Actigraphy Enables Home Screening of Rapid Eye Movement Behavior Disorder in Parkinson's Disease.

OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is a potentially harmful, often overlooked sleep disorder affecting up to 70% of Parkinson's disease patients. Current diagnosis relies on nocturnal video-polysomnography, which is an expensive and cumbersome examination requiring specific clinical expertise. Here, we explored the use of wrist actigraphy to enable automatic RBD diagnoses in home settings. METHODS: A total of 26 Parkinson's disease patients underwent 2-week home wrist actigraphy, followed by two in-laboratory evaluations. Patients were classified as RBD versus non-RBD based on dream enactment history and video-polysomnography. We comprehensively characterized patients' movement patterns during sleep using actigraphic signals. We then trained machine learning classification algorithms to discriminate patients with or without RBD using the most relevant features. Classification performance was quantified with respect to clinical diagnosis, separately for in-laboratory and at-home recordings. Performance was further validated in a control group of non-Parkinson's disease patients with other sleep conditions. RESULTS: To characterize RBD, actigraphic features extracted from both (1) individual movement episodes and (2) global nocturnal activity were critical. RBD patients were more active overall, and showed movements that were shorter, of higher magnitude, and more scattered in time. Using these features, our classification algorithms reached an accuracy of 92.9 ± 8.16% during in-clinic tests. When validated on home recordings in Parkinson's disease patients, accuracy reached 100% over a 2-week window, and was 94.4% in non-Parkinson's disease control patients. Features showed robustness across tests and conditions. INTERPRETATION: These results open new perspectives for faster, cheaper, and more regular screening of sleep disorders, both for routine clinical practice and clinical trials. ANN NEUROL 2023;93:317-329.

Tau seeds from patients induce progressive supranuclear palsy pathology and symptoms in primates.

Progressive supranuclear palsy is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that progressive supranuclear palsy tauopathy may spread in the brain from cell to cell in a 'prion-like' manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of patients with progressive supranuclear palsy. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of progressive supranuclear palsy-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pentameric formyl thiophene acetic acid positive) and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of progressive supranuclear palsy-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that progressive supranuclear palsy-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as 6 months after injection, remaining present until euthanasia at 18 months. An object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in progressive supranuclear palsy-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in progressive supranuclear palsy-tau injected macaques. Characteristic pathological hallmarks of progressive supranuclear palsy, including globose and neurofibrillary tangles, tufted astrocytes and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in progressive supranuclear palsy (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that progressive supranuclear palsy patient-derived tau aggregates can induce motor and behavioural impairments in non-human primates related to the prion-like seeding and spreading of typical pathological progressive supranuclear palsy lesions. This pilot study paves the way for supporting progressive supranuclear palsy-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease.

Reactive Exercises with Interactive Objects: Interim Analysis of a Randomized Trial on Task-Driven NMES Grasp Rehabilitation for Subacute and Early Chronic Stroke Patients.

Enriched environments and tools are believed to promote grasp rehabilitation after stroke. We designed S2, an interactive grasp rehabilitation system consisting of smart objects, custom orthoses for selective grasp constraining, and an electrode array system for forearm NMES. Motor improvements and perceived usability of a new enriched upper limb training system for sub-acute stroke patients was assessed in this interim analysis. INCLUSION CRITERIA: sub-acute stroke patients with MMSE>20, ipsilesional MI>80%, and contralesional MI<80%. Effects of 30-min therapy supplements, conventional vs. S2 prototype, are compared through a parallel two-arms dose-matched open-label trial, lasting 27 sessions. Clinical centres: Asklepios Neurologische Klinik Falkenstein, Königstein im Taunus, Germany, and Clinica Villa Beretta, Costa Masnaga, Italy. Assessment scales: ARAT, System Usability, and Technology Acceptance. METHODOLOGY: 26 participants were block randomized, allocated to the study (control N=12, experimental N=14) and underwent the training protocol. Among them, 11 participants with ARAT score at inclusion below 35, n = 6 in the experimental group, and n = 5 in the control group were analysed. RESULTS: participants in the enriched treatment group displayed a larger improvement in the ARAT scale (+14.9 pts, pval=0.0494). Perceived usability differed between clinics. No adverse effect was observed in relation to the treatments. Trial status: closed. CONCLUSIONS: The S2 system, developed according to shared clinical directives, was tested in a clinical proof of concept. Variations of ARAT scores confirm the feasibility of clinical investigation for hand rehabilitation after stroke.

A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD.

A Wearable Multi-Site System for NMES-Based Hand Function Restoration.

Reaching and grasping impairments significantly affect the quality of life for people who have experienced a stroke or spinal cord injury. The long-term well-being of patients varies greatly according to the restorable residual capabilities. Electrical stimulation could be a promising solution to restore motor functions in these conditions, but its use is not clinically widespread. Here, we introduce the HandNMES, an electrode array (EA) for neuromuscular electrical stimulation (NMES) aimed at grasp training and assistance. The device was designed to deliver electrical stimulation to extrinsic and intrinsic hand muscles. Six independent EAs, positioned on the user forearm and hand, deliver NMES pulses originating from an external stimulator equipped with demultiplexers for interfacing with a large number of electrodes. The garment was designed to be adaptable to user needs and anthropometric characteristics; size, shape, and contact materials can be customized, and stimulation characteristics such as intensity of stimulation and virtual electrode location, and size can be adjusted. We performed extensive tests with nine healthy subjects showing the efficacy of the HandNMES in terms of stimulation performance and personalization. Because encouraging results were achieved, in the coming months, the HandNMES device will be tested in pilot clinical trials.