Parkinson’s disease
Parkinson’s disease (PD) is a progressive neurodegenerative disorder with no current treatments to slow its progression. The 2019 LEAP study explored the effects of delaying levodopa treatment but found no significant differences in disease progression. In the follow-up five-year analysis (1), the prevalence of motor fluctuations including dyskinesia was not different between groups, suggesting that the timing of levodopa initiation does not reduce the risk of motor fluctuations, highlighting disease duration as a stronger factor.
Dementia is a significant concern in PD, with early studies estimating a 46-58% likelihood of dementia after 10 years. However, more recent research, including the PPMI and Pennsylvania University cohorts, found much lower incidences at 10 years—8.5% and 27%, respectively (2). Nevertheless, such variation in dementia rates between these studies is unknown.
The PD GENEration and ROPAD studies, which assessed large PD cohorts, found that 13-15% of patients had identifiable genetic mutations, with GBA and LRRK2 being the most common (3, 4). Patients with early onset, affected family members, or high-risk ancestry had a higher rate of genetic diagnoses. Recessive mutations in the PRKN gene are linked to young-onset PD, however some mutations can be missed by conventional testing. Long-read sequencing has improved the diagnosis of patients with only one PRKN mutation, potentially increasing the diagnostic yield in future studies (5, 6).
In terms of treatment, levodopa infusion therapies show promise for managing motor fluctuations in PD (7, 8). The BouNDless trial demonstrated that continuous subcutaneous levodopa-carbidopa infusion (ND0612) improved ON time without troublesome dyskinesias by 1.72-hours and reduced OFF time by 1.4-hours. Another trial of subcutaneous foslevodopa/foscarbidopa showed similar improvements in ON and OFF times, though infusion-site reactions remain a challenge.
Atypical Parkinsonism
A study of pathological proven MSA cases found that while MRI criteria did not improve diagnostic sensitivity, clinical criteria alone had better diagnostic accuracy (9). However, the low sensitivity of early MSA diagnosis suggests the need for additional biomarkers.
Deep Brain Stimulation for dystonia
Deep brain stimulation (DBS) has shown promise in treating paediatric dystonia. A systematic review indicated a ~60% improvement in dystonia scores after one year of GPi-DBS, with the best outcomes in patients with TOR1A, SCGE, KMT2B, and idiopathic dystonia (10). Bilateral GPi-DBS has also proven effective in treating status dystonicus, with a lower mortality rate compared to pharmacotherapy (11).
Genetics in Movement Disorders
Paroxysmal Kinesigenic Dyskinesias are commonly caused by PRRT2 mutations. Two recent studies have independently identified dominant KCNJ10 variants as a novel cause of PKD (12, 13). Recessive KCNJ10 cause EAST syndrome (epilepsy, ataxia, sensorineural deafness, seizures and tubulopathy), and interestingly, PKD patients due to KCNJ10 may have some attenuated features of EAST syndrome. Intronic FGF14 expansions is one of the most common causes of late onset ataxia. Recent studies have highlighted the slow progression nature, but also presentations as episodic ataxia in up to 13% (14). A recent study reported that 75% of FGF14 patients treated with 4-aminopyridine improve the frequency and intensity of episodic symptoms (15).