Alteration of Tremor Dominant and Postural Instability Gait Difficulty Subtypes During the Progression of Parkinson's Disease: Analysis of the PPMI Cohort

Abstract

Background: Classifying PD into tremor dominant (TD) and postural instability gait difficulty (PIGD) subtypes may have several limitations, such as its diagnostic inconsistency and inability to reflect disease stage. In this study, we investigated the patterns of progression and dopaminergic denervation, by prospective evaluation at regular time intervals. Methods: 325 PD dopamine replacement drug-naïve patients (age 61.2 ± 9.7, M:F = 215:110) were enrolled. Patients were grouped into TD, indeterminant, and PIGD subtypes. Clinical parameters and I-123 FP-CIT SPECT images of each groups were analyzed and compared at baseline, 1, 2, and 4 years of follow up periods. Results: Baseline I-123 FP-CIT uptakes of the striatum were significantly higher in the TD group compared with the indeterminant group and PIGD group ( p < 0.01). H & Y stage and MDS-UPDRS part III scores of the indeterminant group were significantly worse at baseline, compared with the TD and PIGD groups ( p < 0.001 and p < 0.01, respectively), and MDS-UPDRS part II scores of the indeterminant group were significantly worse than the PIGD group ( p < 0.001). There were no other significant differences of age, gender, weight, duration of PD, SCOPA-AUT, MOCA, usage of dopamine agonists, and levodopa equivalent daily doses at baseline. After 4 years of follow up, there were no differences of I-123 FP-CIT uptakes or clinical parameters, except for the MDS-UPDRS part II between the TD and indeterminant group ( p < 0.05). The motor-subtypes were reevaluated at the 4 years period, and the proportion of patients grouped to the PIGD subtype increased. In the reevaluated PIGD group, MDS-UPDRS part II score ( p < 0.001), SCOPA-AUT ( p < 0.001), the proportion of patients who developed levodopa induced dyskinesia were higher than the reevaluated TD group, and the striatal I-123 FP-CIT uptakes were significantly lower ( p < 0.01). Conclusion: There are no significant differences of symptoms and dopaminergic innervation between the TD and PIGD group after a certain period of follow up. Significant portion of patients switched from the TD subtype to the PIGD subtype during disease progression, and had a worse clinical prognosis.

Plasma Exosomal Brain-Derived Neurotrophic Factor Correlated with the Postural Instability and Gait Disturbance–Related Motor Symptoms in Patients with Parkinson’s Disease

“…Compared with PD patients with optimal plasma exosomal BDNF, patients with low plasma exosomal BDNF levels in this study were likely to exhibit more significant dysfunction in PIGD-associated motor symptoms, which affect the quality of life and are often unmitigated by medical treatment [20]. Considering that PIGD is an unfavorable subtype of PD that may transform from benign subtypes of PD [21], plasma exosomal BDNF level may potentially predict and monitor disease progression in PD.…”

“…These patients require unique management and should not be treated the same way as other PD patients, especially deep brain stimulation [43]. Besides, patients with PD of non-PIGD subtypes may convert to the PIGD subtype as the disease progresses [21]; thus, a reliable blood biomarker is required to make early prediction possible.…”

Neuroimaging Detectable Differences between Parkinson's Disease Motor Subtypes: A Systematic Review

“…Although reference 97 showed no significant differences in dopaminergic uptake between TD and AR, two later studies of theirs showed TD had increased dopaminergic uptake in the caudate and anterior putamen compared to AR patients 94, 98 and a separate study showed TD to have less severe striatal dopaminergic defects compared to AR 99 . Further comparisons between TD and PIGD show increased dopamine uptake in TD in the caudate, putamen, and IPL (Brodmann area [BA] 40), 100 and although one study showed no differences in FP‐CIT uptake in the striatum between the TD and nTD 95 another reported TD to have enhanced GPi–MC and putamen–MC coupling compared to nTD in the MAH 34 …”

Parkinson’s Disease Subtypes: Critical Appraisal and Recommendations

“…aspects such as motor phenotype tend to be more ing to a common phenotype toward the end [14,15] of individuals with the TD phenotype will switch 344 to a PIGD phenotype over time [14,15,18]. An (alpha-synuclein [21], 5-hydroxyindoleacetic acid, glycine [12]) and degree of cardiac sympathetic denervation, for example [21].…”