Neuronal activity and early neurofibrillary tangles in Alzheimer's disease

Hatanpaa, Kimmo J.; Brady, Daniel R.; Stoll, James; Rapoport, Stanley I.; Chandrasekaran, Krish

doi:10.1002/ana.410400310

Cited by 64 publications

(42 citation statements)

References 47 publications

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“…This view is consistent with in vitro data on postmortem brains of Alzheimer's disease patients that demonstrated that neurons containing neurofibrillary tangles maintain some cytochrome oxidase activity (10). However, it is not known how such neurons would respond to extra stress during sensory or cognitive stimulation.…”

supporting

confidence: 82%

Low glucose metabolism during brain stimulation in older Down's syndrome subjects at risk for Alzheimer's disease prior to dementia

Pietrini

Dani

Furey

et al. 1997

AJP

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causes all subjects with Down's syndrome over the age of 40 years to show some degree of neuropathological and neurochemical abnormalities postmortem that are indistinguishable from those seen in Alzheimer's disease (1, 2). Cognitive dysfunction and dementia are increasingly more common with aging, and 75% of persons with Down's syndrome over age 60 are demented (3, 4). Thus, Down's syndrome is a unique human model with which to study the preclinical stages of Alzheimer's disease and transition to dementia (5, 6).Longitudinal neuropsychological evaluations of nonmemory cognitive functions showed two stages of cognitive decline in Down's syndrome: a stable phase of at least 7 years preceding dementia and a subsequent period of linear decline, coincident with the onset of dementia (3, 7). Positron emission tomography (PET) with [ 18 F]fluorodeoxyglucose (FDG) is a well-established in vivo technique for measuring rates of regional cerebral glucose metabolism in humans; these rates primarily are Preliminary data presented as an abstract at the 10th annual meeting of the

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supporting

confidence: 82%

Low glucose metabolism during brain stimulation in older Down's syndrome subjects at risk for Alzheimer's disease prior to dementia

Pietrini

Dani

Furey

et al. 1997

AJP

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“…They found no reduction in mRNA levels in the proximal neurons or their processes compared with more plaquedistant neurons. However, Hatanpaa et al (1996) found levels of CO mRNA decreased by 26% in neurons bearing early-stage neurofibrillary tangles compared with tangle-free neurons. Unsurprisingly, tangle-bearing neurons do not produce as much CO, and likely other enzymes and proteins, as tangle-free neurons.…”

Section: Discussionmentioning

confidence: 99%

Energy Hypometabolism in Posterior Cingulate Cortex of Alzheimer's Patients: Superficial Laminar Cytochrome Oxidase Associated with Disease Duration

2001

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Among brain regions affected in Alzheimer's disease (AD), the posterior cingulate shows the earliest and largest decrement in energy metabolism. Positron emission tomography (PET) studies have shown that these decrements appear before the onset of memory deficits or other symptoms in persons at genetic risk for AD. This study compares in vivo imaging results and in situ postmortem analyses by examining the posterior cingulate (area 23) in 15 AD patients and 13 age-matched nondemented controls using quantitative cytochrome oxidase histochemistry as an intracellular measure of oxidative energy metabolic capacity. Each of the six layers of the posterior cingulate demonstrated a decline in cytochrome oxidase activity in AD relative to controls, whereas adjacent motor cortex showed no significant differences. This decrement did not appear to be mainly secondary to nonspecific decrement in mitochondrial enzymes, oxidative stress, cell loss, or histopathology. The cytochrome oxidase decrement was most severe in the superficial layer I (Ϫ39%), which demonstrated a correlation to disease duration. Covariance analyses suggest that superficial laminas undergo a functional uncoupling from the deeper layers of posterior cingulate cortex in AD, whereas no such effects are found in motor cortex or controls. These findings expand on previous results from PET studies by illuminating the layer-specific cytochrome oxidase contributions to energy hypometabolism. The findings suggest a decrement of cytochrome oxidase in posterior cingulate cortex, with progressive reduction within the superficial laminas linked to disease duration. Such decrement could contribute to some of the behavioral symptoms displayed by AD patients. This decrement appeared greater in women.Key words: cytochrome oxidase; energy metabolism; posterior cingulate cortex; Alzheimer's disease; brain mapping; gender Decrements in energy metabolism are one of the earliest detectable abnormalities in Alzheimer's disease (AD). Positron emission tomography (PET) studies on subjects homozygotic for the ⑀4 allele of the apolipoprotein E (APOE) gene, with no symptoms of AD, demonstrate metabolic reductions in posterior cingulate, parietal, temporal, and prefrontal cortices (Reiman et al., 1996;Small et al., 2000). Their largest decrement was in the posterior cingulate cortex (PCC) (Reiman et al., 1996), as in the case of AD (Minoshima et al., 1994). Another PET study (Minoshima et al., 1997) confirmed that although normal subjects show intense PCC metabolic activity, early-stage AD patients suffered a PCC decrement (21-22%) that was significantly greater than that seen in other cortical regions. This greater hypometabolism determined by PET is not merely an artifact of generalized atrophy (Ibanez et al., 1998) or AD histopathology that is lower in PCC than the other regions (Braak and Braak, 1998), although degeneration of PCC occurs in AD (Brun and Gustafson, 1976). Severity of AD symptoms is correlated with hypoactivity in PCC but not temporal regions, as measured with PE...

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“…147 (2) Regional hypometabolism found in Alzheimer brains does not appear to result from neurodegenerative damage or senile plaque formation but is present before significant tissue pathology. 195,196 While it could be argued that hypometabolism in AD may elicit microvascular changes at some point, a considerable number of animal experiments have revealed that chronic brain hypoperfusion can trigger oxidative stress, energy metabolic deficits, and memory loss before any neuronal structural pathology materializes, 149 -159 whereas we are aware of no data that demonstrate that the reverse process can or does occur. Moreover, the recent discovery of "neuroglobin" in rodent and human brain could partly explain why CA1 hippocampal neurons are exquisitely sensitive to hypoperfusion and hypometabolism.…”

Section: Cerebral Hypoperfusion and Hypometabolism In Ad: Chicken Or mentioning

confidence: 98%

“…147 (2) Regional hypometabolism found in Alzheimer brains does not appear to result from neurodegenerative damage or senile plaque formation but is present before significant tissue pathology. 195,196 (3) Abundant density of senile plaques, neurofibrillary tangles, and neurodegenerative changes that met neuropathological criteria for AD have been found in a large percentage of cognitively normal, elderly brains at autopsy. 197 (4) The same structural capillary aberrations seen in AD have been also been observed in Down syndrome at a young age, when no senile plaque or neurofibrillary tangle formation has yet formed.…”

Section: Cerebral Hypoperfusion and Hypometabolism In Ad: Chicken Or mentioning

confidence: 99%

Alzheimer Disease as a Vascular Disorder

Torre

2002

Stroke

777

491

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Background-The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now. Summary of Review-Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) confirmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular risk factors or indicators of vascular disease. Conclusions-Since the value of scientific evidence generally revolves around probability and chance, it is concluded that the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is recommended that current clinical management of patients, treatment targets, research designs, and disease prevention efforts need to be critically reassessed and placed in perspective in light of these important findings. Key Words: Alzheimer disease Ⅲ dementia Ⅲ microcirculation Ⅲ risk factors Ⅲ vascular disorders A lzheimer disease (AD) is an insidious disorder that progressively ravages the brain, destroying its memory, intellect, and dignity in the process. The main stumbling block in the clinical management and in the search for a cure of AD is that the cause of this disorder has remained uncertain until now. For more than 30 years, AD has been classified and managed as a neurodegenerative disorder, 1,2 following a report by Roth in 1955 3 that suggested that dementia should be classified into 2 distinct disorders according to the variable mental changes caused by each: vascular dementia (VaD), caused by vascular lesions, and AD, resulting from a neurodegenerative process.Most investigators in the field have supported Roth's notion that dementing processes will d...

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Neuronal activity and early neurofibrillary tangles in Alzheimer's disease

Cited by 64 publications

References 47 publications

Low glucose metabolism during brain stimulation in older Down's syndrome subjects at risk for Alzheimer's disease prior to dementia

Low glucose metabolism during brain stimulation in older Down's syndrome subjects at risk for Alzheimer's disease prior to dementia

Energy Hypometabolism in Posterior Cingulate Cortex of Alzheimer's Patients: Superficial Laminar Cytochrome Oxidase Associated with Disease Duration

Alzheimer Disease as a Vascular Disorder

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