Clinico-Pathologic Studies in Dementia: Nondemented Subjects With Pathologically Confirmed Alzheimer’s Disease

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461.
Neurology (Impact Factor: 8.29). 12/1988; 38(11):1682-7. DOI: 10.1212/WNL.38.11.1682
Source: PubMed

ABSTRACT We compared neuropsychological findings in 28 longitudinally evaluated elderly subjects with their postmortem neuropathology, including senile plaque and neurofibrillary tangle counts from standardized sections. Nine of the subjects were not demented when evaluated just prior to their death. Numerous cortical senile plaques and other changes of Alzheimer's disease (AD) occurred in six of nine nondemented old-old subjects. Five of these six subjects had shown decline on yearly neuropsychological tests but their cognitive impairment was too mild to meet clinical criteria for dementia. Whereas cortical senile plaque count did not distinguish well between demented and nondemented subjects, every subject with numerous cortical neurofibrillary tangles was demented. The nondemented subjects with Alzheimer pathology may have had "preclinical" AD, or numerous cortical plaques may occur in some elderly subjects who would never develop clinical dementia.

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    • "Our data reveal that the burden of amyloid plaques can be substantially low or undetectable in MA individuals and in mentally healthy nonagenarians suggesting that the physiological mechanisms responsible for triggering amyloid deposition might be absent in some elderly individuals without clinical symptoms of dementia. Multiple studies have also shown that individuals with amyloid plaques can be non-demented [44], [53], [72]–[80] which undermines the idea of these lesions as being the chief culprit for the expression of dementia. In this respect, it has been recently suggested that at equal amyloid plaque loads the difference between demented and non-demented individuals lies upon the higher amount of Aβ oligomers in the former relative to the latter [81]. "
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    ABSTRACT: Defining the biochemical alterations that occur in the brain during "normal" aging is an important part of understanding the pathophysiology of neurodegenerative diseases and of distinguishing pathological conditions from aging-associated changes. Three groups were selected based on age and on having no evidence of neurological or significant neurodegenerative disease: 1) young adult individuals, average age 26 years (n = 9); 2) middle-aged subjects, average age 59 years (n = 5); 3) oldest-old individuals, average age 93 years (n = 6). Using ELISA and Western blotting methods, we quantified and compared the levels of several key molecules associated with neurodegenerative disease in the precuneus and posterior cingulate gyrus, two brain regions known to exhibit early imaging alterations during the course of Alzheimer's disease. Our experiments revealed that the bioindicators of emerging brain pathology remained steady or decreased with advancing age. One exception was S100B, which significantly increased with age. Along the process of aging, neurofibrillary tangle deposition increased, even in the absence of amyloid deposition, suggesting the presence of amyloid plaques is not obligatory for their development and that limited tangle density is a part of normal aging. Our study complements a previous assessment of neuropathology in oldest-old subjects, and within the limitations of the small number of individuals involved in the present investigation, it adds valuable information to the molecular and structural heterogeneity observed along the course of aging and dementia. This work underscores the need to examine through direct observation how the processes of amyloid deposition unfold or change prior to the earliest phases of dementia emergence.
    PLoS ONE 08/2014; 9(8):e105784. DOI:10.1371/journal.pone.0105784 · 3.23 Impact Factor
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    • "Although pathologic Aβ metabolism is clearly the initiating event in autosomal dominant AD, sporadic AD may be a more heterogeneous etiology, with, for example, cerebrovascular pathology contributing to symptoms in some patients [2]. A large overlap in pathology is noted between elderly AD patients and individuals dying of other causes [3-5], which might be explained by combined effects of Alzheimer-type and cerebrovascular pathology in the form of white-matter lesions actually leading to dementia in elderly AD patients [6]. This is supported by neuropathologic studies showing increased frequency of mixed pathologies rather than pure AD pathology in dementia patients in older age groups [7]. "
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    ABSTRACT: The neuronal loss in Alzheimer disease (AD) has been described to affect grey matter in the cerebral cortex. However, in the elderly, AD pathology is likely to occur together with subcortical axonal degeneration on the basis of cerebrovascular disease. Therefore, we hypothesized that biomarkers for AD and subcortical axonal degeneration would correlate in patients undergoing testing for dementia biomarkers, particularly in older age groups. We performed correlation and cluster analyses of cerebrospinal fluid (CSF) biomarker data from 5,542 CSF samples analyzed in our routine clinical neurochemistry laboratory in 2010 through 2012 for the established CSF AD biomarkers total tau (T-tau), phosphorylated-tau (P-tau), amyloid β1-42 (Aβ42), and for neurofilament light (NFL), which is a protein expressed in large-caliber myelinated axons, the CSF levels of which correlate with subcortical axonal injury. Aβ42, T-tau, and P-tau correlated with NFL. By cluster analysis, we found a bimodal data distribution in which a group with a low Aβ42/P-tau ratio (suggesting AD pathology) had high levels of NFL. High levels of NFL also correlated with the presence of an AD biomarker pattern defined by Aβ42/P-tau and T-tau. Only 29% of those with an AD biomarker signature had normal NFL levels. Age was a possible confounding factor for the associations between NFL and established AD biomarkers, but in a logistic regression analysis, both age and NFL independently predicted the AD biomarker pattern. The association between an AD-like signature using the established biomarkers Aβ42, T-tau, and P-tau with increased levels of NFL provides in vivo evidence of an association between AD and subcortical axonal degeneration in this uniquely large dataset of CSF samples tested for dementia biomarkers.
    Alzheimer's Research and Therapy 10/2013; 5(5):47. DOI:10.1186/alzrt212 · 3.98 Impact Factor
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    • "Interestingly, approximately 25% of cognitively healthy elderly people have Aβ plaque and tangle pathology [83], sufficient to meet National Institute on Aging (NIA)-Reagan criteria for AD [84-86]. According to the amyloid cascade hypothesis these individuals would have developed dementia if they had lived longer, hence the name “prodromal Alzheimer patients”. "
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    ABSTRACT: For the last 20 years, the "amyloid cascade hypothesis" has dominated research aimed at understanding, preventing, and curing Alzheimer's disease (AD). During that time researchers have acquired an enormous amount of data and have been successful, more than 300 times, in curing the disease in animal model systems by treatments aimed at clearing amyloid deposits. However, to date similar strategies have not been successful in human AD patients. Hence, before rushing into further clinical trials with compounds that aim at lowering amyloid-beta (Aβ) levels in increasingly younger people, it would be of highest priority to re-assess the initial assumption that accumulation of Aβ in the brain is the primary pathological event driving AD. Here we question this assumption by highlighting experimental evidence in support of the alternative hypothesis suggesting that APP and Aβ are part of a neuronal stress/injury system, which is up-regulated to counteract inflammation/oxidative stress-associated neurodegeneration that could be triggered by a brain injury, chronic infections, or a systemic disease. In AD, this protective program may be overridden by genetic and other risk factors, or its maintenance may become dysregulated during aging. Here, we provide a hypothetical example of a hypothesis-driven correlation between car accidents and airbag release in analogy to the evolution of the amyloid focus and as a way to offer a potential explanation for the failure of the AD field to translate the success of amyloid-related therapeutic strategies in experimental models to the clinic.
    09/2013; 1(1):62. DOI:10.1186/2051-5960-1-62
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