New Clinical Subtypes of Parkinson Disease and Their Longitudinal Progression: A Prospective Cohort Comparison With Other Phenotypes
Fereshtehnejad SM, Romenets SR, Anang JB, Latreille V, Gagnon JF, Postuma RB
JAMA Neurol. 2015;72:863-873
There is considerable heterogeneity in the clinical features and prognosis of patients with Parkinson disease (PD), but specific subtypes of the disease have not been well defined. Identification of distinct subtypes of PD may help clarify its underlying pathophysiology, determine prognosis, and ultimately design personalized treatment strategies. The goals of this prospective cohort study were to identify clinical phenotypes of PD and to compare prognosis and progression rates among these subtypes.In addition, the investigators compared the ability to predict prognosis for these phenotypes with previously identified clinical subtypes in the published literature.
From 2005 to 2013, the investigators enrolled 113 patients with idiopathic PD from two movement disorders clinics in Montreal, Canada. At baseline, they evaluated motor features of severity, motor complications, motor subtypes, and quantitative motor tests, as well as nonmotor features of autonomic dysfunction, psychiatric signs and symptoms, olfaction, color vision, sleep parameters, and neurocognition. There were 76 patients who returned after a mean of 4.5 years from baseline for follow-up assessment. At follow-up, the investigators also determined a global composite outcome by combining standardized scores for motor symptoms, motor signs, cognitive function, and other nonmotor features.
The specific features clustering together and best defining distinct subtypes were orthostatic hypotension, mild cognitive impairment, rapid eye movement sleep behavior disorder (RBD), depression, anxiety, and Unified Parkinson's Disease Rating Scale Part II and Part III scores at baseline. The three resulting subtypes identified were motor/slow progression, diffuse/malignant, and intermediate.
Even among patients of similar age and similar disease duration, those with the diffuse/malignant phenotype were more likely to have mild cognitive impairment, orthostatic hypotension, and RBD at baseline. In addition, these patients had increased odds of a rapid decline in cognition (odds ratio [OR], 8.7; 95% confidence interval [CI], 4.0-18.7; P < .001), other nonmotor symptoms (OR, 10.0; 95% CI, 4.3-23.2; P < .001), motor signs (OR, 4.1; 95% CI, 1.8-9.1; P = .001), motor symptoms (OR, 2.9; 95% CI, 1.3-6.2; P < .01), and the global composite outcome (OR, 8.0; 95% CI, 3.7-17.7; P < .001), compared with patients without the diffuse/malignant phenotype.
The findings of this prospective cohort study suggest that patients with PD and mild cognitive impairment, orthostatic hypotension, and RBD at baseline have roughly nine times greater odds of rapid cognitive decline and 10 times greater odds of other nonmotor symptoms, in addition to having a worse prognosis for motor deterioration. There are, however, some limitations of this study, including a moderately small sample size, loss of more than 30% of patients to follow-up, and possible lack of generalizability to patients outside of Canadian movement disorder clinics.
On the basis of these results, it seems reasonable to screen patients with PD for mild cognitive impairment, orthostatic hypotension, and RBD, even at baseline visits. These nonmotor characteristics appear to define a diffuse/malignant phenotype likely to have the most rapid rate of deterioration.