Article

Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

Department of Anatomy and Neurobiology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Neurobiology of aging (Impact Factor: 5.01). 05/2009; 30(7):1026-36. DOI: 10.1016/j.neurobiolaging.2009.04.002
Source: PubMed

ABSTRACT

To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals.
Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer's Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions.
Washington University Alzheimer's Disease Research Center.
Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years).
About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs.
Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80-85 years, many nondemented older adults have substantial AD pathology.

Download full-text

Full-text

Available from: Walter A Kukull
    • "This study builds on the results from these previous patient studies and critically the focus shifts from differential diagnosis of established dementia to that of MCI. In view of the substantial neuropathological evidence of hippocampal damage in AD occurring prior to the onset of dementia (Braak and Braak, 1991;Arriagada et al., 1992;Price et al., 2009) the central study hypothesis was that spatial memory performance (as tested using the 4MT) is impaired in prodromal AD, manifest as MCI. As proof of hypothesis would have significant implications for the use of this test in clinical diagnostic practice, and in view of the importance attached worldwide to the detection of AD prior to the onset of dementia, several study objectives were defined. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The hippocampus is one of the earliest brain regions affected in Alzheimer's disease (AD) and tests of hippocampal function have the potential to detect Alzheimer's disease (AD) in its earliest stages. Given that the hippocampus is critically involved in allocentric spatial memory, this study applied a short test of spatial memory, the 4 Mountains Test (4MT), to determine whether test performance can differentiate MCI patients with and without CSF biomarker evidence of underlying AD and whether the test can distinguish patients with mild cognitive impairment (MCI) and mild AD dementia when applied in different cultural settings.Healthy controls (HC), patients with MCI and mild AD dementia were recruited from study sites in UK and Italy. Study numbers were: HC (UK 20, Italy 10), MCI (UK 21, Italy 14), AD (UK 11, Italy 9). Nineteen UK MCI patients were grouped into CSF biomarker-positive (MCI+, n=10) and biomarker-negative (MCI-, n=9) subgroups. Behavioural data were correlated with hippocampal volume and cortical thickness of the precuneus and posterior cingulate gyrus.Spatial memory was impaired in both UK and Italy MCI and AD patients. Test performance additionally differentiated between MCI+ and MCI- subgroups (p = 0.001). A 4MT score of ≤ 8/15 was associated with 100% sensitivity and 90% specificity for detection of early AD (MCI+ and mild AD dementia) in the UK population, and with 100% sensitivity and 50% specificity for detection of MCI and AD in the Italy sample. 4MT performance correlated with hippocampal volume in the UK population and cortical thickness of the precuneus in both study populations.In conclusion, performance on a hippocampus-sensitive test of spatial memory differentiates MCI due to AD with high diagnostic sensitivity and specificity. The observation that similar diagnostic sensitivity was obtained in two separate study populations, allied to the scalability and usability of the test in community memory clinics, supports future application of the 4MT in the diagnosis of pre-dementia AD. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2015 · Hippocampus
  • Source
    • "One the other hand, critics have found to focus on limitations in the methodology of clinical trials and on bias in the way the data are introduced, especially in trials sponsored by drug companies, and have concluded that efficay of drugs are inflated (Casey et al., 2010). One of the most important problems leading to difficulty in disease management is AD pathology existed in brain cells many years before the appearance of clinical symptoms (Price et al., 2009). AD is distinguished mainly by neuronal loss. "

    Full-text · Article · Jan 2015 · Saudi Pharmaceutical Journal
  • Source
    • "By itself the ε4 allele does not doom one to certain death by AD or vascular disease, nor does the accumulation of plaques and tangles lead to dementia in all cases. Post mortem analyses of brains have uncovered many cases in which AD type plaques and tangles are present without the expected deficits in cognitive function (Davis et al., 1999; Price et al., 2009; Balasubramanian et al., 2012). Conversely, in studies of very old adults—individuals 80 to 100+ years old—up to 50% of dementias previously diagnosed as AD were later determined to be of unknown etiology (i.e., postmortem analysis failed to identify brain pathology typical of AD or other dementias; Crystal et al., 2000; Imhof et al., 2007; Middleton et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia’s annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer’s disease (AD) is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (Aβ), either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD—though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE) genotype is the strongest genetic risk factor for AD: APOE-ε4 is proinflammatory and individuals with this genotype accumulate more Aβ, are at high risk of developing AD, and almost half of all AD patients have at least one ε4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in Aβ clearance, and getting good quality sleep vs. poor quality sleep might reduce the AD risk associated with neuroinflammation and the ε4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: (1) identify individuals at high risk for dementia who may benefit most from sleep interventions; (2) explore the role poor sleep quality plays in exacerbating AD type dementia; (3) examine the science of sleep interventions to date; and (4) provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia.
    Full-text · Article · Dec 2014 · Frontiers in Aging Neuroscience
Show more