Emergent Functional Network Effects in Parkinson Disease.
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ABSTRACT:
SUBMITTER: Gratton C
PROVIDER: S-EPMC6519699 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC3309803 | biostudies-other
Project description:Networks are mathematical structures that are universally used to describe a large variety of complex systems such as the brain or the Internet. Characterizing the geometrical properties of these networks has become increasingly relevant for routing problems, inference and data mining. In real growing networks, topological, structural and geometrical properties emerge spontaneously from their dynamical rules. Nevertheless we still miss a model in which networks develop an emergent complex geometry. Here we show that a single two parameter network model, the growing geometrical network, can generate complex network geometries with non-trivial distribution of curvatures, combining exponential growth and small-world properties with finite spectral dimensionality. In one limit, the non-equilibrium dynamical rules of these networks can generate scale-free networks with clustering and communities, in another limit planar random geometries with non-trivial modularity. Finally we find that these properties of the geometrical growing networks are present in a large set of real networks describing biological, social and technological systems.
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Project description:Compensatory reorganization of the nigrostriatal system is thought to delay the onset of symptoms in early Parkinson disease (PD). Here we sought evidence that compensation may be a part of a more widespread functional reorganization in sensorimotor networks, including primary motor cortex.Several neurophysiologic measures known to be abnormal in the motor cortex (M1) of patients with advanced PD were tested on the more and less affected side of 16 newly diagnosed and drug-naive patients with PD and compared with 16 age-matched healthy participants. LTP-like effects were probed using a paired associative stimulation protocol. We also measured short interval intracortical inhibition, intracortical facilitation, cortical silent period, and input/output curves.The less affected side in patients with PD had preserved intracortical inhibition and a larger response to the plasticity protocol compared to healthy participants. On the more affected side, there was no response to the plasticity protocol and inhibition was reduced. There was no difference in input/output curves between sides or between patients with PD and healthy participants.Increased motor cortical plasticity on the less affected side is consistent with a functional reorganization of sensorimotor cortex and may represent a compensatory change that contributes to delaying onset of clinical symptoms. Alternatively, it may reflect a maladaptive plasticity that provokes symptom onset. Plasticity deteriorates as the symptoms progress, as seen on the more affected side. The rate of change in paired associative stimulation response over time could be developed into a surrogate marker of disease progression in PD.
| S-EPMC3345788 | biostudies-other
Project description:Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD.We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory-impaired PD (amnestic MCI; n?=?9), PD with nonamnestic MCI (n?=?10), PD without MCI (n?=?11), and healthy controls (n?=?14). Subjects were administered a full neuropsychological test battery for cognitive performance.Memory-impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex [ACC] and the right parahippocampal gyrus [PHG]) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients.Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction.
| S-EPMC4874785 | biostudies-other
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.
| S-EPMC8096770 | biostudies-literature
Project description:OBJECTIVE:Given their reported function in phagocytosis and clearance of protein aggregates in Alzheimer disease (AD), we hypothesized that variants in ATP-binding cassette transporter A7 (ABCA7) might be involved in Parkinson disease (PD). METHODS:ABCA7 variants were identified using whole-exome sequencing (WES) on 396 unrelated patients with PD and 222 healthy controls. In addition, we used the publicly available WES data from the Parkinson's Progression Markers Initiative (444 patients and 153 healthy controls) as a second, independent data set. RESULTS:We observed a higher frequency of loss-of-function (LOF) variants and rare putative highly functional variants (Combined Annotation Dependent Depletion [CADD] >20) in clinically diagnosed patients with PD than in healthy controls in both data sets. Overall, we identified LOF variants in 11 patients and 1 healthy control (odds ratio [OR] 4.94, Fisher exact p = 0.07). Four of these variants have been previously implicated in AD risk (p.E709AfsX86, p.W1214X, p.L1403RfsX7, and rs113809142). In addition, rare variants with CADD >20 were observed in 19 patients vs 3 healthy controls (OR 2.85, Fisher exact p = 0.06). CONCLUSION:The presence of ABCA7 LOF variants in clinically defined PD suggests that they might be risk factors for neurodegeneration in general, especially those variants hallmarked by protein aggregation. More studies will be needed to evaluate the overall impact of this transporter in neurodegenerative disease.
| S-EPMC4817903 | biostudies-literature
Project description:To 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.A secondary analysis and cross-sectional observational study design.University hospital; outpatient balance disorders laboratory.Persons with mild to moderate idiopathic PD (N=76).Not applicable.The 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).All 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.This 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.
| S-EPMC4322903 | biostudies-literature
Project description:Whether it be physical, biological or social processes, complex systems exhibit dynamics that are exceedingly difficult to understand or predict from underlying principles. Here we report a striking correspondence between the excitation dynamics of a laser driven gas of Rydberg atoms and the spreading of diseases, which in turn opens up a controllable platform for studying non-equilibrium dynamics on complex networks. The competition between facilitated excitation and spontaneous decay results in sub-exponential growth of the excitation number, which is empirically observed in real epidemics. Based on this we develop a quantitative microscopic susceptible-infected-susceptible model which links the growth and final excitation density to the dynamics of an emergent heterogeneous network and rare active region effects associated to an extended Griffiths phase. This provides physical insights into the nature of non-equilibrium criticality in driven many-body systems and the mechanisms leading to non-universal power-laws in the dynamics of complex systems.
| S-EPMC7782709 | biostudies-literature
Project description:ObjectiveTo explore longitudinal changes in brain activity in patients with Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) using task-based functional MRI (fMRI).MethodsA total of 112 individuals were scanned 1 year apart while performing a unimanual grip force task: 46 PD, 13 MSA, 19 PSP, and 34 healthy controls. The outcome measure was percent signal change in prespecified regions of interest: putamen, primary motor cortex (M1), supplementary motor area (SMA), and superior motor regions of the cerebellum (lobules V-VI).ResultsPatients with PD showed a decline in functional activity over the course of 1 year in the putamen and M1 compared to controls. Changes after 1 year in MSA were exclusively extrastriatal, and included a reduction in functional activity in M1, SMA, and superior cerebellum. In PSP, all regions of interest were less active at 1 year compared to baseline. The functional activity of these regions did not change in the control group.ConclusionsWe provide evidence using task-based fMRI for cortical and striatal functional deterioration in PD over a 1-year period of time. Results also describe more widespread and unique patterns of functional changes in MSA and PSP compared to PD, suggesting distinct rates of disease progression in parkinsonian disorders that may assist in future clinical studies testing the potential efficacy of disease-modifying therapies.
| S-EPMC4999161 | biostudies-literature
Project description:ObjectiveTo investigate the relation between orthostatic hypotension (OH) and posture-mediated cognitive impairment in Parkinson disease (PD) using a cross-sectional and within-group design.MethodsIndividuals without dementia with idiopathic PD included 18 with OH (PDOH) and 19 without OH; 18 control participants were also included. Neuropsychological tests were conducted in supine and upright-tilted positions. Blood pressure was assessed in each posture.ResultsThe PD groups performed similarly while supine, demonstrating executive dysfunction in sustained attention and response inhibition, and reduced semantic fluency and verbal memory (encoding and retention). Upright posture exacerbated and broadened these deficits in the PDOH group to include phonemic fluency, psychomotor speed, and auditory working memory. When group-specific supine scores were used as baseline anchors, both PD groups showed cognitive changes following tilt, with the PDOH group exhibiting a wider range of deficits in executive function and memory as well as significant changes in visuospatial function.ConclusionsCognitive deficits in PD have been widely reported with assessments performed in the supine position, as seen in both our PD groups. Here we demonstrated that those with PDOH had transient, posture-mediated changes in excess of those found in PD without OH. These observed changes suggest an acute, reversible effect. Understanding the effects of OH due to autonomic failure on cognition is desirable, particularly as neuroimaging and clinical assessments collect data only in the supine or seated positions. Identification of a distinct neuropsychological profile in PD with OH has quality of life implications, and OH presents itself as a possible target for intervention in cognitive disturbance.
| S-EPMC5200856 | biostudies-literature