Identification of normal and pathological aging in prospectively studied nondemented elderly humans

Dickson, Dennis W.; Crystal, Howard; Mattiace, Linda A.; Masur, David; Blau, Alan D.; Davies, Peter; Yen, Shu Hui; Aronson, Miriam K.

doi:10.1016/0197-4580(92)90027-u

Cited by 580 publications

(312 citation statements)

References 36 publications

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“…The cognitively normal homozygotes, heterozygotes, and noncarriers from our ongoing longitudinal study were demographically well matched, had high MMSE and neuropsychological test scores, and tended to be somewhat younger than the cognitively normal subjects in previously reported neuropathological and brain imaging studies (2,4,6,(8)(9)(10). By directly comparing cognitively normal individuals with differing levels of AD risk, we were able to detect potentially modest increases in fibrillar A␤ in cognitively normal people without the need for to use a minimum A␤ threshold.…”

Section: Discussionmentioning

confidence: 72%

“…The ''amyloid cascade'' hypothesis suggests that certain soluble or fibrillar A␤ species are critically involved in the early pathogenesis of AD (1), that fibrillar A␤ accumulation begins before cognitive decline (2), and that A␤-modifying treatments now in development may be most effective if initiated before significant A␤ neuropathology or symptoms become established (3). Postmortem neuropathological studies find significant fibrillar A␤ burden in many older people who were cognitively normal (2,4,5). Antemortem brain imaging studies are needed to determine the extent to which fibrillar A␤ in cognitively normal people predicts the subsequent development of clinical AD.…”

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confidence: 99%

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Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

Reiman

Chen

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

711

564

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Fibrillar amyloid-beta (A␤) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar A␤ burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar A␤ burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) 4 allele. The 8 4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar A␤ was significantly associated with APOE 4 carrier status and 4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar A␤ burden in cognitively normal older people is associated with APOE 4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar A␤ accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar A␤, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar A␤ imaging in primary prevention trials.apolipoprotein E ͉ Pittsburgh Compound B PET

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Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 99%

Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

Reiman

Chen

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

711

564

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“…Alzheimer's disease (AD) represents the classic example of a slowly progressive neurodegenerative disease, and the hypothesis that neurodegeneration in AD is caused through bystander damage from autoaggressive microglial cells that produce neurotoxins in response to continued amyloid (A␤) exposure has received widespread support (Akiyama et al, 2000;McGeer and McGeer, 2001). However, the bystander damage hypothesis claiming microglial autotoxicity leaves a number of unanswered issues, perhaps most significantly, that there is no clear-cut correlation between presence of A␤ and cognitive dysfunction; that is, significant deposits of A␤ can be found in nondemented individuals (Dickson et al, 1992). The bystander damage hypothesis also does not explain why A␤ accumulates in the first place or why the localization of neurodegenerative changes (neurofibrillary tangles) does not correlate with the localization of activated microglia, i.e., neurofibrillary tangles are not limited to the vicinity of senile plaques, where activated microglia are most prominent.…”

Section: Microglial Activation Neurotoxicity and Dysfunctionmentioning

confidence: 99%

Microglia as neuroprotective, immunocompetent cells of the CNS

Streit

2002

Glia

819

564

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The role of glial cells is to support and sustain proper neuronal function and microglia are no exception to this. This viewpoint article emphasizes the fundamental interdependence of microglia and neurons and takes a look at the possibility of what could happen if microglial cells became dysfunctional as a result of aging, genetics, or epigenetics. Could microglial senescence be a factor in the pathogenesis of Alzheimer's and other neurodegenerative diseases? The cautious answer to that question is 'yes'. Future studies along these lines may provide novel insights into microglial involvement in neurodegenerative disease pathogenesis. GLIA 40:133-139, 2002.

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“…Buildup of these pathological lesions are believed to trigger complex, multifactorial neurodegenerative cascades in AD leading to synaptic loss and neurodegeneration. Dementia severity among AD patients correlates well with synaptic loss and oligomeric Ab species and to a lesser extent, with Ab plaques in the brain (Dickson et al, 1992;Haass and Selkoe, 2007;Hardy and Selkoe, 2002;Scheff et al, 2006;Selkoe, 2002;Tomic et al, 2009). Moreover, increasing Ab levels has been suggested to be an initiating factor in AD pathology (Haass and Selkoe, 2007).…”

Section: Introductionmentioning

confidence: 99%

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

Zumkehr

Rodriguez‐Ortiz

Cheng

et al. 2015

Neurobiology of Aging

132

106

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TauAmyloid b a b s t r a c t Glial glutamate transporter, GLT-1, is the major Na þ -driven glutamate transporter to control glutamate levels in synapses and prevent glutamate-induced excitotoxicity implicated in neurodegenerative disorders including Alzheimer's disease (AD). Significant functional loss of GLT-1 has been reported to correlate well with synaptic degeneration and severity of cognitive impairment among AD patients, yet the underlying molecular mechanism and its pathological consequence in AD are not well understood.Here, we find the temporal decrease in GLT-1 levels in the hippocampus of the 3xTg-AD mouse model and that the pharmacological upregulation of GLT-1 significantly ameliorates the age-dependent pathological tau accumulation, restores synaptic proteins, and rescues cognitive decline with minimal effects on Ab pathology. In primary neuron and astrocyte coculture, naturally secreted Ab species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and Ab-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Ab and tau pathology.

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Identification of normal and pathological aging in prospectively studied nondemented elderly humans

Cited by 580 publications

References 36 publications

Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

Microglia as neuroprotective, immunocompetent cells of the CNS

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

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