Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Current Progress in Magnetic Resonance-Guided Focused Ultrasound to Facilitate Drug Delivery across the Blood-Brain Barrier.

This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently permeabilize the blood-brain barrier (BBB) for drug delivery in neurological disorders and neuro-oncology. Safety trials in humans have followed on from extensive pre-clinical studies, demonstrating a reassuring safety profile and paving the way for numerous translational clinical trials in Alzheimer's disease, Parkinson's disease, and primary and metastatic brain tumors. Future directions include improving ultrasound delivery devices, exploring alternative delivery approaches such as nanodroplets, and expanding the application to other neurological conditions.

If Art Were a Drug: Implications for Parkinson's Disease.

Parkinson's disease (PD) is a chronic and complex neurodegenerative disorder. Conventional pharmacological or surgical therapies alone are often insufficient at adequately alleviating disability. Moreover, there is an increasing shift toward person-centered care, emphasizing the concept of "living well". In this context, arts-based interventions offer great promise, functioning as platforms for creative expression that could provide novel mechanisms to promote quality of life. Here we present a qualitative review of arts-based interventions for PD, including music, dance, drama, visual arts, and creative writing. For each, we discuss their applications to PD, proposed mechanisms, evidence from prior studies, and upcoming research. We also provide examples of community-based projects. Studies to date have had relatively small sample sizes, but their findings suggest that arts-based interventions have the potential to reduce motor and non-motor symptoms. They may also empower people with PD and thereby address issues of self-esteem, foster personal problem-solving, and augment holistic well-being. However, there is a paucity of research determining optimal dosage and symptom-specific benefits of these therapies. If art were a drug, we would have to perform appropriately powered studies to provide these data before incorporating it into routine patient care. We therefore call for further research with properly designed studies to offer more rigorous and evidence-based support for what we intuitively think is a highly promising approach to support individuals living with PD. Given the possible positive impact on people's lives, arts-based approaches merit further development and, if proven to be effective, systematic inclusion within integrated management plans.

Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.

Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration.

Neuroscience fundamentals relevant to neuromodulation: Neurobiology of deep brain stimulation in Parkinson's disease.

Deep Brain Stimulation (DBS) has become a pivotal therapeutic approach for Parkinson's Disease (PD) and various neuropsychiatric conditions, impacting over 200,000 patients. Despite its widespread application, the intricate mechanisms behind DBS remain a subject of ongoing investigation. This article provides an overview of the current knowledge surrounding the local, circuit, and neurobiochemical effects of DBS, focusing on the subthalamic nucleus (STN) as a key target in PD management. The local effects of DBS, once thought to mimic a reversible lesion, now reveal a more nuanced interplay with myelinated axons, neurotransmitter release, and the surrounding microenvironment. Circuit effects illuminate the modulation of oscillatory activities within the basal ganglia and emphasize communication between the STN and the primary motor cortex. Neurobiochemical effects, encompassing changes in dopamine levels and epigenetic modifications, add further complexity to the DBS landscape. Finally, within the context of understanding the mechanisms of DBS in PD, the article highlights the controversial question of whether DBS exerts disease-modifying effects in PD. While preclinical evidence suggests neuroprotective potential, clinical trials such as EARLYSTIM face challenges in assessing long-term disease modification due to enrollment timing and methodology limitations. The discussion underscores the need for robust biomarkers and large-scale prospective trials to conclusively determine DBS's potential as a disease-modifying therapy in PD.

Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo.

BACKGROUND: Deep brain stimulation (DBS) has been widely used to manage debilitating neurological symptoms in movement disorders such as Parkinson's disease (PD). Despite its well-established symptomatic benefits, our understanding of the mechanisms underlying DBS and its possible effect on the accumulation of pathological proteins in neurodegeneration remains limited. Accumulation and oligomerization of the protein alpha-synuclein (α-Syn) are implicated in the loss of dopaminergic neurons in the substantia nigra in PD, making α-Syn a potential therapeutic target for disease modification. OBJECTIVE: We examined the effects of high frequency electrical stimulation on α-Syn levels and oligomerization in cell and rodent models. METHODS: High frequency stimulation, mimicking DBS parameters used for PD, was combined with viral-mediated overexpression of α-Syn in cultured rat primary cortical neurons or in substantia nigra of rats. Bimolecular protein complementation with split fluorescent protein reporters was used to detect and quantify α-Syn oligomers. RESULTS: High frequency electrical stimulation reduced the expression of PD-associated mutant α-Syn and mitigated α-Syn oligomerization in cultured neurons. Furthermore, DBS in the substantia nigra, but not the subthalamic nucleus, decreased overall levels of α-Syn, including oligomer levels, in the substantia nigra. CONCLUSIONS: Taken together, our results demonstrate that direct high frequency stimulation can reduce accumulation and pathological forms of α-Syn in cultured neurons in vitro and in substantia nigra in vivo. Thus, DBS therapy could have a role beyond symptomatic treatment, with potential disease-modifying properties that can be exploited to target pathological proteins in neurodegenerative diseases.

Predictors of Future Deep Brain Stimulation Surgery in de novo Parkinson's Disease.

Background: Deep brain stimulation (DBS) surgery is offered to a subset of Parkinson's disease (PD) patients. It is unclear if there are features at diagnosis that predict future DBS surgery. Objective: To assess predictors of eventual DBS surgery in de novo PD patients. Methods: Subjects from the Parkinson's Progression Marker Initiative (PPMI) database with newly diagnosed, sporadic PD (n = 416) were identified and stratified by their eventual DBS status (DBS+, n = 43; DBS-, n = 373). A total of 50 baseline clinical, imaging, and biospecimen features were extracted for each subject and cross-validated lasso regression was used for feature reduction. Multivariate logistic regression assessed their relationship with DBS status and a receiver operating characteristic curve evaluated model performance. Linear mixed effect models assessed disease progression over 4 years in DBS+ and DBS- patients. Results: Age at symptom onset, Hoehn and Yahr (H&Y) stage, tremor score, and ratio of CSF Tau to amyloid-beta 1-42 (Tau: Ab) were identified as important baseline features for predicting DBS surgery. Each independently predicted DBS surgery (area under the curve = 0.83). DBS- patients had faster memory decline (P < 0.05), while DBS+ patients had faster decline in H&Y stage (P < 0.001) and motor scores (P < 0.05) prior to surgery. Conclusion: The identified features may be used for early identification of patients who may be surgical candidates during the course of their disease. Disease progression in these groups reflects surgical eligibility criteria, with DBS- patients having more rapid decline in memory while DBS+ patients experienced a faster decline in motor scores prior to DBS surgery.

Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson's disease.

Accumulation of α-synuclein into toxic oligomers or fibrils is implicated in dopaminergic neurodegeneration in Parkinson's disease. Here we performed a high-throughput, proteome-wide peptide screen to identify protein-protein interaction inhibitors that reduce α-synuclein oligomer levels and their associated cytotoxicity. We find that the most potent peptide inhibitor disrupts the direct interaction between the C-terminal region of α-synuclein and CHarged Multivesicular body Protein 2B (CHMP2B), a component of the Endosomal Sorting Complex Required for Transport-III (ESCRT-III). We show that α-synuclein impedes endolysosomal activity via this interaction, thereby inhibiting its own degradation. Conversely, the peptide inhibitor restores endolysosomal function and thereby decreases α-synuclein levels in multiple models, including female and male human cells harboring disease-causing α-synuclein mutations. Furthermore, the peptide inhibitor protects dopaminergic neurons from α-synuclein-mediated degeneration in hermaphroditic C. elegans and preclinical Parkinson's disease models using female rats. Thus, the α-synuclein-CHMP2B interaction is a potential therapeutic target for neurodegenerative disorders.

Genetic Testing in Clinical Movement Disorders: A Case-Based Review.

Genetics are fundamental to understanding the pathophysiology of neurological disease, including movement disorders. Genetic testing in clinical practice has changed dramatically over the last few decades. While the likelihood of establishing an etiological diagnosis is greater now with increased access to testing and more advanced technologies, clinicians face challenges when deciding whether to test, then selecting the appropriate test, and ultimately interpreting and sharing the results with patients and families. In this review, we use a case-based approach to cover core aspects of genetic testing for the neurologist, namely, genetic testing in Parkinson's disease, interpretation of inconclusive genetic test reports, and genetic testing for repeat expansion disorders using Huntington disease as a prototype.

Movement disorders in hereditary spastic paraplegia (HSP): a systematic review and individual participant data meta-analysis.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of HSP can extend to include other neurologic features, including movement disorders. Our aim was to investigate genotype-phenotype associations in HSP with a focus on movement disorders. METHODS: We performed a systematic review and individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one patient with a movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1413 HSP cases were eligible. Data were compared between two HSP groups: manifested with (HSP-MD, n = 767) or without (HSP-nMD, n = 646) a movement disorder. RESULTS: The HSP-MD group had an older age of onset (20.5 ± 16.0 vs. 17.1 ± 14.2 yr, p < 0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%, p < 0.001) compared to HSP-nMD. SPG7 (31.2%) and SPG11 (23.8%) were the most frequent genotypes in the HSP-MD group. HSP-MD with SPG7 had higher frequency of later onset during adulthood (82.9% vs. 8.5%), ataxia (OR = 12.6), extraocular movement disturbances (OR = 3.4) and seizure (OR = 3.7) compared to HSP-MD with SPG11. Conversely, SPG11 mutations were more frequently associated with consanguinity (OR = 4.1), parkinsonism (OR = 7.8), dystonia (OR = 5.4), peripheral neuropathy (OR = 26.9), and cognitive dysfunction (OR = 34.5). CONCLUSION: This systematic IPD-level meta-analysis provides the largest data on genotype-phenotype associations in HSP-MD. Several clinically relevant phenotypic differences were found between various genotypes, which can possibly facilitate diagnosis in resource-limited settings.

Cavitation Feedback Control of Focused Ultrasound Blood-Brain Barrier Opening for Drug Delivery in Patients with Parkinson's Disease.

Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and safety of BBB modulation in the putamen were evaluated for biweekly therapeutic agent delivery in patients with Parkinson's disease. The performance of the clinical MRgFUS system's cavitation feedback controller for active power modulation throughout the exposures was examined. The putamen was targeted unilaterally by an ExAblate Neuro MRgFUS system operating at 220 kHz. Definity microbubbles were infused via a saline bag gravity drip at a rate of 4 µL/kg per 5 min. A cavitation emissions-based feedback controller was employed to modulate the acoustic power automatically according to prescribed target cavitation dose levels. BBB opening was measured by Gadolinium (Gd)-enhanced T1-weighted MR imaging, and the presence of potential micro-hemorrhages induced by the exposures was assessed via T2*-weighted MR imaging. A total of 12 treatment sessions were carried out across four patients, with target cavitation dose levels ranging from 0.20-0.40. BBB permeability in the targeted putamen was elevated successfully in all treatments, with a 14% ± 6% mean increase in Gd-enhanced T1-weighted MRI signal intensity relative to the untreated contralateral side. No indications of red blood cell extravasations were observed on MR imaging scans acquired one day following each treatment session. The cavitation emissions-based feedback controller was effective in modulating acoustic power levels to ensure BBB permeability enhancement while avoiding micro-hemorrhages, however, further technical advancements are warranted to improve its performance for use across a wide variety of brain diseases.