In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease

Terada, Tatsuhiro; Obi, Tomokazu; Bunai, Tomoyasu; Matsudaira, Takashi; Yoshikawa, Etsuji; Ando, Ichiro; Futatsubashi, Masami; Tsukada, Hideo; Ouchi, Yasuomi

doi:10.1212/wnl.0000000000009249

Cited by 83 publications

(55 citation statements)

References 41 publications

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“…While various pathophysiological mechanisms including genetic and environmental factors have been proposed for the pathogenesis of Alzheimer's disease [163], a number of investigations using postmortem specimens or serum samples have emphasized the involvement of oxidative stress and mitochondrial dysfunction, similar to other neurodegenerative disorders [6,167,168]. In support of this hypothesis, a recent PET study with 18 F-BCPP-EF, a radioligand to image mitochondrial complex I activity, demonstrated decreased uptake in the parahippocampus in patients with early-stage Alzheimer's disease [169], which supports the involvement of mitochondrial dysfunction.…”

Section: Pet Imaging For Oxidative Stress In Patients With Alzheimer'mentioning

confidence: 94%

PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

et al. 2020

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Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission tomography (PET) can directly evaluate subtle biological changes, including the redox status. The present review focuses on recent advances in PET imaging for oxidative stress, in particular the use of the Cu-ATSM radioligand, in neurodegenerative disorders associated with mitochondrial dysfunction. Since reactive oxygen species are mostly generated by leakage of excess electrons from an over-reductive state due to mitochondrial respiratory chain impairment, PET with 62Cu-ATSM, the accumulation of which depends on an over-reductive state, is able to image oxidative stress. 62Cu-ATSM PET studies demonstrated enhanced oxidative stress in the disease-related brain regions of patients with mitochondrial disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, the magnitude of oxidative stress increased with disease severity, indicating that oxidative stress based on mitochondrial dysfunction contributes to promoting neurodegeneration in these diseases. Oxidative stress imaging has improved our insights into the pathological mechanisms of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant therapies.

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Section: Pet Imaging For Oxidative Stress In Patients With Alzheimer'mentioning

confidence: 94%

PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

et al. 2020

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“…For example, a recent study measured mitochondrial complex I availability quantitatively in the human brain, suggesting that mitochondrial dysfunction in the parahippocampus manifests in the early stages of AD. 144 Janelidze et al found that both of neuroinflammation and cerebrovascular dysfunction were early events occurring at the presymptomatic stage of AD by measure of biomarkers in cerebrospinal fluid (CSF). 145 Schöll et al used 18F-AV-1451 tau positron emission tomography (PET) and structural magnetic resonance imaging (MRI) to examine whether early-and late-onset AD showed differential, regional tau pathology and atrophy patterns.…”

Section: Endophenotype Impact On Different Stages Of Ad Pathologymentioning

confidence: 99%

Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing

Fang

Pieper

Nussinov

et al. 2020

Medicinal Research Reviews

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Following two decades of more than 400 clinical trials centered on the "one drug, one target, one disease" paradigm, there is still no effective disease-modifying therapy for Alzheimer's disease (AD). The inherent complexity of AD may challenge this reductionist strategy. Recent observations and advances in network medicine further indicate that AD likely shares common underlying mechanisms and intermediate pathophenotypes, or endophenotypes, with other diseases. In this review, we consider AD pathobiology, disease comorbidity, pleiotropy, and therapeutic development, and construct relevant endophenotype networks to guide future therapeutic development. Specifically, we discuss six main endophenotype hypotheses in AD: amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction. We further consider how

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“…The PET data were analyzed with PMOD image software (version 3.7; PMOD Technologies Ltd, Zurich, Switzerland). The SUVRs for 11 C-PiB and 18 F-BCPP-EF were estimated by dividing the target SUV by the cerebellar SUV, with the latter being taken to indicate the background level [8,15]. The SUVs were calculated as the measured radioactivity divided by the ratio of the total injected dose to the mouse body weight.…”

Section: Data and Statistical Analysesmentioning

confidence: 99%

“…Speci cally, this probe can visualize the availability of complex I, the rst component of four electron transport complexes in the inner mitochondrial membrane, and which can be speci cally inhibited by rotenone. Using this probe, we successfully monitored dysfunction in mitochondrial activity in a rat cortical ischemia model [7] and in the parahippocampal region of the early-stage human AD brain [8].…”

Section: Introductionmentioning

confidence: 99%

In Vivo Elevation of Mitochondrial Activity and Amyloid Deposition, but Inversely Correlated, in Early-stage Senescence-Accelerated Mice: A Positron Emission Tomography Study

Yamagishi

Iga

Ikegaya

et al. 2020

Preprint

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Background: While marked reductions in neural activity and mitochondrial function have been reported in Alzheimer’s disease (AD), the degree of mitochondrial activity in mild cognitive impairment (MCI) or early-stage AD remains unexplored. Here, we used positron emission tomography (PET) to examine the direct relationship between mitochondrial activity (18F-BCPP-EF) and β-amyloid (Aβ) deposition (11C-PiB), followed by immunohistochemistry for ATPB (an ATP synthase on the mitochondrial inner membrane), in the same brains of senescence-accelerated mouse prone 10 (SAMP10) mice, an Aβ-developing neuroinflammatory animal model showing accelerated senescence with deterioration in cognitive functioning similar to that in MCI.Results: The SUVRs of 18F-BCPP-EF and 11C-PiB were significantly higher in the 15-week-old SAMP10 mice than in the control and 5-week-old SAMP10 mice. The two parameters were found to negatively correlate with each other. Consistent with these binding results, the immunohistochemical analysis demonstrated upregulation of ATPB in neurons, astrocytes, and microglia, but not in pericytes, in the 15-week-old SAMP10 mice. Conclusions: The present results provide in vivo evidence of an increase in mitochondrial energy production and amyloid burden at an early stage in SAMP10 mice. The inverse correlation between these two phenomena suggests a concurrent compensatory increase in neuronal energy production and Aβ-induced elevation of neuroinflammatory responses in glial cells, as confirmed immunohistochemically. The combination of PET and immunohistochemistry allowed in vivo evaluation of altered mitochondrial activity during neuropathological processes, including Aβ accumulation, in an animal model of AD spectrum disorder.

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In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease

Cited by 83 publications

References 41 publications

PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing

In Vivo Elevation of Mitochondrial Activity and Amyloid Deposition, but Inversely Correlated, in Early-stage Senescence-Accelerated Mice: A Positron Emission Tomography Study

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