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


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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    • "Based on the assumption that treatment needed to be timely, extended treatment of asymptomatic individuals with naproxen reduced the incidence of AD, supporting a benefit when NSAIDs are administered in early asymptomatic phases of the disease [28]. Moreover, some patients with high plaque burden exhibit no dementia [29] and also demonstrate almost no evidence of neuroinflammation or neurodegeneration [30]. This actually is in accordance with observations made in several transgenic mouse models of AD often devoid of strong neuroinflammatory response or neurodegeneration [31]. "
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    ABSTRACT: Aging can lead to decline in cognition, notably due to neurodegenerative processes overwhelming the brain over time. As people live longer, numerous concerns are rightfully raised toward long-term slowly incapacitating diseases with no cure, such as Alzheimer's disease. Since the early 2000's, the role of neuroinflammation has been scrutinized for its potential role in the development of diverse neurodegenerative diseases notably because of its slow onset and chronic nature in aging. Despite the lack of success yet, treatment of chronic neuroinflammation could help alleviate process implicated in neurodegenerative disease. A growing number of studies including our own have aimed at the endocannabinoid system and unfolded unique effects of this system on neuroinflammation, neurogenesis and hallmarks of Alzheimer's disease and made it a reasonable target in the context of normal and pathological brain aging.
    Aging and Disease 10/2015; 6(5):400-5. DOI:10.14336/AD.2015.0617 · 3.07 Impact Factor
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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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    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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