Decrease in Aβ42 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 from which a battery of CSF biomarkers was measured: β-amyloid 1-42 and 1-40 (Aβ42 and Aβ40), total and phosphorylated tau protein (t-tau/p-tau181), and α-synuclein (αSyn). Linear mixed models examined the association between CSF and dopa-resistant gait characteristics (defined as substantial progression despite optimal medication).


RESULTS
Low baseline CSF Aβ42, and to a lesser extend Aβ40, 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 Aβ metabolism may be a biomarker for dopa-resistant 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.
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. lynn.rochester@ncl.ac.uk.
Lynn
L
Rochester
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.
Brook
B
Galna
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.
Sue
S
Lord
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.
Alison J
AJ
Yarnall
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.
Rosie
R
Morris
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.
Gordon
G
Duncan
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.
Tien K
TK
Khoo
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.
Brit
B
Mollenhauer
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.
David J
DJ
Burn
D000368:Aged; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001696:Biomechanical Phenomena; D018450:Disease Progression; D015259:Dopamine Agents / Q000627:therapeutic use*; D005260:Female; D005684:Gait / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D010300:Parkinson Disease / Q000134:cerebrospinal fluid* / Q000188:drug therapy*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D011379:Prognosis; D011446:Prospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome; D051844:alpha-Synuclein / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D000978:Antiparkinson Agents; D015415:Biomarkers; D015259:Dopamine Agents; C054369:MAPT protein, human; D010446:Peptide Fragments; C497604:SNCA protein, human; D051844:alpha-Synuclein; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins