Decrease in Aβ42 predicts dopa-resistant gait progression in early Parkinson disease

Abstract

Objective: This prospective observational study investigates the role of CSF biomarkers in predicting progression of dopa-resistant gait impairments in Parkinson disease (PD) in the first 36 months from diagnosis.Methods: Quantitative gait analysis was carried out longitudinally using an instrumented walkway (GAITRite) in 108 people with PD and 130 age-matched controls. A subgroup of 44 people with PD underwent lumbar puncture from which a battery of CSF biomarkers was measured: b-amyloid 1-42 and 1-40 (Ab42 and Ab40), total and phosphorylated tau protein (t-tau/p-tau 181 ), and a-synuclein (aSyn). Linear mixed models examined the association between CSF and doparesistant gait characteristics (defined as substantial progression despite optimal medication).Results: Low baseline CSF Ab42, and to a lesser extend Ab40, predicted decline in gait characteristics in the first 3 years following diagnosis, independently explaining up to 12% of progression of step time variability (single task) and step length variability (dual-task). Interestingly, these findings were independent of age and cognition.Conclusions: These findings implicate underlying amyloid pathology in neural networks involved in locomotor control. Results suggest that disturbed Ab metabolism may be a biomarker for doparesistant gait impairments in early PD. Our findings raise interesting questions regarding therapeutic interventions such as compounds or molecules aimed at reducing amyloid burden to mitigate gait disturbance in early PD and potentially falls risk. Finally, progression of discrete gait characteristics suggests they may have potential as clinical biomarkers of pathology and disease progression. Parkinson disease (PD) is a common neurodegenerative disorder, second to Alzheimer disease. 1Gait impairments are significant in very early disease, and even at this stage dominate as risk factors for falls.2 While some aspects of gait are well-controlled by dopaminergic therapies in the early stages, resistance to levodopa makes clinical management challenging.Recent work highlights the significant contribution of cholinergic disturbance to gait, 3,4 and recent trials targeting the cholinergic system have met with moderate success.5 CSF proteins (e. g., b-amyloid [Ab] 40 and Ab42; total and p-tau 181 ), traditionally biomarkers of dementia and dementia risk, 6-9 have also been implicated in motor impairment, highlighting a role for pathologic protein accumulation other than Lewy body and PD-specific a-synuclein (aSyn). Crosssectional studies in early and advanced PD show an association between CSF biomarkers and postural instability and gait (PIGD) phenotype. 10,11 However, lack of quantitative gait analysisFrom the Institute of Neuroscience

Gait analysis with wearables predicts conversion to Parkinson disease

“…This finding is in agreement with previous studies that looked at gait progression in PD and found that pace (step length) decreased over both shorter (ie, 18 months) and longer (ie, 36 months) 49 periods of time. This finding is in agreement with previous studies that looked at gait progression in PD and found that pace (step length) decreased over both shorter (ie, 18 months) and longer (ie, 36 months) 49 periods of time.…”

“…We found that over time, walking speed and step length were reduced in both groups, but variability increased. This finding is in agreement with previous studies that looked at gait progression in PD and found that pace (step length) decreased over both shorter (ie, 18 months) and longer (ie, 36 months) 49 periods of time.…”

Noninvasive vagus nerve stimulation to target gait impairment in Parkinson's disease

“…The exact underlying mechanism of action of nVNS is poorly understood, but an indirect effect mediated through the cholinergic anti‐inflammatory pathway has been postulated through the altered regulation of acetylcholine . Therefore, our aim was to assess the effect of a single dose of nVNS on dopa‐resistant gait characteristics (step time variability and step length variability) in a pilot feasibility study in PD.…”

Goalkeeper Game: A New Assessment Tool for Prediction of Gait Performance Under Complex Condition in People With Parkinson's Disease

“…Gait performance is strongly affected by the overlap between motor and cognitive impairments due to dysfunction of both dopaminergic and cholinergic pathways in PD (Kelly et al, 2015). Besides, low baseline CSF Aβ42 and, to a lesser extent, Aβ40 predicted gait alterations in the first 3 years following diagnosis, suggesting a role for amyloid pathology in gait-cognitive decline (Rochester et al, 2017). An association between axial signs and different aspects of cognition, particularly visuospatial learning and memory, was found in people at intermediate stages of PD (Schneider et al, 2015).…”

“…MoCA scores were also associated with gait performance, freezing of gait, postural stability according to models adjusted for age, sex, education, enrollment site, disease duration, and motor symptoms severity (Kelly et al, 2015). The significant association between MoCA and step time variability is considered additional evidence of interplay between motor and cognitive networks (Rochester et al, 2017). These association may reflect less effective behavioral responses due to attentional control deficits and/or impaired cognitive function.…”