David A. Loewenstein

Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank

Alzheimer disease (AD) is the most common dementing illness in the elderly, but there is equivocal evidence regarding the frequency of other disorders such as Lewy body disease (LBD), vascular dementia (VaD), frontotemporal dementia (FTD), and hippocampal sclerosis (HS). This ambiguity may be related to factors such as the age and gender of subjects with dementia. Therefore, the objective of this study was to calculate the relative frequencies of AD, LBD, VaD, FTD, and HS among 382 subjects with dementia from the State of Florida Brain Bank and to study the effect of age and gender on these frequencies. AD was the most frequent pathologic finding (77%), followed by LBD (26%), VaD (18%), HS (13%), and FTD (5%). Mixed pathology was common: Concomitant AD was present in 66% of LBD patients, 77% of VaD patients, and 66% of HS patients. The relative frequency of VaD increased with age, whereas the relative frequencies of FTD and LBD declined with age. Males were overrepresented among those with LBD, whereas females were overrepresented among AD subjects with onset age over 70 years. These estimates of the a priori probabilities of dementing disorders have implications for clinicians and researchers.

Cerebral metabolic effects of a verbal fluency test: A PET scan study

Sixteen normal volunteers were studied with [F-18] fluorodeoxyglucose and positron emission tomography scans during behavioral activation with a verbal fluency test, and 35 age-matched controls were studied with resting-state scans. There was an overall increase of the cerebral glucose metabolic rate of 23.3% during verbal fluency activation, compared to the resting state, with the greatest activation in bilateral temporal and frontal lobes. A negative correlation between test performance scores and indices of metabolism was found in frontal, temporal, and parietal regions. Damage to the left frontal lobe maximally affects scores on verbal fluency tests, but performing the test activates a network of regions, of which the left frontal lobe is only one. Proficient performance in verbal fluency seems to require less metabolic activation than poor performance, perhaps because of the efficiency of cognitive strategies employed.

Mild cognitive impairment Directions for future research

Mild cognitive impairment (MCI), an intermediate state between normal aging and dementia, is characterized by acquired cognitive deficits, without significant decline in functional activities of daily living. Studies conducted on MCI have introduced new concepts regarding the possible distinctions between normal and pathologic aging of the brain. Neuroimaging and genetic testing have aided in the identification of individuals at increased risk for dementia. The measurement of change in cognitive and functional status in MCI remains challenging, because it requires instruments that are more sensitive and specific than those considered adequate for research in dementia. The authors provide an overview of the many methods that have been used to study MCI and directions that may help achieve greater uniformity in methodology. Considerable heterogeneity exists in research methodology used to study the epidemiology, thresholds for cognitive and functional impairment, rate of progression, risk factors, and defining subtypes of MCI. This article emphasizes the need for uniformity in the use of 1) appropriate and sensitive neuropsychological and functional measures to diagnose MCI, 2) reliable methods to determine progression or improvement of cognitive impairment, and 3) instruments in epidemiologic studies to establish population estimates for diverse ethnic and cultural groups. Greater consensus is needed to standardize definitions and research methodology for MCI, so as to make future studies more comparable and more useful for designing effective treatment strategies.

Cognitive Rehabilitation of Mildly Impaired Alzheimer Disease Patients on Cholinesterase Inhibitors

OBJECTIVE The authors evaluated the efficacy of a new cognitive rehabilitation program on memory and functional performance of mildly impaired Alzheimer disease (AD) patients receiving a cholinesterase inhibitor. METHODS Twenty-five participants in the Cognitive Rehabilitation (CR) condition participated in two 45-minute sessions twice per week for 24 total sessions. CR training included face-name association tasks, object recall training, functional tasks (e.g., making change, paying bills), orientation to time and place, visuo-motor speed of processing, and the use of a memory notebook. Nineteen participants in the Mental Stimulation (MS) condition had equivalent therapist contact and number of sessions, which consisted of interactive computer games involving memory, concentration, and problem-solving skills. RESULTS Compared with the MS condition, participants in CR demonstrated improved performance on tasks that were similar to those used in training. Gains in recall of face-name associations, orientation, cognitive processing speed, and specific functional tasks were present post-intervention and at a 3-month follow-up. CONCLUSION A systematic program of cognitive rehabilitation can result in maintained improvement in performance on specific cognitive and functional tasks in mildly impaired AD patients.

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.

Sensitivity of Cerebral Glucose Metabolism to Age, Gender, Brain Volume, Brain Atrophy, and Cerebrovascular Risk Factors

In 76 normal volunteers studied by positron emission tomography, with [18F]fluorodeoxyglucose, CMRglu was significantly lower in the elderly as compared with young subjects and significantly higher in females relative to males. However, in 58 of these subjects who also had magnetic resonance imaging scans, age and gender were found to be unrelated to CMRglu, when the effects of brain volume and brain atrophy on CMRglu were partialed out using covariate analyses. Individually, brain volume was found to have a significant effect on CMRglu, explaining ∼17% of the variability in CMRglu measures and brain atrophy explaining ∼8% of the variance in CMRglu. Together these two measures accounted for ∼21% of the variance. Cerebrovascular risk factors in normal subjects were not found to affect mean CMRglu or the variability of CMRglu measures. In this study almost 80% of the variance in CMRglu could not be explained by any of the factors that had been considered. This implies a lack of sensitivity of absolute values of global CMRglu to the mild effects of brain dysfunction. Although some of the unexplained variance is probably methodological in origin, physiological factors that are difficult to quantify, such as the state of arousal, are likely to be contributory as well.

Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease

Background: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD. Methods: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated. Results: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up. Conclusion: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD. AD = Alzheimer disease; ADRDA = Alzheimers Disease and Related Disorders Association; aMCI = amnestic mild cognitive impairment; ANOVA = analysis of variance; CDRSB = Clinical Dementia Rating Sum of Boxes; ERC = entorhinal cortex; FADRC-CC = Florida Alzheimers Disease Research Center–Clinical Core; HPC = hippocampus; HR = hazard ratio; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; MTA = medial temporal lobe atrophy; MTL = medial temporal lobe; NACC = National Alzheimers Coordinating Center; naMCI = nonamnestic mild cognitive impairment; NCI = no cognitive impairment; NINCDS = National Institute of Neurological and Communicative Disorders and Stroke; NS = not significant; PRC = perirhinal cortex; VRS = visual rating system.

Nonpharmacological Cognitive Interventions in Aging and Dementia

There have been increasing efforts to develop cognitive interventions to ameliorate cognitive problems experienced by older adults. In healthy elderly populations, cognitive training has centered on the enhancement of memory and speed of processing, with the goal of maximizing current function and reducing the risk of cognitive decline. Among elderly persons with nonprogressive neurological conditions such as traumatic brain injury (TBI) and stroke, there has been an emphasis on rehabilitation to help restore function. Most recently, there has been increased attention on the development of new cognitive techniques to treat persons with progressive neurodegenerative conditions such as Alzheimer disease. The literature is reviewed on current approaches to cognitive interventions in elderly healthy populations, and a particular emphasis is placed on the most recent strides in progressive neurocognitive conditions, particularly Alzheimer disease. Important issues such as study design, the use of ecologically and functionally valid outcome measures, the need to examine heterogeneous populations and cross-cultural variables, and the incorporation of technologically based systems are examined. It is concluded that cognitive interventions in the elderly show considerable promise and deserve further study. (J Geriatr Psychiatry Neurol 2007;20:239—249)

Alzheimer's disease Interaction of apolipoprotein E genotype, family history of dementia, gender, education, ethnicity, and age of onset

We evaluated 197 patients with predominantly late-onset Alzheimers disease (AD) who belonged to several ethnic groups and analyzed the relationship of age of onset of AD to the presence or absence of several risk factors in this entire group of patients. The apolipoprotein E (apoE) epsilon 4 allele frequency, which was 29% in all patients (compared with the reported population mean of 13.7%, p < 0.001, did not vary significantly between ethnic groups but declined significantly with increasing age. The apoE epsilon 2 allele frequency was 3%, compared with the reported population mean of 7.4% (p = 0.001). The frequency of a positive family history of dementia in first-degree relatives (FH+) (overall 45%) did not vary significantly between ethnic groups. ApoE epsilon 4-positive (epsilon 4+) patients tended to have a higher FH+ rate (58%) than apoE epsilon 4-negative (epsilon 4-) patients (40%) (p = 0.02). When the potential risk factors of gender, education, FH+ status, and epsilon 4+ status were examined together in a multiple linear-regression analysis, FH+ and epsilon 4+ status (but not gender or education) were significant (they were both associated with an earlier age of onset of AD). In a post-hoc analysis, we found a reduced age of onset in women, but not men, who were both FH+ and epsilon 4+. Additionally, those probands who were epsilon 4+ were more likely to inherit the disease from their mothers than their fathers. The mechanism by which epsilon 4+ and FH+ status operate as risk factors may be by their effect on the age of onset of AD. NEUROLOGY 1996;46: 1575-1579

Category fluency test : normative data for English- and Spanish-speaking elderly

Category fluency tasks are an important component of neuropsychological assessment, especially when evaluating for dementia syndromes. The growth in the number of Spanish-speaking elderly in the United States has increased the need for appropriate neuropsychological measures and normative data for this population. This study provides norms for English and Spanish speakers, over the age of 50, on 3 frequently used measures of category fluency: animals, vegetables, and fruits. In addition, it examines the impact of age, education, gender, language, and depressed mood on total fluency scores and on scores on each of these fluency measures. A sample of 702 cognitively intact elderly, 424 English speakers, and 278 Spanish speakers, participated in the study. Normative data are provided stratified by language, age, education, and gender. Results evidence that regardless of the primary language of the examinee, age, education, and gender are the strongest predictors of total category fluency scores, with gender being the best predictor of performance after adjusting for age and education. English and Spanish speakers obtained similar scores on animal and fruit fluency, but English speakers generated more vegetable exemplars than Spanish speakers. Results also indicate that different fluency measures are affected by various factors to different degrees.