__Background__ Parkinsonian tremor usually starts unilaterally. The mid-term prognosis of this lateralized tremor is unknown, as is the development of tremor in the contralateral arm. __Objective__ To investigate the emergence of contralateral tremor in the Parkinson-Progression-Marker-Initiative database, with data available for 7 years. __Methods__ Tremor Amenable for surgery (TAS) was defined as any rest, postural or kinetic tremor with amplitude >1 cm (MDS-UPDRS score ≥2) as this criterion is commonly accepted for inclusion in surgical studies. Tremor was analyzed by side mainly in the off-medication state. __Results__ At baseline, 348 (87.7%) of the 397 patients with Parkinson’s disease had tremor at least on one side of the body. 183 (46%) had only mild tremors but 165 (41.6%) had TAS. 159 patients (40.1%) had lateralized TAS and 6 (1.6%) had bilateral TAS. Among patients with unilateral TAS, 40 patients (25.8%) developed contralateral TAS at 3 years, 49 patients (30.8%) at 5 years, and 61 patients (39%) at 7 years. The side more affected by tremor was also more affected by other cardinal symptoms. In 159 patients with initially unilateral TAS, tremor severity did not increase on the tremor-dominant side over the 7-year period. However, there was an increase in tremor on the contralateral side. This was associated with a clear increase in bradykinesia and rigidity on both sides. __Conclusion__ The study findings may prove beneficial in counselling patients with TAS, and may also provide an explanation as to why the worsening of tremor is not correlated with overall disease progression.

__Background__ Falls are a major source of morbidity in Parkinson’s disease (PD), yet their evolution over time remains unclear. __Objectives__ To compare fall risk and outcomes among PD, prodromal alpha-synucleinopathy, (PAS) and healthy controls (HC); estimate fall frequency across PD progression; and characterize clinical features of PD faller subgroups. __Methods__ We analyzed fall-related outcomes in the Parkinson’s Progression Markers Initiative. Yearly rates of rare and frequent falls were estimated by time since diagnosis. Unique PD participants were grouped as never, rare, or frequent fallers. Clinical variables included motor, cognitive, behavioral, sleep, and autonomic measures. Outcomes included injuries and healthcare utilization. Regression models adjusted for age, sex, and disease duration, with Benjamini-Hochberg correction. __Results__ Across 6,977 visits from 3,100 participants (937 PD, 1,926 PAS, 237 HC), PD participants had higher odds of falling than PAS (OR=1.66, 95% CI ) and HC (OR=4.03, 95% CI ). PD participants were also more likely to report fall-related injuries and healthcare use than PAS (OR=1.70, 1.71) and HC (OR=3.26, 3.81). Falls occurred in 15.5% of visits at diagnosis and 69.2% after 14 years, increasing across Neuronal Synuclein Disease-Integrated Staging System (NSD-ISS) stages. Frequent fallers had longer disease duration, higher NSD-ISS, and worse clinical profiles. Women were more likely to fall than men (46.1% vs 34.9%, p=0.002) despite milder symptoms. __Conclusion__ Falls and related morbidity increase with disease duration and NSD-ISS. Risk reflects sex and motor and non-motor factors, supporting a multifactorial model. Fall frequency may represent a practical marker of progression and guide prevention strategies in PD.

Parkinson’s disease is a highly heterogeneous condition with symptoms spanning motor and non-motor domains. Clinical scales like the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), are standard in clinical trials where disease progression is monitored. They rely on summing item values, assuming uniform item importance and score increments. Here we propose a novel data-driven approach to optimize weights for such scales — so that total scores better reflect the underlying disease severity. By leveraging large-scale longitudinal data from the Parkinson’s Progression Markers Initiative (PPMI), our methods identified which items (and value increments) most strongly indicate PD progression, down-weighting or excluding less informative items. The learned weights substantially improve the monotonic relationship between total scores and clinical progression. We validated our weights using both held-out PPMI data and an independent dataset (BeaT-PD), demonstrating their robustness. Applying such weights in clinical trials may increase power and reduce the required sample size.

__Objective__ People with Parkinson’s disease (PD) who carry a pathogenic GBA1 variant (PDGBA1) are at higher risk of cognitive impairment than those without the variant (PDGBA1_wildtype). To date, little is known about the pattern and evolution of cognitive decline in PDGBA1. This multi-center study characterized the cognitive profile of PDGBA, focusing on the longitudinal trajectories and the group-specific onset times among cognitive functions, as well as their clinical relevance. __Methods__ In this longitudinal multicohort-study (PPMI, ABC-PD, Luxembourg Parkinson’s Study), comprehensive neuropsychological assessments were standardized across 548 healthy controls (follow-up-years=2.84±4.33), 906 PDGBA1_wildtype (follow-up-years=4.29±4.16), and 210 PDGBA1 (follow-up-years=4.09±3.35). We evaluated performance across age and disease duration using regression (generalized) linear mixed models within each cognitive domain. Time-to-first-event models, assessing risks of clinically relevant performance impairment (test-score z≤-1.5, MoCA<26), and an expanding-time-window approach identified the course of cognitive impairment. Additionally, correlations between cognitive functions were calculated. __Results__ At baseline, PDGBA1 showed lower performance in attention (processing speed) and memory (verbal learning) than PDGBA1_wildtype, but more widespread probability of performance impairment. Over time, attention, visuoperception, memory, and semantic fluency performance declined more rapidly in PDGBA1 compared to PDGBA1_wildtype. Impairment in processing speed occurred earlier in the disease process of PDGBA1. Risks for clinically relevant cognitive impairment in PDGBA1 during the disease course were generally increased. Moderate-to-strong correlations between cognitive functions were observed within and across cognitive domains in PDGBA1 and PDGBA1_wildtype, particularly in attentional-executive functions. __Interpretation__ PDGBA1 exhibits accelerated domain-generalized cognitive decline compared to PDGBA1_wildtype, with susceptibility of semantic fluency, attention, and memory.

__Background__ Neuronal synuclein disease (NSD) involves pathological α-synuclein presence and often dopaminergic dysfunction, initially preceding overt clinical symptoms. NSD-ISS identifies Stage 2A (no dopaminergic dysfunction) and 2B (dopaminergic dysfunction) as prodromal phases marked by subtle clinical signs without functional impairment. Intraindividual variability/dispersion (IIV-D), reflecting within-person inconsistency across cognitive tasks, has emerged as a potential marker of early neurodegenerative changes. __Objectives__ This study examined whether IIV-D differentiates NSD Stage 2 participants from healthy controls and predicts progression to more advanced NSD stages. __Methods__ Data from the Parkinson’s Progression Markers Initiative were used to assess performance across 11 neuropsychological tests in 934 participants (832 Stage 2; 102 controls). IIV-D was quantified using the total coefficient of variation (CoV) and a domain-specific attention/executive CoV. Group comparisons and logistic regression assessed associations between IIV-D, clinical characteristics, and disease progression. __Results__ Stage 2 participants exhibited significantly greater CoV than controls (p = .003). Higher IIV-D was associated with worse motor symptoms, non-motor burden, and functional impairment. Among Stage 2 participants, subsequent converters to Stage 3+ (n = 100) had significantly higher total CoV (p = .008) and attention/executive CoV (p = .020) at baseline. CoV independently predicted conversion after one year (OR = 1.44, p = .008), controlling for baseline motor severity. __Conclusions__ IIV-D, particularly CoV, may be a sensitive cognitive marker of early NSD and predict short-term disease progression. Findings support integrating cognitive dispersion metrics into early detection strategies for prodromal synucleinopathies, though replication is needed to confirm generalizability and clinical utility.