Role of the Neuropathology of Alzheimer Disease in Dementia in the Oldest-Old

James J. Peters VA Medical Center, 130 W Kingsbridge Rd, Bronx, NY 10468, USA.
Archives of neurology (Impact Factor: 7.42). 10/2008; 65(9):1211-7. DOI: 10.1001/archneur.65.9.1211
Source: PubMed

ABSTRACT Neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in the brain, especially in the hippocampus, entorhinal cortex, and isocortex, are hallmark lesions of Alzheimer disease and dementia in the elderly. However, this association has not been extensively studied in the rapidly growing population of the very old.
To assess the relationship between estimates of cognitive function and NP and NFT pathologic conditions in 317 autopsied persons aged 60 to 107 years.
We studied the relationship between severity of dementia and the density of these characteristic lesions of Alzheimer disease in young-old, middle-old, and oldest-old persons. The relationship of the severity of dementia as measured by the Clinical Dementia Rating scale to the density of NPs and NFTs was then assessed in each age group.
Three hundred seventeen brains of persons aged 60 years and older were selected to have either no remarkable neuropathological lesions or only NP and NFT lesions. Brains with any other neuropathological conditions, either alone or in addition to Alzheimer disease findings, were excluded. The study cohort was then stratified into the youngest quartile (aged 60-80 years), middle 2 quartiles (aged 81-89 years), and oldest quartile (aged 90-107 years).
While the density of NPs and NFTs rose significantly by more than 10-fold as a function of the severity of dementia in the youngest-old group, significant increases in the densities of NPs and NFTs were absent in the brains of the oldest-old. This lack of difference in the densities of NPs and NFTs was due to reduced lesion densities in the brains of oldest-old persons with dementia rather than to increased density of these lesions in the brains of nondemented oldest-old persons.
These findings suggest that the neuropathological features of dementia in the oldest-old are not the same as those of cognitively impaired younger-old persons and compel a vigorous search for neuropathological indices of dementia in this most rapidly growing segment of the elderly population.

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Available from: Daniel P Perl, Sep 28, 2015
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    • "The Clinical Dementia Rating (CDR) scale [70]–[72] was used to define the severity or absence of dementia for each case. As previously described [73], a multi-step consensus approach was applied to the postmortem assignment of CDR scores based on cognitive and functional status during the last 6 months of life as described previously [65], [74]. Assignment of CDR included consideration of other measures of cognition, including longitudinally measured MMSE and neuropsychological test performance when available. "
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    ABSTRACT: Increasing evidence suggests an association between neuronal cell cycle (CCL) events and the processes that underlie neurodegeneration in Alzheimer's disease (AD). Elevated levels of oxidative stress markers and mitochondrial dysfunction are also among early events in AD. Recent studies have reported the role of CCL checkpoint proteins and tumor suppressors, such as ATM and p53 in the control of glycolysis and oxidative metabolism in cancer, but their involvement in AD remains uncertain. In this postmortem study, we measured gene expression levels of eight CCL checkpoint proteins in the superior temporal cortex (STC) of persons with varying severities of AD dementia and compare them to those of cognitively normal controls. To assess whether the CCL changes associated with cognitive impairment in AD are specific to dementia, gene expression of the same proteins was also measured in STC of persons with schizophrenia (SZ), which is also characterized by mitochondrial dysfunction. The expression of CCL-checkpoint and DNA damage response genes: MDM4, ATM and ATR was strongly upregulated and associated with progression of dementia (cognitive dementia rating, CDR), appearing as early as questionable or mild dementia (CDRs 0.5-1). In addition to gene expression changes, the downstream target of ATM-p53 signaling - TIGAR, a p53-inducible protein, the activation of which can regulate energy metabolism and protect against oxidative stress was progressively decreased as severity of dementia evolved, but it was unaffected in subjects with SZ. In contrast to AD, different CCL checkpoint proteins, which include p53, CHEK1 and BRCA1 were significantly downregulated in SZ. These results support the activation of an ATM signaling and DNA damage response network during the progression of AD dementia, while the progressive decrease in the levels of TIGAR suggests loss of protection initiated by ATM-p53 signaling against intensifying oxidative stress in AD.
    PLoS ONE 07/2013; 8(7):e68361. DOI:10.1371/journal.pone.0068361 · 3.23 Impact Factor
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    • "There is mounting evidence that the underlying neuropathological basis of dementia among the oldest old is quite different from that of younger old patients. Two large autopsy series have reported decreasing density of AD pathology and decreasing association between AD pathology and dementia with advancing age [41,42]. Interestingly, cortical cerebral atrophy remained strongly associated with dementia despite advancing age [41]. "
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    ABSTRACT: The population of oldest old, or people aged 85 and older, is growing rapidly. A better understanding of dementia in this population is thus of increasing national and global importance. In this review, we describe the major epidemiological studies, prevalence, clinical presentation, neuropathological and imaging features, risk factors, and treatment of dementia in the oldest old. Prevalence estimates for dementia among those aged 85+ ranges from 18 to 38%. The most common clinical syndromes are Alzheimer's dementia, vascular dementia, and mixed dementia from multiple etiologies. The rate of progression appears to be slower than in the younger old. Single neuropathological entities such as Alzheimer's dementia and Lewy body pathology appear to have declining relevance to cognitive decline, while mixed pathology with Alzheimer's disease, vascular disease (especially cortical microinfarcts), and hippocampal sclerosis appear to have increasing relevance. Neuroimaging data are sparse. Risk factors for dementia in the oldest old include a low level of education, poor mid-life general health, low level of physical activity, depression, and delirium, whereas apolipoprotein E genotype, late-life hypertension, hyperlipidemia, and elevated peripheral inflammatory markers appear to have less relevance. Treatment approaches require further study, but the oldest old may be more prone to negative side effects compared with younger patients and targeted therapies may be less efficacious since single pathologies are less frequent. We also highlight the limitations and challenges of research in this area, including the difficulty of defining functional decline, a necessary component for a dementia diagnosis, the lack of normative neuropsychological data, and other shortcomings inherent in existing diagnostic criteria. In summary, our understanding of dementia in the oldest old has advanced dramatically in recent years, but more research is needed, particularly among varied racial, ethnic, and socioeconomic groups, and with respect to biomarkers such as neuroimaging, modifiable risk factors, and therapy.
    Alzheimer's Research and Therapy 07/2013; 5(4):27. DOI:10.1186/alzrt181 · 3.98 Impact Factor
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    • "Alzheimer's disease (AD) is a progressive, neurodegenerative disease and the most common type of adultonset dementia (Cerpa et al., 2008). Although the etiologic and pathogenic events that lead to this disease are still unknown , highly typical neuropathological changes (amyloid plaques, neurofibrillary tangles and an intense glial reactivity ) are observed in the patients' brains (Maccioni et al., 2001; Watson et al., 2005; Haroutunian et al., 2008). Cholinergic dysfunction signaling is an early hallmark of AD (Ikonomovik et al., 2011), one of the most important being a reduction in Choline Acetyltransferase (ChAT) enzyme activity in the cholinergic neurons of the temporal and parietal cortices, the hippocampus, the entorhinal cortex, and the amygdala (Mufson et al., 2003; Abel et al., 2008; Geula et al., 2008) Decreased ChAT activity in the cerebral cortex has been reported to be related to the severity of Alzheimer's Disease. "
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    ABSTRACT: Decreased Choline Acetyltransferase (ChAT) brain level is one of the main biochemical disorders in Alzheimer's Disease (AD). In rodents, recent data show that the CHAT gene can be regulated by a neural restrictive silencer factor (NRSF). The aim of the present work was to evaluate the gene and protein expression of CHAT and NRSF in frontal, temporal, entorhinal and parietal cortices of AD patient brains. Four brains from patients with AD and four brains from subjects without dementia were studied. Cerebral tissues were obtained and processed by the guanidine isothiocyanate method for RNA extraction. CHAT and NRSF gene and protein expression were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. CHAT gene expression levels were 39% lower in AD patients as compared to the control group (p < 0.05, U test). ChAT protein levels were reduced by 17% (p = 0.02, U test). NRSF gene expression levels were 86% higher in the AD group (p = 0.001, U test) as compared to the control group. In the AD subjects, the NRSF protein levels were 57% higher (p > 0.05, U test) than in the control subjects. These findings suggest for the first time that in the brain of AD patients high NRSF protein levels are related to low CHAT gene expression levels.
    Genetics and Molecular Biology 03/2013; 36(1):28-36. DOI:10.1590/S1415-47572013000100005 · 1.20 Impact Factor
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