Measurement and Structure of Cognition in the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia.

OBJECTIVES: To test whether a relatively complex model of human cognitive abilities based on Cattell-Horn-Carroll (CHC) theory, developed mainly in English-speaking samples, adequately describes correlations among tests in the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD), and to develop accurate measures of cognition for older individuals in India. DESIGN: LASI-DAD participants were recruited from participants aged 60 years and older from 14 states in the core LASI survey, with a stratified sampling design. SETTING: Participants were interviewed at home or in a participating hospital, according to their preferences. PARTICIPANTS: Community-residing older adults aged 60 years and older (N = 3,224). MEASUREMENTS: A variety of cognitive tests were administered during two pretests and chosen for their appropriateness for measuring cognition in older adults in India and suitability for calibration with the core LASI survey and the Harmonized Cognitive Assessment Protocol. RESULTS: We evaluated the factor structure of the test battery and its conformity with a classical CHC factor model that incorporated measurement models for general cognition, five broad domains (orientation, executive functioning, language/fluency, memory, and visuospatial), and five narrow domains (reasoning, attention/speed, immediate memory, delayed memory, and recognition memory) of cognitive performance. Model fit was adequate (root mean square error of approximation = 0.051; comparative fit index = 0.916; standardized root mean squared residual = 0.060). CONCLUSION: We demonstrated configural factorial invariance of a cognitive battery in the Indian LASI-DAD using CHC theory. Broad domain factors may be used in future research to rank individuals with respect to cognitive performance and classify cognitive impairment. J Am Geriatr Soc 68:S11-S19, 2020.

Long-term changes in retinal vascular diameter and cognitive impairment in type 1 diabetes.

OBJECTIVE: To assess associations between cognitive impairment and longitudinal changes in retinal microvasculature, over 18 years, in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: Participants of the Pittsburgh Epidemiology of Diabetes Complications Study received ≥3 fundus photographs between baseline (1986-1988) and time of cognitive assessment (2010-2015: N = 119; 52% male; mean age and type 1 diabetes duration 43 and 34 years, respectively). Central retinal arteriolar equivalent and central retinal venular equivalent were estimated via computer-based methods; overall magnitude and speed of narrowing were quantified as cumulative average and slope, respectively. Median regression models estimated associations of central retinal arteriolar equivalent and central retinal venular equivalent measures with cognitive impairment status, adjusted for type 1 diabetes duration. Interactions with HbA1c, proliferative retinopathy and white matter hyperintensities were assessed. RESULTS: Compared with participants without cognitive impairment, those with clinically relevant cognitive impairment experienced 1.8% greater and 31.1% faster central retinal arteriolar equivalent narrowing during prior years (t = -2.93, p = 0.004 and t = -3.97, p < 0.0001, respectively). Interactions with HbA1c, proliferative retinopathy and white matter hyperintensities were not significant. No associations were found between central retinal arteriolar equivalent at baseline, at time of cognitive testing, or any central retinal venular equivalent measures, and cognitive impairment. CONCLUSION: Long-term arterial retinal changes could indicate type 1 diabetes-related cognitive impairment. Studies examining longitudinal central retinal arteriolar equivalent changes as early biomarkers of cognitive impairment risk are warranted.

Genetic Risk Score Predicts Late-Life Cognitive Impairment.

Introduction. A family history of Alzheimer's disease is a significant risk factor for its onset, but the genetic risk associated with possessing multiple risk alleles is still poorly understood. Methods. In a sample of 95 older adults (Mean age = 75.1, 64.2% female), we constructed a genetic risk score based on the accumulation of risk alleles in BDNF, COMT, and APOE. A neuropsychological evaluation and consensus determined cognitive status (44 nonimpaired, 51 impaired). Logistic regression was performed to determine whether the genetic risk score predicted cognitive impairment above and beyond that associated with each gene. Results. An increased genetic risk score was associated with a nearly 4-fold increased risk of cognitive impairment (OR = 3.824, P = .013) when including the individual gene polymorphisms as covariates in the model. Discussion. A risk score combining multiple genetic influences may be more useful in predicting late-life cognitive impairment than individual polymorphisms.

Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife.

OBJECTIVES: The development of Type 1 diabetes mellitus (T1DM) within the first 7 years of life has been linked to poorer cognitive performance. Adults with T1DM have altered functional brain connectivity, but no studies have examined whether earlier age of T1DM onset is associated with functional connectivity later in life. Accordingly, we tested the relationship between age of onset and resting state functional connectivity in a cohort of middle-aged adults with childhood-onset T1DM. METHODS: Participants were from a subsample of the Pittsburgh Epidemiology of Diabetes Complications cohort and included 66 adults (mean age = 47.54 years, 32 men). Resting state blood oxygen level-dependent activity was used to calculate mean connectivity for eight functional brain networks. A multivariate analysis of variance examined associations between age of onset and network connectivity. Diffusion tensor and fluid-attenuated inversion recovery images were analyzed to identify microstructural alterations and white-matter hyperintensity volumes. RESULTS: Later childhood onset of T1DM was associated with lower connectivity (F(8,57) = 2.40, p = .026). A significant interaction was present for current age such that an inverse association with age of onset for functional connectivity was present in older individuals (F(8,55) = 2.88, p = .035). Lower connectivity was associated with older age, increased white-matter hyperintensity volume, and lower microstructural integrity. CONCLUSIONS: Diagnosis of T1DM later in childhood may be associated with lower brain functional connectivity, particularly in those surviving into older ages. These alterations may be an early marker for subsequent cognitive decrements. Future studies are warranted to understand the pathways underlying these associations.

Clinically Relevant Cognitive Impairment in Middle-Aged Adults With Childhood-Onset Type 1 Diabetes.

OBJECTIVE: The aim of this study was to investigate the presence and correlates of clinically relevant cognitive impairment in middle-aged adults with childhood-onset type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: During 2010-2013, 97 adults diagnosed with T1D and aged <18 years (age and duration 49 ± 7 and 41 ± 6 years, respectively; 51% female) and 138 similarly aged adults without T1D (age 49 ± 7 years; 55% female) completed extensive neuropsychological testing. Biomedical data on participants with T1D were collected periodically since 1986-1988. Cognitive impairment status was based on the number of test scores ≥1.5 SD worse than demographically appropriate published norms: none, mild (only one test), or clinically relevant (two or more tests). RESULTS: The prevalence of clinically relevant cognitive impairment was five times higher among participants with than without T1D (28% vs. 5%; P < 0.0001), independent of education, age, or blood pressure. Effect sizes were large (Cohen d 0.6-0.9; P < 0.0001) for psychomotor speed and visuoconstruction tasks and were modest (d 0.3-0.6; P < 0.05) for measures of executive function. Among participants with T1D, prevalent cognitive impairment was related to 14-year average A1c >7.5% (58 mmol/mol) (odds ratio [OR] 3.0; P = 0.009), proliferative retinopathy (OR 2.8; P = 0.01), and distal symmetric polyneuropathy (OR 2.6; P = 0.03) measured 5 years earlier; higher BMI (OR 1.1; P = 0.03); and ankle-brachial index ≥1.3 (OR 4.2; P = 0.01) measured 20 years earlier, independent of education. CONCLUSIONS: Clinically relevant cognitive impairment is highly prevalent among these middle-aged adults with childhood-onset T1D. In this aging cohort, chronic hyperglycemia and prevalent microvascular disease were associated with cognitive impairment, relationships shown previously in younger populations with T1D. Two additional potentially modifiable risk factors for T1D-related cognitive impairment, vascular health and BMI, deserve further study.

Cognitive aging in persons with minimal amyloid-ß and white matter hyperintensities.

Substantial individual differences exist in the magnitude of the cognitive decline associated with normal aging. Potential contributors to this intersubject variability include white matter hyperintensities (WMH) and preclinical Alzheimer's disease, evident as increased brain amyloid. This study examined whether older individuals with minimal evidence of WMH and/or brain amyloid-beta (seen on positron emission tomography with the Pittsburgh compound B radiotracer-PiB) still showed significant cognitive decrements compared to the young. Older individuals, conservatively screened for normal range performance on an extensive neuropsychological battery, underwent structural magnetic resonance imaging (MRI) and PiB scans and performed tests of information processing speed, working memory and inhibitory function. The elderly were divided into PiB(+) and PiB(-) groups based on radiotracer retention. There were no significant differences in cognitive performance between PiB(+) and PiB(-) elderly. However, both PiB groups performed significantly worse than did the young on cognitive testing. WMH burden in the same individuals was quantified by consensus ratings using a 10 point scale with a median split defining two groups, WMH(+) and WMH(-). There were no differences in cognitive performance between WMH(+) and WMH(-) individuals, but both WMH groups performed significantly worse than did the young. Older participants who were both PiB(-) and WMH(-) also performed significantly worse than did the young in all three cognitive domains. The present results suggest that normal-elderly individuals whose brain scans show minimal evidence of amyloid deposition or WMH, still demonstrate a major decrement in comparison to younger persons on measures of processing resources and inhibitory efficiency.

In vivo assessment of amyloid-ß deposition in nondemented very elderly subjects.

OBJECTIVE: This study examined amyloid-ß (Aß) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aß-positive scans and associations with cognition, apolipoprotein E (APOE) status, brain volume, and Ginkgo biloba (Gb) treatment. METHODS: Subjects who agreed to participate had a brain magnetic resonance imaging and positron emission tomography scan with (11) C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82 years, and the mean age of the subjects was 85.5 years at the time of the scans; 152 (80%) were cognitively normal, and 38 (20%) were diagnosed with mild cognitive impairment (MCI) at the time of the PiB study. RESULTS: A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language, and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however, no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aß deposition as determined by PiB. INTERPRETATION: The data revealed a 55% prevalence of PiB positivity in nondemented subjects age >80 years and 85% PiB positivity in the APOE*4 nondemented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aß deposition.

Classification of amyloid-positivity in controls: comparison of visual read and quantitative approaches.

UNLABELLED: An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aß) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aß deposition from those in which Aß deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(-)] subjects. METHODS: We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(-) subjects was not so distinct. RESULTS: The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence. CONCLUSION: The visual read and SKM methods, applied together, may optimize the identification of early Aß deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.

Association between Cognitive Decline in Older Adults and Use of Primary Care Physician Services in Pennsylvania.

OBJECTIVE: To assess the relationship between cognitive decline of older patients (≥ 65 y) and use of primary care physician (PCP) services over 24 months. DESIGN: Retrospective analysis of prospectively collected data from a cluster randomized trial that took place from 2006-2010 and investigated the relationship between formal neuropsychological evaluation and patient outcomes in primary care. SETTING: Twenty-four PCPs in 11 practices in southwestern Pennsylvania. Most practices were suburban and included more than 5 PCPs. PARTICIPANTS: A sample of 423 primary care patients 65 years old or older. MEASUREMENTS: The association between the number of PCP visits and a decline in cognitive status, as determined by multivariable analyses that controlled for patient-level, physician-level, and practice-level factors (eg, patient age, comorbidities, and symptoms of depression; practice location and size; PCP age and sex) and used a linear mixed model with a random intercept to adjust for clustering. RESULTS: Over a 2-year follow-up, 199 patients (47.0%) experienced a decline in cognitive status. Patients with a cognitive decline had a mean of 0.69 more PCP visits than did patients without a cognitive decline (P < .05). CONCLUSIONS: Early signs of cognitive decline may be an indicator of greater use of primary care. Given the demographic trends, more PCPs are likely to be needed to meet the increasing needs of the older population.

The greater sensitivity of elderly APOE ε4 carriers to anticholinergic medications is independent of cerebrovascular disease risk.

BACKGROUND: Recent studies found use of anticholinergic medications to be associated with greater performance decrements in older persons who carry an ε4 allele of the apolipoprotein E (APOE) gene than in those carrying only ε2 or ε3 alleles. OBJECTIVES: The present study examined whether the apparently greater behavioral toxicity of anticholinergic drugs in ε4 carriers may result from an increased risk of cerebrovascular disease, which is more common in ε4 carriers. METHODS: Cross-sectional data were available from 240 elderly community volunteers who had participated in 2 different studies of the cognitive and motor effects of normal aging. As part of these studies, information was gathered on subjects' use of anticholinergic medications (based on an inventory of medications taken within 24 hours of testing), risk of cerebrovascular disease (Framingham Stroke Risk Profile), and APOE genotype. Performance data were also available from measures of general cognitive status (Mini-Mental State Examination), executive function (Trail Making Test), mood (Geriatric Depression Scale), sleep (Pittsburgh Sleep Quality Index), and walking speed. Logistic and linear regression models were used to examine how outcomes differed between genotypes and drug use, independent of the risk of cerebrovascular disease. RESULTS: In persons with a non-ε4 genotype, anticholinergic medication use did not significantly affect any of the behavioral measures. By contrast, among ε4 carriers, those taking anticholinergic drugs performed significantly worse than did those not taking such drugs on tests of general cognitive status, executive function, mood, and sleep. Adjusting for participants' stroke risk had a minimal effect on these results. CONCLUSIONS: Anticholinergic medication use was associated with poorer performance on measures of cognition, sleep, and mood only in older persons who carried 1 or more ε4 alleles of the APOE gene; this effect did not appear to be the result of an increased risk of cerebrovascular disease.

Outcomes of mild cognitive impairment by definition: a population study.

BACKGROUND: Mild cognitive impairment (MCI) has been defined in several ways. OBJECTIVE: To determine the 1-year outcomes of MCI by different definitions at the population level. DESIGN: Inception cohort with 1-year follow-up. Participants were classified as having MCI using the following definitions operationalized for this study: amnestic MCI by Mayo criteria, expanded MCI by International Working Group criteria, Clinical Dementia Rating (CDR) = 0.5, and a purely cognitive classification into amnestic and nonamnestic MCI. SETTING: General community. PARTICIPANTS: Stratified random population-based sample of 1982 individuals 65 years and older. MAIN OUTCOME MEASURES: For each MCI definition, there were 3 possible outcomes: worsening (progression to dementia [CDR ≥ 1] or severe cognitive impairment), improvement (reversion to CDR = 0 or normal cognition), and stability (unchanged CDR or cognitive status). RESULTS: Regardless of MCI definition, over 1 year, a small proportion of participants progressed to CDR > 1 (range, 0%-3%) or severe cognitive impairment (0%-20%) at rates higher than their cognitively normal peers. Somewhat larger proportions of participants improved or reverted to normal (6%-53%). Most participants remained stable (29%-92%). Where definitions focused on memory impairment and on multiple cognitive domains, higher proportions progressed and lower proportions reverted on the CDR. CONCLUSIONS: As ascertained by several operational definitions, MCI is a heterogeneous entity at the population level but progresses to dementia at rates higher than in normal elderly individuals. Proportions of participants progressing to dementia are lower and proportions reverting to normal are higher than in clinical populations. Memory impairments and impairments in multiple domains lead to greater progression and lesser improvement. Research criteria may benefit from validation at the community level before incorporation into clinical practice.

Cognitive slowing associated with elevated serum anticholinergic activity in older individuals is decreased by caffeine use.

OBJECTIVES: This study examined whether some of the age-associated decrements in basic cognitive resources (information-processing speed and working memory) result from anticholinergic medication use (as measured by serum anticholinergic activity [SAA]) and whether such decrements are lessened by caffeine. DESIGN: Cross-sectional observational study. SETTING: University medical center. PARTICIPANTS: One hundred fifty-two normal-elderly community volunteers. MEASUREMENTS: Two tests each of information-processing speed and of working memory were administered, and blood samples were drawn before and after cognitive testing to determine serum levels of anticholinergic activity and of paraxanthine-a caffeine metabolite. RESULTS: Elevated SAA was associated with a significant but modest slowing in information-processing time but only in those individuals who had low levels of serum paraxanthine. SAA did not correlate with performance on tests of working memory. CONCLUSIONS: These results suggest that anticholinergic medications are a relatively minor contributor to the decrements in basic processing resources commonly found in studies of normal aging.

Temporal stability of receptiveness to clinical research on Alzheimer disease.

Research advance directives are a proposed mechanism for ensuring that decisions with regard to research participation adhere to preferences voiced by persons with Alzheimer disease (AD) before losing decisional capacity. Although this approach rests on the assumption that preferences with regard to research participation are consistent over time, little is known about the stability of such preferences. The purpose of this study was to evaluate the temporal stability of older adults' receptiveness to participation in clinical trials, neuroimaging studies, and psychosocial investigations on AD. One hundred and four participants in the University of Pittsburgh Alzheimer Disease Research Center were annually surveyed with regard to their willingness to be contacted with regard to clinical drug trials, neuroimaging studies, and psychosocial research for which they might be eligible. Receptiveness to contact with regard to AD research was compared at 2 time points, 1 year apart. At baseline, most respondents were willing to be contacted with regard to their eligibility for drug trials, imaging studies, and psychosocial research. Thirty-seven percent of respondents voiced a different set of preferences at year 2 as compared with year 1. Differences included both increased and decreased willingness to be contacted. Neither stability of preferences nor direction of change (more vs. less willing) varied by diagnostic group. Bivariate analyses revealed that participation in at least 1 ancillary research study was associated with an overall increase in willingness to be contacted. We conclude that a significant proportion of research-friendly individuals voice different sets of preferences with regard to the possibility of research participation when queried at different points in time. Amenability to participating in clinical research on AD is a relatively dynamic personal attribute that may be influenced by personal experience with research participation. This finding has relevance for the policy debate around research advance directives, an approach which assumes that preferences with regard to research participation are consistent over time.

Cognitive test performance predicts change in functional status at the population level: the MYHAT Project.

In the community at large, many older adults with minimal cognitive and functional impairment remain stable or improve over time, unlike patients in clinical research settings, who typically progress to dementia. Within a prospective population-based study, we identified neuropsychological tests predicting improvement or worsening over 1 year in cognitively driven everyday functioning as measured by Clinical Dementia Rating (CDR). Participants were 1682 adults aged 65+ and dementia-free at baseline. CDR change was modeled as a function of baseline test scores, adjusting for demographics. Among those with baseline CDR = 0.5, 29.8% improved to CDR = 0; they had significantly better baseline scores on most tests. In a stepwise multiple logistic regression model, tests which remained independently associated with subsequent CDR improvement were Category Fluency, a modified Token Test, and the sum of learning trials on Object Memory Evaluation. In contrast, only 7.1% with baseline CDR = 0 worsened to CDR = 0.5. They had significantly lower baseline scores on most tests. In multiple regression analyses, only the Mini-Mental State Examination, delayed memory for visual reproduction, and recall susceptible to proactive interference, were independently associated with CDR worsening. At the population level, changes in both directions are observable in functional status, with different neuropsychological measures predicting the direction of change.

Prevalence of mild cognitive impairment by multiple classifications: The Monongahela-Youghiogheny Healthy Aging Team (MYHAT) project.

OBJECTIVES: To estimate and compare the frequency and prevalence of mild cognitive impairment (MCI) and related entities using different classification approaches at the population level. DESIGN: Cross-sectional epidemiologic study of population-based cohort recruited by age-stratified random sampling from electoral rolls. SETTING: Small-town communities in western Pennsylvania. PARTICIPANTS: Of 2,036 individuals aged 65 years and older, 1,982 participants with normal or mildly impaired cognition (age-education-corrected Mini-Mental State scores ≥ 21). MEASUREMENTS: Demographics, neuropsychological assessment expressed as cognitive domains, functional ability, and subjective reports of cognitive difficulties; based on these measurements, operational criteria for the Clinical Dementia Rating (CDR) scale, the 1999 criteria for amnestic MCI, the 2004 Expanded criteria for MCI, and new, purely cognitive criteria for MCI. RESULTS: A CDR rating of 0.5 (uncertain/very mild dementia) was obtained by 27.6% of participants, whereas 1.2% had CDR ≥ 1 (mild or moderate dementia). Among those with CDR <1, 2.27% had amnestic MCI and 17.66% had expanded MCI, whereas 35.17% had MCI by purely cognitive classification. Isolated executive function impairment was the least common, whereas impairment in multiple domains including executive function was the most common. Prevalence estimates weighted against the U.S. Census are also provided. CONCLUSIONS: The manner in which criteria for MCI are operationalized determines the proportion of individuals who are thus classified and the degree of overlap with other criteria. Prospective follow-up is needed to determine progression from MCI to dementia and thus empirically develop improved MCI criteria with good predictive value.

Age and education effects and norms on a cognitive test battery from a population-based cohort: the Monongahela-Youghiogheny Healthy Aging Team.

OBJECTIVES: Performance on cognitive tests can be affected by age, education, and also selection bias. We examined the distribution of scores on several cognitive screening tests by age and educational levels in a population-based cohort. METHOD: An age-stratified random sample of individuals aged 65+ years was drawn from the electoral rolls of an urban US community. Those obtaining age and education-corrected scores > or = 21/30 on the Mini-Mental State Examination (MMSE) were designated as cognitively normal or only mildly impaired, and underwent a full assessment including a battery of neuropsychological tests. Participants were also rated on the Clinical Dementia Rating (CDR) scale. The distribution of neuropsychological test scores within demographic strata, among those receiving a CDR of 0 (no dementia), are reported here as cognitive test norms. After combining individual test scores into cognitive domain composite scores, multiple linear regression models were used to examine associations of cognitive test performance with age and education. RESULTS: In this cognitively normal sample of older adults, younger age and higher education were associated with better performance in all cognitive domains. Age and education together explained 22% of the variation of memory, and less of executive function, language, attention, and visuospatial function. CONCLUSION: Older age and lesser education are differentially associated with worse neuropsychological test performance in cognitively normal older adult representatives of the community at large. The distribution of scores in these participants can serve as population-based norms for these tests, and can be especially useful to clinicians and researchers assessing older adults outside specialty clinic settings.

Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve.

Inverse correlations between amyloid-beta (Abeta) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [(18)F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimer's disease (AD) patients, suggest local Abeta-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Abeta deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Abeta deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Abeta deposition or increasing the level of Abeta necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Abeta deposition has been present for longer periods of time does Abeta become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

A brief instrument to assess treatment response in the patient with advanced Alzheimer disease.

The availability of effective treatments for severe Alzheimer disease (AD) has accentuated the need for brief, simple tools to evaluate treatment response in busy clinical settings for patients with advanced dementia. To develop such a tool, data on 875 patients from 4 double-blind-randomized studies of donepezil in severe AD [Mini-Mental State Examination (MMSE) 0 to 12 inclusive] were pooled and analyzed to identify Severe Impairment Battery (SIB) items, which are sensitive to change over time. Eight of the 51 SIB items were chosen based on effect sizes and relative ease of administration. The resulting SIB-8 was then applied to a validation data set (not used to generate the short form) to characterize its usefulness. The items, Month, Months of Year, Write Name, Sentence, Fluency, Confrontational Naming-Spoon, Using Spoon-Photograph, and Digit Span, were sensitive to change with treatment (P<0.0001) and easy to administer. Baseline SIB-8 scores were correlated with baseline MMSE and full-scale SIB scores, and provided a good distribution of scores in patients at the lower end of the MMSE. The SIB-8 is a brief (< or =3 min) assessment for patients with severe AD that is sensitive to change and able to detect treatment response.

High medical co-morbidity and family history of dementia is associated with lower cognitive function in older patients.

BACKGROUND: Risk factors for cognitive decline in ageing are multifactorial, including medical co-morbidities and familial genetic risk. OBJECTIVES: To assess the effect of medical co-morbidity and family history of dementia on cognitive performance in older outpatients of family practitioners. METHODS: Analysis of 535 outpatients from 11 practices aged 65 and older, without a diagnosis of dementia. Information on medical co-morbidities, family history of dementia and cognitive test data were obtained. RESULTS: Patients were classified into high or low medical co-morbidities (<7 versus >8) and positive or negative family history of dementia. After controlling for age, education, gender and depression, global cognitive test scores, as well as memory, executive function, spatial ability and attention were significantly lower for persons having a high number of medical co-morbidities. Cognitive test scores were not significantly different for persons with or without a family history of dementia. A significant interaction between medical co-morbidities and family history of dementia was observed for the global cognitive score, executive function and spatial ability. Those persons with a high number of medical co-morbidities and positive family history of dementia had the lowest performance. Separate regression analysis assessing individual disease risk factors (e.g. hypertension and diabetes) did not find any relationship between specific medical variables and cognitive test scores for any of the subgroups. CONCLUSIONS: A high number of medical co-morbidities in addition to a reported family history of dementia are particularly detrimental to cognitive performance in elderly non-demented family practice patients.