Microglial Activation and Progression of Nigrostriatal Dysfunction in Isolated REM Sleep Behavior Disorder.

BACKGROUND: Using 11 C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. OBJECTIVES: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. METHODS: Fifteen iRBD patients previously scanned with 11 C-(R)-PK11195 and 18 F-DOPA-PET underwent repeat 18 F-DOPA-PET after 3 years. 18 F-DOPA Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18 F-DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11 C-(R)-PK11195 binding at baseline was a predictor of 18 F-DOPA Ki reduction in left caudate (coef = -0.0426, P = 0.016). CONCLUSIONS: Subjects with increased baseline 11 C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Molecular Imaging of the GABAergic System in Parkinson's Disease and Atypical Parkinsonisms.

PURPOSE OF REVIEW: During recent years, there has been a growing interest in GABAergic alterations in parkinsonian disorders. This paper aims to review the latest literature published, focusing on in vivo neuroimaging, and to suggest potential future avenues of research in the field. RECENT FINDINGS: A growing number of neuroimaging studies have focused on the association with different symptoms of Parkinson's disease, thereby suggesting a GABAergic role in motor symptoms, gait disturbances, frontal cognition, somatic symptom disorder, and hallucinations. However, there are a number of conflicting results, and further investigations in larger, clinically well-defined cohorts are needed to elucidate possible correlations. In progressive supranuclear palsy, recent evidence suggests a decrease of GABA in the frontal lobe. In this narrative review, we discuss the possible GABAergic role in the symptoms of PD and atypical parkinsonisms and outline possible research strategies for future neuroimaging of GABAergic changes in parkinsonian disorders.

A Pragmatic Review on Spinal Cord Stimulation Therapy for Parkinson's Disease Gait Related Disorders: Gaps and Controversies.

BACKGROUND: Parkinson's Disease (PD) is a progressive neurological disorder that results in potentially debilitating mobility deficits. Recently, spinal cord stimulation (SCS) has been proposed as a novel therapy for PD gait disorders. The highest levels of evidence remain limited for SCS. OBJECTIVES: In this systematic review and narrative synthesis, the literature was searched using combinations of key phrases indicating spinal cord stimulation and PD. METHODS: We included pre-clinical studies and all published clinical trials, case reports, conference abstracts as well as protocols for ongoing clinical trials. Additionally, we included trials of SCS applied to atypical parkinsonism. RESULTS: A total of 45 human studies and trials met the inclusion criteria. Based on the narrative synthesis, a number of knowledge gaps and future avenues of potential research were identified. This review demonstrated that evidence for SCS is currently not sufficient to recommend it as an evidence-based therapy for PD related gait disorders. There remain challenges and significant barriers to widespread implementation, including issues regarding patient selection, effective outcome selection, stimulation location and mode, and in programming parameter optimization. Results of early randomized controlled trials are currently pending. SCS is prone to placebo, lessebo and nocebo as well as blinding effects which may impact interpretation of outcomes, particularly when studies are underpowered. CONCLUSION: Therapies such as SCS may build on current evidence and be shown to improve specific gait features in PD. Early negative trials should be interpreted with caution, as more evidence will be required to develop effective methodologies in order to drive clinical outcomes.

Surgical Advances in Parkinson's Disease.

While symptomatic pharmacological therapy remains the main therapeutic strategy for Parkinson's disease (PD), over the last two decades, surgical approaches have become more commonly used to control levodopa-induced motor complications and dopamine-resistant and non-motor symptoms of PD. In this paper, we discuss old and new surgical treatments for PD and the many technological innovations in this field. We have initially reviewed the relevant surgical anatomy as well as the pathological signaling considered to be the underlying cause of specific symptoms of PD. Subsequently, early attempts at surgical symptom control will be briefly reviewed. As the most well-known surgical intervention for PD is deep brain stimulation, this subject is discussed at length. As deciding on whether a patient stands to benefit from DBS can be quite difficult, the different proposed paradigms for precisely this are covered. Following this, the evidence regarding different targets, especially the subthalamic nucleus and internal globus pallidus, is reviewed as well as the evidence for newer proposed targets for specific symptoms. Due to the rapidly expanding nature of knowledge and technological capabilities, some of these new and potential future capabilities are given consideration in terms of their current and future use. Following this, we have reviewed newer treatment modalities, especially magnetic resonance-guided focused ultrasound and other potential surgical therapies, such as spinal cord stimulation for gait symptoms and others. As mentioned, the field of surgical alleviation of symptoms of PD is undergoing a rapid expansion, and this review provides a general overview of the current status and future directions in the field.

Spinal cord stimulation therapy for patients with Parkinson's disease and gait problems (STEP-PD): study protocol for an exploratory, double-blind, randomised, placebo-controlled feasibility trial.

Introduction: Gait difficulties are common in Parkinson's disease (PD) and cause significant disability. These symptoms are often resistant to treatment. Spinal cord stimulation (SCS) has been found to improve gait, including freezing of gait, in a small number of patients with PD. The mechanism of action is unclear, and some patients are non-responders. With this double-blind, placebo-controlled efficacy and feasibility clinical and imaging study, we aim to shed light on the mechanism of action of SCS and collect data to inform development of a scientifically sound clinical trial protocol. We also aim to identify clinical and imaging biomarkers at baseline that could be predictive of a favourable or a negative outcome of SCS and improve patient selection. Methods and analysis: A total of 14 patients will be assessed with clinical rating scales and gait evaluations at baseline, and at 6 and 12 months after SCS implantation. They will also receive serial 18F-deoxyglucose and 18FEOBV PET scans to assess the effects of SCS on cortical/subcortical activity and brain cholinergic function. The first two patients will be included in an open pilot study while the rest will be randomised to receive active treatment or placebo (no stimulation) for 6 months. From this point, the entire cohort will enter an open label active treatment phase for a subsequent 6 months. Ethics and dissemination: This study was reviewed and approved by the Committee on Health Research Ethics, Central Denmark RM. It is funded by the Danish Council for Independent Research. Independent of outcome, the results will be published in peer-reviewed journals and presented at national and international conferences. Trial registration number: NCT05110053; ClinicalTrials.gov Identifier.