Neurodegenerative basis of age-related cognitive decline (e–Pub ahead of print)(CME)

Rush Alzheimer's Disease Center, Rush University Medical Center, 600 South Paulina Ave., Suite 1038, Chicago, IL 60612, USA.
Neurology (Impact Factor: 8.3). 09/2010; 75(12):1070-8. DOI: 10.1212/WNL.0b013e3181f39adc
Source: PubMed

ABSTRACT To assess the contribution of dementia-related neuropathologic lesions to age-related and disease-related change in cognitive function.
A total of 354 Catholic nuns, priests, and brothers had annual clinical evaluations for up to 13 years, died, and underwent brain autopsy. The clinical evaluations included detailed testing of cognitive function from which previously established composite measures of global cognition and specific cognitive functions were derived. As part of a uniform neuropathologic evaluation, the density of neurofibrillary tangles was summarized in a composite measure and the presence of Lewy bodies and gross and microscopic cerebral infarction was noted.
During follow-up, rate of global cognitive decline was gradual at first and then more than quadrupled in the last 4 to 5 years of life consistent with the onset of progressive dementia. Neurofibrillary tangles, cerebral infarction, and neocortical Lewy bodies all contributed to gradual age-related cognitive decline and little age-related decline was evident in the absence of these lesions. Neurofibrillary tangles and neocortical Lewy bodies contributed to precipitous disease-related cognitive decline, but substantial disease-related decline was evident even in the absence of these lesions.
Mild age-related decline in cognitive function is mainly due to the neuropathologic lesions traditionally associated with dementia.

Download full-text


Available from: Patricia A Boyle, Apr 02, 2014
  • Source
    • "There have been several previous studies of factors reported to be associated with cognitive decline in AD patients that have not examined genetic factors. One suggests that the pathological findings such as neurofibrillary tangles, cerebral infarction, and Lewy bodies that mediate normal and pathological age-related cognitive decline also mediate more rapid cognitive decline in some AD patients [6]. Other reports have postulated superimposed medical factors to be associated with rate of decline in AD, including diabetes [7] and other vascular risk factors [8], kidney function [9], and muscle strength [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Substantial interindividual variability exists in the disease trajectories of Alzheimer's disease (AD) patients. Some decline rapidly whereas others decline slowly, and there are no known explanations for this variability. We describe the first genome-wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition. METHODS: The discovery sample was 303 AD cases recruited in the Alzheimer's Disease Neuroimaging Initiative and the replication sample was 323 AD cases from the Religious Orders Study and Rush Memory and Aging Project. In the discovery sample, Alzheimer's Disease Assessment Scale-cognitive subscale responses were tested for association with genome-wide single-nucleotide polymorphism (SNP) data using linear regression. We tested the 65 most significant SNPs from the discovery sample for association in the replication sample. RESULTS: We identified SNPs in the spondin 1 gene (SPON1), the minor alleles of which were significantly associated with a slower rate of decline (rs11023139, P = 7.0 × 10(-11)) in the discovery sample. A SPON1 SNP 5.5 kb upstream was associated with decline in the replication sample (rs11606345, P = .002). CONCLUSION: SPON1 has not been previously associated with AD risk, but it is plausibly related because the gene product binds to the amyloid precursor protein and inhibits its cleavage by β-secretase. These data suggest that SPON1 may be associated with the differential rate of cognitive decline in AD.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2013; 10(1). DOI:10.1016/j.jalz.2013.01.008 · 17.47 Impact Factor
  • Source
    • "All clinical data collection and clinical classification were done without knowledge of previously collected data. Further information on this clinical classification system (Bennett, Schneider, Buchman, et al. 2005; Bennett, Schneider, Aggarwal, et al. 2006) and supporting neuropathological (Bennett, Schneider, Bienias, et al. 2005; Bennett, Schneider, Arvanitakis, et al. 2006) and clinical (Wilson, Krueger, et al., 2010; Boyle et al. 2006) data are published elsewhere. As part of each annual clinical evaluation, a modified version (Bennett et al. 1997) of the motor portion of the Unified Parkinson's Disease Rating Scale (Fahn and Elton 1987) was administered. "
    [Show abstract] [Hide abstract]
    ABSTRACT: As part of a clinical-pathologic project, older people completed a standard odor identification test at study entry. During a mean of 3.5 years of observation, 201 people died and underwent brain autopsy and neuropathologic examination (6 with a history of Parkinson's disease were excluded). Lewy bodies were identified with antibodies to alpha-synuclein and classified as nigral, limbic, or neocortical based on their distribution in 6 brain regions. Plaques and tangles in 5 regions were summarized with a previously established composite measure, and neuron loss in the substantia nigra was rated on 6-point scale. Odor identification scores ranged from 0 to 12 correct (mean = 8.0, standard deviation = 2.6). On neuropathologic examination, 26 persons had Lewy bodies (13 neocortical, 9 limbic, and 4 nigral). In an analysis adjusted for age, sex, education, and time from olfactory testing to death, limbic (estimate = -2.47, standard error [SE] = 0.73, P < 0.001) and neocortical (estimate = -4.36, SE = 0.63, P < 0.001) Lewy body subgroups were associated with impaired olfaction. Results were comparable in analyses that controlled for dementia or parkinsonism during the study or postmortem measures of plaques and tangles or nigral cell loss. A final set of analyses suggested that impaired olfactory performance may aid detection of underlying Lewy body disease. The findings indicate that Lewy body disease impairs late life olfactory function even in otherwise asymptomatic individuals.
    Chemical Senses 04/2011; 36(4):367-73. DOI:10.1093/chemse/bjq139 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetes mellitus is associated with an increased risk of cognitive decline and dementia. We examined brain imaging correlates and vascular and metabolic risk factors of accelerated cognitive decline in patients with type 2 diabetes. Cognitive functioning and brain volume as well as metabolic and vascular risk factors were assessed twice in 68 patients with no dementia with type 2 diabetes with a 4-year interval. Thirty-eight control participants served as a reference group. Volumetric measurements of the total brain, lateral ventricles and white-matter hyperintensities were performed on 1.5T magnetic resonance imaging scans. A regression-based index score was calculated on the basis of the reference group to assess changes in cognitive performance over time, adjusted for age, sex and estimated intelligence quotient. Brain volumes were compared between patients with and without accelerated cognitive decline. Logistic regression analyses were used to identify baseline risk factors for accelerated cognitive decline within the diabetes group. Accelerated cognitive decline was found in 17 (25%) patients with type 2 diabetes and was associated with a greater increase in ventricular volume [mean difference (95% confidence interval): 0.23% (0.08-0.38); p = 0.003] and white-matter hyperintensities volume [0.16% (0.05-0.27); p = 0.006] over the 4-year period. There were no specific vascular or metabolic risk factors associated with accelerated cognitive decline. Accelerated cognitive decline in patients with type 2 diabetes was associated with progressive changes on brain magnetic resonance imaging, comprising both vascular damage and global atrophy. Exploration of vascular and metabolic risk factors revealed no specific determinants of accelerated cognitive decline.
    Diabetes/Metabolism Research and Reviews 02/2011; 27(2):195-202. DOI:10.1002/dmrr.1163 · 3.59 Impact Factor
Show more