Po H. Lu

<h3>Background</h3> Imaging and postmortem studies provide converging evidence that, beginning in adolescence, gray matter volume declines linearly until old age, while cerebrospinal fluid volumes are stable in adulthood (age 20-50 years). Given the fixed volume of the cranium in adulthood, it is surprising that most studies observe no white matter volume expansion after approximately age 20 years. We examined the effects of the aging process on the frontal and temporal lobes. <h3>Methods</h3> Seventy healthy adult men aged 19 to 76 years underwent magnetic resonance imaging. Coronal images focused on the frontal and temporal lobes were acquired using pulse sequences that maximized gray vs white matter contrast. The volumes of total frontal and temporal lobes as well as the gray and white matter subcomponents were evaluated. <h3>Results</h3> Age-related linear loss in gray matter volume in both frontal (<i>r</i>= −0.62,<i>P</i>&lt;.001) and temporal (<i>r</i>= −0.48,<i>P</i>&lt;.001) lobes was confirmed. However, the quadratic function best represented the relationship between age and white matter volume in the frontal (<i>P</i>&lt;.001) and temporal (<i>P</i>&lt;.001) lobes. Secondary analyses indicated that white matter volume increased until age 44 years for the frontal lobes and age 47 years for the temporal lobes and then declined. <h3>Conclusions</h3> The changes in white matter suggest that the adult brain is in a constant state of change roughly defined as periods of maturation continuing into the fifth decade of life followed by degeneration. Pathological states that interfere with such maturational processes could result in neurodevelopmental arrests in adulthood.

Human and non-human primate data suggest that the structural integrity of myelin sheaths deteriorates during normal aging, especially in the late-myelinating association regions and may result in "disconnection" of widely distributed neural networks. Magnetic resonance imaging (MRI) was used to assess the heterogeneity of this process and its impact on brain aging and Alzheimer's disease (AD) by evaluating early- and later-myelinating regions of the corpus callosum, the splenium (Scc) and genu (Gcc), respectively. Calculated transverse relaxation rates (R2), an indirect measure of white matter structural integrity for the Gcc and Scc, were examined. The relationship between age and R2 differed in the two regions. A quadratic (inverted U) function with an accelerating rate of decline beginning at age 31 best represented the Gcc pattern while the Scc decline was three-fold smaller, gradual, and linear. These data suggest that the severity of age-related myelin breakdown is regionally heterogeneous, consistent with the hypothesis that differences in myelin properties make later-myelinating regions more susceptible to this process. In AD this process is globally exacerbated, consistent with an extracellular deleterious process such as amyloid beta-peptide toxicity. Non-invasive measures such as R2 may be useful in primary prevention studies of AD.

Brain iron promotes oxidative damage and protein oligomerization that result in highly prevalent age-related proteinopathies such as Alzheimer's disease (AD), Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB). Men are more likely to develop such diseases at earlier ages than women but brain iron levels increase with age in both genders. We hypothesized that brain iron may influence both the age- and gender-related risks of developing these diseases.The amount of iron in ferritin molecules (ferritin iron) was measured in vivo with MRI by utilizing the field dependent relaxation rate increase (FDRI) method. Ferritin iron was measured in four subcortical nuclei [caudate (C), putamen (P), globus pallidus (G), thalamus (T)], three white matter regions [frontal lobe (Fwm), genu and splenium of the corpus callosum (Gwm, Swm)] and hippocampus (Hipp) in 165 healthy adults aged 19-82.There was a high correlation (r>0.99) between published post-mortem brain iron levels and FDRI. There were significant age-related changes in ferritin iron (increases in Hipp, C, P, G, and decreases in Fwm). Women had significantly lower ferritin iron than men in five regions (C, T, Fwm, Gwm, Swm).This is the first demonstration of gender differences in brain ferritin iron levels. It is possible that brain iron accumulation is a risk factor that can be modified. MRI provides the opportunity to assess brain iron levels in vivo and may be useful in targeting individuals or groups for preventive therapeutic interventions.

Myelination of the human brain results in roughly quadratic trajectories of myelin content and integrity, reaching a maximum in mid-life and then declining in older age. This trajectory is most evident in vulnerable later myelinating association regions such as frontal lobes and may be the biological substrate for similar trajectories of cognitive processing speed. Speed of movement, such as maximal finger tapping speed (FTS), requires high-frequency action potential (AP) bursts and is associated with myelin integrity. We tested the hypothesis that the age-related trajectory of FTS is related to brain myelin integrity.A sensitive in vivo MRI biomarker of myelin integrity (calculated transverse relaxation rates (R(2))) of frontal lobe white matter (FLwm) was measured in a sample of very healthy males (N=72) between 23 and 80 years of age. To assess specificity, R(2) of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured.FLwm R(2) and FTS measures were significantly correlated (r=.45, p<.0001) with no association noted in the early-myelinating region (splenium). Both FLwm R(2) and FTS had significantly quadratic lifespan trajectories that were virtually indistinguishable and both reached a peak at 39 years of age and declined with an accelerating trajectory thereafter.The results suggest that in this very healthy male sample, maximum motor speed requiring high-frequency AP burst may depend on brain myelin integrity. To the extent that the FLwm changes assessed by R(2) contribute to an age-related reduction in AP burst frequency, it is possible that other brain functions dependent on AP bursts may also be affected. Non-invasive measures of myelin integrity together with testing of basic measures of processing speed may aid in developing and targeting anti-aging treatments to mitigate age-related functional declines.

Iron can catalyze damaging free radical reactions. With age, iron accumulates in brain gray matter regions and may contribute to the risk of developing age-related diseases such as Alzheimer's disease (AD). Prior MRI studies demonstrated increased iron deposits in basal ganglia regions; however, the hippocampus (Hipp), which is heavily damaged in AD, and comparator regions that are resistant to AD damage, such as thalamus (Th), have rarely been examined.To assess iron levels and evidence of tissue damage in Hipp and Th of AD subjects and healthy controls.Thirty-one AD and sixty-eight healthy control subjects participated in this study. High- and low-field strength MRI instruments were used in combination to quantify iron content of ferritin molecules (ferritin iron) using the field dependent relaxation rate increase (FDRI) method. Decreased transverse relaxation rate (R2) was used as an index of tissue damage.Compared with healthy controls, AD subjects had increased ferritin iron in Hipp (p = 0.019) but not Th (p = 0.637), and significantly decreased R2 in Hipp (p < 0.001) but not Th (p = 0.37). In the entire sample, FDRI and R2 were negatively correlated.The data shows that in AD, Hipp damage occurs in conjunction with ferritin iron accumulation. Prospective studies are needed to evaluate how increasing iron levels may influence the trajectory of tissue damage and cognitive and pathologic manifestations of AD.

Digit Span Age-Corrected Scaled Score (ACSS) and Reliable Digit Span (RDS) have been suggested as effective in assessing credibility. The purpose of this study was to confirm the efficacy of suggested cutoffs for ACSS and RDS and to explore the utility of other Digit Span variables in a large sample (N = 66) of "real-world" > or = suspect effort patients versus clinic patients with no motive to feign (N = 56) and controls (N = 32). With specificity at > or = 90%, sensitivity of ACSS increased from 32% to 42% when a < or = 5 cutoff was used instead of the recommended < or = 4. The RDS recommended cutoff of < or = 7 resulted in a sensitivity of 62% but with an unacceptably high false positive rate (23%); dropping the cutoff to < or = 6 raised the specificity to 93% but sensitivity fell to 45%. Cutoffs for other Digit Span scores did not exceed 45% sensitivity with the exception of 50% sensitivity (11% false positive rate) for average time per digit for all attempted items > 1.0 second. A criterion of ACSS < or = 5 or RDS < or = 6 was associated with 51% sensitivity (91% specificity) while RDS < or = 6 or longest string with at least one item correct < or = 4 was associated with 54% sensitivity (88% specificity). While only moderately sensitive, Digit Span scores, including new time variables, may have a unique and effective role in the detection of suspect effort.

Numerous publications on the Rey 15-item Memorization Test have cited limitations primarily in test sensitivity, as well as to some extent in specificity. In the current study, 49 patients with suspect effort, 36 neuropsychology clinic patients not in litigation or attempting to secure disability, 33 learning disabled college students, and 60 normal controls were administered the Rey Test in standard format followed by a recognition trial. A free recall score &lt;9 was found to have excellent specificity (97–100%), although sensitivity was modest (47%). However, use of a combined recall and recognition score (i.e., free recall+[recognition–false positives] &lt;20) substantially increased sensitivity (71%) while maintaining high specificity (=92%).

Neuropsychiatric disturbances are common in mild cognitive impairment (MCI). Depression and apathy may identify a subset of MCI subjects at higher risk of progression to Alzheimer's disease (AD). However, it remains uncertain whether a broader spectrum of psychopathology is associated with progression to AD.Fifty-one MCI subjects were assessed for neuropsychiatric symptoms using the Neuropsychiatric Inventory. Subjects were followed for an average of 2 years. Twelve subjects (23.5%) progressed from MCI to possible/probable AD and 39 subjects (76.5%) remained stable or improved. Baseline Neuropsychiatric Inventory indices were compared between groups.Subjects progressing to AD had a significantly higher prevalence of psychopathology than subjects who remained stable or improved (100 vs. 59%). Depression (67 vs. 31%) and apathy (50 vs. 18%) were more common in subjects who were later diagnosed with AD. After statistical adjustments for other baseline demographic variables, these specific symptoms were less robust predictors of progression to AD than the presence of any psychopathology.These findings suggest that neuropsychiatric symptoms in MCI are a predictor of progression to AD. Depression and apathy appear to be most useful for identifying MCI subjects at highest risk of developing dementia.

There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD).To evaluate the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with mild AD and healthy elderly men.Twenty-four-week, randomized, double-blind, placebo-controlled, parallel-group study.Memory disorders clinics as well as general neurology and medicine clinics from University of California medical centers at Los Angeles, San Francisco, and Irvine.Sixteen male patients with AD and 22 healthy male control subjects. Healthy elderly control men were recruited from the community through advertisements as well as through the university-based clinics.Testosterone and placebo, in the form of hydroalcoholic gel (75 mg), were applied daily to the skin of the participants.Instruments assessing cognitive functioning (Alzheimer's Disease Assessment Scale-Cognitive Subscale, California Verbal Learning Test, Block Design Subtest, Judgment of Line Orientation, Developmental Test of Visual-Motor Integration), neuropsychiatric symptoms (Neuropsychiatric Inventory), global functioning (Clinician's Interview-Based Impression of Change), and quality of life (Quality of Life-Alzheimer Disease Scale).For the patients with AD, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale (P = .01). No significant treatment group differences were detected in the cognitive scores at end of study, although numerically greater improvement or less decline on measures of visuospatial functions was demonstrated with testosterone treatment compared with placebo. In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group (P = .09) compared with placebo treatment. No difference between the treatment groups was detected in the remaining outcome measures. Testosterone treatment was well tolerated with few adverse effects relative to placebo.Results suggest that testosterone replacement therapy improved overall quality of life in patients with AD. Testosterone had minimal effects on cognition.

Tissue iron can promote oxidative damage. Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Higher iron levels in males may contribute to higher risk for younger-onset PD and recent studies have linked the presence of the hemochromatosis gene with a younger age at onset of AD. We examined whether age at onset of PD and AD was associated with increased brain ferritin iron. Ferritin iron can be measured with specificity in vivo with MRI utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in three basal ganglia regions (caudate, putamen, and globus pallidus) and frontal lobe white matter for younger- and older-onset male PD and AD patients and healthy controls. Significant increases in basal ganglia FDRI levels were observed in the younger-onset groups of both diseases compared to their respective control groups, but were absent in the older-onset patients. The results support the suggestion that elevated ferritin iron and its associated toxicity is a risk factor for age at onset of neurodegenerative diseases such as AD and PD. Clinical phenomena such as gender-associated risk of developing neurodegenerative diseases and the age at onset of such diseases may be associated with brain iron levels. In vivo MRI can measure and track brain ferritin iron levels and provides an opportunity to design therapeutic interventions that target high-risk populations early in the course of illness, possibly even before symptoms appear.

To assess the relationship between performance- and informant-based measures of activities of daily living (ADLs) in patients with early dementia and burden or psychological distress experienced by the patients' caregivers.Descriptive study.Ambulatory center.Thirty-four patient-caregiver dyads in which the patient had mild dementia (Mini-Mental State Examination score >17).A performance-based ADL measure (the Direct Assessment of Functional Status (DAFS)) was administered to patients with mild dementia. Caregivers completed an informant-based measure of patient functional status (instrumental activities of daily living). Caregivers also completed the Caregiver Burden Inventory (CBI) and the Brief Symptom Inventory (BSI).Significant correlations were found between the informant-based ADL measure and caregiver burden (CBI) and psychological distress (BSI) (correlation coefficient (r)=-0.34 to -0.71, all P<.05). Alternatively, fewer and weaker relationships were observed between the DAFS (performance-based) ADL measure and caregiver burden or distress ratings (r=-0.32 to -0.43, all P<.05). Of the seven tasks assessed using the DAFS, impairments in orientation, communication, financial, and transportation skills in patients were associated with greater time and developmental burden and greater hostility in caregivers. Impairment in financial skills in patients was the strongest predictor of time-dependence burden and hostility in caregivers, whereas impairment in patient transportation skills was the best predictor of developmental burden.The ADL abilities of cognitively impaired patients can predict caregiver burden and psychological distress, with informant-based measures having the greatest association with patient impairment.

<h3>Background</h3> The efficacy and safety of risperidone was evaluated in veteran patients with chronic combat-related posttraumatic stress disorder (PTSD) who were referred to a residential treatment program. <h3>Methods</h3> Seventy-three subjects volunteered to participate in this double-blind, placebo-controlled study, which comprised of a 5 week residential program followed by a 3-month outpatient follow-up. Risperidone was added to a stable psychotropic medication regimen in 92% of subjects. Primary outcome measures were the Clinician-Administered PTSD scale (CAPS-total) and its three subscales; B (Re-experiencing), C (Avoidance) and D (Arousal). Secondary outcome measures were the Hamilton Anxiety (HAM-A) and Depression (HAM-D) scales, and the Positive and Negative Syndrome Scale, Positive Subscale (PANSS-P). <h3>Results</h3> Sixty-five subjects were randomized and 48 completed the 4-month study. Significantly greater improvement in symptoms was observed in subjects receiving risperidone compared to placebo on the CAPS-total and CAPS-D subscale scores and also on HAM-A and PANSS-P. Numerically greater improvements in all the remaining measures were noted with risperidone, but the differences did not reach statistical significance. Risperidone was well tolerated. <h3>Conclusions</h3> These results suggest that adjunctive risperidone improved a broad range of psychiatric symptoms in patients with chronic combat-related PTSD. The data support the concept that atypical antipsychotic medications may have a wider therapeutic spectrum that goes beyond the treatment of psychosis.

Current criteria for mild cognitive impairment (MCI) require “essentially intact” performance of activities of daily living (ADLs), which has proven difficult to operationalize. We sought to determine how well the Functional Activities Questionnaire (FAQ), a standardized assessment of instrumental ADLs, delineates the clinical distinction between MCI and very mild Alzheimer disease (AD). We identified 1801 individuals in the National Alzheimer's Coordinating Center Uniform Data Set with MCI (n=1108) or very mild AD (n=693) assessed with the FAQ and randomized them to the development or test sets. Receiver-operator curve (ROC) analysis of the development set identified optimal cut-points that maximized the sensitivity and specificity of FAQ measures for differentiating AD from MCI and were validated with the test set. ROC analysis of total FAQ scores in the development set produced an area under the curve of 0.903 and an optimal cut-point of 5/6, which yielded 80.3% sensitivity, 87.0% specificity, and 84.7% classification accuracy in the test set. Bill paying, tracking current events, and transportation (P's<0.005) were the FAQ items of greatest diagnostic utility. These data suggest that the FAQ exhibits adequate sensitivity and specificity when used as a standardized assessment of instrumental ADLs in the diagnosis of AD versus MCI.

Past studies indicate that patients with incentive to fake neuropsychological symptoms are likely to have lower finger tapping scores than credible patients. The present study builds upon past research by investigating finger tapping performance for seven groups: (a) noncredible patients (as determined by failed psychometric and behavioral criteria), and patients with (b) closed head injury, (c) dementia, (d) mental retardation, (e) psychosis, or (f) depression, and (g) healthy older controls. Results showed that men tapped faster than women, requiring that groups be divided by gender. Noncredible male and female patients tapped slower than their comparison group counterparts. Dominant hand score proved to be more sensitive to noncredible performance than other scores (nondominant, sum of both hands, difference between dominant and nondominant), especially for women. Sensitivity, specificity, and positive and negative predictive value tables are presented. With specificity set at 90% for the comparison groups combined, a dominant hand cutoff score of </=35 for men yielded 50% sensitivity, while a score of </=28 yielded 61% sensitivity for women. Specificity values for specific cutoff scores varied significantly across the comparison groups, indicating that cutoffs should be adjusted for the particular differential diagnosis. In conclusion, results indicate that when using finger tapping scores to detect noncredible performance: (a) Dominant hand performance is more sensitive, and (b) cutoffs should be selected based on gender and claimed diagnosis.

Postmortem and volumetric imaging data suggest that brain myelination is a dynamic lifelong process that, in vulnerable late-myelinating regions, peaks in middle age. We examined whether known regional differences in axon size and age at myelination influence the timing and rates of development and degeneration/repair trajectories of white matter (WM) microstructure biomarkers.Healthy subjects (n = 171) 14-93 years of age were examined with transverse relaxation rate (R(2)) and four diffusion tensor imaging measures (fractional anisotropy [FA] and radial, axial, and mean diffusivity [RD, AxD, MD, respectively]) of frontal lobe, genu, and splenium of the corpus callosum WM (FWM, GWM, and SWM, respectively).Only R(2) reflected known levels of myelin content with high values in late-myelinating FWM and GWM regions and low ones in early-myelinating SWM. In FWM and GWM, all metrics except FA had significant quadratic components that peaked at different ages (R(2) < RD < MD < AxD), with FWM peaking later than GWM. Factor analysis revealed that, although they defined different factors, R(2) and RD were the metrics most closely associated with each other and differed from AxD, which entered into a third factor.The R(2) and RD trajectories were most dynamic in late-myelinating regions and reflect age-related differences in myelination, whereas AxD reflects axonal size and extra-axonal space. The FA and MD had limited specificity. The data suggest that the healthy adult brain undergoes continual change driven by development and repair processes devoted to creating and maintaining synchronous function among neural networks on which optimal cognition and behavior depend.

Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and may be a marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Thus, we examined the neuroanatomical changes associated with depressive symptoms in MCI.Two-hundred forty-three MCI subjects from the Alzheimer's Disease Neuroimaging Initiative who had brain magnetic resonance imaging scans at baseline and 2-year follow-up were classified into depressed (n = 44), nondepressed with other neuropsychiatric symptoms (n = 93), and no-symptom (NOSYMP; n = 106) groups based on the Neuropsychiatric Inventory Questionnaire. Tensor-based morphometry was used to create individual three-dimensional maps of 2-year brain changes that were compared between groups.Depressed subjects had more frontal (p = .024), parietal (p = .030), and temporal (p = .038) white matter atrophy than NOSYMP subjects. Those whose depressive symptoms persisted over 2 years also had higher conversion to AD and more decline on measures of global cognition, language, and executive functioning compared with stable NOSYMP subjects. Nondepressed with other neuropsychiatric symptoms and NOSYMP groups exhibited no differences in rates of atrophy.Depressive symptoms were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes, including prodromal AD, and may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD.

We hypothesized that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte- and myelin-associated iron that promotes amyloid beta (A beta) oligomerization, its associated toxicity, and the deposition of oligomerized A beta and iron in neuritic plaques observed in Alzheimer's disease (AD). The model was tested by using published maps of cortical myelination from 1901 and recent in vivo imaging maps of A beta deposits in humans. The data show that in AD, radiolabeled ligands detect A beta deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the strikingly lower ability of this imaging ligand to bind A beta in animal models is consistent with the much lower levels of myelin and associated iron levels in rodents when compared with humans. The hypotheses derived from the "myelin model" are testable with current imaging methods and have important implications for therapeutic interventions that should be expanded to include novel targets such as oligodendrocytes, myelin, and brain iron.

To determine whether quality-of-life (QOL) ratings are reduced in mild cognitive impairment (MCI) and analyze correlations between QOL ratings and cognitive, neuropsychiatric, and functional indices in MCI.Cross-sectional.The Easton Center for Alzheimer's Disease Research at the University of California, Los Angeles.A total of 205 individuals who met criteria for normal cognition (n = 97) or MCI (n = 108). The MCI group included amnestic (n = 72) and nonamnestic (n = 36) MCI.QOL was assessed using subject and informant ratings on the Quality of Life-Alzheimer's Disease (QOL-AD) scale. Cognitive performance was assessed with the National Alzheimer's Disease Coordinating Center Uniform Data Set neuropsychological battery. Neuropsychiatric symptoms were assessed with the Geriatric Depression Scale (GDS) and the Neuropsychiatric Inventory. Functional abilities were assessed with the Functional Activities Questionnaire (FAQ).The normal cognition group had significantly higher QOL-AD scores than the MCI group on both subject and informant assessments. Individual item analyses indicated that the largest group differences were seen on the mood and memory items. Similar QOL-AD scores were seen in the amnestic and nonamnestic MCI subgroups. Multiple regression analyses within the MCI group indicated that QOL-AD ratings were not correlated with neuropsychological performance. Subject QOL-AD ratings were inversely correlated with GDS scores and informant QOL-AD ratings were inversely correlated with GDS, Neuropsychiatric Inventory, and FAQ scores.Significant declines in QOL are seen in MCI and are associated with neuropsychiatric symptoms and functional decline. Interventions targeting mood symptoms and/or instrumental activities of daily living may improve QOL in MCI.

Performance on measures of cognitive processing speed (CPS) slows with age, but the biological basis associated with this cognitive phenomenon remains incompletely understood. We assessed the hypothesis that the age-related slowing in CPS is associated with myelin breakdown in late-myelinating regions in a very healthy elderly population. An in vivo magnetic resonance imaging (MRI) biomarker of myelin integrity was obtained from the prefrontal lobe white matter and the genu of the corpus callosum for 152 healthy elderly adults. These regions myelinate later in brain development and are more vulnerable to breakdown due to the effects of normal aging. To evaluate regional specificity, we also assessed the splenium of the corpus callosum as a comparison region, which myelinates early in development and primarily contains axons involved in visual processing. The measure of myelin integrity was significantly correlated with CPS in highly vulnerable late-myelinating regions but not in the splenium. These results have implications for the neurobiology of the cognitive changes associated with brain aging.

The Rey-Osterrieth Complex Figure Test (ROCFT) is a popular measure of visuoconstructive skills and visual memory. A recognition memory trial was recently developed by Meyers and Meyers (1995) and attached to the standard administration of the ROCFT. The addition of this recognition paradigm (comprised of 12 small designs from the original ROCFT stimulus interspersed among 12 foils) makes ROCFT a potentially useful instrument in capturing suspect effort because patients attempting to feign memory difficulties typically operate from the misconception that recognition memory is as impaired as free recall in brain injury and, as a result, suppress recognition performance. The ROCFT (copy, immediate recall [i.e., 3-min recall], and the recognition trial) was administered to four sets of participants: 58 patients with suspect effort; 23 neuropsychology clinic patients with verbal memory impairment, 17 clinic patients with visual memory impairment, and 30 clinic patients without memory impairment. Group comparisons revealed significant group differences in direct copy, immediate recall, and recognition scores of the ROCFT (p &lt;.0001), with the suspect effort group displaying significantly lower performance on the copy and immediate recall scores than the verbal memory impaired and nonmemory impaired clinic patient groups, and significantly lower recognition scores than all three clinical groups. Furthermore, qualitative examination of the recognition trial revealed the presence of “atypical recognition errors” that were endorsed with significantly higher frequency by the suspect effort patients. A combination score incorporating the copy, true positive recognition, and atypical recognition error scores yielded a sensitivity of 74% while misclassifying only approximately 4% of verbal memory impaired clinic patients, 12% of visual memory impaired clinic patients, and 3% of nonmemory impaired clinic patients. Thus, the ROCFT + recognition trial show considerable potential for detecting noncredible effort.

Apolipoprotein E (APOE) genotype is the most influential Alzheimer disease (AD) risk factor after advanced age. The APOE4 alleles decrease and the APOE2 alleles increase age at onset of AD. Human and nonhuman primate data suggest that in midlife, the structural integrity of myelin sheaths begins breaking down, with an accelerating age-related trajectory most evident in the brain's later-myelinating association regions. This may result in a progressive "disconnection" of widely distributed neural networks that may underlie the age risk factor for AD.To assess, using magnetic resonance imaging, whether the shift in age at onset of AD observed with the APOE genotype is associated with the trajectory of age-related myelin breakdown.Cross-sectional.Metropolitan university medical center.Healthy individuals (N = 104) aged 55 to 75 years who underwent genotyping for APOE.Calculated transverse relaxation rates, an indirect measure of white matter structural integrity, for late-myelinating frontal lobe white matter (Fwm) and early- and later-myelinating regions of the corpus callosum, the splenium (Swm) and the genu (Gwm).The presence of the protective APOE2 allele was associated with significantly higher relaxation rates in Fwm and Gwm but not in Swm. Furthermore, APOE status impacted the trajectory of age-related myelin breakdown in late-myelinating regions (Fwm and Gwm) but not in Swm. In Fwm and Gwm, APOE4+ individuals had a steeper slope of decline in relaxation rates with age than APOE2+ individuals; those with APOE3/3 alleles had an intermediate slope.In later-myelinating regions, the severity and rate of myelin breakdown in healthy older individuals are associated with APOE status and support the hypothesis that this process may contribute to age at onset of AD. Combining APOE status with noninvasive measures of myelin breakdown may be useful in assessing treatment strategies for the primary prevention of AD.

Abstract There is very little research regarding the relationship between tests of executive functioning and actual functional ability in patients with dementia. Thirty-three patients diagnosed with dementia and 35 age- and education-matched healthy controls were administered tests of executing functioning and an observation- and informant-based activities of daily living (ADL). As expected, the results revealed that the controls outperformed the dementia patients on the executive and ADL tests. Additionally, executive functioning correlated significantly with aspects of functional ability in patients with dementia. This relationship was strongest for tests of verbal fluency and a complex test of cognitive flexibility and reasoning ability (i.e., Wisconsin Card Sorting Test). These findings suggest that some executive function tests are more sensitive than others for predicting specific functional abilities and that they may be most useful to healthcare professionals for treatment planning. Key words: activities of daily livingAlzheimer's diseasedementiaexecutive functioningfunctional ability ACKNOWLEDGMENTS This study was supported by NIGMS grant S06GM048680 to JR. Additional support for the project was provided by NIGMS grants GM63787 (Minority Biomedical Research Support Program—Research Initiative for Scientific Enhancement) & GM08395 (Minority Access to Research Career). Notes MMSE = Mini Mental State Examination; D-KEFS = Delis-Kaplan Executive Function System; TMT = Trail Making Test; WCST = Wisconsin Card Sorting Test; DAFS = Direct Assessment of Functional Status; I-ADL = Instrumental Activities of Daily Living. a p ≤ .025 b p ≤ .01 c p ≤ .001 I-ADL = Instrumental Activities of Daily Living; MMSE = Mini Mental State Exam; D-KEFS = Delis-Kaplan Executive Function System; TMT = Trail Making Test; WCST = Wisconsin Card Sorting Test. ∗p < .05 ∗∗p < .01 ∗∗∗p < .001 I-ADL = Instrumental Activities of Daily Living; DAFS = Direct Assessment of Functional Status; WCST = Wisconsin Card Sorting Test; D-KEFS = Delis-Kaplan Executive Function System.

Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 +/- 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group x time interactions.

Age-related myelin breakdown is most evident in later-myelinating white matter (LMwm) brain regions. This process might degrade cognitive processing speed (CPS) underlying age-related cognitive decline and the predominance of age as a risk factor for Alzheimer's disease (AD). Apolipoprotein E (ApoE) 4 allele is the second most important AD risk factor. We tested the hypothesis that ApoE4 accelerates age-related slowing in CPS through the process of myelin breakdown.Calculated transverse relaxation rates (R(2)), an indirect magnetic resonance imaging measure of myelin breakdown in LMwm, and measures of CPS were obtained in 22 ApoE4+ and 80 ApoE4-, healthy "younger-old" individuals. To assess specificity, contrasting early-myelinating white matter region and memory task were also examined.The CPS versus LMwm R(2) remained significant in the ApoE4+ group even after age was statistically adjusted (r = .65, p = .001) and differed from the correlation observed in the ApoE4- group (Fisher's z test = 3.22, p < .002). No significant associations were observed with the contrast region and memory task in either ApoE subgroup.A specific association between CPS and myelin breakdown in LMwm exists in asymptomatic "younger-old" individuals at increased genetic risk for AD. Although inferences of change over time and causality are limited by the cross-sectional study design, this finding lends support to the hypotheses that myelin breakdown underlies age-related slowing in CPS and that by altering the trajectory of myelin breakdown, ApoE alleles shift the age at onset of cognitive decline. Combined use of biomarkers and CPS measures might be useful in developing and targeting primary prevention treatments for AD.

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON-) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON- status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=-0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON- group (r=-0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

Imaging and post-mortem studies provide converging evidence that subjects with schizophrenia (SZ) have a dysregulated trajectory of frontal lobe myelination. Prior MRI studies suggested that early in treatment of SZ, antipsychotic medications initially increase frontal lobe white matter (WM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of WM decline associated with chronic disease may be due to medication non-adherence, it may be modifiable by long acting injection (LAI) formulations.Examine the impact of antipsychotic formulation on the myelination trajectory during a randomized six-month trial of LAI risperidone (RLAI) versus oral risperidone (RisO) in first-episode SZ subjects.Two groups of SZ subjects (RLAI, N=11; and RisO, N=13) that were matched in pre-randomization oral medication exposure and 14 healthy controls (HCs) were prospectively examined. Frontal lobe WM volume was estimated using inversion recovery (IR) MRI images. A brief neuropsychological battery that focused on reaction times was performed at the end of the study.WM volume change scores.WM volume remained stable in the RLAI and decreased significantly in the RisO groups resulting in a significant differential treatment effect, while the HC had a WM change intermediate and not significantly different from the two SZ groups. WM increase was associated with faster reaction times in tests involving frontal lobe function.The results suggest that RLAI may improve the trajectory of myelination in first-episode patients and have a beneficial impact on cognitive performance. Better adherence provided by LAI may underlie the modified trajectory of myelin development. In vivo MRI biomarkers of myelination can help clarify mechanisms of action of treatment interventions.

To assess the hypothesis that in a sample of very healthy elderly men selected to minimize risk for Alzheimer’s disease (AD) and cerebrovascular disease, myelin breakdown in late-myelinating regions mediates age-related slowing in cognitive processing speed (CPS). The prefrontal lobe white matter and the genu of the corpus callosum myelinate later in brain development (late-myelinating white matter; LMWM) and are more vulnerable to breakdown due to the effects of normal aging. An in vivo MRI biomarker of myelin integrity (transverse relaxation rates; R2) of LMWM was obtained for 38 very healthy elderly adult men (mean age = 66.3 years; SD = 6.0; range = 55–76). To evaluate regional specificity, we also assessed a contrasting early-myelinating region (splenium of the corpus callosum; SWM), which primarily contains axons involved in visual processing. CPS was assessed using the Trail Making Test. LMWM R2 and CPS measures were significantly correlated (r = .515, p = .0009), but no significant association between R2 and CPS was detected in the splenium (p = .409). LMWM R2, but not SWM R2, was a significant mediator of the relationship between age and CPS (p = .037). In this very healthy elderly sample, age-related slowing in CPS is mediated by myelin breakdown in highly vulnerable late-myelinating regions but not in the splenium.

Greater cognitive and functional deficits in mild cognitive impairment (MCI) are associated with higher rates of dementia. We explored the relationship between these factors by comparing instrumental activities of daily living (IADLs) among cognitive subtypes of MCI and examining associations between IADL and neuropsychological indices.We analyzed data from 1,108 MCI and 3,036 normal control subjects included in the National Alzheimer's Coordinating Center Uniform Data Set who were assessed with the Functional Activities Questionnaire (FAQ).IADL deficits were greater in amnestic than nonamnestic MCI, but within these subgroups, did not differ between those with single or multiple domains of cognitive impairment. FAQ indices correlated significantly with memory and processing speed/executive function.IADL deficits are present in both amnestic MCI and nonamnestic MCI but are not related to the number of impaired cognitive domains. These cross-sectional findings support previous longitudinal reports suggesting that cognitive and functional impairments in MCI may be independently associated with dementia risk.

Imaging and post-mortem studies suggest that frontal lobe intracortical myelination is dysregulated in schizophrenia (SZ). Prior MRI studies suggested that early in the treatment of SZ, antipsychotic medications initially increase frontal lobe intracortical myelin (ICM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of ICM decline in chronic SZ is due to medication non-adherence or pharmacokinetics, it may be modifiable by long acting injection (LAI) formulations. Assess the effect of risperidone formulation on the ICM trajectory during a six-month randomized trial of LAI (RLAI) versus oral (RisO) in first-episode SZ subjects. Two groups of SZ subjects (RLAI, N = 9; and RisO, N = 13) matched on pre-randomization oral medication exposure were prospectively examined at baseline and 6 months later, along with 12 healthy controls (HCs). Frontal lobe ICM volume was assessed using inversion recovery (IR) and proton density (PD) MRI images. Medication adherence was tracked. ICM volume change scores were adjusted for the change in the HCs. ICM volume increased significantly (p = .005) in RLAI and non-significantly (p = .39) in the RisO groups compared with that of the healthy controls. A differential between-group treatment effect was at a trend level (p = .093). SZ subjects receiving RLAI had better medication adherence and more ICM increases (chi-square p < .05). The results suggest that RLAI may promote ICM development in first-episode SZ patients. Better adherence and/or pharmacokinetics provided by LAI may modify the ICM trajectory. In vivo MRI myelination measures can help clarify pharmacotherapeutic mechanisms of action.

Children and adolescents with Klinefelter syndrome (XXY) have been reported to show deficits in language processing including VIQ < PIQ and a learning disability in reading and spelling. However, whether this is characteristic of adults with Klinefelter syndrome has not been established. Thirty-five men with Klinefelter syndrome, aged 16 to 61, and 22 controls were evaluated with a comprehensive neuropsychological battery. The Klinefelter patients scored significantly below controls in language skills, verbal processing speed, verbal and nonverbal executive abilities, and motor dexterity. Within the Klinefelter sample, three cognitive subgroups were identified: VIQ 7 or more points below PIQ (n = 10), VIQ within 6 points of PIQ (n = 12), and PIQ 7 or more points below VIQ (n = 12). The deficits detected in language, verbal processing speed, and verbal executive skills were found to be isolated to the VIQ < PIQ subgroup, while the abnormalities in motor dexterity and nonverbal executive skills were confined to the PIQ < VIQ subgroup. Older age was significantly correlated with increases in VIQ relative to PIQ in the patient group, which suggests the intriguing possibility that the PIQ < VIQ subgroup primarily emerges in young adulthood, perhaps in response to the reported hormonal abnormalities detected in Klinefelter syndrome patients during puberty.

Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination even in adulthood. Atypical antipsychotics have been shown to have a wide spectrum of efficacy across multiple psychiatric diseases and to be particularly efficacious in treatment resistant cases of disorders such as schizophrenia.To test the a priori hypothesis that antipsychotic medications may differentially impact frontal lobe myelination in patients with schizophrenia.Participants ranged in age from 18-35 years, were all male, and were recruited by a single group of investigators using the same criteria. Two cohorts of subjects with schizophrenia early in their disease who were treated either with oral risperidone (Ris) or fluphenazine decanoate (Fd) were imaged in conjunction with cohorts of healthy controls. Each cohort was imaged using a different MRI instrument using identical imaging sequences.MRI measures of frontal lobe white matter volume.We estimated differences due to differences in the MRI instruments used in the two studies in the two healthy control groups matched to the patient samples, adjusting for age and other covariates. We then statistically removed those differences (which we assumed were due to instrument effects) from the data in the schizophrenia samples by subtraction. Relative to the differences seen in controls, the two groups of schizophrenic patients differed in their pattern of frontal lobe structure with the Ris-treated group having significantly larger white matter volume than the Fd group.The results suggest that the choice of antipsychotic treatment may differentially impact brain myelination in adults with schizophrenia. Prospective studies are needed to confirm this finding. MRI can be used to dissect subtle differences in brain tissue characteristics and thus could help clarify the effect of pharmacologic treatments on neurodevelopmental and pathologic processes in vivo.

Previous studies have recommended that multiple measures be employed concurrently to provide converging evidence regarding the presence of suspect effort during neuropsychological assessment. However, if the tests are highly correlated they do not represent independent sources of information. To date, no study has examined correspondence between effort tests. The present study assessed the relationships between eight measures which can be used to assess effort (Rey 15-item, Rey Dot Counting Test, Rey Word Recognition Test, RAVLT recognition trial, Rey-Osterrieth Complex Figure Test effort equation, Digit Span, Warrington Recognition Memory Test-Words, and "b" Test) in a sample of 105 patients in litigation or attempting to obtain/maintain disability compensation and who displayed noncredible symptoms based on psychometric performance and behavioral criteria. Modest to moderate correlations were observed between test summary scores with only two measures sharing more than 50% score variance (Digit Span and Dot Counting). Moderate correlations were also observed between individual test scores reflecting indices of response time, free recall, recognition, and false positive errors, providing possible evidence that patients may use specific strategies when producing noncredible performances. Overall the results suggest that the use of these various tests generally provides nonredundant data regarding patient credibility in neuropsychological evaluations.

Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination. The hypothesis that typical and atypical medications may differentially impact brain myelination in adults with schizophrenia was previously assessed with inversion recovery (IR) images. Increased white matter (WM) volume suggestive of increased myelination was detected in the patient group treated with an atypical antipsychotic compared to a typical one. In a follow-up reanalysis of MRI images from the original study, we used a novel method to assess whether the difference in WM volumes could be caused by a differential effect of medications on the intracortical myelination process. Two different male cohorts of healthy controls ranging in age from 18–35 years were compared to cohorts of subjects with schizophrenia who were treated with either oral risperidone (Ris) or fluphenazine decanoate (Fd). A novel MRI method that combines the distinct tissue contrasts provided by IR and proton density (PD) images was used to estimate intracortical myelin (ICM) volume. When compared with their pooled healthy control comparison group, the two groups of schizophrenic patients differed in the frontal lobe ICM measure with the Ris group having significantly higher volume. The data suggest that in adults with schizophrenia antipsychotic treatment choice may be specifically and differentially impacting later-myelinating intracortical circuitry. In vivo MRI can be used to dissect subtle differences in brain tissue characteristics and thus help clarify the effect of pharmacologic treatments on developmental and pathologic processes.

We investigated the associations between Boston naming and the animal fluency tests and cortical atrophy in 19 probable AD and 5 multiple domain amnestic mild cognitive impairment patients who later converted to AD. We applied a surface-based computational anatomy technique to MRI scans of the brain and then used linear regression models to detect associations between animal fluency and Boston Naming Test (BNT) performance and cortical atrophy. The global permutation-corrected significance for the maps associating BNT performance with cortical atrophy was p=.0124 for the left and p=.0196 for the right hemisphere and for the animal fluency maps p=.055 for the left and p=.073 for the right hemisphere. The degree of language impairment correlated with cortical atrophy in the left temporal and parietal lobes (BA 20, 21, 37, 39, 40, and 7), bilateral frontal lobes (BA 8, 9, and 44) and the right temporal pole (BA 38). Using a novel 3D mapping technique, we demonstrated that in AD language abilities are strongly influenced by the integrity of the perisylvian cortical regions.

Apolipoprotein E (ApoE) ε4 genotype is a strong risk factor for developing Alzheimer's disease (AD). Conversely, the presence of the ε2 allele has been shown to mitigate cognitive decline. Tensor-based morphometry (TBM), a novel computational approach for visualizing longitudinal progression of brain atrophy, was used to determine whether cognitively intact elderly participants with the ε4 allele demonstrate greater volume reduction than those with the ε2 allele. Healthy "younger elderly" volunteers, aged 55-75, were recruited from the community and hospital staff. They were evaluated with a baseline and follow-up MRI scan (mean scan interval = 4.72 years, s.d. = 0.55) and completed ApoE genotyping. Twenty-seven participants were included in the study of which 16 had the ε4 allele (all heterozygous ε3ε4 genotype) and 11 had the ε2ε3 genotype. The two groups did not differ significantly on any demographic characteristics and all subjects were cognitively "normal" at both baseline and follow-up time points. TBM was used to create 3D maps of local brain tissue atrophy rates for individual participants; these spatially detailed 3D maps were compared between the two ApoE groups. Regional analyses were performed and the ε4 group demonstrated significantly greater annual atrophy rates in the temporal lobes (p = 0.048) and hippocampus (p = 0.016); greater volume loss was observed in the right hippocampus than the left. TBM appears to be useful in tracking longitudinal progression of brain atrophy in cognitively asymptomatic adults. Possession of the ε4 allele is associated with greater temporal and hippocampal volume reduction well before the onset of cognitive deficits.

Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer's disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson's disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON- men (p=0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases.

This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria.

A Rey-Osterrieth Complex Figure Test (ROCFT) equation incorporating copy and recognition was found to be useful in detecting negative response bias in neuropsychological assessments (ROCFT Effort Equation; Lu, P. H., Boone, K. B., Cozolino, L., & Mitchell, C. (2003). Effectiveness of the Rey-Osterrieth Complex Figure Test and the Meyers and Meyers recognition trial in the detection of suspect effort. Clinical Neuropsychologist, 17, 426–440). In the current cross validation of this validity, the credible patient group (n = 146; 124 with equation data) outperformed the noncredible group (n = 157; 115 with equation data) on copy, 3-min recall, total recognition correct and the Effort Equation, but the latter was most effective in classifying subjects. A cut-off of ≤50 maintained specificity of 90% and achieved sensitivity of 80%. Results of the current cross validation provide corroboration that the ROCFT Effort Equation is an effective measure of neurocognitive response bias.

Objective Prior studies of US Hispanics, largely performed on the East Coast, have found a younger age of dementia onset than in White non‐Hispanics. We performed a cross‐sectional study to examine clinical and sociodemographic variables associated with age of dementia diagnosis in older Hispanics and White, non‐Hispanics in southern California. Methods Two hundred ninety (110 Hispanic and 180 White non‐Hispanic) community dwelling, cognitively symptomatic subjects, aged 50 years and older, were assessed and diagnosed with probable Alzheimer's disease or probable vascular dementia. Apolipoprotein E (APOE) genotype was assessed in a subset of cases. Analysis of variance and multiple stepwise linear regression were used to assess main effects and interactions of ethnicity with dementia severity (indexed by mini mental state examination scores) and other sociodemographic and clinical variables on age of dementia diagnosis. Results Hispanics were younger by an average of 4 years at the time of diagnosis, regardless of dementia subtype, despite a similar prevalence of the APOE ε4 genotype. The earlier age at diagnosis for Hispanics was not explained by gender, dementia severity, years of education, history of hypercholesterolemia, hypertension, or diabetes. Only ethnicity was significantly associated with age of onset. Conclusions These findings confirm that US Hispanics living in the southwestern USA tend to be younger at the time of dementia diagnosis than their White non‐Hispanic counterparts. As this is not explained by the presence of the APOE ε4 genotype, further studies should explore other cultural, medical, or genetic risk factors influencing the age of dementia onset in this population. Copyright © 2014 John Wiley &amp; Sons, Ltd.

Animal and human newborn studies suggest that exposure to cocaine in utero delays glial maturation and white matter myelination. Postmortem data show that in the frontal and temporal lobes, white matter myelination continues into middle age. Recent magnetic resonance imaging (MRI) data have confirmed continued white matter volume increase in these regions, reaching a maximum at age 47.Thirty-seven male cocaine dependent (CD) and 52 normal control subjects between ages 19 and 47 were evaluated with MRI. Coronal images focused on the frontal and temporal lobes were acquired using pulse sequences that maximized gray/white matter contrast.Highly significant positive correlations between white matter volume and age were observed in both the frontal and temporal lobes of the control group (r =.52, p =.0001 and r =.54, p =.0001, respectively); however, CD subjects did not demonstrate any age-related increase in white matter volume of the frontal (r = -.001; p =.99) and temporal (r = -.07; p =.67) lobes in this age range.The age-related expansion in white matter volume occurring in normal control subjects was absent in CD subjects. The findings suggest that in adults, cocaine dependence may arrest normal white matter maturation in the frontal and temporal lobes of addicts who continue using cocaine.

Cocaine and its metabolites can produce vasospasm. Cocaine-dependent (CD) patients are at increased risk for stroke, and a high frequency of brain perfusion defects has been observed in clinically asymptomatic CD subjects. This is the first controlled magnetic resonance imaging (MRI) study of clinically asymptomatic CD subjects.Two age-matched groups of male subjects (61 CD and 57 control) participated in the study. Subjects with a history of neurologic symptoms or major medical or neurologic illness, such as hypertension, diabetes, or significant head trauma, were excluded. The severity of hyperintense lesions observed on T2-weighted MRI images were rated on a 0-3-point scale by an experienced radiologist who was blind to all clinical data. Ratings of 3 were felt to be significant indicators of a possible disease process and were used in the data analysis. Three regions were separately rated: the cerebral white matter, subinsular white matter, and subcortical gray matter (basal ganglia and thalamus region).Despite the exclusion criteria minimizing risk factors for cerebrovascular events, 17 of the 61 (27.9%) CD subjects and 4 of 57 (7%) of the control subjects had severe hyperintense lesions suggestive of subclinical or "silent" anoxic vascular events. Significant group differences were observed in the two white matter regions but not in the subcortical gray matter region. The risk of severe white matter lesions in the CD group increased with age, reaching 50% in the oldest age quartile (46-58 years), and this increase was not related to the number of years cocaine was used.The data suggest that asymptomatic CD patients are a heterogeneous population with a significantly increased age-related risk of white matter neurovascular toxicity. Premature neurovascular damage may impact treatment outcomes and, as the CD population ages, may manifest as an increased incidence of cognitive deficits.

Myelin plays an essential role in brain structure and function and the human brain is uniquely dependent on the elaboration of this late invention of evolution. Our brain has the most extensive and protracted process of myelination that extends to approximately age 50 in cortical regions that have the highest risk for developing Alzheimer's disease (AD) pathology. This myelin-centered model of the human brain asserts that unique vulnerabilities of myelin, especially late-developed myelin, and the oligodendrocytes that produce it are directly pertinent to many uniquely human neuropsychiatric diseases including late-life neurodegenerative disorders such as AD. Magnetic resonance imaging (MRI) technology permits the in vivo assessment of the roughly quadratic (inverted U) lifelong trajectory of human myelin development and its subsequent breakdown. There is close agreement between neuropsychology, neuropathology, and imaging measures suggesting that the process of myelin breakdown begins in adulthood, accelerates as aging progresses, and underlies both age-related cognitive declines and the most powerful risk factor of dementia-causing disorders such as AD: age. This myelin-centered model together with the technology that makes it possible to measure the trajectory of myelin breakdown provide a framework for developing novel treatments, as well as assessing efficacy of currently available treatments, intended to slow or reverse the breakdown process in both clinically healthy as well as symptomatic populations. Such treatments can be expected to have a wide spectrum of efficacy and impact multiple human disease processes including potentially slowing brain aging and thus provide opportunities for primary prevention of age-related degenerative disorders such as AD.

The Mini-mental State Examination (MMSE) is a brief cognitive screening instrument frequently used to track Alzheimer disease (AD) progression. We investigated the structural neuroimaging correlates of MMSE performance in patients with clinical and preclinical AD. We analyzed structural magnetic resonance imaging data from 29 probable AD and 5 MCI patients who later converted to probable AD using an advanced 3D cortical mapping technique. MMSE scores were entered as covariates in a general linear model that predicted the gray matter density at each cortical surface point. The results were corrected for multiple comparisons by permutation testing. The global permutation-corrected significance for the maps linking gray matter loss and cognitive decline was P=0.005 for the left and P=0.012 for the right hemisphere. Strongest correlations between MMSE score and gray matter integrity were seen in the entorhinal, parahippocampal, precuneus, superior parietal, and subgenual cingulate/orbitofrontal cortices. Significant correlations were also seen bilaterally in the temporal, the middle frontal and the left angular and supramarginal gyri. As a global cognitive measure, MMSE depends on the integrity of widely distributed cortical areas in both brain hemispheres with left-sided predominance.

&lt;i&gt;Background:&lt;/i&gt; Patients with Alzheimer disease consistently demonstrate impaired performance on tests of facial emotion processing. However, it remains unclear how early in the neurodegenerative process these deficits emerge. &lt;i&gt;Methods:&lt;/i&gt; We approached this question by examining facial emotional processing in a ‘pre-dementia’ condition, amnestic mild cognitive impairment (MCI). Nine single-domain amnestic MCI subjects, 14 multiple-domain amnestic MCI subjects (MCI-MD), and 68 normal control subjects were assessed with the Florida Affect Battery. &lt;i&gt;Results:&lt;/i&gt; After adjustment for age and gender, analyses of performance across the facial affect processing subtests of the Florida Affect Battery demonstrated intact performance in the single-domain MCI group but significantly impaired performance in the MCI-MD group, particularly on a test of facial affect discrimination. Within the MCI-MD group, men performed disproportionately worse than women. Performance on facial affect discriminations in the MCI-MD group correlated most robustly with performance on tests of frontal/executive function. &lt;i&gt;Conclusion:&lt;/i&gt; These data suggest that facial emotion processing can be impaired in MCI prior to the more marked cognitive deficits seen with clinically diagnosed Alzheimer disease.

Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer's disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer's disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives.Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects.MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume.Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD.

The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups.Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects.Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology.The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.

Disproportionately greater deficits in semantic relative to phonemic verbal fluency are seen in Alzheimer's disease (AD) and have been attributed to neurodegenerative changes in the temporal lobe. Amnestic (AMN) mild cognitive impairment (MCI), which often represents incipient AD, is also characterized by early temporal lobe neuropathology, but previous comparisons of verbal fluency between AD and AMN MCI have yielded mixed results. We examined semantic and phonemic verbal fluency performance in 399 individuals (78 AD, 138 AMN MCI, 72 non-amnestic MCI, and 111 cognitively normal controls). Similar verbal fluency patterns were seen in AMN MCI and AD; both groups exhibited disproportionately poorer performance on semantic verbal fluency relative to normal controls. However, relative verbal fluency indices performed more poorly than individual semantic or phonemic verbal fluency indices for discriminating AMN MCI or AD participants from normal controls, suggesting that they are unlikely to provide additional utility for predicting progression from MCI to AD.

White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting.We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale for Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants.Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group.The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.

The Montreal Cognitive Assessment Chinese-Language Los Angeles version (MoCA-ChLA) was developed and administered during an in-home interview to 1,192 participants (mean age 62.5 years, mean education 11.6 years) in a population-based Chinese American Eye Study (CHES) in Los Angeles. The MoCA-ChLA score (mean ± SD) was 23.8 ± 4.2 with little ceiling and no floor effects. The score increased with higher education, decreased with advancing age, and was not related to gender. Compared to the education 1-6 years group, the mean MoCA-ChLA score was 2.6 and 4.6 higher in the education 7-11 and 12-20 years groups, respectively. The Mandarin- (n = 612) and Cantonese- (n = 612) speaking subgroups performed comparably; Cronbach's alpha of the MoCA-ChLA score was 0.78 and 0.79 for these two groups, respectively. Item response theory analysis showed good discriminating power for executive function and memory. These properties support the MoCA-ChLA as a useful screening tool for aging and dementia studies for Mandarin or Cantonese speakers.

Postmortem and imaging studies provide converging evidence that the frontal lobe myelination trajectory is dysregulated in schizophrenia (SZ) and suggest that early in treatment, antipsychotic medications increase intracortical myelin (ICM). We used magnetic resonance imaging to examine whether the ICM trajectory in SZ is dysregulated and altered by antipsychotic treatment.We examined 93 subjects with SZ (64 men and 29 women) taking second-generation oral antipsychotics with medication exposures of 0-333 months in conjunction with 80 healthy control subjects (52 men and 28 women). Frontal lobe ICM volume was estimated using a novel dual contrast magnetic resonance imaging method that combines two images that track different tissue components.When plotted against oral antipsychotic exposure duration, ICM of subjects with SZ was higher as a function of medication exposure during the first year of treatment but declined thereafter. In the age range examined, ICM of subjects with SZ was lower with increased age, while ICM of healthy control subjects was not.In adults with SZ, the relationship between length of exposure to oral second-generation antipsychotics and ICM was positive during the first year of treatment but was negative after this initial period, consistent with suboptimal later adherence after initial adherence. This ICM trajectory resembles clinically observed antipsychotic response trajectory with high rates of remission in the first year followed by progressively lower response rates. The results support postmortem evidence that SZ pathophysiology involves ICM deficits and suggest that correcting these deficits may be an important mechanism of action for antipsychotics.

Even though the veracity of children's claim of psychiatric symptoms has received increased attention in recent years, identification of noncredible neuropsychological symptoms in children has been virtually overlooked in clinical practice and research. A case is presented of a 9-year-old child involved in litigation regarding a head injury sustained when he was struck by a car. Neuropsychological evaluation revealed evidence of feigned cognitive symptoms; the child displayed noncredible performance on several specialized tests designed to discreetly assess effort and an atypical pattern of responses on standard cognitive measures, as well as discrepancies between neuropsychological scores and tests administered in school and the rehab setting. Results demonstrate that children as young as 9 years of age are capable of feigning cognitive impairment, which highlights the need for routine evaluation of effort, irrespective of the age of the patient.

In two litigating patients with histories of severe brain injury (i.e., coma > or =2 days and residual brain imaging abnormalities), noncredible cognitive symptomatology was demonstrated by: (1) "failed" performance on multiple cognitive "effort" tests, (2) noncredible performance on standard neuropsychological instruments, (3) questionable validity of personality inventory profiles, and (4) marked inconsistency in test performance across testing evaluations or marked inconsistency between test scores and activities of daily living documented through surveillance videotapes. Some patients with severe traumatic brain injury show substantial, if not full recovery, and in a litigating context, may feign cognitive symptoms. These cases indicate that tests to verify cognitive effort should be routinely administered to all patients in litigation or who have other motive to feign symptoms, not just patients with mild or questionable brain injury.

To describe a case of young-onset Alzheimer disease (AD) due to mosaicism for trisomy 21.Case report of a single patient.Tertiary referral dementia clinic.A 55-year-old man with a mild degree of developmental delay but no previous diagnosis of Down syndrome and only minimal physical manifestations of Down syndrome presented with gradually progressive cognitive impairment consistent with probable AD.Fluorescent in situ hybridization analysis of interphase chromosomes revealed trisomy 21 in 10% of peripheral lymphocytes.As mosaicism for trisomy 21 can present with no or minimal manifestations of Down syndrome, it may be underdiagnosed as a cause of early-onset AD. Occult mosaicism for trisomy 21 may explain in part the previously described association between family history of Down syndrome and risk of AD. Screening for mosaicism with fluorescent in situ hybridization is indicated in selected patients with mild developmental delay and those with AD of young onset.

The degree to which changes in caregiver burden over a one-year period can be predicted by functioning of dementia patients and caregiver psychological stress was examined. The Direct Assessment of Functional Status (DAFS) was administered to 44 patients and the Caregiver Burden Inventory and the Brief Symptom Inventory were administered to their next-of-kin caregivers. All patients and caregivers were assessed at baseline and again in approximately one year with the same measures. Hierarchical regression revealed that baseline patient functioning predicted overall changes in caregiver burden, but that increases in psychological symptoms of caregivers such as depression, anxiety, and hostility were the best predictors for specific types of increased caregiver burden, such as social, developmental, or physical burden. These results suggest that interventions should target reduction of particular psychological symptoms in order to reduce caregiver burden over time.

Members of the National Academy of Neuropsychology were surveyed in 2005 to assess then current practices regarding Boston Naming Test (BNT) administration, interpretation, and reporting procedures. Nearly half of 445 respondents followed discontinuation rules that differed from instructions published with the test, and nearly 10% did not administer items in reverse order to achieve the required 8 consecutive item basal. Of further concern, between 40% and 55% of respondents indicated that they did not interpret BNT scores in light of linguistic and ethnic background, and over 25% reported that they did not consider educational level. Despite the fact that non-normal distribution of BNT test scores renders use of percentiles misleading, nearly 60% of respondents endorsed using percentiles when reporting BNT data. The implications of these results are discussed, and recommendations are provided.

Cocaine and its metabolites can produce vasospasm, and cocaine-dependent patients are at increased risk for stroke. Based on previous case reports, we hypothesized that the incidence of hyperintense brain lesions observed on T2-weighted MR images would also be increased in asymptomatic cocaine-dependent individuals.Sixty-two male "crack" (smoked) cocaine-dependent participants ranging in age from 25 to 66 years were compared with 116 normal male control participants ranging in age from 25 to 80 years. Those with histories of neurologic symptoms or illnesses were excluded. The severity of hyperintense lesions was rated on a 0- to 3-point scale, and ratings of 3 were used in the data analysis as an indicator of a probable pathologic process. Three regions were separately rated: the cerebral white matter, insular subcortex white matter, and subcortical gray matter (basal ganglia and thalamus region).Significantly increased risk of severe lesions was observed in the two white matter regions of the cocaine-dependent group (odds ratio of 16.7 and 20.3) but not in the subcortial gray matter region (odds ratio of 1.4). In the insula subcortex white matter, the risk of lesions increased with age in the cocaine-dependant sample, but remained essentially absent among normal controls through the age of 80 years. In the cerebral white matter, the relationship of age and risk of lesion among normal participants was similar in shape to that in cocaine-dependent participants, but equivalent risk was seen 20 years earlier among cocaine-dependent participants.Cocaine-dependent participants had a significantly increased age-related risk of white matter damage. The possible clinical implications of this damage are discussed.

Although the detection of conscious fabrication (i.e., malingering) of cognitive symptoms has been the recipient of burgeoning interest within the last 10 years in the empirical and clinical neuropsychological literature, whether conversion/somatization results in similarly noncredible cognitive profiles has not been formally investigated. Two thirds (13 of 19) of subjects with cognitive complaints and 1-3/3-1 code types on the MMPI/MMPI-2 showed evidence of noncredible cognitive performance (i.e., failure on malingering tests and/or a “malingering’” pattern on standard neuropsychological tests). These results suggest that symptom fabrication associated with somatization/conversion personality orientations can extend to noncredible cognitive complaints and not just the oft-described physical manifestations.

To evaluate the severity of choreoathetoid movements in cocaine dependent (CD) subjects and age-matched normal control subjects.Choreoathetoid movements were evaluated using the Abnormal Involuntary Movement Scale (AIMS) in samples of 71 CD, 56 normal control, and 9 amphetamine-dependent male subjects.The CD subjects had a significantly increased nonfacial (limbs plus body) AIMS subscore. When the nonfacial AIMS scores of the two groups were compared in relation to age, a significant age by diagnosis interaction was observed, indicating that the differences between groups were most marked in the younger age groups. The facial AIMS scores were also increased but only in the youngest CD cohort (under 32 years of age). The comparison group of 9 younger amphetamine-dependent subjects also showed increased AIMS scores.Increases in choreoathetoid movements in younger cocaine and amphetamine-dependent subjects may be related to their psychostimulant use. The absence of differences in choreoathetoid movements between the older CD subjects and normal control subjects may represent an age-related self-selection effect.

Bernard (1990), and Bernard, Houston, and Natoli (1993) identified a discriminant function, derived from Rey figure recall score and RAVLT trial 1 and recognition, which discriminated simulators and controls with 77--85% accuracy. However, in the current study, application of the discriminant function to patients with suspect effort, brain injured patients, and controls, revealed excellent sensitivity (95%) but low specificity (33% for patients, 61% for controls). A new discriminant function using the same Rey figure and RAVLT scores, derived from actual patients with documented suspect effort and patients with confirmed brain injury, resulted in an overall classification of 85% correct, with only 16% of suspect effort and 15% of brain injured patients misidentified. Use of a discriminant function score of </=-.40 resulted in sensitivity of 71% while maintaining specificity of >/=91%.

Patients with dementia, particularly those with frontotemporal dementia (FTD), are reported to display marked negative symptoms, including apathy, lack of initiative, and flattened affect, similar to those observed in schizophrenic patients. However, negative symptoms have yet to be formally quantified in an FTD population. Twenty-seven patients with FTD (11 primarily right-sided, 8 primarily left-sided, and 4 symmetric) and 7 patients with Alzheimer's disease were rated on the Scale for the Assessment of Negative Symptoms, the Positive and Negative Syndrome Scale, and the Emotional Blunting scale. The FTD patients registered significantly more negative symptoms than the Alzheimer's patients, averaging a threefold increase; groups did not significantly differ in positive symptoms. Negative symptom scale scores were negatively correlated with nonverbal executive skills (23-44% shared variance), verbal executive skills (up to 25% shared variance) and verbal memory (up to 20% shared variance), but were unrelated to measures of attention, verbal and nonverbal information processing, nonverbal memory, language, and constructional skill. In contrast, positive symptoms were positively correlated with constructional skill (19% shared variance) and attentional scores (15% shared variance). These findings add to the existing literature relating negative symptoms to anterior cerebral hypofunction, and suggest that positive symptoms, at least in this population, may be tied to increased posterior activation.

&lt;i&gt;Background:&lt;/i&gt; The significant variability across studies of mild cognitive impairment (MCI) in rates of progression to Alzheimer’s disease (AD) and reversion to normal cognition may be due to differences in specific neuropsychological tests and thresholds used to define MCI. &lt;i&gt;Methods:&lt;/i&gt; We assessed 115 subjects with amnestic (AMN) or non-amnestic (NON) MCI on a standardized neuropsychological battery at baseline and after a mean follow-up of 16.4 months to determine the prevalence and persistence of deficits identified with specific tests. &lt;i&gt;Results:&lt;/i&gt; The prevalence of impaired performance varied widely across tests. Deficits were more persistent in the AMN group than in the NON group. Baseline deficits in Visual Reproduction II and the California Verbal Learning Test were the best predictors of persistent memory impairment. Subjects who at baseline were impaired on multiple memory tests or had poorer overall memory performance were more likely to exhibit persistent memory deficits. &lt;i&gt;Conclusions:&lt;/i&gt; The use of different neuropsychological tests and thresholds to diagnose MCI identified subsets of subjects with different rates of persistence of cognitive impairment. Standardization of the operational definition of cognitive impairment in MCI may result in more consistent predictions of progression to AD.

The Mini-Mental State Examination is a widely used cognitive screening measure. The purpose of the present study was to assess how 5 specific clusters of Mini-Mental State Examination items (ie, subscores) correlate with and predict specific areas of daily functioning in dementia patients, 61 patients with varied forms of dementia were administered the Mini-Mental State Examination and an observation-based daily functional test (the Direct Assessment of Functional Status). The results revealed that the orientation and attention subscores of the Mini-Mental State Examination correlated most significantly with most functional domains. The Mini-Mental State Examination language items correlated with all but the shopping and time orientation tasks, while the Mini-Mental State Examination recall items correlated with the Direct Assessment of Functional Status time orientation and shopping tasks. Stepwise regression analyses found that among the Mini-Mental State Examination subscores, orientation was the single, best independent predictor of daily functioning.

Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia.We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimer's disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume.Twenty-five individuals with bvFTD (n = 11) and early-onset AD (n = 14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared on SEB ratings and MRI-derived brain volume using tensor-based morphometry. Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores.The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant.Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB appears to measure symptoms of emotional blunting that are localized to the right anterior temporal lobe.

Cognitive abilities decline with age and older adults, as a group, are at increased risk for developing age-related cognitive disorders. Neuropsychological evaluation provides objective quantification of the type and severity of cognitive deficits that can affect the elderly population and elucidates a pattern of scores that provides diagnostic clues regarding etiology. It can also detect mild cognitive impairment that may not be evident on bedside assessment or mental status examination and provides critical information regarding the progression of cognitive changes through serial evaluations. Such information assists in counseling patients and family members and can guide therapeutic decisions.

Iron is essential for triggering oligodendrocytes to myelinate, however, in gray matter (GM) iron increases with age and is associated with age-related degenerative brain diseases. Women have lower iron levels than men, both in the periphery and in the brain, particularly in white matter (WM), possibly due to iron loss through menstruation. We tested the hypothesis that hysterectomy could increase WM iron levels. We assessed 3 WM and 5 gray matter regions in 39 postmenopausal women, of whom 15 had premenopausal hysterectomy, utilizing a validated magnetic resonance imaging technique called field-dependent R2 increase (FDRI) that quantifies ferritin iron. A group of 54 matched male subjects was included for comparison. Amongst women, hysterectomy was associated with significantly higher frontal lobe WM iron. Men had higher iron levels than women without hysterectomy in 3 brain regions but did not differ from women with hysterectomy in any region. The results suggest that menstruation-associated blood loss is a source of gender differences in brain iron. It is possible that brain iron can be influenced by peripheral iron levels and may thus be a modifiable risk factor for age-related degenerative diseases.

Neuropsychologists frequently include proverb interpretation as a measure of executive abilities. A concrete interpretation of proverbs, however, may reflect semantic impairments from anterior temporal lobes, rather than executive dysfunction from frontal lobes. The investigation of proverb interpretation among patients with different dementias with varying degrees of temporal and frontal dysfunction may clarify the underlying brain-behavior mechanisms for abstraction from proverbs. We propose that patients with behavioral variant frontotemporal dementia (bvFTD), who are characteristically more impaired on proverb interpretation than those with Alzheimer's disease (AD), are disproportionately impaired because of anterior temporal-mediated semantic deficits.Eleven patients with bvFTD and 10 with AD completed the Delis-Kaplan Executive Function System (D-KEFS) Proverbs Test and a series of neuropsychological measures of executive and semantic functions. The analysis included both raw and age-adjusted normed data for multiple choice responses on the D-KEFS Proverbs Test using independent samples t-tests. Tensor-based morphometry (TBM) applied to 3D T1-weighted MRI scans mapped the association between regional brain volume and proverb performance. Computations of mean Jacobian values within select regions of interest provided a numeric summary of regional volume, and voxel-wise regression yielded 3D statistical maps of the association between tissue volume and proverb scores.The patients with bvFTD were significantly worse than those with AD in proverb interpretation. The worse performance of the bvFTD patients involved a greater number of concrete responses to common, familiar proverbs, but not to uncommon, unfamiliar ones. These concrete responses to common proverbs correlated with semantic measures, whereas concrete responses to uncommon proverbs correlated with executive functions. After controlling for dementia diagnosis, TBM analyses indicated significant correlations between impaired proverb interpretation and the anterior temporal lobe region (left>right).Among two dementia groups, those with bvFTD, demonstrated a greater number of concrete responses to common proverbs compared to those with AD, and this performance correlated with semantic deficits and the volume of the left anterior lobe, the hub of semantic knowledge. The findings of this study suggest that common proverb interpretation is greatly influenced by semantic dysfunction and that the use of proverbs for testing executive functions needs to include the interpretation of unfamiliar proverbs.

The definition of mild cognitive impairment (MCI) as a precursor for Alzheimers disease (AD) represented an important step forward in diagnosing the illness in its earliest stage. However, diagnoses based principally on cognitive performance have limitations in that there is variability between centers in which tests are employed and in how they are interpreted. Advances in our understanding of imaging and biochemical changes occurring early in the illness have improved our ability to diagnose AD in this early phase and diagnostic criteria for AD have been proposed recently based on such biomarkers. Persons inheriting autosomal dominant mutations causing familial AD (FAD) are essentially certain to develop the disease. In our studies of preclinical persons at-risk for inheriting FAD, we applied MCI diagnostic criteria to carriers of FAD mutations to ascertain the extent to which they identified persons in the earliest stages of the clinical illness. Our results indicate the relative prevalence of MCI subtypes varies considerably depending on the tests used to measure cognition. Furthermore, we found that cognitive complaints in such persons were less predictive of mutation status than were informants reports of cognitive loss. The study of FAD provides an opportunity to test various criteria for early AD and these observations should be taken into consideration in future iterations of such diagnostic criteria. Keywords: Mild cognitive impairment, alzheimer's disease, biomarkers, familial, presenilin-1, amyloid precursor protein, neuropsychology, presymptomatic

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Previous cross-sectional studies suggest that assessments of instrumental activities of daily living (IADLs) may be useful for operationalizing the differences in functional deficits seen in mild cognitive impairment (MCI) and dementia. However, their utility for longitudinal changes in IADLs in the transition between MCI and dementia remains unclear. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We analyzed longitudinal IADL data with the Functional Activities Questionnaire (FAQ) in stable (MCI-S; n = 1,318) or progressive (MCI-P; n = 1,108) MCI patients. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Larger increases in FAQ scores were seen in the MCI-P group across a 14.5-month interval, but overlapping distributions in the two groups yielded poorer discriminatory power than prior cross-sectional reports. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Our findings emphasize the difficulties in operationalizing the criterion of ‘essentially intact' IADLs in MCI, which may complicate the interpretation of disease progression in MCI treatment trials. © 2014 S. Karger AG, Basel

We analyzed the relationship between cocaine-induced euphoria and measures of frontal and temporal gray matter volumes in eleven cocaine-dependent (CD) patients who underwent magnetic resonance imaging (MRI). Self-reported ratings of the intensity of euphoric response to cocaine infusion were obtained from the CD subjects at 3, 10, and 30 minutes after cocaine infusion. Significant positive correlation between frontal and temporal cortical gray matter volume and the intensity of euphoria was observed at 10 minutes after IV cocaine. The data suggest that frontal and temporal lobe gray matter volume is associated with some of the reinforcing effects of cocaine. Given the well-established negative linear relationship between cortical gray matter volume and age, cortical gray matter volume may be a marker for the neurobiological substrate of the age-related reduction in addiction rates.

To assess whether the production of profanity during letter fluency testing distinguishes frontotemporal dementia (FTD) and Alzheimer disease (AD) patients.Alterations in language and social behavior typify FTD spectrum disorders. Nonetheless, in can be difficult to distinguish pathologically defined frontotemporal lobar degeneration (FTLD) from AD clinically. Assessing verbal fluency by having patients generate words beginning with specific letters in a given period of time can yield diverse information of diagnostic use.Words produced during FAS letter fluency testing were reviewed, and instances of the use of "f*ck," "*ss," and "sh*t" and other words felt to be inappropriate were sought. The frequency of these words was compared between clinically diagnosed FTD and AD patients using χ(2) tests.We found that 6/32 (18.8%) patients with FTD generated the word "f*ck" during the "F" trial as opposed to none of 38 patients with AD (P=0.007). Patients who said "f*ck" had diagnoses of either behavioral variant FTD (3/15), progressive nonfluent aphasia (2/8), or semantic dementia (1/3).Though the specific neuropathology in these cases is uncertain, generation of "f*ck" during letter fluency testing seems to have use in differentiating FTD from AD.

Normative data for the Kaplan version of the Stroop Test are presented for 153 healthy, cognitively intact older adults aged 50-89 years. Increasing age was associated with decreased performance on all three subtests (Stroop A, Stroop B, and Stroop C), while years of education was only associated with Stroop B performance. Hence the normative data were stratified by age into three groups (50-64, 65-74, 75-89). Completion times for the first half of each trial (half-time scores) were found to have good split-half reliability and correlated highly with the original full administration scores. Means and standard deviations for the half-time administration are also presented for this sample. The current study provides more comprehensive normative data for older adults than previously available, as well as normative information for half-time scores that may have future clinical utility as an alternative, abbreviated version of the Kaplan Stroop Test.

Abstract This study investigates the effects of argument stance on knowledge inquiry skills. Sixty-two participants were assigned to three argument stance conditions (proponent, opponent, or control) to receive scaffolded argumentation practice on two science issues in random order. After the argumentation treatment, participants were asked to write down their own opinions regarding the claim. Their responses were analysed according to argument structure, argument content, methods of refutation, and number of new propositions. Results revealed that taking a proponent's stance increased the use of evidence in argumentation, while taking an opponent's stance enhanced both the use of evidence and alternative-based refutations to the claim, number of falsifications, and number of new propositions. This implies that arguing from an opponent's stance may increase the search for multiple causes behind observed phenomena and the need for evidence, thereby alleviating the confirmation bias in thinking. Keywords: ArgumentationArgument stanceScientific inquiry skillsScience text Acknowledgements This study was supported by Taiwan National Science Council Grant NSC 96-2511-S-009-003) to Ruey-Yun Horng. We are most grateful to two anonymous reviewers’ helpful comments on earlier drafts.

We present 6 patients who displayed noncredible effort on neuropsychological testing (verified by failures on specialized measures designed to discreetly assess effort status and multiple behavioral inconsistencies) and complained of complete illiteracy secondary to impoverished educational history, learning disability, or acquired brain injury. The Stroop Test, a measure of a specific aspect of executive function requiring inhibition of an automatized oral reading response in favor of a less habitual, competing color-naming response, was administered to these patients. All six subjects claimed that they were unable to perform the Word-Reading trial as a consequence of total reading disability, but on the Color-Word Interference trial, they all committed “errors” by reading the written words. Five of the six subjects also performed substantially slower on the Interference condition relative to the Color-Naming trial, indicating that they were in fact inhibiting a reading response. However, in cases involving complaints of complete reading illiteracy, the observation of these individuals performing an act that they claimed to be unable to do was the most powerful and pathognomonic indicator of deliberate feigning or exaggeration of impairment in these cases.

To identify regional differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) using customized preprocessing before voxel-based analysis (VBA) in 14 normal subjects with the specific genes that decrease (apolipoprotein [APO] E ε2) and that increase (APOE ε4) the risk of Alzheimer's disease.Diffusion tensor images (DTI) acquired at 1.5 Tesla were denoised with a total variation tensor regularization algorithm before affine and nonlinear registration to generate a common reference frame for the image volumes of all subjects. Anisotropic and isotropic smoothing with varying kernel sizes was applied to the aligned data before VBA to determine regional differences between cohorts segregated by allele status.VBA on the denoised tensor data identified regions of reduced FA in APOE ε4 compared with the APOE ε2 healthy older carriers. The most consistent results were obtained using the denoised tensor and anisotropic smoothing before statistical testing. In contrast, isotropic smoothing identified regional differences for small filter sizes alone, emphasizing that this method introduces bias in FA values for higher kernel sizes.Voxel-based DTI analysis can be performed on low signal to noise ratio images to detect subtle regional differences in cohorts using the proposed preprocessing techniques.

Methods: Seventy healthy adult men aged 19 to 76 years underwent magnetic resonance imaging. Coronal images focused on the frontal and temporal lobes were acquired using pulse sequences that maximized gray vs white matter contrast. The volumes of total frontal and temporal lobes as well as the gray and white matter subcomponents were evaluated. Results: Age-related linear loss in gray matter volume in both frontal (r=˛0.62, P,.001) and temporal (r=˛0.48, P,.001) lobes was confirmed. However, the quadratic function best represented the relationship between age and white matter volume in the frontal (P,.001) and temporal (P,.001) lobes. Secondary analyses indicated that white matter volume increased until age 44 years for the frontal lobes and age 47 years for the temporal lobes and then declined. Conclusions: The changes in white matter suggest that the adult brain is in a constant state of change roughly defined as periods of maturation continuing into the fifth decade of life followed by degeneration. Pathological states that interfere with such maturational processes could result in neurodevelopmental arrests in adulthood. Arch Gen Psychiatry. 2001;58:461-465

The understanding of the human brain has been hampered by an inadequate examination of the brain from the integrative perspective of the entire life span. Such a perspective is essential for understanding the continually changing nature of the brain’s infrastructure and function. Postnatal brain development is primarily driven by the process of myelination that continues to improve the connectivity of the brain’s ‘Internet’ through middle age. The developmental process is eventually overcome by degenerative processes, resulting in the breakdown and loss of myelin that roughly recapitulates the developmental process in reverse. This quadratic trajectory of brain myelin over the life span can help explain multiple inconsistencies in the postmortem and imaging literatures. Ultimately, the life span perspective of this myelin model of the brain suggests powerful new approaches to understanding and treating many uniquely human neuropsychiatric disorders, ranging from schizophrenia to Alzheimer’s disease.

Although "Depression and Fluctuation" was proposed by Du Fu and often used to summarize the profound and winding style characteristics of Du Fu's poetry, its scope of application is not limited to Du Fu's poetry, but can also be used to describe ancient literature, ci, fu, and even calligraphy art works. Yao Ying's explanation of "literary value and frustration" highlights the emphasis on writing techniques and breaks through the stereotype of "talent, learning, and knowledge" in papers, thus gaining new connotations. The connection and root cause between the emphasis on "economy" for learning and the emphasis on "depression and setbacks" for literature lies in the sense of hardship caused by the Jiadao Incident in the intellectual circles. From the perspective of the mutual infiltration of literary styles, the proposal of "literary value and depression" can be seen as an effective way to find "using poetry to supplement literature" based on the theory of "poetry and literature are interconnected". The situation is changing day by day, and the influence of "Wengui's depression" is limited to the Tongcheng school; Gong and Wei Xinsheng have not always adhered to the gentleness and kindness of Confucianism. Liang Qichao's "new style" has abandoned the tradition of "frustration". Fu Ssu-nien and others have pushed Tongcheng's literary theory, including the method of frustration, onto the stage of criticism.

Abstract Patients with frontotemporal dementia (FTD) manifest severe behavioral and personality alterations associated with orbitofrontal cortex (OFC) dysfunction. This chapter provides a review of the clinical features, neuropathology, neuroimaging, genetics, and neuropsychology of FTD as well as presenting two prototypical cases that provide a clinical picture of the disorder. Neuropathological and neuroimaging studies have identified the OFC as the brain region most prominently involved in the frontal-variant of FTD. The neuroanatomy, circuitry, and functions of the OFC are summarized, emphasizing its role in emotional and social cognition. Theories involving deficits in recognition of emotional expression, decision-making, and theory of mind have been proposed to explain the mechanism underlying the clinical expression of FTD, and the OFC is intimately involved in studies examining the neural basis underlying these deficits.

Several publications have reviewed the effects of gender on individual neuropsychological measures, however, to date there has been no review of the impact of gender on a wide range of neuropsychological tests. This type of information is critical in that to the extent that there are gender differences on cognitive measures, test normative data must be stratified by sex, otherwise the available norms will render inaccurate results; that is, they will overpathologize the scores of the underperforming gender and at the same time fail to detect true declines in the gender with the higher baseline.

This chapter contains sections titled: Introduction. Puzzling Changes in Cell Numbers in Huntington's Disease Brain Human Brain Development and Disease Phenotypes Oligodendrocytes and Iron in Brain Development and Degeneration Transition Metal Metabolism and Proteinopathies In Vivo Measurement of Brain Iron Novel Treatment Considerations Conclusions Acknowledgments Abbreviations References

The advent of optical coherence tomography (OCT) revolutionized both clinical assessment and research of vitreoretinal conditions. Since then, extraordinary advances have been made in this imaging technology, including the relatively recent development of swept-source OCT (SS-OCT). SS-OCT enables a fast scan rate and utilizes a tunable swept laser, thus enabling the incorporation of longer wavelengths than conventional spectral-domain devices. These features enable imaging of larger areas with reduced motion artifact, and a better visualization of the choroidal vasculature, respectively. Building on the principles of OCT, swept-source OCT has also been applied to OCT angiography (SS-OCTA), thus enabling a non-invasive in depth-resolved imaging of the retinal and choroidal microvasculature. Despite their advantages, the widespread use of SS-OCT and SS-OCTA remains relatively limited.In this review, we summarize the technical details, advantages and limitations of SS-OCT and SS-OCTA, with a particular emphasis on their relevance for the study of retinal conditions. Additionally, we comprehensively review relevant studies performed to date to the study of retinal health and disease, and highlight current gaps in knowledge and opportunities to take advantage of swept source technology to improve our current understanding of many medical and surgical chorioretinal conditions. We anticipate that SS-OCT and SS-OCTA will continue to evolve rapidly, contributing to a paradigm shift to more widespread adoption of new imaging technology to clinical practice.

Using an item analytic method, the Item Specific Deficit Approach (ISDA), we recently found evidence that Alzheimer's disease (AD)-related verbal memory impairment was driven by encoding and consolidation deficits. Verbal memory deficits in individuals with amnestic mild cognitive impairment (aMCI) are generally more heterogeneous than those observed in AD. In the current study, we utilized ISDA indices extracted from a list-learning test to determine if a specific subgroup of aMCI participants exhibited an “AD type” verbal memory profile. We administered the California Verbal Learning Test (CVLT) to 35 AD, 93 aMCI, and 48 neurologically intact healthy control (HC) participants. Using the ISDA, we extracted indices of encoding, consolidation, and retrieval deficits from item level responses on the CVLT. The aMCI participants were considered to exhibit an “AD type” memory profile if they exhibited both encoding and consolidation deficits at least one standard deviation greater than the HCs. Following subtyping, we compared the “AD type” aMCI (aMCI-ADT), the other aMCI (aMCI-O), the HC, and the AD groups on their CVLT performances. Using the HCs as a normative reference, 61 participants were subtyped as aMCI-ADT and 32 were subtyped as aMCI-O. Covarying for age and education, univariate ANCOVAs revealed aMCI-O participants performed similarly to HC participants on list learning, recognition discriminability, and semantic clustering. HC participants performed significantly better than the aMCI-O group on short- and long-delayed free recall. Similar to but to a lesser degree than the AD group, the aMCI-ADT group performed significantly worse than the HC and aMCI-O groups on list learning, short- and long-delayed recall, recognition, and semantic clustering. There were no significant differences between the aMCI-ADT and AD groups on recognition and semantic clustering, but the aMCI-ADT group recalled significantly more items on short- and long-delayed free recall. The results suggest a heterogeneity with respect to memory deficits displayed by individuals with aMCI. One subgroup of persons with aMCI exhibited a memory profile similar to individuals with AD, with both groups displaying encoding and consolidation deficits. Moreover, this aMCI group displayed overall greater memory impairment than other individuals with aMCI.

OBJECTIVE: To examine longitudinal changes in instrumental activities of daily living (IADLs) associated with mild cognitive impairment (MCI) and progression to dementia. BACKGROUND: A key distinction between MCI and dementia is the presence of essentially intact IADLs in MCI. However, previous studies revealed subtle IADL deficits in MCI that were associated with subsequent progression to dementia. IADL deficits increase from MCI to dementia, but their longitudinal course and magnitude remain uncertain. DESIGN/METHODS: We identified 2451 participants from the National Alzheimer9s Coordinating Center (NACC) Uniform Data Set who met criteria for MCI at baseline and had at least one annual follow-up visit. IADLs were longitudinally assessed with the Functional Activities Questionnaire (FAQ). Participants were divided into stable (sMCI; n=1331) or progressive (pMCI; n=1120) MCI groups based on progression to dementia during follow-up. Longitudinal FAQ changes were compared between groups. Data from pMCI visits subsequent to initial dementia diagnosis were censored. RESULTS: Across each subject9s last two visits, the pMCI group exhibited greater mean changes in both total FAQ (6.13, SD=6.94) and average FAQ item (0.63, SD=0.68) scores than the sMCI group (total FAQ: 0.89, SD=3.53; average FAQ item: 0.10, SD=0.37). Increases in global FAQ indices for the pMCI group were broadly driven by disproportionately worsening performance across 7 of 10 IADL categories. Analyses of earlier time-points indicated that global FAQ indices in the two groups began to diverge by 28 months prior to the final visit. CONCLUSIONS: Our results suggest that progressive deterioration in IADLs can be detected in MCI as early as two years prior to diagnosis of dementia. Progression from MCI to dementia was associated with accelerated declines across multiple categories of IADL performance. Further analyses will focus upon comparisons of the relative magnitude and time course of longitudinal changes in cognitive, functional, and behavioral indices associated with the transition from MCI to dementia. Supported by: National Institute on Aging (P50 AG 16570, K23 AG 028727 [to PL], and K08 AG 34628 [to ET; jointly sponsored by NIA, AFAR, the John A. Hartford Foundation, the Atlantic Philanthropies, the Starr Foundation and an anonymous donor]), the Alzheimer9s Disease Research Centers of California, and the Sidell-Kagan Foundation. The NACC database is funded by NIA (U01 AG016976). Disclosure: Dr. Hsiao has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Lu has nothing to disclose. Dr. Tenghas received personal compensation for activities with Neurovision Imaging as a consultant. Dr. Teng holds stock and/or stock options in GE Healthcare and Cerner Corporation.

OBJECTIVE: To examine neuroanatomical correlates of social dysfunction in patients with behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer's disease (EOAD).BACKGROUND: Declines in social functioning are a characteristic feature of bvFTD, whereas social functioning in EOAD patients remains relatively intact. We compared the two groups' scores on the Social Dysfunction Scale (SDS), and we used tensor-based morphometry (TBM) to map the association between SDS scores and regional brain volumes.DESIGN/METHODS: 19 participants (mean age=60.0, sd=7.9), including 9 with bvFTD and 10 with EOAD, underwent MRI and clinical assessment. The bvFTD and EOAD subjects did not differ on any demographic characteristics. SDS scores were compared using an independent-samples t-test, and TBM was applied to 3D T1-weighted MRI scans. Each individual image was warped to a common brain template, and Jacobian maps showing the expansion or compression factor at each voxel were created. Mean Jacobian values within selected regions of interest were computed for each subject to provide a numeric summary of regional volume. Voxel-wise regression was performed on the Jacobian maps.RESULTS: bvFTD subjects (mean SDS=145.78, sd=27.15) scored significantly higher than EOAD patients (mean SDS=78.10, sd=27.47) on the SDS (t=5.39, p<.001). In the overall sample, SDS scores were not significantly correlated with frontal (r=-.32, p=.18), temporal (r=.30, p=.22), or parietal (r=.12, p=.63) lobe volume. A more regionally specific analysis of the orbitofrontal cortex and anterior temporal lobe revealed that SDS scores were significantly associated with orbitofrontal volume (r=-.63, p=.004), but not anterior temporal volume (r=-.19, p=.45). Within-group correlations were non-significant, but were in the same general direction (FTD: r=-.23, p=.54; AD: r=-.33, p=.35).CONCLUSIONS: bvFTD subjects demonstrated more social dysfunction than EOAD subjects. Impaired social functioning in bvFTD and EOAD, as assessed by the SDS, appears to be associated specifically with orbitofrontal volume, but not with anterior temporal, parietal or overall frontal volume.Supported by: NIH grants K23-AG028727 and R01-AG034499 from the National Institute of Aging (NIA), the Alzheimer's Disease Research Center grant P50 AG-16570, California Alzheimer's Disease Centers, and the Department of Veterans Affairs.Disclosure: Dr. Melchor has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Lu has nothing to disclose. Dr. Shapira has nothing to disclose. Dr. Mather has nothing to disclose. Dr. Kaiser has nothing to disclose. Dr. Jimenez has nothing to disclose. Dr. Thompson has nothing to disclose. Dr. Mendez has received personal compensation in an editorial capacity for UpToDate.

Verbal memory changes are common in mild cognitive impairment (MCI), which is a risk state for Alzheimer's disease. Poor attention can have a negative impact on initial learning of verbal material, while memory cues can enhance performance. The purpose of this study was to determine the role of attention in both cued and uncued learning in healthy aging and MCI. This study included 34 healthy older controls and 35 participants with MCI who were matched for age, education, and gender. Participants were administered two alternate stories in a counterbalanced order. At initial learning, a thematic cue was provided before presentation of one story, while the other story was uncued. Two learning trials were administered, followed by free and cued recall trials after a 10-minute delay. Multiple regression models were conducted, with measures of attention (Trails A, Letter Number Span, Symbol Digit Modalities Test) as predictors and first trial learning as the outcome measure. For healthy controls, attention predicted uncued story learning, with Letter Number Span emerging as an independent predictor. Attention did not predict their cued learning. In contrast, attention predicted cued story learning in the MCI group, and the Symbol Digit Modalities Test was an independent predictor. Attention was not predictive of uncued story memory in MCI. The current results indicate that healthy older adults rely more on attention span to memorize large amounts of information. When they are given cues, their learning is less attention-dependent. For individuals with MCI, attention (specifically processing speed) only affects their learning performances when they are given a memory cue.

Mild cognitive impairment (MCI) is a risk state for Alzheimer's disease (AD). It has been well established that behavioral symptoms are commonly observed in AD. Our objective was to determine if the profile of neuropsychiatric symptoms in MCI was qualitatively unique to the profile found in AD. The data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal study on healthy aging, MCI, and AD. These analyses included 393 individuals with MCI and 191 individuals with AD who all completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant-based rating scale for assessing the presence and severity of 12 behavioral symptoms. For the MCI and AD groups, factor analyses were conducted on the NPI-Q data. Factors were selected based on the number of eigenvalues > 1, and factor loadings > .40 were considered significant. For the MCI group, ‘mood’ (depression and anxiety) and ‘frontal’ (agitation, disinhibition, and irritability) factors emerged. The analysis for the AD group yielded ‘frontal-behavioral’ (elation and disinhibition), ‘frontal-emotional’ (agitation, apathy, irritability), and ‘psychosis’ (delusions and hallucinations) factors. Our findings indicate that although the two groups share some similar frontal symptoms, mood problems are more common in MCI, while psychotic symptoms are more common in AD. Furthermore, a wider range of frontal symptoms is found in AD. Overall, the behavioral patterns in these groups are qualitatively dissimilar.

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders including Alzheimer's disease (AD). Studies have liked higher iron levels in males with younger age at onset and presence of the HFE hemochromatosis and transferrin C2 gene variants (iron genes) with AD. Examine whether cognitive performance in healthy older individuals is associated with increased brain ferritin iron and highly prevalent iron genes. Ferritin iron can be measured with specificity in vivo with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. FDRI was assessed in basal ganglia, hippocampus, and white matter. 48% of the sample carried neither gene (the IRON- group) and 52% carried one and/or the other (IRON+ group). A robust gender by gene group interaction was observed. IRON+ men had significantly higher FDRI compared to the IRON- group but in secondary analyses only the caudate nucleus showed a significant FDRI increase in IRON+ compared to IRON- men (t=2.31, p=.027). This gene effect was not observed in women. Independent of genes, memory performance was significantly associated with hippocampal iron in men but not in women. This is the first evidence that these prevalent mutations can influence brain iron levels in men. Irrespective of gene status, verbal memory is negatively associated with hippocampal iron accumulation in men. Clinical phenomena such as gender-associated risk of developing neurodegenerative diseases and age at onset may be associated with the interactions between iron genes and brain ferritin iron accumulation. Reducing brain iron accumulations in old age may be a worthwhile therapeutic target for age-related neurodegenerative diseases.

Both Alzheimer's disease (AD) and the frontotemporal dementia syndromes (FTDs) are ultimately accompanied by the disintegration of social proprieties though this is an early and characteristic feature of many patients with FTD. Examples of changes in social behavior that have been reported in the FTDs include excessive familiarity with strangers, increased use of profanity or inappropriate humor, and disinhibited sexual behaviors such as inappropriate propositions, public disrobing, and exhibitionism. In this study we explored the possibility that generation of profanity during verbal fluency testing might distinguish between patients with AD and the FTDs. Words generated during letter fluency (FAS) testing from 32 patients with clinically-diagnosed FTD spectrum disorders (15 behavioral variant FTD, 8 progressive nonfluent aphasia, 4 semantic dementia, 4 corticobasal degeneration, 1 progressive supranuclear palsy) from the Easton Center for AD Research at UCLA database were compared to that of 39 subjects with AD (35 probable AD, 4 possible AD) matched for gender, MMSE score and education. The number of patients that generated “f*ck,” “*ss,” and “sh*t” as well as other profane words were compared between groups by chi-square analyses. Patients with the FTDs were significantly younger than AD patients (63 vs. 71 years of age, p < 0.001). Subjects with FTD were significantly more likely to generate “f*ck” than were patients with AD (22% vs. 0%, p = 0.002). The frequency of other profane words or the use of profanity overall did not differentiate the groups. In our sample, generation of the word “f*ck” during FAS testing was 100% specific for distinguishing the FTDs from AD though lacked sensitivity. This confirms that social impropriety, as reflected in the use of profanity during letter fluency testing, can help to distinguish patients with the FTDs from those with AD.

Cognitive impairment is exceedingly common among patients with Parkinson's disease (PD), and a variety of cognitive domains are impaired early in PD. Both mild cognitive impairment (PDMCI) and dementia (PDD) are associated with PD. The brain changes accompanying cognitive decline in PD are still not fully established. We applied tensor based morphometry (TBM) to 3D T1-weighted MRI scans of 20 age-matched cognitively normal elderly (NC), 9 cognitively normal PD (PDND), 6 PDMCI, and 15 PDD subjects. We warped each individual image to the unbiased geometrical NC average template and created Jacobian maps showing the expansion or compression factor at each image point and statistical maps of between-group differences. Like voxel-based morphometry (VBM), TBM detects volumetric differences throughout the brain revealing 3D profiles of tissue excess or loss, creating statistical p maps. Relative to NC, PDD subjects showed significant atrophy (p<0.01) bilaterally in frontopolar and temporo-occipital areas; on the right in the posterior medial frontal, lateral medial temporal, lateral parieto-occipital and precuneal areas and on the left in the inferior and middle temporal areas. Relative to NC, PDMCI subjects showed significant atrophy (p<0.01) in the left pregenual cingulate, right frontopolar, and precuneal, and bilaterally in the medial temporal areas. Relative to NC, in the PDND group only a few areas of significant tissue loss (p<0.01) were found on the right side in the parahippocampal gyrus/medial temporal lobe, lateral medial temporal, medial frontal and postcentral areas. Cognitive decline in PD is associated with tissue loss. PDD subjects show detectable atrophy in more areas of the brain than PDMCI subjects. Cognitive decline in PD seems to be associated with medial and lateral frontal, medial and inferior temporal, precuneal and parietal atrophy. The dementia profile of PDD is characterised by executive, visuospatial and attentional impairment. This corresponds well with the areas of tissue loss shown in this study.

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders including Alzheimer's disease (AD). Studies have liked higher iron levels in males with younger age at onset and presence of the HFE hemochromatosis and transferrin C2 gene variants (iron genes) with AD. Examine whether cognitive performance in healthy older individuals is associated with increased brain ferritin iron and highly prevalent iron genes. Ferritin iron can be measured with specificity in vivo with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. FDRI was assessed in basal ganglia, hippocampus, and white matter. 48% of the sample carried neither gene (the IRON- group) and 52% carried one and/or the other (IRON+ group). A robust gender by gene group interaction was observed. IRON+ men had significantly higher FDRI compared to the IRON- group but in secondary analyses only the caudate nucleus showed a significant FDRI increase in IRON+ compared to IRON- men (t = 2.31, p = .027). This gene effect was not observed in women. Independent of genes, memory performance was significantly associated with hippocampal iron in men but not in women. This is the first evidence that these prevalent mutations can influence brain iron levels in men. Irrespective of gene status, verbal memory is negatively associated with hippocampal iron accumulation in men. Clinical phenomena such as gender-associated risk of developing neurodegenerative diseases and age at onset may be associated with the interactions between iron genes and brain ferritin iron accumulation. Reducing brain iron accumulations in old age may be a worthwhile therapeutic target for age-related neurodegenerative diseases.

Cognitive impairment is exceedingly common among patients with Parkinson's disease (PD), and a variety of cognitive domains are impaired early in PD. Both mild cognitive impairment (PDMCI) and dementia (PDD) are associated with PD. The brain changes accompanying cognitive decline in PD are still not fully established. We applied tensor based morphometry (TBM) to 3D T1-weighted MRI scans of 20 age-matched cognitively normal elderly (NC), 9 cognitively normal PD (PDND), 6 PDMCI, and 15 PDD subjects. We warped each individual image to the unbiased geometrical NC average template and created Jacobian maps showing the expansion or compression factor at each image point and statistical maps of between-group differences. Like voxel-based morphometry (VBM), TBM detects volumetric differences throughout the brain revealing 3D profiles of tissue excess or loss, creating statistical p maps. Relative to NC, PDD subjects showed significant atrophy (p < 0.01) bilaterally in frontopolar and temporo-occipital areas; on the right in the posterior medial frontal, lateral medial temporal, lateral parieto-occipital and precuneal areas and on the left in the inferior and middle temporal areas. Relative to NC, PDMCI subjects showed significant atrophy (p < 0.01) in the left pregenual cingulate, right frontopolar, and precuneal, and bilaterally in the medial temporal areas. Relative to NC, in the PDND group only a few areas of significant tissue loss (p < 0.01) were found on the right side in the parahippocampal gyrus/medial temporal lobe, lateral medial temporal, medial frontal and postcentral areas. Cognitive decline in PD is associated with tissue loss. PDD subjects show detectable atrophy in more areas of the brain than PDMCI subjects. Cognitive decline in PD seems to be associated with medial and lateral frontal, medial and inferior temporal, precuneal and parietal atrophy. The dementia profile of PDD is characterised by executive, visuospatial and attentional impairment. This corresponds well with the areas of tissue loss shown in this study.

The extensive scope of myelination is the single-most unique aspect in which the human brain differs from that of other species. In this “myelin model” of human evolution and development, our brain's extensive myelination accounts for the high processing speeds underlying our higher cognitive and behavioral functions as well as our unique susceptibility to develop Alzheimer's Disease (AD). In older age the breakdown of myelin integrity likely underlies both the trajectory of age-related decline in cognitive functions as well as the “age risk factor” for the increasing protein deposits that have been used to define the pathology of AD. To test the hypothesis that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte- and myelin-associated iron thus promoting amyloid beta (Aβ) oligomerization, its associated toxicity, and the deposition of oligomerized Aβ and iron in neuritic plaques observed in AD. The model was tested using published maps of cortical myelination from year 1901 and recent in vivo imaging maps of Aβ deposits in humans. The data show that in AD, radio labeled ligands detect Aβ deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the failure of imaging ligands to bind Aβ in animal models is consistent with their much lower levels of myelin and associated iron levels when compared to humans. The hypotheses derived from the myelin model of the human brain are testable with current imaging methods that can measure myelin integrity, brain iron levels, and protein deposits in vivo. The myelin model of the human brain has important implications for preventive and therapeutic interventions and suggests that such interventions should be expanded to include novel targets such as oligodendrocytes, myelin, and brain iron.

The process of myelination peaks in middle age followed by myelin breakdown and loss. Investigations of information processing speed performance across the lifespan reveal a trajectory that parallels myelination and subsequent myelin breakdown. Myelin breakdown may result in a progressive “disconnection” of widely distributed neural networks and may underlie age–related cognitive decline and Alzheimer's disease (AD). This study tests the “myelin model”/hypothesis that in older individuals, myelin breakdown in late–myelinating regions is associated with slowed processing speed and contributes to the continuum of cognitive decline that ultimately results in AD. Healthy older (>55 years) individuals (N=92) and 8 subjects with Alzheimer's disease (AD) had neurocognitive testing. The late–myelinating frontal lobe white matter (Fwm) as well as early– and later–myelinating regions of the corpus callosum, the splenium (Swm) and genu (Gwm) respectively, were assessed using MRI and transverse relaxation rates (R2) were calculated. R2 is an indirect measure of white matter structural integrity; it declines with age–related myelin breakdown and is significantly lower in AD. As hypothesized, cognitive processing speed tasks (Trails A and Digit Symbol) were significantly associated with R2 in late–myelinating regions (Fwm, p<.0001 and Gwm, p<.004) but not in the early myelinating Swm region (p>.2). These data suggest that myelin breakdown in healthy older individuals underlies the age–related cognitive decline that ultimately results in AD. MRI measures of myelin breakdown and cognitive measures may be useful in AD primary prevention studies.

The process of myelination peaks in middle age followed by myelin breakdown and loss. Investigations of information processing speed performance across the lifespan reveal a trajectory that parallels myelination and subsequent myelin breakdown. Myelin breakdown may result in a progressive “disconnection” of widely distributed neural networks and may underlie age–related cognitive decline and Alzheimer's disease (AD). This study tests the “myelin model”/hypothesis that in older individuals, myelin breakdown in late–myelinating regions is associated with slowed processing speed and contributes to the continuum of cognitive decline that ultimately results in AD. Healthy older (>55 years) individuals (N=92) and 8 subjects with Alzheimer's disease (AD) had neurocognitive testing. The late–myelinating frontal lobe white matter (Fwm) as well as early– and later–myelinating regions of the corpus callosum, the splenium (Swm) and genu (Gwm) respectively, were assessed using MRI and transverse relaxation rates (R2) were calculated. R2 is an indirect measure of white matter structural integrity; it declines with age–related myelin breakdown and is significantly lower in AD. As hypothesized, cognitive processing speed tasks (Trails A and Digit Symbol) were significantly associated with R2 in late–myelinating regions (Fwm, p<.0001 and Gwm, p<.004) but not in the early myelinating Swm region (p>.2). These data suggest that myelin breakdown in healthy older individuals underlies the age–related cognitive decline that ultimately results in AD. MRI measures of myelin breakdown and cognitive measures may be useful in AD primary prevention studies.