Capture of Somatic mtDNA Point Mutations with Severe Effects on Oxidative Phosphorylation in Synaptosome Cybrid Clones from Human Brain

2014 ◽  
Vol 35 (12) ◽  
pp. 1476-1484 ◽  
Author(s):  
Matthew McKenzie ◽  
Maria Chiotis ◽  
Jana Hroudová ◽  
Maria I.G. Lopez Sanchez ◽  
Sze Chern Lim ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Human Brain ◽  
Point Mutations

scholarly journals Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Hans-Ulrich Klein ◽  
Caroline Trumpff ◽  
Hyun-Sik Yang ◽  
Annie J. Lee ◽  
Martin Picard ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cognitive Function ◽  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Cognitive Decline ◽  
Point Mutations ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Posterior Cingulate ◽  
Small Indels

Abstract Background Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimer’s disease (AD). Changes in the mitochondrial DNA copy number (mtDNAcn) and increased mitochondrial DNA mutation burden have both been associated with neurodegenerative diseases and cognitive decline. This study aims to systematically identify which common brain pathologies in the aged human brain are associated with mitochondrial recalibrations and to disentangle the relationship between these pathologies, mtDNAcn, mtDNA heteroplasmy, aging, neuronal loss, and cognitive function. Methods Whole-genome sequencing data from n = 1361 human brain samples from 5 different regions were used to quantify mtDNAcn as well as heteroplasmic mtDNA point mutations and small indels. Brain samples were assessed for 10 common pathologies. Annual cognitive test results were used to assess cognitive function proximal to death. For a subset of samples, neuronal proportions were estimated from RNA-seq profiles, and mass spectrometry was used to quantify the mitochondrial protein content of the tissue. Results mtDNAcn was 7–14% lower in AD relative to control participants. When accounting for all 10 common neuropathologies, only tau was significantly associated with lower mtDNAcn in the dorsolateral prefrontal cortex. In the posterior cingulate cortex, TDP-43 pathology demonstrated a distinct association with mtDNAcn. No changes were observed in the cerebellum, which is affected late by pathologies. Neither age nor gender was associated with mtDNAcn in the studied brain regions when adjusting for pathologies. Mitochondrial content and mtDNAcn independently explained variance in cognitive function unaccounted by pathologies, implicating complex mitochondrial recalibrations in cognitive decline. In contrast, mtDNA heteroplasmy levels increased by 1.5% per year of life in the cortical regions, but displayed no association with any of the pathologies or cognitive function. Conclusions We studied mtDNA quantity and quality in relation to mixed pathologies of aging and showed that tau and not amyloid-β is primarily associated with reduced mtDNAcn. In the posterior cingulate cortex, the association of TDP-43 with low mtDNAcn points to a vulnerability of this region in limbic-predominant age-related TDP-43 encephalopathy. While we found low mtDNAcn in brain regions affected by pathologies, the absence of associations with mtDNA heteroplasmy burden indicates that mtDNA point mutations and small indels are unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases.

scholarly journals Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain: No evidence of regional differences of aerobic glycolysis

2016 ◽  
Vol 36 (5) ◽  
pp. 903-916 ◽  
Author(s):  
Fahmeed Hyder ◽  
Peter Herman ◽  
Christopher J Bailey ◽  
Arne Møller ◽  
Ronen Globinsky ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Oxidative Phosphorylation ◽  
Human Brain ◽  
Gray Matter ◽  
Glucose Oxidation ◽  
Aerobic Glycolysis ◽  
Oxygen Extraction Fraction ◽  
Oxygen Extraction ◽  
Extraction Fraction ◽  
Normal Human

Regionally variable rates of aerobic glycolysis in brain networks identified by resting-state functional magnetic resonance imaging (R-fMRI) imply regionally variable adenosine triphosphate (ATP) regeneration. When regional glucose utilization is not matched to oxygen delivery, affected regions have correspondingly variable rates of ATP and lactate production. We tested the extent to which aerobic glycolysis and oxidative phosphorylation power R-fMRI networks by measuring quantitative differences between the oxygen to glucose index (OGI) and the oxygen extraction fraction (OEF) as measured by positron emission tomography (PET) in normal human brain (resting awake, eyes closed). Regionally uniform and correlated OEF and OGI estimates prevailed, with network values that matched the gray matter means, regardless of size, location, and origin. The spatial agreement between oxygen delivery (OEF≈0.4) and glucose oxidation (OGI ≈ 5.3) suggests that no specific regions have preferentially high aerobic glycolysis and low oxidative phosphorylation rates, with globally optimal maximum ATP turnover rates (VATP ≈ 9.4 µmol/g/min), in good agreement with 31P and 13C magnetic resonance spectroscopy measurements. These results imply that the intrinsic network activity in healthy human brain powers the entire gray matter with ubiquitously high rates of glucose oxidation. Reports of departures from normal brain-wide homogeny of oxygen extraction fraction and oxygen to glucose index may be due to normalization artefacts from relative PET measurements.

scholarly journals Quantitative positron emission tomography reveals regional differences in aerobic glycolysis within the human brain

2018 ◽  
Vol 39 (10) ◽  
pp. 2096-2102 ◽  
Author(s):  
Tyler Blazey ◽  
Abraham Z Snyder ◽  
Yi Su ◽  
Manu S Goyal ◽  
John J Lee ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Oxidative Phosphorylation ◽  
Human Brain ◽  
Gray Matter ◽  
Regional Differences ◽  
Aerobic Glycolysis ◽  
Oxygen Metabolism ◽  
Emission Tomography ◽  
Published Data ◽  
Positron Emission

Glucose and oxygen metabolism are tightly coupled in the human brain, with the preponderance of the brain’s glucose supply used to generate ATP via oxidative phosphorylation. A fraction of glucose is consumed outside of oxidative phosphorylation despite the presence of sufficient oxygen to do so. We refer to this process as aerobic glycolysis. A recent positron emission tomography study reported that aerobic glycolysis is uniform within gray matter. Here, we analyze the same data and demonstrate robust regional differences in aerobic glycolysis within gray matter, a finding consistent with previously published data.

Language processing is not a race against time

2016 ◽  
Vol 39 ◽  
Author(s):  
Giosuè Baggio ◽  
Carmelo M. Vicario
Keyword(s):  
Information Processing ◽  
Human Brain ◽  
Language Processing ◽  
Cognitive Functions ◽  
Memory Systems ◽  
Language System ◽  
Moderating Factors

AbstractWe agree with Christiansen & Chater (C&C) that language processing and acquisition are tightly constrained by the limits of sensory and memory systems. However, the human brain supports a range of cognitive functions that mitigate the effects of information processing bottlenecks. The language system is partly organised around these moderating factors, not just around restrictions on storage and computation.

Structural and Chemical Studies of Pathological Fibers in Human Neurofibrillary Degeneration

1985 ◽  
Vol 43 ◽  
pp. 726-729
Author(s):  
K.S. Kosik ◽  
L.K. Duffy ◽  
S. Bakalis ◽  
C. Abraham ◽  
D.J. Selkoe
Keyword(s):  
Monoclonal Antibodies ◽  
Alzheimer Disease ◽  
Human Brain ◽  
Neurofibrillary Tangles ◽  
Morphological Analysis ◽  
High Specificity ◽  
Cytoskeletal Proteins ◽  
Neuritic Plaque ◽  
Protein Chemistry ◽  
Chemical Studies

The major structural lesions of the human brain during aging and in Alzheimer disease (AD) are the neurofibrillary tangles (NFT) and the senile (neuritic) plaque. Although these fibrous alterations have been recognized by light microscopists for almost a century, detailed biochemical and morphological analysis of the lesions has been undertaken only recently. Because the intraneuronal deposits in the NFT and the plaque neurites and the extraneuronal amyloid cores of the plaques have a filamentous ultrastructure, the neuronal cytoskeleton has played a prominent role in most pathogenetic hypotheses.The approach of our laboratory toward elucidating the origin of plaques and tangles in AD has been two-fold: the use of analytical protein chemistry to purify and then characterize the pathological fibers comprising the tangles and plaques, and the use of certain monoclonal antibodies to neuronal cytoskeletal proteins that, despite high specificity, cross-react with NFT and thus implicate epitopes of these proteins as constituents of the tangles.

Toward a neuroscope: An application of high-performance computing for real-time evaluation of brain function using MRI

1994 ◽  
Vol 52 ◽  
pp. 922-923
Author(s):  
C. S. Potter ◽  
C. D. Gregory ◽  
H. D. Morris ◽  
Z.-P. Liang ◽  
P. C. Lauterbur
Keyword(s):  
Human Brain ◽  
Brain Function ◽  
High Performance ◽  
Complex Signal ◽  
Time Step ◽  
Brain Organization ◽  
Cognitive Studies ◽  
Positron Emission ◽  
Imaging And Spectroscopy ◽  
3D Anatomy

Over the past few years, several laboratories have demonstrated that changes in local neuronal activity associated with human brain function can be detected by magnetic resonance imaging and spectroscopy. Using these methods, the effects of sensory and motor stimulation have been observed and cognitive studies have begun. These new methods promise to make possible even more rapid and extensive studies of brain organization and responses than those now in use, such as positron emission tomography.Human brain studies are enormously complex. Signal changes on the order of a few percent must be detected against the background of the complex 3D anatomy of the human brain. Today, most functional MR experiments are performed using several 2D slice images acquired at each time step or stimulation condition of the experimental protocol. It is generally believed that true 3D experiments must be performed for many cognitive experiments. To provide adequate resolution, this requires that data must be acquired faster and/or more efficiently to support 3D functional analysis.

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