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Cognition as a mediator for gait and balance impairments in GBA-related Parkinson's disease.

ABSTRACT: The extent to which the heterogeneity of gait and balance problems in PD may be explained by genetic variation is unknown. Variants in the glucocerebrosidase (GBA) gene are the strongest known genetic risk factor for PD and are associated with greater motor and cognitive severity. However, the impact of GBA variants on comprehensive measures of gait and balance and their relationship to cognition remains unknown. We aimed to determine differences in gait and balance impairments in those with and without GBA variants (mutation carriers and E326K polymorphism) and explore direct and indirect effects of GBA status on gait, balance, and cognition. 332 participants, 43 of whom had GBA variants, were recruited. Participants completed a comprehensive, objective assessment of gait and standing balance using body-worn inertial sensors. Group differences in gait and balance between PD with and without GBA variants were assessed with linear regression, adjusting for age, gender, clinical testing site, disease duration, and apolipoprotein E (APOE) ɛ4 status. Structural equation modeling (SEM) explored direct relationships between GBA status and gait and balance and indirect relationships between GBA status and gait and balance via cognition. The GBA variant group had more impaired gait (pace and variability) and balance (sway area/jerk and sway velocity), than the non-GBA variant group. SEM demonstrated cognition as a mediator of GBA status on gait and balance. The close relationships among GBA, gait/balance, and cognition suggest potential for novel therapeutics to target the GBA pathway and/or cognition to improve mobility in PD GBA variants.

SUBMITTER: Morris R

PROVIDER: S-EPMC9209443 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Cognition as a mediator for gait and balance impairments in GBA-related Parkinson's disease.

Morris Rosie R Martini Douglas N DN Ramsey Katrina K Kelly Valerie E VE Smulders Katrijn K Hiller Amie A Chung Kathryn A KA Hu Shu-Ching SC Zabetian Cyrus P CP Poston Kathleen L KL Mata Ignacio F IF Edwards Karen L KL Lapidus Jodi J Cholerton Brenna B Montine Thomas J TJ Quinn Joseph F JF Horak Fay F

NPJ Parkinson's disease 20220620 1

The extent to which the heterogeneity of gait and balance problems in PD may be explained by genetic variation is unknown. Variants in the glucocerebrosidase (GBA) gene are the strongest known genetic risk factor for PD and are associated with greater motor and cognitive severity. However, the impact of GBA variants on comprehensive measures of gait and balance and their relationship to cognition remains unknown. We aimed to determine differences in gait and balance impairments in those with and ...[more]

PMID: 35725575

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Project description:The cholinergic system has been implicated in postural deficits, in particular falls, in Parkinson's disease (PD). Falls and freezing of gait typically occur during dynamic and challenging balance and gait conditions, such as when initiating gait, experiencing postural perturbations, or making turns. However, the precise cholinergic neural substrate underlying dynamic postural and gait changes remains poorly understood. The aim of this study was to investigate whether brain vesicular acetylcholine transporter binding, as measured with [18F]-fluoroethoxybenzovesamicol binding PET, correlates with dynamic gait and balance impairments in 125 patients with PD (mean age 66.89 ± 7.71 years) using the abbreviated balance evaluation systems test total and its four functional domain sub-scores (anticipatory postural control, reactive postural control, dynamic gait, and sensory integration). Whole brain false discovery-corrected (P < 0.05) correlations for total abbreviated balance evaluation systems test scores included the following bilateral or asymmetric hemispheric regions: gyrus rectus, orbitofrontal cortex, anterior part of the dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, cingulum, frontotemporal opercula, insula, fimbria, right temporal pole, mesiotemporal, parietal and visual cortices, caudate nucleus, lateral and medial geniculate bodies, thalamus, lingual gyrus, cerebellar hemisphere lobule VI, left cerebellar crus I, superior cerebellar peduncles, flocculus, and nodulus. No significant correlations were found for the putamen or anteroventral putamen. The four domain-specific sub-scores demonstrated overlapping cholinergic topography in the metathalamus, fimbria, thalamus proper, and prefrontal cortices but also showed distinct topographic variations. For example, reactive postural control functions involved the right flocculus but not the upper brainstem regions. The anterior cingulum associated with reactive postural control whereas the posterior cingulum correlated with anticipatory control. The spatial extent of associated cholinergic system changes were least for dynamic gait and sensory orientation functional domains compared to the anticipatory and reactive postural control functions. We conclude that specific aspects of dynamic balance and gait deficits in PD associate with overlapping but also distinct patterns of cerebral cholinergic system changes in numerous brain regions. Our study also presents novel evidence of cholinergic topography involved in dynamic balance and gait in PD that have not been typically associated with mobility disturbances, such as the right anterior temporal pole, right anterior part of the dorsomedial prefrontal cortex, gyrus rectus, fimbria, lingual gyrus, flocculus, nodulus, and right cerebellar hemisphere lobules VI and left crus I.

Project description:BackgroundPatients with Parkinson's disease (PD) and GBA gene mutations (GBA-PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA-PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved.ObjectivesTo provide instrumental measures of pattern and severity of autonomic dysfunction in GBA-PD and explore their correlation with other non-motor symptoms and implications for clinical practice.MethodsIn this cross-sectional study, 21 GBA-PD and 24 matched PD noncarriers underwent extensive assessment of motor and non-motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R-R intervals and blood pressure short-term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post-ganglionic sudomotor dysfunction.ResultsDespite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA-PD than noncarriers (overcoming relatively preserved compensatory peripheral sympathetic function), suggesting more prominent cardiac sympatho-vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA-PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment.ConclusionsCompared to PD noncarriers, GBA-PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA-PD, regardless of clinically overt symptoms.

Project description:BackgroundDespite the benefits of balance exercise in clinical populations, balance training programs tend to be poorly described, which in turn makes it difficult to evaluate important training components and compare between programs. However, the use of wearable sensors may have the potential to monitor certain elements of balance training. Therefore, this study aimed to investigate the feasibility of using wearable sensors to provide objective indicators of the levels and progression of training activity during gait-related balance exercise in individuals with Parkinson's disease.MethodsTen individuals with Parkinson's disease participated in 10 weeks of group training (three sessions/week) addressing highly-challenging balance exercises. The training program was designed to be progressive by gradually increasing the amount of gait-related balance exercise exercises (e.g. walking) and time spent dual-tasking throughout the intervention period. Accelerometers (Actigraph GT3X+) were used to measure volume (number of steps/session) and intensity (time spent walking >1.0 m/s) of dynamic training activity. Training activity was also expressed in relation to the participants' total daily volume of physical activity prior to the training period (i.e. number of steps during training/the number of steps per day). Feasibility encompassed the adequacy of data sampling, the output of accelerometer data and the participants' perception of the level of difficulty of training.ResultsTraining activity data were successfully obtained in 98% of the training sessions (n = 256) and data sampling did not interfere with training. Reflecting the progressive features of this intervention, training activity increased throughout the program, and corresponded to a high level of the participants' daily activity (28-43%). In line with the accelerometer data, a majority of the participants (n = 8) perceived the training as challenging.ConclusionsThe findings of this proof-of-concept study support the feasibility of applying wearable sensors in clinical settings to gain objective informative measures of gait-related balance exercise in individuals with Parkinson's disease. Still, this activity monitoring approach needs to be further validated in other populations and programs including gait-related balance exercises.Trial registrationNCT01417598 , 15th August 2011.

Project description:IntroductionCognitive and gait deficits are common symptoms in Parkinson's disease (PD). Motor-cognitive dual tasks (DTs) are used to explore the interplay between gait and cognition. However, it is unclear if DT gait performance is indicative for cognitive impairment. Therefore, the aim of this study was to investigate if cognitive deficits are reflected by DT costs of spatiotemporal gait parameters.MethodsCognitive function, single task (ST) and DT gait performance were investigated in 67 PD patients. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) followed by a standardized, sensor-based gait test and the identical gait test while subtracting serial 3's. Cognitive impairment was defined by a MoCA score <26. DT costs in gait parameters [(DT - ST)/ST × 100] were calculated as a measure of DT effect on gait. Correlation analysis was used to evaluate the association between MoCA performance and gait parameters. In a linear regression model, DT gait costs and clinical confounders (age, gender, disease duration, motor impairment, medication, and depression) were correlated to cognitive performance. In a subgroup analysis, we compared matched groups of cognitively impaired and unimpaired PD patients regarding differences in ST, DT, and DT gait costs.ResultsCorrelation analysis revealed weak correlations between MoCA score and DT costs of gait parameters (r/rSp ≤ 0.3). DT costs of stride length, swing time variability, and maximum toe clearance (|r/rSp| > 0.2) were included in a regression analysis. The parameters only explain 8% of the cognitive variance. In combination with clinical confounders, regression analysis showed that these gait parameters explained 30% of MoCA performance. Group comparison revealed strong DT effects within both groups (large effect sizes), but significant between-group effects in DT gait costs were not observed.ConclusionThese findings suggest that DT gait performance is not indicative for cognitive impairment in PD. DT effects on gait parameters were substantial in cognitively impaired and unimpaired patients, thereby potentially overlaying the effect of cognitive impairment on DT gait costs. Limits of the MoCA in detecting motor-function specific cognitive performance or variable individual response to the DT as influencing factors cannot be excluded. Therefore, DT gait parameters as marker for cognitive performance should be carefully interpreted in the clinical context.

Dataset Information

Cognition as a mediator for gait and balance impairments in GBA-related Parkinson's disease.

Publications

Cognition as a mediator for gait and balance impairments in GBA-related Parkinson's disease.

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