate the continuum of PM2.5 neurotoxicity that contributes to early decline of immediate free recall/new learning at the preclinical stage, which is mediated by progressive atrophy of grey matter indicative of increased Alzheimer’s disease risk, independent of cerebrovascular damage.

Macrophages are important players in the maintenance of tissue homeostasis1. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma2, and their role in CNS physiology has not been sufficiently well studied. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs that express high levels of CD163 and LYVE1 (scavenger receptor proteins), closely associated with the brain arterial tree, and show that LYVE1+ PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces and impairing CNS perfusion and clearance. Ageing-associated alterations in PBMs and impairment of CSF dynamics were restored after intracisternal injection of macrophage colony-stimulating factor. Single-nucleus RNA sequencing data obtained from patients with Alzheimer's disease (AD) and from non-AD individuals point to changes in phagocytosis, endocytosis and interferon-γ signalling on PBMs, pathways that are corroborated in a mouse model of AD. Collectively, our results identify PBMs as new cellular regulators of CSF flow dynamics, which could be targeted pharmacologically to alleviate brain clearance deficits associated with ageing and AD.

Abnormally phosphorylated tau, an indicator of Alzheimer's disease, accumulates in the first decades of life in the locus coeruleus (LC), the brain's main noradrenaline supply. However, technical challenges in in-vivo assessments have impeded research into the role of the LC in Alzheimer's disease. We studied participants with or known to be at-risk for mutations in genes causing autosomal-dominant Alzheimer's disease (ADAD) with early onset, providing a unique window into the pathogenesis of Alzheimer's largely disentangled from age-related factors. Using high-resolution MRI and tau PET, we found lower rostral LC integrity in symptomatic participants. LC integrity was associated with individual differences in tau burden and memory decline. Post-mortem analyses in a separate set of carriers of the same mutation confirmed substantial neuronal loss in the LC. Our findings link LC degeneration to tau burden and memory in Alzheimer's, and highlight a role of the noradrenergic system in this neurodegenerative disease.

Causes of cognitive impairment in subcortical ischemic vascular disease (SIVD) are less well understood than in AD, but have been thought to result from direct effects of subcortical lacunes and white matter lesions, perhaps related to disruption of important cortical-subcortical pathways.To examine the relation between cognitive abilities and quantitative MRI measures of subcortical cerebrovascular disease and cortical and hippocampal atrophy.Subjects were 157 participants in a multicenter study of SIVD and AD who included cognitively normal, cognitively impaired, and demented individuals with and without subcortical lacunar infarcts. Dependent variables were neuropsychological tests of global cognitive function, memory, language, and executive function. Independent variables were quantitative MRI measures of volume of lacunar infarcts in specific subcortical structures, volume of white matter lesion (WML), volume of cortical gray matter (cGM), and total hippocampal volume (HV). Multiple regression analyses were used to identify MRI predictors of cognition.Subcortical lacunes were not related to cognitive measures independent of effects of other MRI variables. WML was independently related to selected, timed measures. HV and cGM were strong and independent predictors of cognitive variables, with effects that did not differ in subjects with and without subcortical lacunes.Results suggest that cognitive impairment associated with subcortical ischemic vascular disease is primarily a result of associated hippocampal and cortical changes.

<b>Objective: </b> To examine how baseline and change of volumetric MRI relate to cognitive decline in older individuals. <b>Background: </b> Memory is associated with hippocampal integrity, whereas executive function has been linked to impaired frontal lobe function. Previous studies have shown that hippocampal and cortical atrophy are more strongly related to cognition than are measures of subcortical cerebrovascular disease (CVD). The authors hypothesized that memory (MEM) decline would be related to change in hippocampal volume (HC), whereas decline in executive function (EXEC) would be related to change of cortical gray matter volume (CGM) and measures of subcortical CVD. <b>Methods: </b> Subjects from a multicenter study (n = 103) included cognitively normal, mildly impaired, and demented cases with and without subcortical lacunes. All had longitudinal cognitive evaluation (mean = 4.8 years) and two or more MRI scans at least one year apart (mean = 3.4 years). MRI measures included HC, CGM, total lacune volume (LAC), and white matter hyperintensity volume (WMH). Random effects modeling of longitudinal data assessed effects of MRI baseline and MRI change on baseline and change of psychometrically matched measures of MEM and EXEC. <b>Results: </b> Change in MEM was related to HC baseline and HC change. Change in EXEC was related to baseline CGM and to change in CGM, HC, and LAC. Results were unchanged when demented cases were excluded. WMH was not associated with change in MEM or EXEC independent of HC, CGM, and LAC. <b>Conclusion: </b> Hippocampal volume was the primary determinant of memory decline, whereas executive function (EXEC) decline was related to multiple brain components. Results support a hypothesis that MEM decline is strongly influenced by Alzheimer disease (AD), whereas EXEC decline may be complexly determined by cerebrovascular disease and AD.

Ischemic vascular dementia (IVD) is a relatively uncommon entity, in the course of which multiple ischemic brain lesions result in progressive cognitive and memory impairment. Ischemic brain lesions may also aggravate the neuropsychologic deficit of Alzheimer disease (AD). In this review we summarize our experience based upon autopsy examination of the central nervous system in 20 patients (age range 68-92 years) enrolled in a longitudinal investigation of structural, neurochemical, functional neuroimaging, and neuropsychologic components of IVD, especially dementia associated with cerebral microvascular disease. While cystic infarcts were present in the CNS of 5 patients, the most commonly observed neuropathologic abnormalities were lacunar infarcts and microinfarcts--both types of lesion were encountered in over half of patients' brains. Evidence of (remote) hippocampal injury was found in 11/20 patients. Severe atherosclerosis and arterio/ arteriolosclerosis were both associated with the occurrence of multiple lacunar infarcts. Pronounced cerebral amyloid angiopathy (CAA) was noted in a single patient, who also showed other microscopic changes of severe AD. While fairly unusual as a nosologic entity, IVD appears to correlate with widespread small ischemic lesions distributed throughout the CNS. We furthermore propose an approach to quantifying the burden of ischemic vascular and parenchymal disease that may be associated with a dementia syndrome. A brief review of neuropathologic features of vascular dementia (both familial and sporadic) is presented.

Despite recent advances in the molecular genetics of Alzheimer's disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly.

Mild cognitive impairment (MCI) is widely viewed as the transition phase between normal aging and Alzheimer disease (AD). Given that MCI can also result from cerebrovascular disease (CVD), the authors used clinical, MRI, and cognitive measures of AD and CVD to test the hypothesis that CVD increases the likelihood of progression from MCI to dementia within 3 years.To examine the impact of CVD on progression of MCI to dementia.Fifty-two consecutive patients with MCI (71% men) including many with symptomatic CVD were longitudinally evaluated for 3.1 +/- 1.3 years. MCI was defined as a Clinical Dementia Rating Scale (CDR) score of 0.5. Dementia was defined as progression to a CDR score of > or =1.0.Forty-four percent of the MCI patients had MRI infarcts, 50% of which were symptomatic. Thirty-three percent of patients progressed to dementia, and 37.8% of these had MRI infarcts. Clinically probable or possible AD was diagnosed in approximately 82% of converters. Of the clinical and MRI measures, only hippocampal volume was associated with increased risk to progression (hazard ratio [HR] = 0.31 [95% CI 0.1 to 0.92], p = 0.03). When neuropsychological measures were included in the analysis, memory (HR = 0.90 [95% CI 0.84 to 0.96], p = 0.002) and executive function (HR = 0.96 [95% CI 0.92 to 1.0], p = 0.045) were associated with increased risk of dementia progression, whereas APOE genotype, cerebrovascular risk factors, clinical stroke, presence or absence of lacunes, and extent of white matter hyperintensities did not predict progression.Within a heterogenous group of MCI patients, including many with clinically significant CVD, baseline memory and executive performance significantly predicted likelihood to develop dementia.

To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimer's disease [AD]), cognitive status, and apolipoprotein E genotype.We report clinicopathological correlations from 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease and AD.Thirty percent of the cases had significant cerebrovascular parenchymal pathology scores (CVDPS), 54% had significant AD pathology, and 18% had HS. In an ordinal logistic regression analysis that included interaction terms to assess the effects of each pathological variable when the other variables are interpolated to zero, each of the three pathology variables contributed independently to cognitive status: Braak and Braak stage odds ratio (OR) = 2.84 (95% confidence interval, 1.81-4.45), HS score OR = 2.43 (95% confidence interval, 1.01-5.85), and CVDPS OR = 1.02 (95% confidence interval, 1.00-1.04). Only Braak and Braak stage contributed to a global neuropsychological measure of cognitive impairment. Apolipoprotein E4 genotype was associated with Braak and Braak stage (OR, 1.31 [95% confidence interval, 1.03-1.68]), but not CVDPS or HS scores.In this convenience sample enriched for subcortical ischemic vascular disease, HS was a common unsuspected neuropathological finding. Apolipoprotein E4 genotype was associated with cerebral amyloid angiopathy, but not HS or arteriosclerosis. When Braak and Braak stage was interpolated to zero, both CVDPS and HS contributed to cognitive impairment. However, advancing stages of AD pathology overwhelmed the effects of CVDPS and HS, to become the major determinant of dementia.

Several clinical criteria have been developed to standardize the diagnosis of vascular dementia (VaD). Significant differences in patient classification have been reported, depending on the criteria used. Few studies have examined interrater reliability.To assess the concordance in classification and interrater reliability for the following 4 clinical definitions of VaD: the Hachinski Ischemic Score (HIS), the Alzheimer Disease Diagnostic and Treatment Centers (ADDTC), National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN), and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).Structured diagnostic checklists were developed for 4 criteria for VaD, 2 criteria for Alzheimer disease (AD), and 4 criteria for dementia. Twenty-five case vignettes, representing a spectrum of cognitive impairment and subtypes of dementia, were prepared in a standardized clinical format. Concordance in case classification using different criteria and interrater reliability among 7 ADDTCs given a specific set of criteria was assessed using the kappa statistic.The frequency of a diagnosis of VaD was highest using the modified HIS or DSM-IV criteria, intermediate using the original HIS and ADDTC criteria, and lowest using the NINDS-AIREN criteria. Scores for interrater reliability ranged from kappa = 0.30 (ADDTC) to kappa = 0.61 (original HIS).Clinical criteria for VaD are not interchangeable. Depending on the criteria selected, the reported prevalence of VaD will vary significantly. The traditional HIS has higher interrater reliability than the newer criteria for VaD. Prospective longitudinal studies with clinical-pathological correlation are needed to compare validity.

Alzheimer senile plaques are comprised of extracellular deposits of beta-amyloid. The cell type responsible for the secretion of this amyloid, however, is unknown. In the present study, compact amyloid 'stars' and the cellular elements directly apposed to them were examined at the ultrastructural level. In many cases, amyloid fibrils were closely interdigitated with the plasma membrane of cells with dark cytoplasm, dense bodies and distinctive nuclei. These cells were morphologically identified as microglia, the resident macrophages of the brain. Previous work has described an identical morphologic association between macrophages and several types of systemic and cerebral amyloidoses. Taken together, these data suggest that beta-amyloid may be secreted by microglia.

The cornu ammonis 1 region of the hippocampus (CA1) sector of hippocampus is vulnerable to both Alzheimer's disease (AD)-type neurofibrillary degeneration and anoxia-ischemia. The objective of this article is to compare number and size of neurons in CA1 in AD versus ischemic vascular dementia. Unbiased stereological methods were used to estimate the number and volume of neurons in 28 autopsy-derived brain samples. For each case, the entire hippocampus from one cerebral hemisphere was sliced into 5mm slabs (5-7 slabs/case), cut into 50 microm sections, and stained with gallocyanine. Using the optical dissector, we systematically sampled the number and size of neurons throughout the extent of CA1 and CA2. The total number of neurons was significantly less in AD compared with ischemic vascular dementia (p < 0.02), but there was no significant difference in neuron size. The greatest loss of neurons was observed in two cases with combined AD and hippocampal sclerosis. Regardless of causative diagnosis, the number of CA1 neurons correlates with magnetic resonance imaging-derived hippocampal volume (r = 0.72; p < 0.001) and memory score (r = 0.62; p < 0.01). We conclude that although CA1 neuron loss is more consistently observed in AD than ischemic vascular dementia, severity of loss shows the expected correlation with structure and function across causative subtype. Reductions in magnetic resonance imaging-derived hippocampal volume reflect loss, rather than shrinkage, of CA1 neurons.

Abstract Neurochemical assessments were performed on biopsy samples taken from the right frontal lobe of patients diagnosed with Alzheimer's disease (AD), before the implantation of a ventricular catheter and pump assembly for the infusion of bethanechol chloride as an experimental therapy. The pathologically diagnosed patients with AD (n = 35; mean age, 67 ± 1.5 yr) were compared with a group of samples from normal age‐equivalent autopsied controls (n = 22; mean age, 68 ± 2 yr) and autopsied AD brains (n = 11; mean age, 73 ± 2 yr). Samples were assayed for choline acetyltransferase (ChAT), acetylcholinesterase, binding to { 3 H}quinuclidinyl benzilate as an index of total muscarinic cholinergic binding, and [ 3 H}pirenzepine binding as an index of Ml cholinergic receptor subtype binding. Mean levels of ChAT activity were decreased in the biopsied patients to 36% of age‐matched autopsied controls. The loss of ChAT activity correlated significantly with the Mini‐Mental State Examination, an index of global cognitive function. Mean ChAT activity in autopsied AD cortex was further decreased compared with controls, indicating continuous decline through the course of the disease. Acetylcholinesterase followed a similar, less dramatic decline. No differences were found in { 3 H}quinuclidinyl benzilate binding or { 3 H}pirenzepine binding between biopsied and autopsied controls. Neuritic plaque counts did not correlate with either the Mini‐Mental State Examination or ChAT activity in the biopsy specimens. The correlation of cortical ChAT activity with degree of dementia, although considerably weaker than those of cortical synaptic density with dementia, is the first demonstration of such a relationship in biopsied patients, and suggests another reason why the AD brain may be unresponsive to presynaptic cholinergic manipulations or attempts at enhancement.

To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI).Previous cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI.Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability.Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline.Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.

Abstract Cells of the mononuclear phagocytic system (MPS) present foreign antigen on their cell surfaces bound to major histocompatibility complex (MHC) class II molecules. Previous studies of normal human brain samples reported MHC class II expression primarily by perivascular MPS cells and white matter microglial cells. Marked increases in MHC class II‐expressing microglia have been shown in many neuropathologic disorders, including Alzheimer's disease (AD). A close morphologic association between these cells and Alzheimer senile plaque β‐amyloid has been demonstrated. The present study used a mixed aldehyde fixative to enhance the localization of MHC class II‐expressing MPS cells in non‐AD and AD brain. Two antibodies against MHC class II (HLA‐DR; LN3), as well as the lectin Ricinus communis agglutinin (which recognizes both ramified and activated microglia) were used for light and electron microscopic analyses. We now report that MHC class II‐expressing ramified microglia are distributed in a uniform reticular array throughout the grey, as well as the white matter in non‐AD cases. In AD cases, immunolabelled cells had the morphology of activated microglia, with darkly stained plump somata and short, thick processes. Microglia clustered around senile plaque amyloid and neurofibrillary tangles (NFT), rather than forming the uniform array characteristic of control tissue. Finally, we report that perivascular MPS cells are found in a morphologic relationship with vascular amyloid identical to that seen between microglial cells and senile plaque β‐amyloid. These data suggest that MHC class II‐expressing cells may be involved in the degradation of NFT‐laden neurons and the posttranslational modification of extracellular‐NFT epitopes. In addition, both parenchymal and perivascular MPS cells are ideally situated to uptake and process the β‐amyloid protein precursor and deposit β‐amyloid on senile plaques, NFT, and the cerebrovasculature. © 1992 Wiley‐Liss, Inc.

The effects of age, subcortical vascular disease, apolipoprotein E (APOE) ɛ4 allele and hypertension on entorhinal cortex (ERC) and hippocampal atrophy rates were explored in a longitudinal MRI study with 42 cognitively normal (CN) elderly subjects from 58 to 87 years old. The volumes of the ERC, hippocampus, and white matter hyperintensities (WMH) and the presence of lacunes were assessed on MR images. Age was significantly associated with increased atrophy rates of 0.04 ± 0.02% per year for ERC and 0.05 ± 0.02% per year for hippocampus. Atrophy rates of hippocampus, but not that of ERC increased with presence of lacunes, in addition to age. WMH, APOE ɛ4 and hypertension had no significant effect on atrophy rates. In conclusion, age and presence of lacunes should be taken into consideration in imaging studies of CN subjects and AD patients to predict AD progression and assess the response to treatment trials.

Alzheimer disease (AD) and vascular dementia are among the most frequently occurring causes of dementia in the world, and their accurate differentiation is important because different pharmaceutical strategies may modify the course of each disease.To determine which of 10 neuropsychological test scores can accurately differentiate patients with probable AD from those with subcortical ischemic vascular dementia (SIVD) for use in evidence-based clinical practice.Patients with suspected dementia were referred to the study by family physicians, geriatricians, and neurologists. All participants received a thorough assessment according to standard diagnostic guidelines. Diagnoses of probable AD (n = 31) and probable SIVD (n = 31) were made according to consensus criteria. The diagnosticians were blind to the results of the 10 neuropsychological test scores.There were no significant differences between the groups in age or Mini-Mental State Examination scores. Logistic regression analyses identified 2 neuropsychological tests that best distinguished the groups (sensitivity = 81%; specificity = 84%; positive likelihood ratio = 5.1). These were the recognition memory subtest of the Rey Auditory Verbal Learning Test and the Controlled Oral Word Association Test. The AD group performed better on the oral association test, whereas the SIVD group did better on the recognition memory test.Patients with probable AD and probable SIVD can be distinguished with a high degree of accuracy using these 2 neuropsychological tests.

To identify clinical predictors of cognitive decline in Alzheimer's disease.A cohort of patients was followed up longitudinally and the likelihood of arriving at two cognitive end points was assessed using the Cox proportional hazards model and eight explanatory variables.Subjects were chosen from patients examined for memory loss at two medical centers affiliated with the University of Southern California, Los Angeles.The sample included 135 patients who met National Institute for Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable or definite Alzheimer's disease, had initial Mini-Mental State Examination (MMSE) scores of 14 or greater, and had been seen on at least two occasions.The time to reach either of two end points, ie, MMSE score of 8 and a decline of six points on the MMSE, was assessed.After controlling for initial severity of dementia (eg, by dividing the sample into mild and moderate dementia subgroups or by using the individually defined end point of a six-point decline on the MMSE), the presence at baseline of extrapyramidal signs (risk-hazard ratio, 10.34; 95% confidence interval, 2.76 to 38.68; P = .0005), agitation (risk-hazard ratio, 2.98; 95% confidence interval, 1.35 to 6.61; P = .007), and hallucinations (risk-hazard ratio, 3.85; 95% confidence interval, 1.35 to 11; P = .01) predicted a shorter time to reach an end point.After controlling for initial severity of dementia, the presence of extrapyramidal signs and behavioral symptoms (agitation and hallucinations) significantly predict faster cognitive decline. These findings may reflect the effects of neuroleptic medication, the presence of underlying diffuse Lewy body disease, or alterations in biogenic amine systems.

<b><i>Objectives:</i></b> To explore the atrophy rate of entorhinal cortex (ERC) in AD and normal aging and assess the value of rate measurement of ERC atrophy for classifying subjects with AD from cognitively normal (CN) control subjects. <b><i>Methods:</i></b> Twenty-one AD patients and 23 CN subjects had MRI scans and clinical evaluations twice within 1.8 ± 0.6 years. ERC volumes were manually measured on volumetric T1-weighted MR images. <b><i>Results:</i></b> Patients with AD had a greater annual percentage volume change of ERC than CN subjects on both sides (left: 6.8 ± 4.3%/year for AD vs 1.4 ± 2.5%/year for CN [F_1,42 = 25.6, <i>p</i> &lt; 0.001]; right: 6.3 ± 3.3%/year for AD vs 1.4 ± 2.3%/year for CN [F_1,42 = 25.6, <i>p</i> &lt; 0.001]). Furthermore, increased ERC atrophy rate was correlated (<i>r</i> = −0.56, <i>p</i> = 0.01) with decreased memory performance in AD. CN subjects had on average annual ERC atrophy rates greater than zero (<i>p</i> &lt; 0.01). Baseline volume of ERC predicted atrophy rate of ERC (left: <i>r</i> = −0.53, <i>p</i> &lt; 0.01; right: <i>r</i> = −0.42, <i>p</i> &lt; 0.05) in CN subjects but not in AD subjects. Using ERC baseline volumes alone resulted in 77% overall correct classification (<i>p</i> &lt; 0.01) between AD and CN subjects, with 76% sensitivity and 78% specificity and an area under receiver operator characteristic (ROC) curve of 0.83. Adding annual atrophy rate of ERC to the model accounted for most of the variance (<i>p</i> &lt; 0.01), diminishing contributions from baseline volume and yielding 82% overall classification, with 76% sensitivity and 86% specificity and an area under the ROC curve of 0.93. <b><i>Conclusion:</i></b> ERC volume loss over time may be a better indicator for AD than cross-sectional measurements.

To determine if atrophy rates were higher for entorhinal cortex (ERC) than for hippocampus in Alzheimer disease (AD), to determine the relationship between hippocampal atrophy rate and memory impairment, and to compare atrophy rates of ERC and hippocampus in differentiating between patients with AD and cognitively normal (CN) controls.Twenty patients with AD and 25 CN subjects had MRI scans and clinical evaluations twice approximately 1.9 years apart. ERC volumes were measured manually and hippocampal volumes were measured semiautomatically on volumetric T1-weighted MR images.In AD, the atrophy rate of ERC (7.1 +/- 3.2%/year) was higher (p < 0.02) than that of hippocampus (5.9 +/- 2.4%/year). Furthermore, memory deficit in mild AD, measured with the Delayed List Verbal Recall test, correlated significantly with atrophy rates of both ERC (r = -0.61) and hippocampus (r = -0.59). Atrophy rates of ERC and hippocampus were comparable in differentiating between AD and CN. Using atrophy rates of ERC or hippocampus to detect a 20% treatment effect with 90% power (p < 0.05) would require about 100 completed patients per arm in a 2-year study.The finding in AD that the atrophy rate in the entorhinal cortex is higher than in the hippocampus is consistent with the view that AD pathology begins in the entorhinal cortex.

Impaired ability to conduct daily activities is a diagnostic criterion for dementia and a determinant of healthcare services utilization and caregiver burden. What predicts decline in instrumental activities of daily living (IADLs) is not well understood. This study examined measures of episodic memory, executive function, and MRI brain volumes in relation to baseline IADLs and as predictors of rate of IADL change. Participants were 124 elderly persons with cognitive function between normal and moderate dementia both with and without significant small vessel cerebrovascular disease. Random effects modeling showed that baseline memory and executive function (EXEC) were associated with baseline IADL scores, but only EXEC was independently associated with rate of change in IADLs. Whereas hippocampal and cortical gray matter volumes were significantly associated with baseline IADL scores, only hippocampal volume was associated with IADL change. In a model including cognitive and neuroimaging predictors, only EXEC independently predicted rate of decline in IADL scores. These findings indicate that greater executive dysfunction at initial assessment is associated with more rapid decline in IADLs. Perhaps executive function is particularly important with respect to maintaining IADLs. Alternatively, executive dysfunction may be a sentinel event indicating widespread cortical involvement and poor prognosis.

The present review focuses on the vascular basement membrane (VBM) and its relationship to the lesions of Alzheimer's disease (AD). Examination of the fine structure of the microvasculature reveals AD-associated VBM alterations, which include both thickening and vacuolization. Immunocytochemistry confirms that all three intrinsic VBM components [collagen type IV, laminin, and heparan sulfate proteoglycan (HSPG)] outline the capillary bed, which is pathologically altered in AD patients (microangiopathy). Ultrastructural analyses of AD tissue samples demonstrate that HSPG's normal staining pattern is disrupted on the endothelial surface of the VBM in brain regions affected by Alzheimer lesions. Similarly altered VBM is reported to occur in the kidney of patients with diabetes mellitus, where it is associated with a leakage of protein. All three VBM components immunolabel capillaries, amyloid and plaque-associated glial processes, suggesting a link between microangiopathy and senile plaque formation. In addition, the consistent colocalization of HSPG with several forms of amyloid implies an involvement in amyloidogenesis. Finally, the neurotrophic effects of beta-amyloid, combined with neurite-promoting effects of laminin and HSPG, could create a strong focus for an aberrant sprouting response. Such a response is postulated to result in plaque-associated degenerating neurites. Thus, VBM components could serve as a nidus for plaque formation, playing a role in the development of neuritic as well as amyloidotic elements.

Back to table of contents Previous article Next article No AccessMulticenter clinicopathological correlation in dementiaPublished Online:1 Apr 2006https://doi.org/10.1176/ajp.152.10.1476AboutSectionsView articleAbstractPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleAbstractOBJECTIVE: The aim of the present study was to determine the accuracy of clinical diagnoses of dementia in a large group of patients evaluated in a multicenter, university-based, Alzheimer's disease diagnostic and treatment program. METHOD: Clinical diagnoses and neuropathological results from seven collaborating Alzheimer's disease research centers were compared for 196 cases of dementia. RESULTS: When diagnoses of probable Alzheimer's disease, possible Alzheimer's disease, and Alzheimer's disease plus another condition were combined, 163 (83%) of the patients were clinically regarded as likely to have had Alzheimer's disease. Of those patients, 134 (82%) were found to have neuropathological changes diagnostic of Alzheimer's disease or Alzheimer's disease plus another condition. A total of 116 patients were diagnosed as having probable Alzheimer's disease; 100 (86%) of those were found to have pathological diagnoses of Alzheimer's disease or Alzheimer's disease plus another condition. Cerebral infarcts were found in 17% of the patients clinically diagnosed with probable Alzheimer's disease. Lewy bodies with variable Alzheimer's disease-type pathological changes were found in 7% of the patients with clinical diagnoses of probable Alzheimer's disease. Conversely, significant Alzheimer's disease-type pathological changes were found in 55% of the patients clinically diagnosed as having vascular dementia. CONCLUSIONS: Clinicians accurately predict Alzheimer's disease-type neuropathological findings in a high proportion of cases of dementia but may not predict cerebrovascular pathology and Lewy bodies in some patients with apparent clinical Alzheimer's disease and may often fail to predict Alzheimer's disease-type pathological findings in patients with apparent vascular dementia. With the emergence of effective treatments for Alzheimer's disease, there is an increasing need to optimize methods for ante-mortem diagnosis of dementia. Access content To read the fulltext, please use one of the options below to sign in or purchase access. Institutional Login Sign in via OpenAthens Purchase Save for later Item saved, go to cart PPV Articles - American Journal of Psychiatry $35.00 Add to cart PPV Articles - American Journal of Psychiatry Checkout Please login/register if you wish to pair your device and check access availability. Not a subscriber? 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We report the clinical and neuropathological characteristics occurring in 180 demented individuals from 24 kindreds with familial Alzheimer's disease (FAD). Each family had at least two affected generations, and at least one autopsy or brain biopsy was compatible with the diagnosis of AD. Forty-nine neuropathological specimens or reports were reviewed. Mean age of onset for the total group was 54.7 years +/- 11.5, with a large range of 30 to 84 years. Mean age at death was 63.5 years +/- 12.2, with a range of 46 to 85. Mean duration of disease was 8.8 years +/- 4.4, with a range of 1 to 23 years. Six findings suggested phenotypic heterogeneity in FAD. (1) Five families represented an early age of onset group with mean onset at 42 years (range 30 to 51 years) and mean disease duration of 6.7 years. (2) Eight families represented a late onset group with mean onset at 68 years (range 59 to 78 years) and a mean duration of 8.5 years. (3) Seven families were of Volga German ancestry, all originating from the same two villages in Russia. Mean age of onset was 55.9 years (range 40 to 72 years), with a mean disease duration of 10 years. This group probably represents the genetic founder effect of an autosomal dominant gene for AD. (4) One family had the unusual characteristics of neurofibrillary tangles and granulovacuolar change but no amyloid plaques, a mean disease duration of more than 11 years, and a "schizophrenia-like" onset. (5) One family with late onset also had clinical and pathological evidence for anterior horn cell disease. (6) Two autopsies in 1 family both showed remarkable rarefaction of myelin and expansion of perivascular spaces in centrum semiovale (état criblé), with marked leptomeningeal and cortical amyloid angiopathy, distinct from the other FAD brains. It remains to be determined whether the clinical and pathological differences between these families represent genetic heterogeneity at the biochemical or molecular level.

Subcortical ischemic vascular dementia (SIVD) has been proposed as a subtype of vascular cognitive impairment. MRI often discloses “silent” hyperintensities in 20% to 40% of community-dwelling elderly. Efforts to relate MRI-measured lacunes and white matter changes to cognitive impairment have not been straightforward. The possibility that Alzheimer's disease pathology contributes to cognitive impairment increases with age. A rare disorder known as cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) provides an opportunity to study SIVD in the absence of Alzheimer's disease. Lacunes and deep white matter changes are associated with dysexecutive syndrome. Hypertension, the leading risk factor for sporadic SIVD, is treatable. High priority must be given to reducing vascular risk profiles.

Histopathologic studies of the cerebral cortex, hippocampus, and three subcortical nuclei were performed in four patients with Parkinson's disease whose mental status had been evaluated by neuropsychologic testing. Clinicopathologic correlations suggest that dementia with marked visuospatial disturbance as well as severe aphasia may be associated with severe neuronal loss in subcortical nuclei, without significant numbers of plaques or tangles in the hippocampus and cerebral cortex. Furthermore, memory loss may not be consistently related to neuronal loss in the nucleus basalis of Meynert, particularly in non-Lewy body parkinsonism.

β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI's influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.Clinically normal (mean age, 77.1 years [N = 30]), cognitively impaired (mean age, 78.0 years [N = 24]), and mildly demented (mean age, 79.8 years [N = 7]) participants.Magnetic resonance imaging, Aβ (Pittsburgh Compound B-positron emission tomographic [PiB-PET]) imaging, and cognitive testing.Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P < .05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.

<h3>Importance</h3> The apolipoprotein E ε4 (<i>APOE4</i>) allele identifies a unique population that is at significant risk for developing Alzheimer disease (AD). Docosahexaenoic acid (DHA) is an essential ω-3 fatty acid that is critical to the formation of neuronal synapses and membrane fluidity. Observational studies have associated ω-3 intake, including DHA, with a reduced risk for incident AD. In contrast, randomized clinical trials of ω-3 fatty acids have yielded mixed and inconsistent results. Interactions among DHA,<i>APOE</i>genotype, and stage of AD pathologic changes may explain the mixed results of DHA supplementation reported in the literature. <h3>Observations</h3> Although randomized clinical trials of ω-3 in symptomatic AD have had negative findings, several observational and clinical trials of ω-3 in the predementia stage of AD suggest that ω-3 supplementation may slow early memory decline in<i>APOE4</i>carriers. Several mechanisms by which the<i>APOE4</i>allele could alter the delivery of DHA to the brain may be amenable to DHA supplementation in predementia stages of AD. Evidence of accelerated DHA catabolism (eg, activation of phospholipases and oxidation pathways) could explain the lack of efficacy of ω-3 supplementation in AD dementia. The association of cognitive benefit with DHA supplementation in predementia but not AD dementia suggests that early ω-3 supplementation may reduce the risk for or delay the onset of AD symptoms in<i>APOE4</i>carriers. Recent advances in brain imaging may help to identify the optimal timing for future DHA clinical trials. <h3>Conclusions and Relevance</h3> High-dose DHA supplementation in<i>APOE4</i>carriers before the onset of AD dementia can be a promising approach to decrease the incidence of AD. Given the safety profile, availability, and affordability of DHA supplements, refining an ω-3 intervention in<i>APOE4</i>carriers is warranted.

The present study evaluated cerebrovascular disease (CVD), β-amyloid (Aβ), and cognition in clinically normal elderly adults. Fifty-four participants underwent magnetic resonance imaging (MRI), Pittsburgh compound B (PIB)-positron emission tomography (PET) imaging, and neuropsychological evaluation. High white matter hyperintensity burden and/or presence of infarct defined CVD status (CVD−: n = 27; CVD+: n = 27). PIB-positron emission tomography ratios of Aβ deposition were extracted using Logan plotting (cerebellar reference). Presence of high levels of Aβ in prespecified regions determined PIB status (PIB−: n = 33; PIB+: n = 21). Executive functioning and episodic memory were measured using composite scales. CVD and Aβ, defined as dichotomous or continuous variables, were unrelated to one another. CVD+ participants showed lower executive functioning (p = 0.001) when compared with CVD− individuals. Neither PIB status nor amount of Aβ affected cognition (ps ≥ 0.45), and there was no statistical interaction between CVD and PIB on either cognitive measure. Within this spectrum of normal aging CVD and Aβ aggregation appear to be independent processes with CVD primarily affecting cognition.

AD is a public health epidemic, which seriously impacts cognition, mood and daily activities; however, one type of activity, exercise, has been shown to alter these states. Accordingly, we sought to investigate the relationship between exercise and mood, in early-stage AD patients (N = 104) from California, over a 1-year period. Patients completed the Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Blessed-Roth Dementia Rating Scale (BRDRS), while their caregivers completed the Yale Physical Activity Survey (YALE), Profile of Mood States (POMS), the Neuropsychiatric Inventory (NPI) and Functional Abilities Questionnaire (FAQ). Approximately half of the participants were female, from a variety of ethnic groups (Caucasian = 69.8%; Latino/Hispanic Americans = 20.1%). Our results demonstrated that the patients spent little time engaged in physical activity in general, their overall activity levels decreased over time, and this was paired with a change in global cognition (e.g., MMSE total score) and affect/mood (e.g., POMS score). Patients were parsed into Active and Sedentary groups based on their Yale profiles, with Active participants engaged in walking activities, weekly, over 1 year. Here, Sedentary patients had a significant decline in MMSE scores, while the Active patients had an attenuation in global cognitive decline. Importantly, among the Active AD patients, those individuals who engaged in walking for more than 2 h/week had a significant improvement in MMSE scores. Structured clinical trials which seek to increase the amount of time AD patients were engaged in walking activities and evaluate the nature and scope of beneficial effects in the brain are warranted.

The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of β-amyloid (Aβ). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation in vivo are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower Aβ degradation capacity. Human CSF from APOE ε4/ε4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from APOE ε3/ε3 carriers. Enhancing ABCA1 activity rescued impaired Aβ degradation in ApoE4-treated cells and reduced both ApoE and ABCA1 aggregation in the hippocampus of male ApoE4-targeted replacement mice. Together, our data demonstrate that aggregated and lipid-poor ApoE4 increases ABCA1 aggregation and decreases ABCA1 cell membrane recycling. Enhancing ABCA1 activity to reduce ApoE and ABCA1 aggregation is a potential therapeutic strategy for the prevention of ApoE4 aggregation-driven pathology. SIGNIFICANCE STATEMENT ApoE protein plays a key role in the formation of amyloid plaques, a hallmark of Alzheimer's disease (AD). ApoE4 is more aggregated and hypolipidated compared with ApoE3, but whether enhancing ApoE lipidation in vivo can reverse ApoE aggregation is not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). In this study, we demonstrated that the greater propensity of lipid-poor ApoE4 to aggregate decreased ABCA1 membrane recycling and its ability to lipidate ApoE. Importantly, enhancing ABCA1 activity to lipidate ApoE reduced ApoE and ABCA1 aggregation. This work provides critical insights into the interactions among ABCA1, ApoE lipidation and aggregation, and underscores the promise of stabilizing ABCA1 activity to prevent ApoE-driven aggregation pathology.

Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the ε4 allele of the apolipoprotein E (APOE) gene is associated with the presence of CAA, both APOE-ε4 and ε2 are associated with lobar ICH. The generally accepted explanation is that APOE-ε4 promotes vascular amyloid deposition, while APOE-ε2 promotes progression to severe CAA with associated vasculopathic changes that cause vessel rupture and ICH. We assessed the evidence for these allele-specific effects.We systematically identified published studies with data on APOE genotype and histopathological assessment of postmortem brains for CAA severity. We obtained unpublished data from these for meta-analyses of the effects of ε4-containing (ε4+) and ε2-containing (ε2+) genotypes on progression to severe CAA.Of six eligible studies (543 eligible participants), data were available from 5 (497 participants, 353 with CAA). Meta-analyses showed a possible association of ε4+ genotypes with severe CAA (ε4+ vs ε4-: severe vs mild/moderate CAA, OR 2.5, 95% CI 1.4 to 4.5, p=0.002; severe vs moderate CAA, OR 1.7, 95% CI 0.9 to 3.1, p=0.11). For ε2+ versus ε2- genotypes, there was no significant association, but the very small number of participants with ε2+ genotypes (22) precluded reliable estimates.We found a possible association of severe CAA with APOE-ε4 but not APOE-ε2. However, our findings do not exclude a biologically meaningful association between APOE-ε2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms.

This study examined longitudinal changes in coping and defense mechanisms in an age- and gender-stratified sample of 392 European American adults. Nonlinear age-related changes were found for the coping mechanisms of sublimation and suppression and the defense mechanisms of intellectualization, doubt, displacement, and regression. The change trajectories for sublimation and suppression showed that their use increased from adolescence to late middle age and early old age and remained mostly stable into late old age. The change trajectory for intellectualization showed that the use of this defense mechanism increased from adolescence to middle age, remained stable until late midlife, and started to decline thereafter. The defense mechanisms of doubt, displacement, and regression showed decreases from adolescence until early old age, with increases occurring again after the age of 65. Linear age-related decreases were found for the coping mechanism of ego regression and the defense mechanisms of isolation and rationalization. Gender and socioeconomic status were associated with the mean levels of several coping and defense mechanisms but did not moderate age-related changes. Increases in ego level were associated with increased use of the defense mechanism intellectualization and decreased use of the defense mechanisms of doubt and displacement. Overall, these findings in a European American sample suggest that most individuals showed development in the direction of more adaptive and less maladaptive coping and defense strategies from adolescence until late middle age or early old age. However, in late old age this development was reversed, presenting potential challenges to the adaptive capacity of older adults.

Objective: Exposure to ambient fine particulate matter (PM2.5: PM with aerodynamic diameters < 2.5 μm) has been linked with cognitive deficits in older adults. Using fine-grained voxel-wise analyses, we examined whether PM2.5 exposure also affects brain structure. Methods: Brain MRI data were obtained from 1365 women (aged 71-89) in the Women's Health Initiative Memory Study and local brain volumes were estimated using RAVENS (regional analysis of volumes in normalized space). Based on geocoded residential locations and air monitoring data from the U.S. Environmental Protection Agency, we employed a spatiotemporal model to estimate long-term (3-year average) exposure to ambient PM2.5 preceding MRI scans. Voxel-wise linear regression models were fit separately to gray matter (GM) and white matter (WM) maps to analyze associations between brain structure and PM2.5 exposure, with adjustment for potential confounders. Results: Increased PM2.5 exposure was associated with smaller volumes in both cortical GM and subcortical WM areas. For GM, associations were clustered in the bilateral superior, middle, and medial frontal gyri. For WM, the largest clusters were in the frontal lobe, with smaller clusters in the temporal, parietal, and occipital lobes. No statistically significant associations were observed between PM2.5 exposure and hippocampal volumes. Conclusions: Long-term PM2.5 exposures may accelerate loss of both GM and WM in older women. While our previous work linked smaller WM volumes to PM2.5, this is the first neuroimaging study reporting associations between air pollution exposure and smaller volumes of cortical GM. Our data support the hypothesized synaptic neurotoxicity of airborne particles.

The co-occurrence of both Alzheimer disease (AD) pathology and vascular brain injury (VBI) is very common, especially amongst the oldest of old. In neuropathologic studies, the prevalence of AD, VBI, and mixed AD/VBI lesions ranks ahead of Lewy bodies and hippocampal sclerosis. In the modern era of structural magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) imaging, this review examines 1) the prevalence of mixed AD and VBI pathology, 2) the significance of these pathologies for cognitive impairment (AD and vascular cognitive impairment (VCI)), and 3) the diagnosis and treatment of mixed AD/VCI. Although epidemiologic studies report that vascular risk factors for arteriosclerosis increase the risk of incident AD, both autopsy and amyloid PET studies indicate that AD and VBI contribute additively, but independently, to the risk of dementia. The literature confirms the malignancy of AD and highlights the adverse effects of microinfarcts on cognitive function. For the clinical diagnosis of mixed AD/VCI, the presence of AD can be recognized by neuropsychological profile, structural imaging, cerebrospinal fluid biomarkers, and glucose PET and amyloid PET imaging. The diagnosis of VBI, however, still hinges predominantly on the structural MRI findings. Severe amnesia and atrophy of the hippocampus are characteristic of early AD, whereas the cognitive profile for VCI is highly variable and dependent on size and location of VBI. The cognitive profile of mixed AD/VBI is dominated by AD. With the notable exception of microinfarcts (which elude in vivo detection), infarcts, hemorrhages, and white matter hyperintensities on structural MRI currently represent the best markers for the presence VBI. Better markers that reflect the health and reactivity of intracerebral blood vessels are needed. For prevention and treatment, the type of underlying cerebrovascular disease (for example, arteriosclerosis or cerebral amyloid angiopathy) should be considered. It is likely that reduction of vascular risk factors for arteriosclerosis can significantly reduce vascular contributions to mixed dementia.

The objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD).Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [(11)C]Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index.Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aβ. These frontotemporal regions are also affected in individuals with Aβ deposition, but the latter show additional thinning in parietal cortices. Aβ and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aβ has its greatest effect. In this way, the negative effect of Aβ in posterior regions is increased by the presence of vascular risk.Aβ and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD.

The incidence and severity of cerebrovascular disease (CVD) increase with advancing age, as does the risk of developing Alzheimer's disease (AD). Not surprisingly, heterogeneous forms of CVD may coexist with AD changes in the 'ageing brain'. These include angiopathies (affecting both large and small arteries) that result from 'classical' risk factors (hypertension, smoking and diabetes) and others (cerebral amyloid angiopathy) that are biochemically closely linked to AD. The morphologic consequences of these various vascular diseases are infarcts and/or haemorrhages of varying sizes within the brain, which lead to neurocognitive decline that may mimic AD - though the vascular abnormalities are usually detectable by neuroimaging. More subtle effects of CVD may include neuroinflammation and biochemical 'lesions' that have no reliable morphologic correlate and thus escape the attention of even an experienced Neuropathologist. The pathogenesis of hippocampal injury resembling ischaemic change - commonly seen in the brains of geriatric subjects - remains controversial. In recent years, genetically determined forms of microangiopathy (e.g. CADASIL, CARASIL, Trex1-related microangiopathies, CARASAL, familial forms of cerebral amyloid angiopathy or CAA) have provided interesting cellular and molecular clues to the pathogenesis of sporadic microvascular disease such as arteriolosclerosis and AD-related CAA.

Higher dietary intake of the essential fatty acid docosahexaenoic (DHA) has been associated with better cognitive performance in several epidemiological studies. Animal and in vitro studies also indicate that DHA prevents amyloid deposition in the brain.To determine the association between serum DHA levels, cerebral amyloidosis, and the volumes of brain areas affected by Alzheimer disease.Cross-sectional analysis of serum DHA levels together with measures of amyloid deposition (Pittsburgh Compound B index), brain volumes, and neuropsychological testing scores from 61 participants in the Aging Brain Study. The study was conducted between June 2008 and May 2013, and the data were analyzed between October 2015 and April 2016. Linear models were adjusted for age, sex, years of education, and apolipoprotein E status.Serum DHA levels with cerebral amyloidosis measured using PIB PET.Samples were available from 61 Aging Brain Study participants (41 women and 20 men) who underwent amyloid PET imaging. The mean (SD) age of the participants was 77 (6) years and ranged from 67 to 88 years. Serum DHA levels (percentage of total fatty acids) were 23% lower in participants with cerebral amyloidosis than those without (0.97 vs 1.25, P = .007) and were inversely correlated with brain amyloid load (r = -0.32, P = .01) independent of age, sex, apolipoprotein E genotype, and years of education. Moreover, greater serum DHA levels were positively associated with brain volume in several subregions affected by AD, in particular the left subiculum (r = 0.38, P = .005) and the left entorhinal volumes (r = 0.51, P = .001). Serum DHA levels were also associated with nonverbal memory scores (r = 0.28, P = .03).In this study, serum DHA levels were associated with pathogenesis of cerebral amyloidosis and with preservation of entorhinal and hippocampal volumes. These findings suggest an important role for DHA metabolism in brain amyloid deposition during the preclinical or early symptomatic stages of Alzheimer disease.

BackgroundPast clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment.Methods33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition.FindingsA 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups.InterpretationDementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers. Trial Registration: NCT02541929.FundingHNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

<h3>Objective:</h3> To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the <i>ATP-binding cassette, subfamily A</i> (<i>ABC1</i>), <i>member 7</i> (<i>ABCA7</i>) gene, a known risk factor for late-onset AD. <h3>Methods:</h3> Custom capture sequencing was performed on ∼150 kb encompassing <i>ABCA7</i> in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an <i>ABCA7</i> deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. <h3>Results:</h3> A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and <i>APOE</i> status, was significantly associated with disease (<i>p</i> = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, <i>p</i> = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (<i>p</i> = 1.414 × 10⁻⁵, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. <h3>Conclusions:</h3> This common <i>ABCA7</i> deletion could represent an ethnic-specific pathogenic alteration in AD.

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease.

Abstract Introduction There is insufficient understanding of diagnosis of etiologic dementia subtypes and contact with specialized dementia care among older Americans. Methods We quantified dementia diagnoses and subsequent health care over five years by etiologic subtype and physician specialty among Medicare beneficiaries with incident dementia diagnosis in 2008/09 (226,604 persons/714,015 person‐years). Results Eighty‐five percent of people were diagnosed by a nondementia specialist physician. Use of dementia specialists within one year (22%) and five years (36%) of diagnosis was low. “Unspecified” dementia diagnosis was common, higher among those diagnosed by nondementia specialists (33.2%) than dementia specialists (21.6%). Half of diagnoses were Alzheimer's disease. Discussion Ascertainment of etiologic dementia subtype may inform hereditary risk and facilitate financial and care planning. Use of dementia specialty care was low, particularly for Hispanics and Asians, and associated with more detection of etiological subtype. Dementia‐related professional development for nonspecialists is urgent given their central role in dementia diagnosis and care.

Retinal imaging technology is rapidly advancing and can provide ever-increasing amounts of information about the structure, function and molecular composition of retinal tissue in humans in vivo. Most importantly, this information can be obtained rapidly, non-invasively and in many cases using Food and Drug Administration-approved devices that are commercially available. Technologies such as optical coherence tomography have dramatically changed our understanding of retinal disease and in many cases have significantly improved their clinical management. Since the retina is an extension of the brain and shares a common embryological origin with the central nervous system, there has also been intense interest in leveraging the expanding armamentarium of retinal imaging technology to understand, diagnose and monitor neurological diseases. This is particularly appealing because of the high spatial resolution, relatively low-cost and wide availability of retinal imaging modalities such as fundus photography or OCT compared to brain imaging modalities such as magnetic resonance imaging or positron emission tomography. The purpose of this article is to review and synthesize current research about retinal imaging in neurodegenerative disease by providing examples from the literature and elaborating on limitations, challenges and future directions. We begin by providing a general background of the most relevant retinal imaging modalities to ensure that the reader has a foundation on which to understand the clinical studies that are subsequently discussed. We then review the application and results of retinal imaging methodologies to several prevalent neurodegenerative diseases where extensive work has been done including sporadic late onset Alzheimer's Disease, Parkinson's Disease and Huntington's Disease. We also discuss Autosomal Dominant Alzheimer's Disease and cerebrovascular small vessel disease, where the application of retinal imaging holds promise but data is currently scarce. Although cerebrovascular disease is not generally considered a neurodegenerative process, it is both a confounder and contributor to neurodegenerative disease processes that requires more attention. Finally, we discuss ongoing efforts to overcome the limitations in the field and unmet clinical and scientific needs.

Tau pathology and vascular dysfunction are important contributors to Alzheimer's disease (AD), but vascular-tau associations and their effects on cognition are poorly understood. We investigated these associations in male and female humans by conducting voxelwise comparisons between cerebral blood flow (CBF) and tau positron emission tomography (PET) images in independent discovery [cognitively normal (CN), 19; mild cognitive impairment (MCI) risk, 43; MCI, 6] and replication (CN,73; MCI, 45; AD, 20) cohorts. In a subgroup, we assessed relationships between tau and soluble platelet-derived growth factor β (sPDGFRβ), a CSF marker of pericyte injury. We tested whether CBF/sPDGFRβ-tau relationships differed based on Montreal Cognitive Assessment (MoCA) global cognition performance, or based on amyloid burden. Mediation analyses assessed relationships among CBF/sPDGFRβ, tau, and cognition. Negative CBF-tau correlations were observed predominantly in temporal-parietal regions. In the replication cohort, early negative CBF-tau correlations increased in spatial extent and in strength of correlation with increased disease severity. Stronger CBF-tau and sPDGFRβ-tau correlations were observed in participants with greater amyloid burden and lower MoCA scores. Importantly, when stratifying by amyloid status, stronger CBF-tau relationships in individuals with lower MoCA scores were driven by amyloid+ participants. Tau PET was a significant mediator CBF/sPDGFRβ-MoCA relationships in numerous regions. Our results demonstrate vascular-tau associations across the AD spectrum and suggest that early vascular-tau associations are exacerbated in the presence of amyloid, consistent with a two-hit model of AD on cognition. Combination treatments targeting vascular health, as well as amyloid-β and tau levels, may preserve cognitive function more effectively than single-target therapies.SIGNIFICANCE STATEMENT Emerging evidence demonstrates a role for vascular dysfunction as a significant contributor to Alzheimer's pathophysiology. However, associations between vascular dysfunction and tau pathology, and their effects on cognition remain poorly understood. Multimodal neuroimaging data from two independent cohorts were analyzed to provide novel in vivo evidence of associations between cerebral blood flow (CBF), an MRI measure of vascular health, and tau pathology using PET. CBF-tau associations were related to cognition and driven in part by amyloid burden. Soluble platelet-derived growth factor β, an independent CSF vascular biomarker, confirmed vascular-tau associations in a subgroup analysis. These results suggest that combination treatments targeting vascular health, amyloid-β, and tau levels may more effectively preserve cognitive function than single-target therapies.

Vascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular spaces (PVS). Using magnetic resonance imaging, we show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered PVS presence and distribution, irrespective of Amyloid-β. Surprisingly, we noted lower PVS presence in the anterosuperior medial temporal lobe (asMTL) (1.29 times lower PVS volume fraction in cognitively impaired individuals, p < 0.0001), which was associated with entorhinal neurofibrillary tau tangle deposition (beta (standard error) = -0.98 (0.4); p = 0.014), one of the hallmarks of early Alzheimer's disease pathology. We also observed higher PVS volume fraction in centrum semi-ovale of the white matter, but only in female participants (1.47 times higher PVS volume fraction in cognitively impaired individuals, p = 0.0011). We also observed PVS changes in participants with history of hypertension (higher in the white matter and lower in the asMTL). Our results suggest that anatomically specific alteration of the PVS is an early neuroimaging feature of cognitive impairment in aging adults, which is differentially manifested in female.

This article gives a broad overview of vascular cognitive impairment and dementia, including epidemiology, pathophysiology, clinical approach, and management. Emphasis is placed on understanding the common underlying types of cerebrovascular disease (including atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) and awareness of rare inherited cerebrovascular disorders.The pathophysiology of vascular cognitive impairment and dementia is heterogeneous, and the most recent diagnostic criteria for vascular cognitive impairment and dementia break down the diagnosis of major vascular dementia into four phenotypic categories, including subcortical ischemic vascular dementia, poststroke dementia, multi-infarct dementia, and mixed dementia. Control of cardiovascular risk factors, including management of midlife blood pressure, cholesterol, and blood sugars, remains the mainstay of prevention for vascular cognitive impairment and dementia. Cerebral amyloid angiopathy requires special consideration when it comes to risk factor management given the increased risk of spontaneous intracerebral hemorrhage. Recent trials suggest some improvement in global cognitive function in patients with vascular cognitive impairment and dementia with targeted cognitive rehabilitation.Thorough clinical evaluation and neuroimaging form the basis for diagnosis. As vascular cognitive impairment and dementia is the leading nondegenerative cause of dementia, identifying risk factors and optimizing their management is paramount. Once vascular brain injury has occurred, symptomatic management should be offered and secondary prevention pursued.

Proteomic studies for Alzheimer’s disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson’s disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.

<h2>Summary</h2><h3>Background</h3> Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people. <h3>Methods</h3> In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25–73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine <i>PSEN1</i>, <i>PSEN2</i>, or <i>APP</i> mutation status. <i>APOE</i> genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, <i>APOE</i> ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated. <h3>Findings</h3> 192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; <i>r</i>=–0·565; p<0·0001) and in people with Down syndrome (n=32; <i>r</i>=–0·801; p<0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). <i>APOE</i> ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset –23·0 <i>vs</i> –17·5; p=0·0002). <i>PSEN1</i> mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome. <h3>Interpretation</h3> Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome. <h3>Funding</h3> The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Importance Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [ P = .001]; ADNI: t = 2.7 [ P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [ P = .002]; ADNI: t = −5.6 [ P &amp;amp;lt; .001]; HABS: t = −2.2 [ P = .03]), greater in older individuals (DIAN: t = 6.8 [ P &amp;amp;lt; .001]; ADNI: t = 9.1 [ P &amp;amp;lt; .001]; HABS: t = 5.4 [ P &amp;amp;lt; .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [ P = .40]; ADNI: t = 0.6 [ P = .50]; HABS: t = 1.8 [ P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P &amp;amp;lt; .001). Conclusions and Relevance The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract INTRODUCTION Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non‐genetic/lifestyle factors impact this multi‐ethnic population. METHODS The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit &gt; 5000 participants to identify genetic and non‐genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under‐investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

This research examines the experience of stigma associated with psychiatric treatment among Chinese patients with schizophrenia in Hong Kong. In focus groups patients described stigma experiences related to clinic visits and the side effects of antipsychotic medications. Additionally, they revealed various adverse treatment experiences during hospitalization which point to the presence of structural discrimination. Based on the focus group findings, a questionnaire was developed and completed by 320 and 160 patients with schizophrenia and diabetes mellitus, respectively. Results showed that patients with schizophrenia were more likely to anticipate stigma, conceal illness, and default on clinic visits than patients with diabetes. Medication-induced stigma occurred in 48% of patients with schizophrenia. It brought about the unwelcome disclosure of illness, workplace difficulties, family rejection, and treatment non-adherence. Adverse experiences during hospitalization were reported by 44% of patients with schizophrenia. They included negative staff attitudes, excessive physical/chemical restraints, inadequate information/complaint systems, and limited rights. We conclude that stigma, at both individual and structural levels, represents a central experience of the treatment of schizophrenia in Hong Kong. Because inequitable health policy, resource allocation, and service organization privilege service providers' control over users, treatment-related stigma may be a prime example of the social production of stigma and discrimination based on power difference between the stigmatizers and the stigmatized. To examine this critically we need to redirect stigma research to tractable clinical circumstances and structural mechanisms that produce and maintain stigmatizing and discriminatory psychiatric practice. Destigmatization programs must be evaluated not only by change in public attitudes but also by how much they reduce structural stigma and improve patients' lives.

While the pathogenic mechanisms responsible for Alzheimer's Disease (AD) remain unknown, blood vessels deformities, thickened vascular basement membrane (VBM), and amyloid fibrils emanating from the VBM all suggest vascular involvement. The present study immunocytochemically localized the VBM constituent heparan sulfate proteoglycan (HSPG), which is said to play a role in filtration of anionic and neutral proteins. In addition, thioflavine S was used to double-label each tissue section for the presence of amyloid. Samples were taken from frontal, temporal and parietal lobes of 8 patients who exhibited the neuropathologic lesions of AD and 6 patients who did not. HSPG immunolabeled the capillary bed in all samples. Tissue from patients with Ad, however, exhibited severe microangiopathic changes: ragged and irregular outer capillary walls, both thickened and attenuated capillary diameters, and regionally increased capillary density. In addition, plaque-like extravascular accumulations of HSPG were seen in all patients with AD. These accumulations were found in the vicinity of capillaries, and were commonly colocalized with amyloid. Neither extravascular clouds of HSPG immunoreactivity nor fluorescing accumulations of amyloid were found in non-AD patients. The pattern of HSPG immunostaining confirms: (1) the high incidence of microangiopathy in AD; (2) the close anatomic relationship between plaque constituents and capillaries; and (3) the colocalization of HSPG with extravascular amyloid. The cerebral vasculature, and specifically the VBM, may thus be actively involved in the pathogenesis of AD.

OBJECTIVES : To identify the percentage of patients with Alzheimer's disease (AD) in a general clinic population who would be provisionally eligible for randomized clinical trials and the extent to which these patients represent the overall clinic‐based population. BACKGROUND : Many randomized clinical trials have restricted enrollment criteria that may limit generalizability, i.e., AD patients who fulfill selection criteria for phase III clinical trials may not be representative of other AD patients in clinical settings. DESIGN AND SETTING : Patients diagnosed as probable or possible AD from the nine clinical sites of the State of California's Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) were selected on the basis of their provisionally fulfilling the inclusion and exclusion criteria of two typical AD clinical trials at the time of their first visit (ECG and brain imaging criteria were not available). RESULTS : From a sample of 3470 subjects with possible or probable AD, overall, only 4.4% or 7.9% would have been provisionally eligible for each of two trials. Patients provisionally eligible were younger, relatively underrepresented by women, better educated, wealthier, and more likely to be white than ineligible patients. The major independent demographic predictors for eligibility were (1) income greater than $15,000 per year, (2) male gender, and (3) college education. More than 60% of probable AD patients were excluded because of significant behavioral problems; approximately one‐quarter each were excluded because of significant medical or neurological problems. Allowing patients with probable or possible AD to enroll would have resulted in 10.6% being eligible. CONCLUSION : Selection criteria for AD clinical trials result in a demographically and clinically constrained subgroup that is not representative of the overall clinic population. J Am Geriatr Soc 45:923–928, 1997.

Abstract Since the time of Aristotle it has been thought that memories can be divided into two basic types; conscious recollections and familiarity‐based judgments. Neuropsychological studies have provided indirect support for this distinction by suggesting that different regions within the human medial temporal lobe (MTL) are involved in these two forms of memory, but none of these studies have demonstrated that these brain regions can be fully dissociated. In a group of nondemented elderly subjects, we found that performance on recall and recognition tests was predicted preferentially by hippocampal and entorhinal volumes, respectively. Structural equation modeling revealed a double dissociation, whereby age‐related reductions in hippocampal volume resulted in decreases in recollection, but not familiarity, whereas entorhinal volume was preferentially related to familiarity. The results demonstrate that the forms of episodic memory supported by the human hippocampus and entorhinal cortex can be fully dissociated, and indicate that recollection and familiarity reflect neuroanatomically distinct memory processes. © 2007 Wiley‐Liss, Inc.

Numerous pathogenetic mechanisms may lead to the progressive loss of memory and intellectual function known as dementia. Currently, the dementias are classified according to clinicopathologic entities, although for clinical diagnosis, this introduces a degree of uncertainty. Characteristic patterns of behavior and anatomic pathology have been associated with specific clinicopathologic entities. Although somewhat simplistic, classification of the dementias as cortical vs subcortical embodies the precept that brain substrate is intimately tied to behavior. Lessons in brain-behavior relationships are reviewed for four clinicopathologic entities: Alzheimer's disease, Pick's disease, vascular dementia, and Parkinson's disease. Dementing illnesses have contributed significantly to our understanding of brain-behavior relationships. Major progress can be anticipated as diagnostic issues are resolved and biological and state-specific markers emerge.

Background and Purpose— The relationship between subcortical ischemic vascular disease (SIVD) and cognition in normal elderly is unclear, in part because of methodological inconsistencies across studies. To clarify this relationship, the current study investigated a well characterized cognitively normal elderly sample (≥55 years) with quantitative MRI and psychometrically robust neuropsychological measures within a multivariate model. Converging evidence suggests that SIVD selectively impairs frontal-executive tasks by disrupting frontal-subcortical circuits. We therefore hypothesized that MRI markers of SIVD would be selectively associated with worse executive functioning. Methods— We studied 94 participants who were cognitively and functionally normal. Volumetric measures of white matter signal hyperintensity (WMH), subcortical lacunes, hippocampal volume, and cortical gray matter were obtained to predict performance on composite measures of executive functioning and episodic memory. Results— Hierarchical regression demonstrated that after controlling for demographic variables, MMSE, and total intracranial volume, the total number of subcortical lacunes was the only significant predictor, with a greater number of lacunes associated with poorer executive performance. Hippocampal volume best predicted episodic memory performance. Conclusions— Results suggest that SIVD in the form of silent lacunes corresponds to poorer executive functioning even in otherwise normal elderly, which is consistent with the hypothesis that SIVD preferentially disrupts frontal-subcortical circuits. The clinical importance of these findings is highlighted by the fact that 33% of the normal elderly participants in this study had lacunar infarcts.

One of the characteristics of Alzheimer's disease is the early loss of neurons in pathways involved in processing olfactory information. Olfactory function was assessed in subjects with Alzheimer's disease using a conventional Smell Identification Test and a simple three odor match-to-sample problem. The patients exhibited a diminished capacity to identify common odors but were severely impaired in their ability to use novel odors in a match-to-sample task. Subjects with Parkinson's disease had a severe deficit for identifying common odors with the majority scoring as anosmic. Multiple sclerosis was not accompanied by detectable changes in olfactory functioning. The results of the Alzheimer's group are similar to recent animal studies that have shown lesions of the piriform-entorhinal cortex produce a variety of memory deficits that are particularly acute in tasks involving novel odors.

The goal of this study was to examine the relationship between subcortical vascular disease and brain atrophy in patients with Alzheimer’s disease (AD) and mixed dementia (i.e., AD and subcortical vascular disease together). MRI was performed on 77 cognitively normal (CN) subjects, 50 AD and 13 mixed dementia patients. Subcortical vascular disease was determined by white matter hyperintensities (WMH) volume and presence of subcortical lacunes. Brain atrophy was measured using total brain cortical gray matter (CGM), entorhinal cortex (ERC) and hippocampal volumes. CGM volume, but not ERC or hippocampal volume was inversely related to WMH volume in patients and controls. In contrast, no relationship was detected between CGM, ERC, or hippocampal volumes and subcortical lacunes. Furthermore, no interaction was found between WMH and diagnosis on cortical atrophy, implying that WMH affect cortical atrophy indifferently of group. These results suggest that subcortical vascular disease, manifested as WMH, may affect cortical atrophy more than ERC and hippocampal atrophy. Further, AD pathology and subcortical vascular disease may independently affect cortical atrophy.

Abstract A relationship between the microvasculature and Alzheimer senile plaques has been suggested by several lines of evidence. Besides close anatomic and biochemical relationships, both extrinsic (fibronectin) and intrinsic [heparan sulfate proteoglycan (HSPG)] components of the vascular basement membrane (VBM) have been colocalized with amyloid plaques. The present study was designed to examine the association between three intrinsic components of the VBM [HSPG, collagen type IV (CIV), and laminin] and the histopathologic lesions of Alzheimer's disease (AD). Six cases with neuropathologically confirmed AD were immunocytochemically labeled for the presence of HSPG, CIV, laminin, or tau‐2 (a marker for degenerating neurites) and examined at the light and electron microscopic levels. For light microscopic analyses, sections were counterstained with a fluorescent marker for amyloid. The present study illustrates an involvement of VBM components in the lesions associated with AD. First, we replicate our previous finding that HSPG antibodies immunolabel a subset of neurons; ultrastructural analyses indicate that at least some of these are actually extracellular neurofibrillary tangles. Second, we report that CIV and laminin immunoreaction product was not associated with neurons but did label several perivascular cells with the morphologic characteristics of microglia. Finally, we demonstrate that all three intrinsic VBM components, CIV and laminin as well as HSPG, are localized to senile plaques. Both light and electron microscopic studies indicate that the VBM components are associated with amyloid rather than degenerating neurites. These findings suggest that the VBM or its components may play a role in the AD pathogenetic cascade.

Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.

Abstract Objectives We examined the magnetic resonance imaging (MRI) correlates of depressed mood, apathy, anhedonia, and anergia in older adults with and without cognitive impairment or dementia. Methods This analysis included 270 community‐dwelling older adults (59% male; 79% Caucasian; mean age 74.4 years) who were recruited into a multi‐center longitudinal observational study of subcortical ischemic vascular disease (SIVD).The distribution of cognitive status included: cognitively intact (38%), cognitively impaired (27%), or demented (35%). All subjects underwent MRI and 41% were classified as having subcortical lacunes. MRI measures included cortical gray and white matter volumes, lacunar volumes in subcortical white and gray matter structures, volume of white matter hyperintensities, and total hippocampal volume. Depressed mood, anhedonia, anergia, and apathy apparent at the time of assessment were assessed using a behavioral assessment Associations between neuropsychiatric symptoms and MRI variables were evaluated using logistic regression. Results Subjects with neuropsychiatric symptoms were more likely to be cognitively impaired or demented than those without neuropsychiatric symptoms. In multivariate models controlling for cognitive status, age, gender, and education, higher lacunar volume in white matter was independently associated with the presence of all four neuropsychiatric symptoms. Conclusions We report an association between the lacunar volumes in the white matter and depressed mood, anhedonia, apathy, and anergia, thus supporting the role of subcortical ischemic vascular disease in the pathogenesis of late‐life neuropsychiatric disorders. Copyright © 2008 John Wiley &amp; Sons, Ltd.