Biology subjects

Factor, S. A.

Publications and source records attributed to Factor, S. A..

7 recordsLinked to original sources

bioRxiv2021

Human-genome gut-microbiome interaction in Parkinson's disease

The causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinsons disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we show that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. This is the first demonstration of interaction between genetic factors in the human genome and the dysbiosis of gut microbiome in PD.

genetics↗

bioRxiv2020

A Metabolomic Study of Cervical Dystonia

BackgroundCervical dystonia is the most common of the adult-onset focal dystonias. Most cases are idiopathic. The current view is that cervical dystonia may be caused by some combination of genetic and environmental factors. Genetic contributions have been studied extensively, but there are few studies of other factors. ObjectiveTo conduct an exploratory metabolomics analysis of cervical dystonia to identify potentially abnormal metabolites or altered biological pathways. MethodsPlasma samples from 100 cases with idiopathic cervical dystonia and 100 controls were compared using liquid chromatography coupled with mass spectrometry-based metabolomics. ResultsA total of 7,346 metabolic features remained after quality control, and 289 demonstrated significant differences between cases and controls, depending on statistical criteria chosen. Pathway analysis revealed 9 biological processes to be significantly associated at p<0.05, 5 pathways were related to carbohydrate metabolism, 3 pathways were related to lipid metabolism. ConclusionThis is the first large scale metabolomics study for any type of dystonia. The results may provide potential novel insights into the biology of cervical dystonia.

neuroscience↗

bioRxiv2020

Abnormal center of mass control during balance is associated with falls in Parkinson's disease

Although Parkinson disease (PD) causes profound balance impairments, we know very little about how PD impacts the sensorimotor networks we rely on for automatically maintaining balance control. In young healthy people and animals, muscles are activated in a precise temporal and spatial organization when the center of body mass (CoM) is unexpectedly moved that is largely automatic and determined by feedback of CoM motion. Here, we show that PD alters the sensitivity of the sensorimotor feedback transformation. Importantly, sensorimotor feedback transformations for balance in PD remain temporally precise, but become spatially diffuse by recruiting additional muscle activity in antagonist muscles during balance responses. The abnormal antagonist muscle activity remains precisely time-locked to sensorimotor feedback signals encoding undesirable motion of the body in space. Further, among people with PD, the sensitivity of abnormal antagonist muscle activity to CoM motion varies directly with the number of recent falls. Our work shows that in people with PD, sensorimotor feedback transformations for balance are intact but disinhibited in antagonist muscles, likely contributing to balance deficits and falls.

neuroscience↗

bioRxiv2020

Characterizing dysbiosis of gut microbiome in PD: Evidence for overabundance of opportunistic pathogens

In Parkinsons disease (PD), gastrointestinal features are common and often precede the motor signs. Braak and colleagues proposed that PD may start in the gut, triggered by a pathogen, and spread to the brain. Numerous studies have examined the gut microbiome in PD, all found it to be altered, but found inconsistent results on associated microorganisms. Studies to date have been small (N=20 to 306) and are difficult to compare or combine due to varied methodology. We conducted a microbiome-wide association study (MWAS) with two large datasets for internal replication (N=333 and 507). We used uniform methodology when possible, interrogated confounders, and applied two statistical tests for concordance, followed by correlation network analysis to infer interactions. Fifteen genera were associated with PD at a microbiome-wide significance level, in both datasets, with both methods, with or without covariate adjustment. The associations were not independent, rather represented 3 clusters of co-occurring microorganisms. Cluster 1 was composed of opportunistic pathogens; all were elevated in PD. Cluster 2 were short-chain-fatty-acid producing bacteria; all were reduced in PD. Cluster 3 were carbohydrate-metabolizing probiotics; elevated in PD. Depletion of anti-inflammatory short-chain-fatty-acid producing bacteria and elevated levels of probiotics are confirmatory. Overabundance of opportunistic pathogens is a novel finding and their identity provides a lead to experimentally test their role in PD.

genomics↗

bioRxiv2019

Perception of whole-body motion during balance perturbations is impaired in Parkinson’s disease and is associated with balance impairment

BackgroundIn addition to motor deficits, Parkinsons disease (PD) may cause perceptual impairments. The role of perceptual impairments in sensorimotor function is unclear, and has typically been studied in single-joint motions. Research Question: We hypothesized that perception of whole-body motion is impaired in PD and contributes to balance impairments. We tested 1) whether directional acuity to whole body perturbations during standing was worse in people with PD compared to neurotypical older adults (NOA), and 2) whether balance ability, as assessed by the MiniBESTest, was associated with poor directional acuity in either group.\n\nMethodsParticipants were exposed to pairs of support-surface translation perturbations in a two-alternative forced choice testing paradigm developed previously in a young healthy population. The first perturbation of each pair was directly backward and the second deviated to the left or right (1{degrees}-44{degrees}). Participants judged and reported whether the perturbations in each pair were in the \"same\" or \"different\" direction. This information was used to calculate directional acuity thresholds corresponding to \"just-noticeable differences\" in perturbation direction. Linear mixed models determined associations between directional thresholds and clinical variables including MDS UPDRS-III score, age, and MiniBESTest score. Results: 20 PD (64{+/-}7 y, 12 male, [>=]12 hours since last intake of antiparkinsonian medications) and 12 NOA (64{+/-}8, 6 male) were assessed. Directional thresholds were higher (worse) among PD participants (17.6{+/-}5.9{degrees} vs. 12.8{+/-}3.3{degrees}, P<0.01). Linear mixed models further showed that higher thresholds were associated with MDS UPDRS-III score (P<0.01), and were associated with poorer balance ability among PD participants (P<0.01), but not among NOA participants (P=0.40). Significance: Perception of whole-body motion is impaired in PD and may contribute to impaired balance and falls.

neuroscience↗

bioRxiv2019

Levodopa Responsiveness Subtypes of Freezing of Gait: Results Using a Levodopa Challenge

ObjectiveTo demonstrate that levodopa-unresponsive freezing of gait (ONOFF-FOG), which is a disabling untreatable feature of Parkinsons disease (PD), is distinct from responsive/OFF only FOG (OFF-FOG) and potentially has a distinct pathophysiology.\n\nMethodsFifty-five PD patients completed levodopa challenges after >12 hours OFF with supratherapeutic doses to classify them as NOFOG, OFF-FOG or ONOFF-FOG. Serum levodopa levels ensured threshold levels were met. An \"ON\" response was defined as [≥]20% improvement in MDS-UPDRS-III score. Main outcome measure was MDS-UPDRS-III based on clinical exam, timed-up-and-go tests and 360{degrees} turns.\n\nResults45 patients exhibited an \"ON\" response to the challenge. Levodopa-equivalent-dose was 142{+/-}56% of patients typical morning doses. Patients could be classified as: 19 ONOFF-FOG, 11 OFF-FOG, 15 NOFOG. The ONOFF-FOG group exhibited significantly higher NFOG-Q, MDS-UPDRS-II/III scores compared to the OFF-FOG group. MDS-UPDRS-III total varied significantly across medication response states (P<0.01) and groups (P=0.03). Among MDS-UPDRS-III subdomains, significant effects of group (highest in ONOFF-FOG group) were identified for measures of lower extremities and gait. Linear mixed models revealed a highly significant association between serum levodopa level and MDS-UPDRS-III score that did not vary across the groups. There was a highly significant group interaction effect on the association between serum levodopa level with MDS-UPDRS-III item 11 \"Freezing of Gait\" (P<0.001).\n\nConclusionsONOFF-FOG is a distinct subtype of FOG in PD, as opposed to OFF-FOG. This is an important step in demonstrating that FOG is not a single entity and, in turn, could lead to better understanding of pathophysiology and development of effective therapies.

neuroscience↗

bioRxiv2019

Lower-limb rigidity is associated with frequent falls in Parkinson disease

BACKGROUND AND OBJECTIVEThe role of muscle rigidity as an etiological factor of falls in Parkinson disease (PD) is poorly understood. Our objective was to determine whether lower leg rigidity was differentially associated with frequent falls in PD compared to upper limb, neck, and total rigidity measures. METHODS: We examined associations between UPDRS-III (motor) rigidity subscores and history of monthly or more frequent falls in N=216 individuals with PD (age, 66{+/-}10 y; 36% female, disease duration, 7{+/-}5 y) with logistic regression. RESULTS: N=35 individuals were frequent fallers. Significant associations were identified between lower limb rigidity and frequent falls (P=0.01) after controlling for age, sex, PD duration, total UPDRS-III score, and presence of FOG. No significant associations (P[≥]0.14) were identified for total, arm, or neck rigidity. CONCLUSION: Lower limb rigidity is related to frequent falls in people with PD. Further investigation may be warranted into how parkinsonian rigidity could cause falls.\n\nFinancial Disclosures/Conflict of Interest concerning the research related to the manuscript: None\n\nFundingNIH K25HD086276, R01HD046922, R21HD075612, UL1TR002378, UL1TR000454; Department of Veterans Affairs R&D Service Career Development Awards E7108M and N0870W, Consolidated Anti-Aging Foundation, and the Sartain Lanier Family Foundation.

neuroscience↗