Clinico‐pathologic studies in dementia

Crystal, Howard; Dickson, Dennis W.; Fuld, Paula Altman; Masur, David; Scott, R. Michael; Mehler, Mark F.; Masdeu, Joseph C.; Kawas, Claudia H.; Aronson, Miriam K.; Wolfson, Leslie

doi:10.1212/wnl.38.11.1682

Cited by 540 publications

(258 citation statements)

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“…Several investigators have noted that close to half of demented individuals in the tenth decade are likely to have no obvious pathology to explain their cognitive and functional loss [30,31]. Conversely, approximately one of every three non-demented individuals at age 85 have been reported to have senile plaques and neurofibrillary tangles at autopsy, suggesting a pathological diagnosis of AD despite the lack of clear clinical dementia syndrome [31][32][33]. Initial results in a small group of centenarians also showed that about one third of non-demented participants meet pathological criteria for AD [34].…”

Section: Clinical-pathological Correleations In the Oldest-oldmentioning

confidence: 99%

Alzheimers and Dementia in the Oldest-Old: A Century of Challenges

Kawas

Corrada²

2006

CAR

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Alzheimer's disease (AD) is the most common type of dementia in the US and much of the world with rates increasing exponentially from age 65. Increases in life expectancy in the last century have resulted in a large number of people living to old ages and will result in a quadrupling of AD cases by the middle of the century. Preventing or delaying the onset of AD could have a huge impact in the number of cases expected to develop. The oldest-old are the fastest growing segment of the population and are estimated to account for 12% of the population over 65. Establishing accurate estimates of dementia and AD rates in this group is crucial for public health planning. Prevalence and incidence estimates above age 85 are imprecise and inconsistent because of the lack of very old individuals in most studies. Moreover, risk and protective factors in our oldest citizens have been studied little, and clinical-pathological correlations appear to be poor. We introduce The 90+ Study, established to address some of the unanswered questions about AD and dementia in the oldest-old. Our preliminary results show that close to half of demented oldest-old do not have known cerebral pathology to account for their cognitive deficits. Furthermore, the APOE-e4 allele appears to be a risk factor for AD only in the women in our study. In addition to the challenge of preventing and treating AD, the oldest-old will require major investigative energy to better understand the concomitants of longevity, the causes of dementia, and the factors that promote successful aging in oldest citizens.

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Section: Clinical-pathological Correleations In the Oldest-oldmentioning

confidence: 99%

Alzheimers and Dementia in the Oldest-Old: A Century of Challenges

Kawas

Corrada²

2006

CAR

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“…In some studies, a correlation has been found between elevated levels of Aβ in the brain and cognitive decline [3], but the quantity of amyloid deposits does not seem to correlate well with the degree of cognitive impairment. Several studies have reported patients without overt symptoms of dementia, yet showing many amyloid deposits in the brain at autopsy [4]. Given the pathologic changes in the AD brain, including accumulation of neurofibrillary tangles and Aβ, reduced levels of synaptophysin, and elevated levels of glial fibrillary acidic protein (GFAP), Ingelsson and colleagues compared neuropathological changes in the temporal association cortex of AD cases with varying disease duration, with those of control brains, in an attempt to define the time course of these changes [5].…”

Section: Introductionmentioning

confidence: 99%

Correlation between Cognitive Impairment and CSF Biomarkers in Amnesic MCI, non-Amnesic MCI, and Alzheimer's Disease

Haldenwanger

Eling

Kastrup

et al. 2010

JAD

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Abstract. Decreased delayed recall, decreased amyloid-β peptides (Aβ1−42), and increased tau protein concentration in cerebrospinal fluid (CSF) are generally regarded to be valid neuropsychological and biological markers for Alzheimer's disease (AD). Previous studies failed to demonstrate clear-cut correlations between neuropsychological impairment and CSF markers. In this study we test recent models of disease progression, that propose that changes in CSF biomarkers already reach a plateau in a preclinical phase, before cognitive decline begins, that is, even before MCI can be diagnosed. We recruited 73 patients with probable AD (n = 36) and mild cognitive impairment (MCI) (amnesic MCI = 25; non-amnesic MCI = 12). We used the CERAD-NP, a widely used neuropsychological battery with norms for different age and education groups, and additional neuropsychological tests for assessing the cognitive profile of these patient groups. We found a significant correlation between Aβ1−42 in the CSF and memory performance for amnesic MCI patients, but not for non-amnesic MCI and AD patients. All other correlations between cognitive tasks and Aβ1−42 were not significant. Tau protein concentration in the CSF was not correlated with any neuropsychological marker in any of the patients groups. We conclude that the decrease of Aβ1−42 in the CSF mirrors disease progression during the early stages up into AD and therefore is not restricted to the preclinical phase. The decrease of Aβ1−42 reaches a plateau only in the full blown demented syndrome and further functional disease progression is then related to neurodegeneration without further reduction of Aβ1−42 in the CSF.

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“…The most prevalent form of age-associated dementia, Alzheimer's disease (AD), is histologically characterized by the formation of neurofibrillary tangles (NFTs) composed of the microtubule-associated protein tau, accompanied by extracellular formation of amyloid plaques composed of the amyloid ␤ peptide (A␤); however, it is the tau pathology in AD that most closely correlates with neuronal loss (Gomez-Isla et al, 1997) and clinical dementia (Grundke-Iqbal et al, 1986;Ihara et al, 1986;Crystal et al, 1988). The discovery that mutations in the gene for tau (MAPT ) cause FTDP-17 (frontotemporal dementia with parkinsonism-linked to chromosome 17) (Hutton et al, 1998;Spillantini et al, 1998), which is associated with tau aggregates within neurons and glia, provided conclusive evidence that abnormalities in tau were sufficient to produce neurodegeneration independent of A␤.…”

Section: Introductionmentioning

confidence: 99%

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

et al. 2006

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Accumulation of the microtubule-associated protein tau into neurofibrillary lesions is a pathological consequence of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Hereditary mutations in the MAPT gene were shown to promote the formation of structurally distinct tau aggregates in patients that had a parkinsonian-like clinical presentation. Whether tau aggregates themselves or the soluble intermediate species that precede their aggregation are neurotoxic entities in these disorders has yet to be resolved; however, recent in vivo evidence supports the latter. We hypothesized that depletion of CHIP, a tau ubiquitin ligase, would lead to an increase in abnormal tau. Here, we show that deletion of CHIP in mice leads to the accumulation of non-aggregated, ubiquitinnegative, hyperphosphorylated tau species. CHIP Ϫ/Ϫ mice also have increased neuronal caspase-3 levels and activity, as well as caspasecleaved tau immunoreactivity. Overexpression of mutant (P301L) human tau in CHIP Ϫ/Ϫ mice is insufficient to promote either argyrophilic or "pre-tangle" structures, despite marked phospho-tau accumulation throughout the brain. These observations are supported in postdevelopmental studies using RNA interference for CHIP (chn-1) in Caenorhabditis elegans and cell culture systems. Our results demonstrate that CHIP is a primary component in the ubiquitin-dependent degradation of tau. We also show that hyperphosphorylation and caspase-3 cleavage of tau both occur before aggregate formation. Based on these findings, we propose that polyubiquitination of tau by CHIP may facilitate the formation of insoluble filamentous tau lesions.

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Clinico‐pathologic studies in dementia

Cited by 540 publications

References 0 publications

Alzheimers and Dementia in the Oldest-Old: A Century of Challenges

Alzheimers and Dementia in the Oldest-Old: A Century of Challenges

Correlation between Cognitive Impairment and CSF Biomarkers in Amnesic MCI, non-Amnesic MCI, and Alzheimer's Disease

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

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