Developing and validating Parkinson’s disease subtypes and their motor and cognitive progression

Abstract

ObjectivesTo use a data-driven approach to determine the existence and natural history of subtypes of Parkinson’s disease (PD) using two large independent cohorts of patients newly diagnosed with this condition.Methods1601 and 944 patients with idiopathic PD, from Tracking Parkinson’s and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models.ResultsWe identified four clusters: (1)  fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and  poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson’s at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1–1.1). In Tracking Parkinson’s, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%.ConclusionsWe have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials.

Epigenetic contributions to hemisphere asymmetry in healthy brain, aging, and Parkinson’s disease

“…We also found that a long PD duration was associated with greater hemispheric asymmetry in DNA methylation. Clinically, PD patients with symmetrical symptom onset are prone to rapid disease progression 12 and, in our study, rapid disease progression was associated with an epigenetic disruption of genes involved in neurodevelopment, cell signaling, and cell death.…”

“…Though PD symptoms eventually affect both body sides as the disease progresses, clinical asymmetry remains directionally stable and detectable even at advanced disease stages 10,11 . Furthermore, asymmetric motor presentation is linked to the rate of disease progression [12][13][14] . Cognitive symptoms also differ between subgroups of lateralized PD patients (i.e., visuospatial tasks, language, verbal memory, and psychosis differ between patients with left vs. right motor symptom predominance) [14][15][16][17][18][19] .…”

Predictors of motor complications in early Parkinson's disease: A prospective cohort study

“…Favorable levodopa response is associated with motor complications, suggesting a potential physiological link between levodopa response and adverse effects. Various clinical phenotypes exist within the PD spectrum, and both medication response and motor complication risk have been proposed as distinguishing features of such phenotypes . Pharmacogenetic variation throughout the levodopa pathway (eg, in the cathechol‐o‐methyltransferase [COMT] gene) has also been suggested to predict medication response and motor complication risk .…”

“…Various clinical phenotypes exist within the PD spectrum, and both medication response and motor complication risk have been proposed as distinguishing features of such phenotypes. 31 Pharmacogenetic variation throughout the levodopa pathway (eg, in the cathechol-o-methyltransferase [COMT] gene) has also been suggested to predict medication response and motor complication risk. 32 Another contributing factor may be that greater benefit from treatment encourages concordance, increasing exposure to levodopa and its complications.…”

“…Results: A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11][12][13][14][15][16] <3.5 years, 16 [13][14][15][16][17][18][19][20][21] 3.5-5.0 years, 19 [14-26] 5-6.5 years, and 23 [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] >6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors.…”