Progression of Self-Perceived Speech and Swallowing Impairment in Early Stage Parkinson's Disease: Longitudinal Analysis of the Unified Parkinson's Disease Rating Scale

Purpose: The purpose of this study was to investigate the presence and progression of self-perceived speech and swallowing impairments in newly diagnosed people with Parkinson's disease (PD) longitudinally across 6 years. Method: Longitudinal data from the Parkinson's Progression Markers Initiative were analyzed across six consecutive years in a cohort of 269 newly diagnosed people with PD, and a subset of those ( n = 211) who were assessed at every time point across the 6 years. Dependent variables included self-perceived ratings of speech and swallowing impairment severity from the Unified Parkinson's Disease Rating Scale. Patient-centered factors of age at diagnosis and motor phenotype were also assessed to determine if they were related to the change in self-perceived speech and swallowing impairments. Results: Overall, self-perceived speech and swallowing impairments were present in newly diagnosed people with PD, although over time, the degree of severity for both remained in the mild range. However, the rate of change over time was significant for perceived speech impairment, F (5.5, 1158.8) = 21.1, p < .001), and perceived swallowing impairment, F (5.2, 1082.6) = 8.6, p < .001. Changes for speech and swallowing impairment were both in the direction of progressive severity. There were no effects of age at diagnosis or motor phenotype on the degree of change for either speech or swallowing. Conclusions: Self-perceptions of speech and swallowing impairment changed significantly over time in newly diagnosed people with PD (PWPD). Consistent with existing literature, self-perceptions of speech impairment were rated as more severe than those of swallowing impairment. These findings reveal that even in the early years postdiagnoses, PWPD are experiencing changes to speech and swallowing function, albeit within the mildly severe range. The presence of self-perceived mild speech and swallowing impairments in the initial years postdiagnosis may support the need for intervention to improve and or sustain function over time.

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism

Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.

Monitoring the Motor Phenotype in Huntington’s Disease by Analysis of Keyboard Typing During Real Life Computer Use

Background: Besides cognitive and psychiatric abnormalities, motor symptoms are the most prominent in Huntington’s disease. The manifest disease is preceded by a prodromal phase with subtle changes such as fine motor disturbances or concentration problems. Objective: Movement disorders show a high variation in their clinical manifestation depending on condition and external influences. Therefore, devices for continuous measurements, which patients use in their daily life and which can monitor motor abnormalities, in addition to the medical examination, might be useful. The aim of current scientific efforts is to find markers that reflect the prodromal phase in gene carriers. This is important for future interventional studies, as future therapies should be applied at the stage of neuronal dysfunction, i.e., before the clinical manifestation. Methods: We performed a software-supported, continuous monitoring of keyboard typing on the participants’ own computer to evaluate this method as a tool to assess the motor phenotype in HD. We included 40 participants and obtained sufficient data from 25 participants, 12 of whom were manifest HD patients, 7 HD gene expansion carriers (HDGEC) and 6 healthy controls. Results: In a cross-sectional analysis we found statistically significant higher typing inconsistency in HD patients compared to controls. Typing inconsistency compared between HDGEC and healthy controls showed a trend to higher inconsistency levels in HDGEC. We found correlations between typing cadence and clinical scores: the UHDRS finger tapping item, the composite UHDRS and the CAP score. Conclusion: The typing cadence inconsistency is an appropriate marker to evaluate fine motor skills of HD patients and HDGEC and is correlated to established clinical measurements.

Tremor in Parkinson's disease inverts the effect of dopamine on reinforcement

This scientific commentary refers to ‘Effects of dopamine on reinforcement learning in Parkinson’s disease depend on motor phenotype’ by van Nuland et al. (doi:10.1093/brain/awaa335).