Exploring the Structure of a Neuropsychological Battery across Healthy Elders and Those with Questionable Dementia and Alzheimer's Disease

An exploratory factor analysis (EFA) and a series of confirmatory factor analyses were conducted on 17 variables designed to assess different cognitive abilities in a sample of healthy older adults. In the EFA, 4 factors emerged corresponding to language, memory, processing speed, and fluid ability constructs. The results of the confirmatory factor analyses suggested that a 5-factor model with an additional Attention factor improved the fit. The invariance of the 5-factor model was examined across 3 groups: a group of cognitively healthy older adults, a group of patients diagnosed with questionable dementia (QD), and a group of patients diagnosed with probable Alzheimer's disease (AD). Results of the invariance analysis suggest that the model may have configural invariance across the 3 groups but not metric invariance. Specifically, preliminary analyses suggest that the memory construct may represent something different in the QD and AD groups as compared to the healthy older adult group, consistent with the underlying pathology in early AD

Agrin isoforms and their role in synaptogenesis

Agrin is thought to mediate the motor neuron-induced aggregation of synaptic proteins on the surface of muscle fibers at neuromuscular junctions. Recent experiments provide direct evidence in support of this hypothesis, reveal the nature of agrin immunoreactivity at sites other than neuromuscular junctions, and have resulted in findings that are consistent with the possibility that agrin plays a role in synaptogenesis throughout the nervous system

Essential tremor associated with pathologic changes in the cerebellum

Background: Although essential tremor (ET) is one of the most common neurologic disorders, there have been few postmortem studies. We recently reported postmortem changes (torpedoes and Bergmann gliosis) in the cerebellar cortex in a few ET cases. Objective: To describe more extensive postmortem changes in the cerebellum in another ET case. Design: Case report. Results: A 90-year-old woman had a 30-year history of ET. At postmortem examination, there was segmental loss of Purkinje cells, presence of torpedoes, and Bergmann gliosis in the cerebellar cortex. Moreover, there were extensive changes in the dentate nucleus, in the form of neuronal loss, neuronal atrophy, microglial clusters, and reduction in the number of efferent fibers (ie, pallor of the hilum). Conclusions: The brain in the current case exhibited more marked cerebellar pathologic features than noted in previously reported ET cases and thereby extends the described cerebellar findings in this common, yet pathologically poorly characterized, neurologic disorder

Plasma Aβ40 and Aβ42 and Alzheimer's Disease: Relation to Age, Mortality, and Risk

BACKGROUND: Plasma amyloid [beta]-peptide (A[beta]) 40 and A[beta]42 levels are increased in persons with mutations causing early-onset familial Alzheimer's disease (AD). Plasma A[beta]42 levels were also used to link microsatellite genetic markers to a putative AD genetic locus on chromosome 10 and were observed in patients with incipient sporadic AD. METHODS: The authors measured plasma A[beta]40 and A[beta]42 levels using a sandwich ELISA after the initial examination of 530 individuals participating in an epidemiologic study of aging and dementia. Participants were examined at 18-month intervals, and plasma A[beta]40 and A[beta]42 levels were repeated in 307 subjects 3 years after baseline. RESULTS: Compared with individuals who never developed AD, patients with AD at baseline and those who developed AD during the follow-up had significantly higher A[beta]42, but not A[beta]40, plasma levels. The risk of AD in the highest quartile of plasma A[beta]42 was increased by more than twofold over that in the lowest quartile. The highest plasma A[beta]42 levels were observed in patients with AD who died during the follow-up. Plasma A[beta]42, but not A[beta]40, levels decreased over time in patients with newly acquired AD. CONCLUSIONS: Plasma A[beta]40 and A[beta]42 increase with age and are strongly correlated with each other. Plasma A[beta]40 and A[beta]42 levels are elevated in some patients before and during the early stages of AD but decline thereafter. High plasma A[beta]42 levels may also be associated with mortality in patients with AD

Measuring cerebral atrophy and white matter hyperintensity burden to predict the rate of cognitive decline in Alzheimer disease

Objective: To determine if baseline measurements of cerebral atrophy and severity of white matter hyperintensity (WMH) predict the rate of future cognitive decline in patients with Alzheimer disease (AD). Design: Data were drawn from the Predictors Study, a longitudinal study that enrolls patients with mild AD and reassesses them every 6 months with use of the Columbia modified Mini-Mental State (mMMS) examination (score range, 0-57). Magnetic resonance images were analyzed to determine the severity of WMH, using the Scheltens scale, and the degree of atrophy, using the bicaudate ratio. Generalized estimating equations were used to determine whether severity of baseline magnetic resonance image measurements and their interaction predicted the rate of mMMS score decline at subsequent visits. Setting: Three university-based AD centers in the United States. Participants: At baseline, 84 patients with AD from the Predictors Study received structural magnetic resonance imaging and were selected for analysis. They had a mean of 6 follow-up evaluations. Main Outcome Measure: The mMMS score. Results: Generalized estimating equation models demonstrated that the degree of baseline atrophy (β = −0.316; P = .04), the severity of WMH (β = −0.173; P = .03), and their interaction (β = −6.061; P = .02) predicted the rate of decline in mMMS scores. Conclusions: Both degree of cerebral atrophy and severity of WMH are associated with the rapidity of cognitive decline in AD. Atrophy and WMH may have a synergistic effect on future decline in AD, such that patients with a high degree of both have a particularly precipitous cognitive course. These findings lend further support to the hypothesis that cerebrovascular pathological abnormalities contribute to the clinical syndrome of AD

Leukocyte telomere length is unrelated to cognitive performance among non-demented and demented persons: An examination of long life family study participants

OBJECTIVE: Leukocyte telomere length (LTL) is a widely hypothesized biomarker of biological aging. Persons with shorter LTL may have a greater likelihood of developing dementia. We investigate whether LTL is associated with cognitive function, differently for individuals without cognitive impairment versus individuals with dementia or incipient dementia. METHOD: Enrolled subjects belong to the Long Life Family Study (LLFS), a multi-generational cohort study, where enrollment was predicated upon exceptional family longevity. Included subjects had valid cognitive and telomere data at baseline. Exclusion criteria were age ≤ 60 years, outlying LTL, and missing sociodemographic/clinical information. Analyses were performed using linear regression with generalized estimating equations, adjusting for sex, age, education, country, generation, and lymphocyte percentage. RESULTS: Older age and male gender were associated with shorter LTL, and LTL was significantly longer in family members than spouse controls (p \u3c 0.005). LTL was not associated with working or episodic memory, semantic processing, and information processing speed for 1613 cognitively unimpaired individuals as well as 597 individuals with dementia or incipient dementia (p \u3c 0.005), who scored significantly lower on all cognitive domains (p \u3c 0.005). CONCLUSIONS: Within this unique LLFS cohort, a group of families assembled on the basis of exceptional survival, LTL is unrelated to cognitive ability for individuals with and without cognitive impairment. LTL does not change in the context of degenerative disease for these individuals who are biologically younger than the general population

Reduced Purkinje cell number in essential tremor : a postmortem study

Background: Clinical and functional imaging evidence suggests that cerebellar dysfunction occurs in essential tremor (ET). In recent postmortem studies, we documented increased numbers of torpedoes (Purkinje cell axonal swellings) in ET patients without Lewy bodies. Purkinje cell loss, however, has never been rigorously assessed. Objective: To quantitatively assess the number of Purkinje cells in brains of ET patients and similarly aged controls. Methods: Postmortem cerebellar tissue was available in 14 ET cases (6 with Lewy bodies and 8 without Lewy bodies) and 11 controls. Calbindin immunohistochemistry was performed on paraffin sections of the cerebellum. Images were digitally recorded and blinded measurements of the number of Purkinje cells per millimeter of cell layer (linear density) were made. Results: Purkinje cell linear density was inversely correlated with age (r=-0.53, P=.006) and number of torpedoes (r=-0.42, P=.04). Purkinje cell linear density differed by diagnosis (mean [SD], controls, 3.46 [1.27] cells/mm; ET cases with Lewy bodies, 3.33 [1.06] cells/mm; and ET cases without Lewy bodies, 2.14 [0.82] cells/mm; P=.04), with the most significant difference between ET cases without Lewy bodies and controls, where the reduction was 38.2% (P=.04). In an adjusted linear regression analysis that compared ET cases without Lewy bodies with controls, decreased linear density (outcome variable) was associated with ET (β=.56, P=.03). Conclusions: We demonstrated a reduction in Purkinje cell number in the brains of patients with ET who do not have Lewy bodies. These data further support the view that the cerebellum is anatomically, as well as functionally, abnormal in these ET cases

Importance of Symptomatic Cerebral Infarcts on Cognitive Performance in Patients with Alzheimer's Disease

The coexistence of cerebral infarcts and Alzheimer's disease (AD) is common, but the influence of symptomatic cerebral infarcts on cognition is uncertain in AD. We hypothesize that symptomatic cerebral infarcts may provide an additive cognitive factor contributing to dementia in the AD population. We studied 1,001 clinically probable or possible AD patients in the Alzheimer Disease Research Center (ADRC) database. Linear regression was used to evaluate for an association between symptomatic cerebral infarcts and memory, language, executive function, abstract reasoning, and visuospatial performance, separately. Models were adjusted for covariates including age, gender, education, ethnicity, hypertension, diabetes mellitus, heart disease, clinical dementia rating, the presence of silent cerebral infarcts, and multiplicity or location of infarcts. Clinical history of stroke was present in 107 patients, radiological infarcts in 308 patients, and 68 patients with both were considered to have symptomatic infarcts. Adjusting for all covariates, AD patients with symptomatic infarcts had more impairment of executive function (P < 0.05). The influence of cerebral infarcts is neither general nor diffuse, and the presence of clinical history may have a more important influence on executive performance in AD

Older onset essential tremor : more rapid progression and more degenerative pathology

There are few data on rate of progression in essential tremor (ET). To quantify the rate of tremor progression in a cross-sectional sample of 348 ET cases in an epidemiological study; characterize the relationship between age of tremor onset and rate of tremor progression in that sample; and characterize the relationship between age of tremor onset, rate of tremor progression, and severity of underlying brain changes in 9 cases from a brain repository. Rate of tremor progression was defined as tremor severity divided by duration. The degeneration index = number of torpedoes per section divided by Purkinje cell linear density. In the epidemiological study, older age of tremor onset was associated with faster rate of tremor progression (P < 0.001). In the brain repository, older age of tremor onset was associated with higher degeneration index (P = 0.037), and higher degeneration index was associated with faster rate of tremor progression (P = 0.018). In a large clinical sample, older age of onset was associated with more rapid tremor progression. In a brain bank, older age of onset was associated with more degenerative pathology in the cerebellum. As in several neurodegenerative disorders, in older onset cases, it is possible that the disease advances more rapidly