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Correlations of Neuropsychological and Metabolic Brain Changes in Parkinson's Disease and Other α-Synucleinopathies.

ABSTRACT: Cognitive impairment is a common feature in Parkinson's disease (PD) and other α-synucleinopathies as 80% of PD patients develop dementia within 20 years. Early cognitive changes in PD patients present as a dysexecutive syndrome, broadly characterized as a disruption of the fronto-striatal dopamine network. Cognitive deficits in other domains (recognition memory, attention processes and visuospatial abilities) become apparent with the progression of PD and development of dementia. In dementia with Lewy bodies (DLB) the cognitive impairment develops early or even precedes parkinsonism and it is more pronounced in visuospatial skills and memory. Cognitive impairment in the rarer α-synucleinopathies (multiple system atrophy and pure autonomic failure) is less well studied. Metabolic brain imaging with positron emission tomography and [18F]-fluorodeoxyglucose (FDG-PET) is a well-established diagnostic method in neurodegenerative diseases, including dementias. Changes in glucose metabolism precede those seen on structural magnetic resonance imaging (MRI). Reduction in glucose metabolism and atrophy have been suggested to represent consecutive changes of neurodegeneration and are linked to specific cognitive disorders (e.g., dysexecutive syndrome, memory impairment, visuospatial deficits etc.). Advances in the statistical analysis of FDG-PET images enabling a network analysis broadened our understanding of neurodegenerative brain processes. A specific cognitive pattern related to PD was identified by applying voxel-based network modeling approach. The magnitude of this pattern correlated significantly with patients' cognitive skills. Specific metabolic brain changes were observed also in patients with DLB as well as in a prodromal phase of α-synucleinopathy: REM sleep behavior disorder. Metabolic brain imaging with FDG-PET is a reliable biomarker of neurodegenerative brain diseases throughout their course, precisely reflecting their topographic distribution, stage and functional impact.

SUBMITTER: Trost M

PROVIDER: S-EPMC6868095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThe aim of this study was to evaluate the neurobehavioral safety of constant-current subthalamic deep brain stimulation and to compare the neuropsychological effects of stimulation versus electrode placement alone.MethodsA total of 136 patients with Parkinson's disease underwent bilateral subthalamic device implantation in this randomized trial. Patients received stimulation either immediately after device implantation (n = 101; active stimulation) or beginning 3 months after surgery (n = 35; delayed activation control). Patients were administered neuropsychological tests before, 3, and 12 months after device implantation.ResultsNeuropsychological change in stimulation and control groups were comparable. Within-group analyses revealed declines in category and switching verbal fluency in both groups, but only the stimulation group had letter verbal fluency and Stroop task declines. Depression symptom improvements occurred in both groups, but more often in the stimulation group. Letter fluency declines were associated with worse Parkinson's Disease Questionnaire Communication subscale scores. Baseline and 12-month comparisons (in the combined group) revealed gains in verbal and visual delayed recall scores and improvement in depression symptoms, but decrements in verbal fluency and Stroop scores.ConclusionsConstant-current bilateral subthalamic stimulation had a good cognitive safety profile except for decrements in verbal fluency and on the Stroop task. These abnormalities are related to device implantation, but stimulation likely had an additive effect. One year after surgery, the cognitive changes did not exert a detrimental effect on quality of life, although letter fluency declines were associated with communication dissatisfaction at 12 months. Improvement in depressive symptom severity appears dependent on stimulation and not placebo or lesion effects. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Project description:BACKGROUND:Parkinson's disease is a widespread neurodegenerative disorder which affects brain metabolism. Although changes in gene expression during disease are often measured, it is difficult to predict metabolic fluxes from gene expression data. Here we explore the hypothesis that changes in gene expression for enzymes tend to parallel flux changes in biochemical reaction pathways in the brain metabolic network. This hypothesis is the basis of a computational method to predict metabolic flux changes from post-mortem gene expression measurements in Parkinson's disease (PD) brain. RESULTS:We use a network model of central metabolism and optimize the correspondence between relative changes in fluxes and in gene expression. To this end we apply the Least-squares with Equalities and Inequalities algorithm integrated with Flux Balance Analysis (Lsei-FBA). We predict for PD (1) decreases in glycolytic rate and oxygen consumption and an increase in lactate production in brain cortex that correspond with measurements (2) relative flux decreases in ATP synthesis, in the malate-aspartate shuttle and midway in the TCA cycle that are substantially larger than relative changes in glucose uptake in the substantia nigra, dopaminergic neurons and most other brain regions (3) shifts in redox shuttles between cytosol and mitochondria (4) in contrast to Alzheimer's disease: little activation of the gamma-aminobutyric acid shunt pathway in compensation for decreased alpha-ketoglutarate dehydrogenase activity (5) in the globus pallidus internus, metabolic fluxes are increased, reflecting increased functional activity. CONCLUSION:Our method predicts metabolic changes from gene expression data that correspond in direction and order of magnitude with presently available experimental observations during Parkinson's disease, indicating that the hypothesis may be useful for some biochemical pathways. Lsei-FBA generates predictions of flux distributions in neurons and small brain regions for which accurate metabolic flux measurements are not yet possible.

Project description:Based on immunostainings and biochemical analyses, certain post-translationally modified alpha-synuclein (aSyn) variants, including C-terminally truncated (CTT) and Serine-129 phosphorylated (pSer129) aSyn, are proposed to be involved in the pathogenesis of synucleinopathies such as Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, quantitative information about aSyn proteoforms in the human brain in physiological and different pathological conditions is still limited. To address this, we generated sequential biochemical extracts of the substantia nigra, putamen and hippocampus from 28 donors diagnosed and neuropathologically-confirmed with different synucleinopathies (PD/PDD/DLB/MSA), as well as Alzheimer's disease, progressive supranuclear palsy, and aged normal subjects. The tissue extracts were used to build a reverse phase array including 65 aSyn antibodies for detection. In this multiplex approach, we observed increased immunoreactivity in donors with synucleinopathies compared to controls in detergent-insoluble fractions, mainly for antibodies against CT aSyn and pSer129 aSyn. In addition, despite of the restricted sample size, clustering analysis suggested disease-specific immunoreactivity signatures in patient groups with different synucleinopathies. We aimed to validate and quantify these findings using newly developed immunoassays towards total, 119 and 122 CTT, and pSer129 aSyn. In line with previous studies, we found that synucleinopathies shared an enrichment of post-translationally modified aSyn in detergent-insoluble fractions compared to the other analyzed groups. Our measurements allowed for a quantitative separation of PDD/DLB patients from other synucleinopathies based on higher detergent-insoluble pSer129 aSyn concentrations in the hippocampus. In addition, we found that MSA stood out due to enrichment of CTT and pSer129 aSyn also in the detergent-soluble fraction of the SN and putamen. Together, our results achieved by multiplexed and quantitative immunoassay-based approaches in human brain extracts of a limited sample set point to disease-specific biochemical aSyn proteoform profiles in distinct neurodegenerative disorders.

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Correlations of Neuropsychological and Metabolic Brain Changes in Parkinson's Disease and Other α-Synucleinopathies.

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