scholarly journals Alzheimer's Disease: Metabolic Uncoupling of Associative Brain Regions

1986 ◽  
Vol 13 (S4) ◽  
pp. 540-545 ◽  
Author(s):  
Stanley I. Rapoport ◽  
Barry Horwitz ◽  
James V. Haxby ◽  
Cheryl L. Grady
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Parietal Lobe ◽  
Brain Regions ◽  
Metabolic Abnormalities ◽  
Alzheimer Type ◽  
Positron Emission ◽  
Partial Correlations ◽  
Metabolic Uncoupling ◽  
Parietal Cortices

Abstract:Evidence indicates that Alzheimer's disease (AD) causes functional disconnection of neocortical association areas. In mildly demented AD patients without measurable neocortically-mediated cognitive abnormalities, positron emission tomography demonstrates reduced parietal lobe glucose metabolism and left/right metabolic asymmetries in neocortical association areas. Similar metabolic abnormalities occur in moderately demented patients, but are accompanied by appropriate language and visuospatial discrepancies. Left/right metabolic asymmetries correspond with reduced numbers of partial correlations between metabolic rates in homologous right and left regions, and in the frontal and parietal cortices, indicating metabolic uncoupling among these regions. The affected association regions are those which demonstrate Alzheimer-type neuropathology post-mortem.

scholarly journals A Meta-Analysis of Alzheimer’s Disease Brain Transcriptomic Data

2018 ◽  
Author(s):  
Hamel Patel ◽  
Richard J.B Dobson ◽  
Stephen J Newhouse
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontal Lobe ◽  
Temporal Lobe ◽  
Parietal Lobe ◽  
Meta Analysis ◽  
Differential Expression Analysis ◽  
Brain Regions ◽  
Biological Pathways ◽  
Transcriptomic Changes

ABSTRACTBackgroundMicroarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer’s disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurodegenerative and mental health disorders exhibit similar perturbations. We are yet to identify robust transcriptomic changes specific to AD brains.Methods and ResultsTwenty-two AD, eight Schizophrenia, five Bipolar Disorder, four Huntington's disease, two Major Depressive Disorder and one Parkinson’s disease dataset totalling 2667 samples and mapping to four different brain regions (Temporal lobe, Frontal lobe, Parietal lobe and Cerebellum) were analysed. Differential expression analysis was performed independently in each dataset, followed by meta-analysis using a combining p-value method known as Adaptively Weighted with One-sided Correction. This identified 323, 435, 1023 and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe and cerebellum brain regions respectively. Seven of these genes were consistently perturbed across all AD brain regions with SPCS1 gene expression pattern replicating in RNA-seq data. A further nineteen genes were perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting possible involvement in AD neuropathology. Biological pathways involved in the “metabolism of proteins” and viral components were significantly enriched across AD brains.ConclusionThis study solely relied on publicly available microarray data, which too often lacks appropriate phenotypic information for robust data analysis and needs to be addressed by future studies. Nevertheless, with the information available, we were able to identify specific transcriptomic changes in AD brains which could make a significant contribution towards the understanding of AD disease mechanisms and may also provide new therapeutic targets.

scholarly journals β-Amyloid is Associated with Aberrant Metabolic Connectivity in Subjects with Mild Cognitive Impairment

2014 ◽  
Vol 34 (7) ◽  
pp. 1169-1179 ◽  
Author(s):  
Felix Carbonell ◽  
Arnaud Charil ◽  
Alex P Zijdenbos ◽  
Alan C Evans ◽  
Barry J Bedell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Disease Process ◽  
Brain Regions ◽  
Apoe Ε4 ◽  
Positron Emission ◽  
Β Amyloid ◽  
Glucose Hypometabolism

Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimer's disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein ε4 (APOE ε4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ε4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ε4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.

scholarly journals Blood metabolite markers of cognitive performance and brain function in aging

2015 ◽  
Vol 36 (7) ◽  
pp. 1212-1223 ◽  
Author(s):  
Brittany N Simpson ◽  
Min Kim ◽  
Yi-Fang Chuang ◽  
Lori Beason-Held ◽  
Melissa Kitner-Triolo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Function ◽  
Memory Performance ◽  
Verbal Learning ◽  
Plasma Concentrations ◽  
Brain Regions ◽  
Older Individuals ◽  
Lower Plasma ◽  
Positron Emission

We recently showed that Alzheimer's disease patients have lower plasma concentrations of the phosphatidylcholines (PC16:0/20:5; PC16:0/22:6; and PC18:0/22:6) relative to healthy controls. We now extend these findings by examining associations between plasma concentrations of these PCs with cognition and brain function (measured by regional resting state cerebral blood flow; rCBF) in non-demented older individuals. Within the Baltimore Longitudinal Study of Aging neuroimaging substudy, participants underwent cognitive assessments and brain 15O-water positron emission tomography. Plasma phosphatidylcholines concentrations (PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6), cognition (California Verbal Learning Test (CVLT), Trail Making Test A&B, the Mini-Mental State Examination, Benton Visual Retention, Card Rotation, and Fluencies—Category and Letter), and rCBF were assessed. Lower plasma phosphatidylcholine concentrations were associated with lower baseline memory performance (CVLT long delay recall task—PC16:0/20:5: −2.17–1.39−0.60 p = 0.001 (β with 95% confidence interval subscripts)) and lower rCBF in several brain regions including those associated with memory performance and higher order cognitive processes. Our findings suggest that lower plasma concentrations of PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6 are associated with poorer memory performance as well as widespread decreases in brain function during aging. Dysregulation of peripheral phosphatidylcholine metabolism may therefore be a common feature of both Alzheimer's disease and age-associated differences in cognition.

scholarly journals Tau-induced focal neurotoxicity and network disruption related to apathy in Alzheimer’s disease

2018 ◽  
Vol 89 (11) ◽  
pp. 1208-1214 ◽  
Author(s):  
Soichiro Kitamura ◽  
Hitoshi Shimada ◽  
Fumitoshi Niwa ◽  
Hironobu Endo ◽  
Hitoshi Shinotoh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Diffusion Tensor ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Subsequent Decrease ◽  
Positron Emission ◽  
Significant Difference ◽  
Network Disruption

ObjectiveApathy is a common neuropsychological symptom in Alzheimer’s disease (AD), and previous studies demonstrated that neuronal loss and network disruption in some brain regions play pivotal roles in the pathogenesis of apathy. However, contributions of tau and amyloid-β (Aβ) depositions, pathological hallmarks of AD, to the manifestation of apathy remain elusive.MethodsSeventeen patients with AD underwent positron emission tomography (PET) with11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) and11C-Pittsburgh compound-B (11C-PiB) to estimate tau and Aβ accumulations using standardised uptake value ratio (SUVR) images.11C-PBB3 and11C-PiB SUVR were compared between AD patients with high and low Apathy Scale (AS) scores. Additionally, volumetric and diffusion tensor MRI was performed in those areas where any significant difference was observed in PET analyses. Correlation and path analyses among AS and estimated imaging parameters were also conducted.ResultsAD patients with high AS scores showed higher11C-PBB3 SUVR in the orbitofrontal cortex (OFC) than those with low AS scores, while11C-PiB SUVR in any brain regions did not differ between them. Elevated11C-PBB3 SUVR in OFC, decreased OFC thickness and decreased fractional anisotropy (FA) in the uncinate fasciculus (UNC), which is structurally connected to OFC, correlated significantly with increased scores of the AS. Path analysis indicated that increased11C-PBB3 SUVR in OFC affects apathy directly and through reduction of OFC thickness and subsequent decrease of FA in UNC.ConclusionsThe present findings suggested that tau pathology in OFC may provoke focal neurotoxicity in OFC and the following disruption of the OFC-UNC network, leading to the emergence and progression of apathy in AD.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

2018 ◽  
Vol 15 (5) ◽  
pp. 429-442 ◽  
Author(s):  
Nishant Verma ◽  
S. Natasha Beretvas ◽  
Belen Pascual ◽  
Joseph C. Masdeu ◽  
Mia K. Markey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Latent Variable ◽  
Brain Regions ◽  
Disease Assessment ◽  
Latent Variable Analysis ◽  
The Relationship ◽  
Selection Of

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

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