Gait Progression Over 6 Years in Parkinson’s Disease: Effects of Age, Medication, and Pathology

Background: Gait disturbance is an early, cardinal feature of Parkinson’s disease (PD) associated with falls and reduced physical activity. Progression of gait impairment in Parkinson’s disease is not well characterized and a better understanding is imperative to mitigate impairment. Subtle gait impairments progress in early disease despite optimal dopaminergic medication. Evaluating gait disturbances over longer periods, accounting for typical aging and dopaminergic medication changes, will enable a better understanding of gait changes and inform targeted therapies for early disease. This study aimed to describe gait progression over the first 6 years of PD by delineating changes associated with aging, medication, and pathology. Methods: One-hundred and nine newly diagnosed PD participants and 130 controls completed at least two gait assessments. Gait was assessed at 18-month intervals for up to 6 years using an instrumented walkway to measure sixteen spatiotemporal gait characteristics. Linear mixed-effects models assessed progression. Results: Ten gait characteristics significantly progressed in PD, with changes in four of these characteristics attributable to disease progression. Age-related changes also contributed to gait progression; changes in another two characteristics reflected both aging and disease progression. Gait impairment progressed irrespective of dopaminergic medication change for all characteristics except step width variability. Conclusions: Discrete gait impairments continue to progress in PD over 6 years, reflecting a combination of, and potential interaction between, disease-specific progression and age-related change. Gait changes were mostly unrelated to dopaminergic medication adjustments, highlighting limitations of current dopaminergic therapy and the need to improve interventions targeting gait decline.

[1]  B. Bloem,et al.  Freezing of Gait and its Levodopa Paradox. , 2019, JAMA neurology.

[2]  N. Bohnen,et al.  Treatment options for postural instability and gait difficulties in Parkinson’s disease , 2019, Expert review of neurotherapeutics.

[3]  Lynn Rochester,et al.  Gait analysis with wearables predicts conversion to Parkinson disease , 2019, Annals of neurology.

[4]  Douglas N. Martini,et al.  Overview of the cholinergic contribution to gait, balance and falls in Parkinson's disease. , 2019, Parkinsonism & related disorders.

[5]  John-Paul Taylor,et al.  The neural correlates of discrete gait characteristics in ageing: A structured review , 2019, Neuroscience & Biobehavioral Reviews.

[6]  B. Bloem,et al.  Freezing of gait before the introduction of levodopa , 2019, The Lancet Neurology.

[7]  Jeffrey M. Hausdorff,et al.  Analysis of Free-Living Gait in Older Adults With and Without Parkinson’s Disease and With and Without a History of Falls: Identifying Generic and Disease-Specific Characteristics , 2019, The journals of gerontology. Series A, Biological sciences and medical sciences.

[8]  Sebastian Heinzel,et al.  Potential Markers of Progression in Idiopathic Parkinson’s Disease Derived From Assessment of Circular Gait With a Single Body-Fixed-Sensor: A 5 Year Longitudinal Study , 2019, Front. Hum. Neurosci..

[9]  Sebastian Heinzel,et al.  Progressive Gait Deficits in Parkinson’s Disease: A Wearable-Based Biannual 5-Year Prospective Study , 2019, Front. Aging Neurosci..

[10]  E. Haq,et al.  Pharmacological Treatment of Parkinson’s Disease , 2018, Parkinson’s Disease: Pathogenesis and Clinical Aspects.

[11]  V. Srikanth,et al.  Medical, Sensorimotor and Cognitive Factors Associated With Gait Variability: A Longitudinal Population-Based Study , 2018, Front. Aging Neurosci..

[12]  Seungmoon Song,et al.  Predictive neuromechanical simulations indicate why walking performance declines with ageing , 2018, The Journal of physiology.

[13]  Lynn Rochester,et al.  Decrease in Aβ42 predicts dopa-resistant gait progression in early Parkinson disease , 2017, Neurology.

[14]  C. Jack,et al.  Cerebral Amyloid Deposition Is Associated with Gait Parameters in the Mayo Clinic Study of Aging , 2017, Journal of the American Geriatrics Society.

[15]  S. Studenski,et al.  The brain map of gait variability in aging, cognitive impairment and dementia—A systematic review , 2017, Neuroscience & Biobehavioral Reviews.

[16]  Lynn Rochester,et al.  Predicting first fall in newly diagnosed Parkinson's disease: Insights from a fall‐naïve cohort , 2016, Movement disorders : official journal of the Movement Disorder Society.

[17]  B. Dawant,et al.  Cortical asymmetry in Parkinson's disease: early susceptibility of the left hemisphere , 2016, Brain and behavior.

[18]  Patricia Carlson-Kuhta,et al.  Pharmacological treatment in Parkinson's disease: Effects on gait. , 2016, Parkinsonism & related disorders.

[19]  Xia Shen,et al.  Effects of Exercise on Falls, Balance, and Gait Ability in Parkinson’s Disease , 2016, Neurorehabilitation and neural repair.

[20]  F. Horak,et al.  Objective Gait and Balance Impairments Relate to Balance Confidence and Perceived Mobility in People With Parkinson Disease , 2016, Physical Therapy.

[21]  T. Ellis,et al.  Identifying clinical measures that most accurately reflect the progression of disability in Parkinson disease. , 2016, Parkinsonism & related disorders.

[22]  Y Ben-Shlomo,et al.  Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial , 2016, The Lancet Neurology.

[23]  Pierre Payoux,et al.  Relationship of regional brain β-amyloid to gait speed , 2016, Neurology.

[24]  Martina Mancini,et al.  Levodopa Is a Double‐Edged Sword for Balance and Gait in People With Parkinson's Disease , 2015, Movement disorders : official journal of the Movement Disorder Society.

[25]  A. Fasano,et al.  Effect of 24-h continuous rotigotine treatment on stationary and non-stationary locomotion in de novo patients with Parkinson disease in an open-label uncontrolled study , 2015, Journal of Neurology.

[26]  Qing X. Yang,et al.  MRI evaluation of asymmetry of nigrostriatal damage in the early stage of early-onset Parkinson's disease. , 2015, Parkinsonism & related disorders.

[27]  E. Amaro,et al.  Factors associated with lower gait speed among the elderly living in a developing country: a cross-sectional population-based study , 2015, BMC Geriatrics.

[28]  Lynn Rochester,et al.  Progression of gait dysfunction in incident Parkinson's disease: Impact of medication and phenotype , 2015, Movement disorders : official journal of the Movement Disorder Society.

[29]  P. Jenner Treatment of the later stages of Parkinson’s disease – pharmacological approaches now and in the future , 2015, Translational Neurodegeneration.

[30]  Robert A Koeppe,et al.  Clinical markers for identifying cholinergic deficits in Parkinson's disease , 2015, Movement disorders : official journal of the Movement Disorder Society.

[31]  Nikolaus R. McFarland,et al.  Defining the Clinically Meaningful Difference in Gait Speed in Persons With Parkinson Disease , 2014, Journal of neurologic physical therapy : JNPT.

[32]  D. Hunter,et al.  The epidemiology of osteoarthritis. , 2014, Best practice & research. Clinical rheumatology.

[33]  T. Robbins,et al.  Characterizing mild cognitive impairment in incident Parkinson disease , 2014, Neurology.

[34]  S. Studenski,et al.  Gait speed in Parkinson disease correlates with cholinergic degeneration , 2013, Neurology.

[35]  Arthur W Toga,et al.  Association of cerebrospinal fluid β-amyloid 1-42, T-tau, P-tau181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. , 2013, JAMA neurology.

[36]  Lynn Rochester,et al.  Moving forward on gait measurement: Toward a more refined approach , 2013, Movement disorders : official journal of the Movement Disorder Society.

[37]  L. King,et al.  Effects of exercise on mobility in people with Parkinson's disease , 2013, Movement disorders : official journal of the Movement Disorder Society.

[38]  Alan Godfrey,et al.  Ambulatory activity in incident Parkinson’s: more than meets the eye? , 2013, Journal of Neurology.

[39]  Lynn Rochester,et al.  Independent domains of gait in older adults and associated motor and nonmotor attributes: validation of a factor analysis approach. , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[40]  Lynn Rochester,et al.  Is gait variability reliable in older adults and Parkinson's disease? Towards an optimal testing protocol. , 2013, Gait & posture.

[41]  R. Barker,et al.  The spectrum of nonmotor symptoms in early Parkinson disease , 2013, Neurology.

[42]  David S. Park,et al.  Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease , 2012, Proceedings of the National Academy of Sciences.

[43]  B. Galna,et al.  Cholinergic dysfunction contributes to gait disturbance in early Parkinson's disease. , 2012, Brain : a journal of neurology.

[44]  Terry D Ellis,et al.  Capturing Ambulatory Activity Decline in Parkinson's Disease , 2012, Journal of neurologic physical therapy : JNPT.

[45]  P. Brown,et al.  Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism , 2012, Brain : a journal of neurology.

[46]  P. Jenner,et al.  Mechanisms underlying the onset and expression of levodopa-induced dyskinesia and their pharmacological manipulation , 2011, Journal of Neural Transmission.

[47]  P. Garcia-Ruiz Gait disturbances in Parkinson disease. Did freezing of gait exist before levodopa? Historical review , 2011, Journal of the Neurological Sciences.

[48]  Lynn Rochester,et al.  Gait variability in Parkinson’s disease: an indicator of non-dopaminergic contributors to gait dysfunction? , 2011, Journal of Neurology.

[49]  C. Clarke,et al.  Systematic review of levodopa dose equivalency reporting in Parkinson's disease , 2010, Movement disorders : official journal of the Movement Disorder Society.

[50]  S. Lehéricy,et al.  Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease. , 2010, The Journal of clinical investigation.

[51]  J. Jordan,et al.  Epidemiology of osteoarthritis. , 2010, Clinics in geriatric medicine.

[52]  B. Pollock,et al.  The Anticholinergic Drug Scale as a Measure of Drug‐Related Anticholinergic Burden: Associations With Serum Anticholinergic Activity , 2006, Journal of clinical pharmacology.

[53]  S. Studenski,et al.  Meaningful Change and Responsiveness in Common Physical Performance Measures in Older Adults , 2006, Journal of the American Geriatrics Society.

[54]  J. Summers,et al.  Stride length regulation in Parkinson's disease. Normalization strategies and underlying mechanisms. , 1996, Brain : a journal of neurology.

[55]  M. Harms Measurement In Neurological Rehabilitation , 1992 .

[56]  J. Williamson,et al.  Association of Brain Amyloid-&bgr; With Slow Gait in Elderly Individuals Without Dementia: Influence of Cognition and Apolipoprotein E &egr;4 Genotype , 2017, JAMA neurology.

[57]  Xuemei Huang,et al.  Dopaminergic modulation of arm swing during gait among Parkinson's disease patients. , 2015, Journal of Parkinson's disease.

[58]  E. Protas,et al.  Effects of levodopa on forward and backward gait patterns in persons with Parkinson's disease. , 2011, NeuroRehabilitation.

[59]  Bastiaan R. Bloem,et al.  Freezing of Gait , 2010 .

[60]  K. Yokote [Pharmacological treatment]. , 2007, Nihon rinsho. Japanese journal of clinical medicine.

[61]  Roderick J. A. Little,et al.  Modeling the Drop-Out Mechanism in Repeated-Measures Studies , 1995 .

[62]  D. Calne,et al.  Pharmacological Treatment of Parkinson’s Disease , 1986 .