Neurofibrillary Tangles in Nondemented Elderly Subjects and Mild Alzheimer Disease

Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA.
JAMA Neurology (Impact Factor: 7.42). 06/1999; 56(6):713-8. DOI: 10.1001/archneur.56.6.713
Source: PubMed


The relationship between neuropathological lesions and mild, "preclinical," cognitive impairments of Alzheimer disease is poorly understood. Identification of the lesions that are most closely associated with the earliest symptoms of Alzheimer disease is crucial to the understanding of the disease process and the development of treatment strategies to affect its progression.
We examined the extent of neurofibrillary tangles (NFTs) in 4 neocortical regions, the hippocampus, the entorhinal cortex, and the amygdala in 65 elderly subjects with no dementia, questionable dementia, mild dementia, or moderate dementia as assessed using the Clinical Dementia Rating Scale (CDR).
Postmortem study of nursing home residents.
Neurofibrillary tangles were present in the entorhinal cortex and the hippocampus of all subjects, including those without cognitive deficits. Neocortical NFTs were mostly absent in the nondemented (CDR score, 0.0) subjects. The density of NFTs in the questionably demented (CDR score, 0.5) subjects was not significantly increased (P>.20) relative to the nondemented group in any of the brain regions studied. Significant increases (P<.04) in NFT density become apparent first in the amygdala and the temporal cortex in subjects rated to be mildly impaired (CDR score, 1.0). By the time that cognitive impairments were judged to be moderately severe (CDR score, 2.0), all regions of the brain examined, except for the occipital cortex, were significantly (P<.05) involved.
Some NFTs are present in the entorhinal cortex and hippocampus of most elderly individuals irrespective of their cognitive status, but the density of NFTs increases as a function of dementia severity.

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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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    • "Human postmortem temporal muscle and hippocampal formation specimens from AD and age-matched non-AD cases were obtained from the Alzheimer's Disease Brain Bank of the Mount Sinai School of Medicine [32]. The cases selected had no significant neuropathological features or had only neuropathological features associated with AD [32] [33]. Cognitive status of the cases was assessed based on the cognitive dementia rating (CDR), which is generated using a multistep evaluation of cognitive and functional status during the last 6 months of life, as previously reported [34]. "
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    ABSTRACT: We investigated the contents of the insulin receptor-beta subunit (IRβ) and [Tyr1162/1163]-phosphorylated IRβ as surrogate indices of total IR content and IR activation in postmortem hippocampal formation brain specimens from nondiabetic sporadic Alzheimer's disease (AD) cases. We found no significant changes in the brain contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases. Moreover, total IRβ and [Tyr1162/1163]-phosphorylated IRβ levels in the hippocampal formation are not correlated with the severity of amyloid or tau-neuropathology. Exploring the regulation of glycogen synthase kinase 3 (GSK3) α/β, key IR-signaling components, we observed significantly lower levels of total GSK3 α/β in brain specimens from nondiabetic AD cases, suggesting that impaired IR signaling mechanisms might contribute to the onset and/or progression of AD dementia. Outcomes from our study support the development of insulin-sensitizing therapeutic strategies to stimulate downstream IR signaling in nondiabetic AD cases.
    International Journal of Alzheimer's Disease 05/2012; 2012(9009):321280. DOI:10.1155/2012/321280
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    • "The loss of cognitive function is the most devastating feature of Alzheimer's disease (AD) and is likely to involve a dysfunction of entorhinal-hippocampal circuitry [1], [2], [3], [4], [5]. The entorhinal cortex (EC) and hippocampus are among the brain regions where neurofibrillary tangles and amyloid-beta (Aβ) plaques first develop in AD patients [6], [7], [8], [9]. Functional and anatomic magnetic resonance imaging reveal a higher activation of hippocampal and EC circuits in patients with mild cognitive impairment compared to Controls, which is followed by a lower activity in AD [10]. "
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    PLoS ONE 02/2011; 6(2):e17397. DOI:10.1371/journal.pone.0017397 · 3.23 Impact Factor
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