The role of carotid intima-media thickness in predicting longitudinal cognitive function in an older adult cohort.

BACKGROUND AND PURPOSE: Carotid atherosclerosis is a risk factor for cerebrovascular disease in older adults. Although age-related cognitive decline has been associated with cerebrovascular disease, not much is known about the consequences of carotid atherosclerosis on longitudinal cognitive function. This study examines the longitudinal relationship between atherosclerosis and cognition in a sample of non-demented older subjects using baseline measurements of carotid intima media thickness (CIMT) and annual cognitive measures of executive function (EXEC) and verbal memory (MEM). METHODS: Baseline measurements included CIMT derived from B-mode carotid artery ultrasound, structural T1-weighted images of white matter hypointensities (WMH), white matter lesions (WML), and cerebral infarct. Hypertension, low-density lipoprotein (LDL), diabetes, and waist to hip ratios (WHR) were included as covariates in our models to control for cerebrovascular risks and central adiposity. Annual composite scores of EXEC and MEM functions were derived from item response theory. Linear mixed models were used to model longitudinal cognitive change. RESULTS: A significant inverse relationship was found between baseline CIMT and annual EXEC score, but not annual MEM score. Subjects included in the highest 4th quartile of CIMT showed a rate of annual decline in EXEC score that was significant relative to subjects in lower quartile groups (p<0.01). The relationship between the 4th quartile of CIMT and annual EXEC score remained significant after independently adjusting for imaging measures of white matter injury and cerebral infarct. CONCLUSIONS: Older adult subjects with the highest index of CIMT showed an annual decline in EXEC scores that was significant relative to subjects with lower quartile measurements of CIMT, independent of our measures of white matter injury and cerebral infarct. Our findings suggest that elevated measures of CIMT may mark an atherosclerotic state, resulting in a decline in executive function and not memory in non-demented older adults.

Everyday cognition in older adults: associations with neuropsychological performance and structural brain imaging.

The recently developed Everyday Cognition scales (ECog) measure multiple cognitively relevant functional domains (e.g., Everyday Memory, Everyday Language, Everyday Visuospatial abilities, and three everyday executive domains). The present study further evaluated the validity of the ECog by examining its relationship with objective measures of neuropsychological function, and neurobiological markers of disease as reflected by structural neuroimaging. Participants included 474 older adults (244 normals, 142 with MCI, 88 with dementia). The neuropsychological domains measured were episodic memory, semantic memory, spatial ability, and executive functioning. Brain MRI volumes included total brain (BV), hippocampus (HC) and dorsolateral prefrontal cortex (DLPFC). Neuropsychological measures of episodic memory and executive function were most consistently related to the ECog domains; spatial abilities had a specific relationship to the Everyday Visuospatial ECog domain. HC and BV volumes were related to most ECog domains, while DLPFC volume was independently related to two everyday executive domains (Everyday Planning and Everyday Organization). The pattern of associations varied somewhat as a function of diagnosis. Episodic memory and HC had more consistent associations with the ECog domains in older adults with MCI/dementia than in cognitively normal elderly.

Cognitive activities during adulthood are more important than education in building reserve.

Cognitive reserve is thought to reflect life experiences. Which experiences contribute to reserve and their relative importance is not understood. Subjects were 652 autopsied cases from the Rush Memory and Aging Project and the Religious Orders Study. Reserve was defined as the residual variance of the regressions of cognitive factors on brain pathology and was captured in a latent variable that was regressed on potential determinants of reserve. Neuropathology variables included Alzheimer's disease markers, Lewy bodies, infarcts, microinfarcts, and brain weight. Cognition was measured with six cognitive domain scores. Determinants of reserve were socioeconomic status (SES), education, leisure cognitive activities at age 40 (CA40) and at study enrollment (CAbaseline) in late life. The four exogenous predictors of reserve were weakly to moderately inter-correlated. In a multivariate model, all except SES had statistically significant effects on Reserve, the strongest of which were CA40 (ß = .31) and CAbaseline (ß = .28). The Education effect was negative in the full model (ß = -.25). Results suggest that leisure cognitive activities throughout adulthood are more important than education in determining reserve. Discrepancies between cognitive activity and education may be informative in estimating late life reserve.

Neuropathological associates of multiple cognitive functions in two community-based cohorts of older adults.

Studies of neuropathology-cognition associations are not common and have been limited by small sample sizes, long intervals between autopsy and cognitive testing, and lack of breadth of neuropathology and cognition variables. This study examined domain-specific effects of common neuropathologies on cognition using data (N = 652) from two large cohort studies of older adults. We first identified dimensions of a battery of 17 neuropsychological tests, and regional measures of Alzheimer's disease (AD) neuropathology. We then evaluated how cognitive factors were related to dimensions of AD and additional measures of cerebrovascular and Lewy Body disease, and also examined independent effects of brain weight. All cognitive domains had multiple neuropathology determinants that differed by domain. Neocortical neurofibrillary tangles were the strongest predictors of most domains, while medial temporal tangles showed a weaker relationship with episodic memory. Neuritic plaques had relatively strong effects on multiple domains. Lewy bodies and macroscopic infarcts were associated with all domains, while microscopic infarcts had more limited associations. Brain weight was related to all domains independent of specific neuropathologies. Results show that cognition is complexly determined by multiple disease substrates. Neuropathological variables and brain weight contributed approximately a third to half of the explained variance in different cognitive domains.

Measuring cognitive reserve based on the decomposition of episodic memory variance.

In later adulthood brain pathology becomes common and trajectories of cognitive change are heterogeneous. Among the multiple determinants of late-life cognitive course, cognitive reserve has been proposed as an important factor that modifies or buffers the impact of brain pathology on cognitive function. This article presents and investigates a novel method for measuring and investigating such factors. The core concept is that in a population where pathology is common and variably present, 'reserve' may be defined as the difference between the cognitive performance predicted by an individual's level of pathology and that individual's actual performance. By this definition, people whose measured cognitive performance is better than predicted by pathology have high reserve, whereas those who perform worse than predicted have low reserve. To test this hypothesis, we applied a latent variable model to data from a diverse ageing cohort and decomposed the variance in a measure of episodic memory into three components, one predicted by demographics, one predicted by pathology as measured by structural MRI and a 'residual' or 'reserve' term that included all remaining variance. To investigate the plausibility of this approach, we then tested the residual component as an operational measure of reserve. Specific predictions about the effects of this putative reserve measure were generated from a general conceptual model of reserve. Each was borne from the results. The results show that the current level of reserve, as measured by this decomposition approach, modifies rates of conversion from mild cognitive impairment to dementia, modifies rates of longitudinal decline in executive function and, most importantly, attenuates the effect of brain atrophy on cognitive decline such that atrophy is more strongly associated with cognitive decline in subjects with low reserve than in those with high reserve. Decomposing the variance in cognitive function scores offers a promising new approach to the measure and study of cognitive reserve.

Cognitive decline in the elderly: an analysis of population heterogeneity.

BACKGROUND: studies of cognitive ageing at the group level suggest that age is associated with cognitive decline; however, there may be individual differences such that not all older adults will experience cognitive decline. OBJECTIVE: to evaluate patterns of cognitive decline in a cohort of older adults initially free of dementia. DESIGN, SETTING AND SUBJECTS: elderly Catholic clergy members participating in the Religious Orders Study were followed for up to 15 years. Cognitive performance was assessed annually. METHODS: performance on a composite global measure of cognition was analysed using random effects models for baseline performance and change over time. A profile mixture component was used to identify subgroups with different cognitive trajectories over the study period. RESULTS: from a sample of 1,049 participants (mean age 75 years), three subgroups were identified based on the distribution of baseline performance and change over time. The majority (65%) of participants belonged to a slow decline class that did not experience substantial cognitive decline over the observation period [-0.04 baseline total sample standard deviation (SD) units/year]. About 27% experienced moderate decline (-0.19 SD/year), and 8% belonged to a class experiencing rapid decline (-0.57 SD/year). A subsample analysis revealed that when substantial cognitive decline does occur, the magnitude and rate of decline is correlated with neuropathological processes. CONCLUSIONS: in this sample, the most common pattern of cognitive decline is extremely slow, perceptible on a time scale measured by decades, not years. While in need of cross validation, these findings suggest that cognitive changes associated with ageing may be minimal and emphasise the importance of understanding the full range of age-related pathologies that may diminish brain function.

The measurement of everyday cognition: development and validation of a short form of the Everyday Cognition scales.

BACKGROUND: This study describes the development and validation of a shortened version of the Everyday Cognition (ECog) scales [Tomaszewski Farias et al. Neuropsychology 2008;22:531-44], an informant-rated questionnaire designed to detect cognitive and functional decline. METHODS: External, convergent, and divergent validities and internal consistency were examined. Data were derived from informant ratings of 907 participants who were either cognitively normal, had mild cognitive impairment (MCI), or had dementia. RESULTS: Twelve items were included in the shortened version (ECog-12). The ECog-12 strongly correlated with established functional measures and neuropsychological scores, only weakly with age and education, and demonstrated high internal consistency. The ECog-12 showed excellent discrimination between the dementia and normal groups (area under the receiver operator characteristic curve = 0.95, CI = 0.94-0.97), and showed promise in discriminating normal older adults from those with any cognitive impairment (i.e., MCI or dementia). Discrimination between the MCI and normal groups was poor. CONCLUSIONS: The ECog-12 shows promise as a clinical tool for assisting clinicians in identifying individuals with dementia.

Recruitment of a community-based cohort for research on diversity and risk of dementia.

We describe the history, development, and success of the recruitment and screening procedures used by researchers at the University of California, Davis Alzheimer's Disease Center (UCD ADC) to facilitate minority enrollment in research. After an initial, unsuccessful approach with satellite clinics in minority neighborhoods, the ADC shifted to an active community outreach approach. Multiple strategies were implemented to remove barriers to research participation such as providing transportation to clinical appointments and offering in-home cognitive screening. Considerable resources were directed toward hiring and training bicultural and bilingual individuals with knowledge of the target populations, both as recruiters and staff involved in clinical assessment. Implementation of these methods resulted in a dramatic increase in the number of ethnic minorities enrolled (and retained) in research protocols, including protocols that are complex and longitudinal. Diversity was achieved on other variables as well; years of education in the cohort range from 0 to 21, with 26% having 8 years or less. The community screen identified candidates for an in depth clinical evaluation and enrollment in longitudinal research, and we examined factors that predicted a positive response to invitation for the clinical evaluation. Individuals with a broader fund of knowledge were more likely to participate independent of other variables including ethnicity and education. When diversity is an important goal active outreach is far more efficacious than clinic-based and advertising-based approaches to recruitment.

Neuropathological basis of magnetic resonance images in aging and dementia.

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

Computer-based cognitive training for mild cognitive impairment: results from a pilot randomized, controlled trial.

We performed a pilot randomized, controlled trial of intensive, computer-based cognitive training in 47 subjects with mild cognitive impairment. The intervention group performed exercises specifically designed to improve auditory processing speed and accuracy for 100 min/d, 5 d/wk for 6 weeks; the control group performed more passive computer activities (reading, listening, visuospatial game) for similar amounts of time. Subjects had a mean age of 74 years and 60% were men; 77% successfully completed training. On our primary outcome, Repeatable Battery for Assessment of Neuropsychological Status total scores improved 0.36 standard deviations (SD) in the intervention group (P=0.097) compared with 0.03 SD in the control group (P=0.88) for a nonsignificant difference between the groups of 0.33 SD (P=0.26). On 12 secondary outcome measures, most differences between the groups were not statistically significant. However, we observed a pattern in which effect sizes for verbal learning and memory measures tended to favor the intervention group whereas effect sizes for language and visuospatial function measures tended to favor the control group, which raises the possibility that these training programs may have domain-specific effects. We conclude that intensive, computer-based mental activity is feasible in subjects with mild cognitive impairment and that larger trials are warranted.

Age and education effects on relationships of cognitive test scores with brain structure in demographically diverse older persons.

This study examined how age and education influence the relationship between neuropsychological test scores and brain structure in demographically diverse older adults spanning the range from normal cognition to dementia. A sample of 351 African Americans, 410 Hispanics, and 458 Whites underwent neuropsychological testing. Volumetric magnetic resonance imaging (MRI) measures of total brain, white matter hyperintensity, and hippocampus were available for 79 African Americans, 102 Hispanics, and 134 Whites. The authors used latent variable modeling to examine effects of age, education, and brain volumes on test scores and determine how much variance brain volumes explained in unadjusted and age- and education-adjusted scores. Age adjustment resulted in weaker relationships of test scores with MRI variables; adjustment for ethnicity yielded stronger relationships. Education adjustment increased relationships with MRI variables in the combined sample and Hispanics, made no difference in Whites, but decreased some associations in African Americans. Results suggest that demographic adjustment is beneficial when demographic variables are strongly related to test scores independent of measures of brain structure, but adjustment has negative consequences when effects of demographic characteristics are mediated by brain structure.

Subcortical lacunes are associated with executive dysfunction in cognitively normal elderly.

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

Diagnosing depression in Alzheimer disease with the national institute of mental health provisional criteria.

OBJECTIVE: To compare the rates of depression in Alzheimer Disease (AD) determined using National Institute of Mental Health (NIMH) provisional criteria for depression in AD (NIMH-dAD) to those determined using other established depression assessment tools. DESIGN: Descriptive longitudinal cohort study. SETTING: The Alzheimer's Disease Research Centers of California. PARTICIPANTS: A cohort of 101 patients meeting NINDS-ADRDA criteria for possible/probable AD, intentionally selected to increase the frequency of depression at baseline. MEASUREMENTS: Depression was diagnosed at baseline and after 3 months using NIMH-dAD criteria and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I Disorders. Depressive symptoms also were assessed with the Cornell Scale for Depression in Dementia (CSDD), the Geriatric Depression Scale (GDS), and the Neuropsychiatric Inventory Questionnaire. RESULTS: The baseline frequency of depression using NIMH-dAD criteria (44%) was higher than that obtained using DSM-IV criteria for major depression (14%; Z = -5.50, df = 101, p <0.001) and major or minor depression (36%; Z = -2.86, df = 101, p = 0.021) or using established cut-offs for the CSDD (30%; Z = -2.86, df = 101, p = 0.004) or GDS (33%; Z = -2.04, df = 101, p = 0.041). The NIMH-dAD criteria correctly identified all patients meeting DSM-IV criteria for major depression, and correlated well with DSM-IV criteria for major or minor depression (kappa = 0.753, p <0.001), exhibiting 94% sensitivity and 85% specificity. The higher rates of depression found with NIMH-dAD criteria derived primarily from its less stringent requirements for the frequency and duration of symptoms. Remission rates at 3 months were similar across instruments. CONCLUSIONS: The NIMH-dAD criteria identify a greater proportion of AD patients as depressed than several other established tools.

The measurement of everyday cognition (ECog): scale development and psychometric properties.

This article describes the development and validation of an instrument to assess cognitively mediated functional abilities in older adults, Everyday Cognition (ECog). The ECog is an informant-rated questionnaire comprised of multiple subscales. Confirmatory factor analysis (CFA) was used to examine its factor structure. Convergent validity was evaluated by comparing it to established measures of everyday function. External validity was evaluated by comparing ECog results across different clinical groups [cognitively normal, mild cognitive impairment (MCI), dementia]. CFA supported a seven-factor model including one global factor and six domain-specific factors (Everyday Memory, Language, Visuospatial Abilities, Planning, Organization, and Divided attention). The ECog correlated with established measures of functional status and global cognition, but only weakly with age and education. The clinical groups performed differently in each domain. In addition to the global factor, the Everyday Memory factor independently differentiated MCI from Normal, while the Everyday Language domain differentiated Dementia from MCI. Different subtypes of MCI also showed different patterns. Results suggest the ECog shows promise as a useful tool for the measurement of general and domain-specific everyday functions in the elderly.

Composite scores for executive function items: demographic heterogeneity and relationships with quantitative magnetic resonance imaging.

Accurate neuropsychological assessment of older individuals from heterogeneous backgrounds is a major challenge. Education, ethnicity, language, and age are associated with scale level differences in test scores, but item level bias might contribute to these differences. We evaluated several strategies for dealing with item and scale level demographic influences on a measure of executive abilities defined by working memory and fluency tasks. We determined the impact of differential item functioning (DIF). We compared composite scoring strategies on the basis of their relationships with volumetric magnetic resonance imaging (MRI) measures of brain structure. Participants were 791 Hispanic, white, and African American older adults. DIF had a salient impact on test scores for 9% of the sample. MRI data were available on a subset of 153 participants. Validity in comparison with structural MRI was higher after scale level adjustment for education, ethnicity/language, and gender, but item level adjustment did not have a major impact on validity. Age adjustment at the scale level had a negative impact on relationships with MRI, most likely because age adjustment removes variance related to age-associated diseases.

Brain behavior relationships among African Americans, whites, and Hispanics.

There is an increasing racial and ethnic diversity within the elderly population of the United States. Although increased diversity offers unique opportunities to study novel influences on aging and dementia, some aspects of racial and ethnic research have been hampered by the lack of culturally and linguistically consistent testing protocols. Structural brain imaging is commonly used to study the biology of normal aging and cognitive impairment and may therefore serve to explore potential biologic differences of cognitive impairment among racially and ethnically diverse individuals. To test this hypothesis, we recruited a cohort of approximately 400 African American, white, and Hispanic subjects with various degrees of cognitive ability. Each subject was carefully evaluated using standardized diagnostic protocols that included clinical review of brain magnetic resonance image (MRI) to arrive at a clinical diagnosis of normal cognition, mild cognitive impairment or dementia. Each MRI was then independently quantified for measures of brain, white matter hyperintensities, and hippocampal volumes by a technician blind to subject age, sex, ethnicity, race, and diagnostic category. The appearance of infarction on MRI was also rated by examining neurologists. Regression analyses were used to assess associations with various MRI measures across clinical diagnostic categories in relation to racial and ethnic differences. Hispanic subjects were, on average, significantly younger and had less years of education than African Americans or whites. Whites with dementia were significantly older than both African American and Hispanic dementia patients. Highly significant differences in MRI measures were associated with clinical diagnoses for the group as a whole after adjusting for the effects of age, sex, education, race, and ethnicity. Subsequent independent analyses by racial and ethnic status revealed consistent relationships between diagnostic category and MRI measures. Clinical diagnoses were associated with consistent differences in brain structure among a group of racially and ethnically diverse individuals. We believe these results help to validate current diagnostic assessment of individuals across a broad range of racial, ethnic, linguistic, and educational backgrounds. Moreover, interesting and potentially biologically relevant differences were found that might stimulate further research related to the understanding of dementia etiology within an increasingly racially and ethnically diverse population.

Profiles of neuropsychological impairment in autopsy-defined Alzheimer's disease and cerebrovascular disease.

Differentiating the cognitive effects of cerebrovascular disease, particularly small vessel disease, from those of Alzheimer's disease is a difficult clinical challenge. An influential model of how subcortical cerebrovascular disease causes cognitive dysfunction posits that damage to frontostriatal loops impairs frontal lobe function, leading to predominant impairment of executive function and secondary impairments of associated cognitive functions such as memory. Consistent with this, neuropsychological studies of clinically diagnosed patients have reported that individuals with vascular dementia do better on memory tests and worse on executive function tests compared with patients with Alzheimer's disease. This observation has led to the suggestion that predominant cognitive executive dysfunction might serve as a useful diagnostic marker for vascular dementia. We sought to test this idea in a series of cases with autopsy-defined pathologies. Subjects were 62 autopsied cases from a prospective study of vascular contributions to dementia. Using neuropathological features alone, 23 were diagnosed with Alzheimer's disease (AD), 11 with cerebrovascular disease (CVD), 9 with both (mixed pathology) and 19 with normal elderly brain (NEB). Three psychometrically matched composite scales of different cognitive abilities were used: Verbal Memory, Nonverbal Memory and Executive Function. Analysis of group data showed that for Alzheimer's disease memory scores were lower than Executive Function by nearly a standard deviation on average. In contrast, and contrary to the model, CVD was rather equally impaired on Executive Function, Verbal Memory and Nonverbal Memory. Individual patterns of cognitive impairment were examined by defining three profiles based on reliable differences between neuropsychological scores to characterize cases with predominant memory impairment, predominant executive dysfunction, and 'other' patterns. Analysis of individual impairment profiles showed that predominant memory impairment was present in 71% of Alzheimer's disease while predominant executive dysfunction described only 45% of CVD. A stronger pattern emerged when cognitively normal cases were excluded; among the six cognitively impaired CVD patients four had predominant executive dysfunction and none had predominant memory impairment. This report, comprised of a substantial sample of autopsy confirmed cases, delineates the patterns of neuropsychological impairment associated with small vessel cerebrovascular disease and Alzheimer's disease While the findings show that memory loss usually exceeds executive dysfunction in patients with Alzheimer's disease, the reverse is not the case in CVD. Taken as a whole, the results indicate that the cognitive effects of the small vessel cerebrovascular disease are variable and not especially distinct, thus raising question about the utility of executive impairment as a diagnostic marker for vascular dementia.

Longitudinal MRI and cognitive change in healthy elderly.

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

Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease.

BACKGROUND: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-ß (Aß), including Aß42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. OBJECTIVE: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other. METHODS: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage. RESULTS: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aß42 and decreased APP and Notch intracellular domain production in vitro. CONCLUSION: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aß.

Association between Cholesterol Exposure and Neuropathological Findings: The ACT Study.

We characterized the relationship between late life cholesterol exposure and neuropathological outcomes in a community-based, older adult cohort. Adult Changes in Thought (ACT) is a cohort study that enrolls consenting, randomly selected, non-demented people aged ≥65 from a healthcare delivery system. We used late life HDL and total cholesterol lab values from Group Health computerized records, and calculated HDL and non-HDL levels. We evaluated neuropathological outcomes of Alzheimer's disease, cerebral amyloid angiopathy, vascular brain injury, and Lewy body disease. Using linear mixed models with age and antilipemic medication as predictors, we obtained predicted cholesterol values at age 70 and 10 years prior to death for individuals with available cholesterol data in 10-year exposure windows. We used logistic regression to determine whether predicted late life cholesterol levels were associated with neuropathological outcomes controlling for age at death, APOE genotype, sex, and their interactions with cholesterol levels. 525 decedents came to autopsy by 08/2014. Of these, plasma cholesterol concentration was available for 318 (age 70, model 1) and 396 (10 years prior to death, model 2) participants. We did not find associations between late life cholesterol and Alzheimer's disease neuropathological changes, and there were no associations between cholesterol levels and amyloid angiopathy or vascular brain injury. We observed an association between predicted non-HDL cholesterol at age 70 and Lewy body disease. Our study suggests an association between late life non-HDL cholesterol exposure and Lewy body disease. We did not observe associations between late life cholesterol levels and Braak stage or CERAD score.