Decrease in Ab42 predicts dopa-resistant gait progression in early Parkinson disease

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 fromwhich a battery of CSF biomarkers wasmeasured: b-amyloid 1–42 and 1–40 (Ab42 and Ab40), total and phosphorylated tau protein (t-tau/p-tau181), 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. Neurology® 2017;88:1501–1511 GLOSSARY aSyn 5 a-synuclein; Ab 5 b-amyloid; ICICLE 5 Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation; LEDD5 levodopa equivalent dose; LP5 lumbar puncture;MoCA5Montreal Cognitive Assessment; PD5 Parkinson disease; PIGD 5 postural instability and gait. Parkinson disease (PD) is a common neurodegenerative disorder, second to Alzheimer disease. Gait impairments are significant in very early disease, and even at this stage dominate as risk factors for falls. 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, and recent trials targeting the cholinergic system have met with moderate success. CSF proteins (e. g., b-amyloid [Ab] 40 and Ab42; total and p-tau181), traditionally biomarkers of dementia and dementia risk, 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. However, lack of quantitative gait analysis From the Institute of Neuroscience (L.R., B.G., S.L., A.J.Y., R.M., G.D., T.K.K., D.J.B.), Clinical Ageing Research Unit, Newcastle University; Department of Geriatric Medicine (G.D.), University of Edinburgh, UK; School of Medicine & Menzies Health Institute (T.K.K.), Griffith University, Australia; and Paracelsus-Elena Klinik, Kassel and University Medical Centre (Institute of Neuropathology and Department of Neurosurgery) (B.M.), Göttingen, Germany. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Parkinson’s UK. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1501 in these studies limits interpretation of findings. More importantly, longitudinal studies are lacking and urgently required in order to establish prediction. The aims of this study were to investigate the role of CSF biomarkers to predict progression of dopa-resistant gait impairments in the first 36 months from diagnosis in PD. We were interested in the mechanisms underpinning dopa-resistant gait progression to provide an essential platform for future therapeutic interventions to mitigate gait disturbance and potential falls risk. Based on previous cross-sectional literature, we hypothesized that Ab42 and p-tau181 would predict progression in dopa-resistant gait characteristics. METHODS Participants. Participants were recruited into Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation (ICICLE)–GAIT a median of 5 months from diagnosis. This is a nested study within ICICLE-PD, an incident cohort study conducted between June 2009 and December 2011. Figure 1 Participant flowchart Flowchart of participants recruited and assessed as part of the ICICLE-Gait study. 1502 Neurology 88 April 18, 2017 A subset of the cohort was recruited into ICICLE-Gait at the same time (figure 1). Controls of a similar age and sex were recruited from community sources. The methods have been described in full in previous publications, and are included as supplemental material at Neurology.org. Participants were tested “on” medication, which was defined as 1 hour after PD medication. Participants were evaluated at the Clinical Ageing Research Unit, Newcastle University, UK. Standard protocol approvals, registrations, and patient consents. The study was approved by the Newcastle and North Tyneside research and ethics committee and all participants gave informed consent. Demographic and clinical measures. Clinical assessments included a standardized neurologic examination and theMovement Disorder Society–revised Unified Parkinson’s Disease Rating Scale, from which Hoehn & Yahr stage and motor phenotype were calculated. Levodopa equivalent dose (LEDD) scores were calculated according to established methods. Global cognition was assessed using Montreal Cognitive Assessment (MoCA). Quantitative gait analysis and gait characteristics. Gait was assessed using a 7 meters long 3 0.6 meters wide instrumented walkway (Platinum model GAITRite, software version 4.5, CIR Systems, Franklin, NJ). Participants were instructed to walk at their comfortable walking pace for 2 minutes around a 25-meter oval circuit under single and dual-task conditions. The dual-task protocol involved walking and memorizing digits, based on the Wechsler Forward Digit Span, which was used as the concurrent cognitive task. Gait was repeatedly sampled as participants walked over the GAITRite mat (included in the 25-meter circuit) for a minimum of 5 passes (.40 steps per participant). Gait was quantified according to an a priori model developed for older adults and validated in PD that describes 16 discrete gait characteristics. We examined change in each gait characteristic over 36 months and characteristics that exhibited substantial change (despite optimal medication) were defined as doparesistant. Figure e-1 provides further details of the acquisition and processing of the gait data. Quantification of CSF biomarkers. CSF biomarkers were measured using a robust protocol. Lumbar puncture (LP) was performed on a subset of consenting participants using a standardized method as detailed previously. All LPs were done between 8 and 10 AM after an overnight fast and while withholding PD medications. Samples were centrifuged within 15 minutes of collection at 2,000 g at 48C for 10 minutes. The supernatant was divided into aliquots and frozen at 2808C, then analyzed for Ab42 and Ab40 using commercially available assays: Ab42: Innotest TH b-amyloid (1–42), Fujirebio Inc./Innogenetics, Gent, Belgium; total and p-tau and Ab40: hAmyloid b40, ELISA AbGmbH, Heidelberg, Germany. Samples with artificial blood contamination (as assessed by visual inspection during LP, erythrocyte count .50/mL, or semiquantitative analysis of hemoglobin [using Hemastix, Siemens Healthcare Diagnostics GmbH, Eschborn, Germany]) were excluded from analysis. No samples were excluded in the current analysis. Statistical analysis. CSF biomarkers were selected for analysis on the basis of previous reports. Dopa-resistant gait impairments were identified as follows: first, change per year for all (16) gait characteristics derived from single and dual task testing was assessed with a linear mixed-effects model (lme4 package, R statistical software version 3.2.2, Vienna, Austria). Participants and time (from baseline assessment to subsequent testing sessions) were included as random effects and age at baseline and sex as fixed effects. We then examined between-group change in gait with group (control, PD) as a fixed effect. Rate of progression was determined in the total cohort (n 5 108 PD and 130 controls) over 36 months (repeat assessments every 18 months from diagnosis) and then extracted for each individual for further analysis. Finally, bivariate correlations between change in LEDD and change in gait over 36 months for all CSF markers were conducted (data not shown), with significant relationships revealing dopa-resistant gait characteristics. These 3 steps validated the dopa-resistant classification; namely, substantial progression of gait impairment despite optimal medication; progression greater than controls; and no association between change in LEDD and gait over 36 months. The second stage of analysis established whether CSF markers could predict progression in dopa-resistant gait characteristics using general linear modeling and controlling for age, global cognition (MoCA), and baseline gait. Preliminary data analysis suggested a potential interaction between baseline gait and CSF markers in predicting gait progress