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: 8.29). 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.

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Available from: Patricia A Boyle, Apr 02, 2014
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    • "To provide a summary score of all tests in the cognitive battery, a global cognitive score was created using all 4 tests described above by averaging the z scores of each test. This method has been shown to minimize problems caused by measurement error on the individual tests.26 However, it does not reflect all aspects of cognition because it is limited by the content of the cognitive test battery. "
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    ABSTRACT: To examine the association between alcohol consumption in midlife and subsequent cognitive decline. Data are from 5,054 men and 2,099 women from the Whitehall II cohort study with a mean age of 56 years (range 44-69 years) at first cognitive assessment. Alcohol consumption was assessed 3 times in the 10 years preceding the first cognitive assessment (1997-1999). Cognitive tests were repeated in 2002-2004 and 2007-2009. The cognitive test battery included 4 tests assessing memory and executive function; a global cognitive score summarized performances across these tests. Linear mixed models were used to assess the association between alcohol consumption and cognitive decline, expressed as z scores (mean = 0, SD = 1). In men, there were no differences in cognitive decline among alcohol abstainers, quitters, and light or moderate alcohol drinkers (<20 g/d). However, alcohol consumption ≥36 g/d was associated with faster decline in all cognitive domains compared with consumption between 0.1 and 19.9 g/d: mean difference (95% confidence interval) in 10-year decline in the global cognitive score = -0.10 (-0.16, -0.04), executive function = -0.06 (-0.12, 0.00), and memory = -0.16 (-0.26, -0.05). In women, compared with those drinking 0.1 to 9.9 g/d of alcohol, 10-year abstainers showed faster decline in the global cognitive score (-0.21 [-0.37, -0.04]) and executive function (-0.17 [-0.32, -0.01]). Excessive alcohol consumption in men (≥36 g/d) was associated with faster cognitive decline compared with light to moderate alcohol consumption.
    Neurology 01/2014; 82(4). DOI:10.1212/WNL.0000000000000063 · 8.29 Impact Factor
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    • "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]. "
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    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 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 · 12.41 Impact Factor
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    • "assessing the independent relationships between WMH and CSF Ab1-42 and tau at baseline and brain volume losses over the following year in 3 diagnostic groups representing the range in clinical status from normal ageing to AD. Our study builds on an emerging model of the vascular contribution to decline in AD, which suggests that vascular damage is associated with cognitive decline in the context of AD predominantly in pre-dementia stages (Carmichael et al., 2012; Debette et al., 2011; Wilson et al., 2010). Furthermore, it may be that in the control group, some subjects have incipient AD, some have incipient vascular cognitive impairment, and some have incipient mixed vascular and AD. "
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    ABSTRACT: This study assessed relationships among white matter hyperintensities (WMH), cerebrospinal fluid (CSF), Alzheimer's disease (AD) pathology markers, and brain volume loss. Subjects included 197 controls, 331 individuals with mild cognitive impairment (MCI), and 146 individuals with AD with serial volumetric 1.5-T MRI. CSF Aβ1-42 (n = 351) and tau (n = 346) were measured. Brain volume change was quantified using the boundary shift integral (BSI). We assessed the association between baseline WMH volume and annualized BSI, adjusting for intracranial volume. We also performed multiple regression analyses in the CSF subset, assessing the relationships of WMH and Aβ1-42 and/or tau with BSI. WMH burden was positively associated with BSI in controls (p = 0.02) but not MCI or AD. In multivariable models, WMH (p = 0.003) and Aβ1-42 (p = 0.001) were independently associated with BSI in controls; in MCI Aβ1-42 (p < 0.001) and tau (p = 0.04) were associated with BSI. There was no evidence of independent effects of WMH or CSF measures on BSI in AD. These data support findings that vascular damage is associated with increased brain atrophy in the context of AD pathology in pre-dementia stages.
    Neurobiology of aging 03/2013; 34(8). DOI:10.1016/j.neurobiolaging.2013.02.003 · 5.01 Impact Factor
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