The Emerging Gait Dysfunction Phenotype in Idiopathic Parkinson's Disease

Objective: Severity of motor symptoms in Parkinson9s disease (PD), and rate of change of these symptoms, suggests the existence of disease subgroups. One important PD subgroup is defined by postural instability and gait dysfunction (PIGD), which is associated with disability, lower quality of life, and cognitive deterioration. In this study, we evaluate what clinical factors at baseline are associated with early development of postural instability in PD. Methods: Data was downloaded from the Parkinson9s Progressive Markers Initiative (PPMI). Several clinical features predict development of postural instability. We provisionally term the associated phenotype the emerging gait disorder (eGD) phenotype. We evaluate validity of the phenotype in two held-out populations. Results: Individuals with the proposed eGD phenotype have a significantly higher risk of developing postural instability in both validation sets (p < 0.00001 in both sets). The proposed eGD phenotype occurred before development of postural instability (HY stage 3 or worse) in 289 of 301 paired comparisons (Fischer Exact Test, p < 0.000001), with a median progression time from development of eGD phenotype to postural instability of 972 days. Individuals with the proposed eGD phenotype at baseline had more rapid cognitive decline as measured by the Montreal Cognitive Assessment (p = 0.002) and Hopkins Verbal Learning Test (Total Recall, p = 0.008). Interpretation: We describe a clinical phenotype, detectable at baseline in a subset of individuals with PD, that is associated with accelerated development of postural instability. Within the sample, development of the eGD phenotype reliably precedes development of disability, and is a harbinger of more rapid cognitive progression.