Dataset Information

Emergent Functional Network Effects in Parkinson Disease.

ABSTRACT: The hallmark pathology underlying Parkinson disease (PD) is progressive synucleinopathy, beginning in caudal brainstem that later spreads rostrally. However, the primarily subcortical pathology fails to account for the wide spectrum of clinical manifestations in PD. To reconcile these observations, resting-state functional connectivity (FC) can be used to examine dysfunction across distributed brain networks. We measured FC in a large, single-site study of nondemented PD (N = 107; OFF medications) and healthy controls (N = 46) incorporating rigorous quality control measures and comprehensive sampling of cortical, subcortical and cerebellar regions. We employed novel statistical approaches to determine group differences across the entire connectome, at the network-level, and for select brain regions. Group differences respected well-characterized network delineations producing a striking "block-wise" pattern of network-to-network effects. Surprisingly, these results demonstrate that the greatest FC differences involve sensorimotor, thalamic, and cerebellar networks, with notably smaller striatal effects. Split-half replication demonstrates the robustness of these results. Finally, block-wise FC correlations with behavior suggest that FC disruptions may contribute to clinical manifestations in PD. Overall, these results indicate a concerted breakdown of functional network interactions, remote from primary pathophysiology, and suggest that FC deficits in PD are related to emergent network-level phenomena rather than focal pathology.

SUBMITTER: Gratton C

PROVIDER: S-EPMC6519699 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Emergent Functional Network Effects in Parkinson Disease.

Gratton Caterina C Koller Jonathan M JM Shannon William W Greene Deanna J DJ Maiti Baijayanta B Snyder Abraham Z AZ Petersen Steven E SE Perlmutter Joel S JS Campbell Meghan C MC

Cerebral cortex (New York, N.Y. : 1991) 20190601 6

The hallmark pathology underlying Parkinson disease (PD) is progressive synucleinopathy, beginning in caudal brainstem that later spreads rostrally. However, the primarily subcortical pathology fails to account for the wide spectrum of clinical manifestations in PD. To reconcile these observations, resting-state functional connectivity (FC) can be used to examine dysfunction across distributed brain networks. We measured FC in a large, single-site study of nondemented PD (N = 107; OFF medication ...[more]

PMID: 29878081

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Project description:To apply a recently developed native-space (or native-surface) method to compare resting functional magnetic resonance (MR) imaging correlations (functional connectivity) measured in patients with Parkinson-related dementia (PRD) to those measured in cognitively unimpaired, age-matched control subjects with or without Parkinson disease (PD).The study was approved by the institutional review board and complied with HIPAA regulations. Participants included cognitively unimpaired elderly individuals (n = 19), cognitively unimpaired patients with PD (n = 19), and patients with PRD (n = 18). Resting functional MR data were assessed by calculating correlation coefficients between blood oxygen level-dependent time series of a seed region and of other regions of interest selected a priori. Two seeds were used: a medial parietal region that contributes to the default network affected in Alzheimer disease and the caudate, which is affected by loss of dopaminergic inputs in PD. Correlation analyses were performed in the native space of individual subjects to avoid confounds from transformation to an average brain. Two-sample t tests were applied to data from each native-surface region of interest, and vertex-wise comparisons were made by using two-sample t tests at each vertex on the group surface; statistical results were corrected for multiple comparisons. Cortical thickness and striatal volumes were also compared across groups for the regions of interest.Corticostriatal functional correlations were decreased in PRD patients relative to elderly control subjects in bilateral prefrontal regions; largest difference was observed in the right caudal middle frontal region (r = 0.48 in PRD patients and 0.81 in elderly control subjects, uncorrected P = .001). Conversely, there was no significant difference across groups in the strength of default-network correlations. There was also no significant difference across groups in cortical thickness or striatal volume.PRD was associated with selective disruption of corticostriatal resting functional MR imaging correlations, which suggests that resting functional MR imaging analyzed in subject-native space may be a useful biomarker in this disease. Additionally, at least in the present cohort, this technique was more sensitive to PRD changes than was quantitative structural MR imaging.

Project description:Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Project description:ObjectivesTo report the frequency, severity, and types of comorbidities in people with Parkinson disease (PD) using a validated self-report comorbidity screening tool, and to determine the relationship between comorbidity and functional mobility.DesignA secondary analysis and cross-sectional observational study design.SettingUniversity hospital; outpatient balance disorders laboratory.ParticipantsPersons with mild to moderate idiopathic PD (N=76).InterventionNot applicable.Main outcome measuresThe Cumulative Illness Rating Scale-Geriatric (CIRS-G) and a comprehensive mobility assessment including gait (distance walked in 3 min), balance (mini-Balance Evaluation Systems Test), and physical function (Physical Performance Test).ResultsAll participants reported comorbidities in addition to their diagnosed PD. The average ± SD number of comorbidities was 6.96 ± 2.0 (range, 2-11), and the total CIRS-G score ± SD was 12.7 ± 4.8. The most commonly reported organ systems with comorbidity were eyes and ears (89%), psychiatric (68%), musculoskeletal (64%), lower gastrointestinal (62%), respiratory (60.5%), upper gastrointestinal (59.2%), and genitourinary (53.9%). The total CIRS-G score was significantly related to functional mobility: gait (r=-.53, P=.0001), balance (r=-.43, P=.0003), and physical performance (r=-.36, P=.0041). Of the original 14 organ systems measured, there were 7 systems that, when combined, best predicted gait performance, 6 systems combined that best predicted balance performance, and 4 systems combined that predicted functional performance.ConclusionsThis study reports a high frequency of multiple medical system comorbidity in people with mild to moderate PD. Furthermore, comorbidity scores were associated with mobility disability: gait, balance, and physical function. Early intervention is important to delay mobility disability in PD, and we recommend that people with PD found to have comorbidities should be screened for balance and gait deficits.

Dataset Information

Emergent Functional Network Effects in Parkinson Disease.

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Emergent Functional Network Effects in Parkinson Disease.

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