Body Weight Support Combined With Treadmill in the Rehabilitation of Parkinsonian Gait: A Review of Literature and New Data From a Controlled Study

Background: Gait disorders represent disabling symptoms in Parkinson's Disease (PD). The effectiveness of rehabilitation treatment with Body Weight Support Treadmill Training (BWSTT) has been demonstrated in patients with stroke and spinal cord injuries, but limited data is available in PD.Aims: The aim of the study is to investigate the efficacy of BWSTT in the rehabilitation of gait in PD patients.Methods: Thirty-six PD inpatients were enrolled and performed rehabilitation treatment for 4-weeks, with daily sessions. Subjects were randomly divided into two groups: both groups underwent daily 40-min sessions of traditional physiokinesitherapy followed by 20-min sessions of overground gait training (Control group) or BWSTT (BWSTT group). The efficacy of BWSTT was evaluated with clinical scales and Computerized Gait Analysis (CGA). Patients were tested at baseline (T0) and at the end of the 4-weeks rehabilitation period (T1).Results: Both BWSTT and Control groups experienced a significant improvement in clinical scales as FIM and UPDRS and in gait parameters for both interventions. Even if we failed to detect any statistically significant differences between groups in the different clinical and gait parameters, the intragroup analysis captured a specific pattern of qualitative improvement associated to cadence and stride duration for the BWSTT group and to the swing/stance ratio for the Control group. Four patients with chronic pain or anxious symptoms did not tolerate BWSTT.Conclusions: BWSTT and traditional rehabilitation treatment are both effective in improving clinical motor functions and kinematic gait parameters. BWSTT may represent an option in PD patients with specific symptoms that limit traditional overground gait training, e.g., severe postural instability, balance disorder, orthostatic hypotension. BWSTT is generally well-tolerated, though caution is needed in subjects with chronic pain or with anxious symptoms.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT0381540

The effects of intensive neurorehabilitation on sequence effect in Parkinson's disease patients with and without freezing of gait

Background: The sequence effect (SE), defined as a reduction in amplitude of repetitive movements, is a common clinical feature of Parkinson's disease (PD) and is supposed to be a major contributor to freezing of gait (FOG). During walking, SE manifests as a step-by-step reduction in step length when approaching a turning point or gait destination, resulting in the so-called destination sequence effect (dSE). Previous studies explored the therapeutic effects of several strategies on SE, but none of them evaluated the role of an intensive rehabilitative program. Objectives: Here we aim to study the effects of a 4-week rehabilitative program on dSE in patients with PD with and without FOG. Methods: Forty-three patients (30 males, 70.6 \ub1 7.5 years old) with idiopathic PD were enrolled. The subjects were divided into two groups: patients with (PD + FOG, n = 23) and without FOG (PD - FOG, n = 20). All patients underwent a standardized 4-week intensive rehabilitation in-hospital program. At hospital admission (T0) and discharge (T1), all subjects were evaluated with an inertial gait analysis for dSE recording. Results: At T0, the dSE was more negative in the PD + FOG group (-0.80 \ub1 0.6) when compared to the PD - FOG group (-0.39 \ub1 0.3) (p = 0.007), even when controlling for several clinical and demographic features. At T1, the dSE was reduced in the overall study population (p = 0.001), with a more pronounced improvement in the PD + FOG group (T0: -0.80 \ub1 0.6; T1: -0.23 \ub1 0.4) when compared to the PD - FOG group (T0: -0.39 \ub1 0.3; T1: -0.22 \ub1 0.5) (p = 0.012). At T1, we described in the overall study population an improvement in speed, cadence, stride duration, and stride length (p = 0.001 for all variables). Conclusions: dSE is a core feature of PD gait dysfunction, specifically in patients with FOG. A 4-week intensive rehabilitative program improved dSE in PD patients, exerting a more notable beneficial effect in the PD + FOG group

From DYMUS to DYPARK: validation of a screening questionnaire for dysphagia in Parkinson's disease

Dysphagia is a common debilitating symptom in people with Parkinson's Disease (PD), adequate screening of swallowing disorders is fundamental. The DYMUS questionnaire has shown very good characteristics for the screening of dysphagia in Multiple Sclerosis, and it might also prove useful for screening dysphagia in PD. The primary aim was to test and validate the DYMUS questionnaire in PD patients. This is an observational multicentric study involving 103 patients affected by PD. All subjects filled in the DYMUS and the Eating Assessment Tool (EAT-10) questionnaires. A subgroup of patients (n = 53) underwent a fiber-optic endoscopic evaluation of swallowing (FEES) and their dysphagia was scored by means of the Dysphagia Outcome Severity Scale (DOSS). DYMUS showed a relatively high level of internal consistency (Cronbach's alpha 0.79). A significant positive correlation was found between the DYMUS and the EAT-10 scores (p < 0.001), while a negative correlation was found between the DYMUS and the DOSS scores (p < 0.001). DYMUS showed a good sensitivity and specificity compared to FEES for detecting dysphagia (area under the curve: 0.82, p < 0.001). The ROC curve analysis showed that a DYMUS score >= 6 represents a reliable cut-off for the risk of dysphagia. The DYMUS questionnaire proved to be a reliable screening tool to detect dysphagia in patients suffering from PD. It is easy to understand, it can be self-administered and therefore adequate for adoption in the clinical practice with the more convenient name of DYPARK

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Background As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Results We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Psychological treatments and psychotherapies in the neurorehabilitation of pain. Evidences and recommendations from the italian consensus conference on pain in neurorehabilitation

BACKGROUND: It is increasingly recognized that treating pain is crucial for effective care within neurological rehabilitation in the setting of the neurological rehabilitation. The Italian Consensus Conference on Pain in Neurorehabilitation was constituted with the purpose identifying best practices for us in this context. Along with drug therapies and physical interventions, psychological treatments have been proven to be some of the most valuable tools that can be used within a multidisciplinary approach for fostering a reduction in pain intensity. However, there is a need to elucidate what forms of psychotherapy could be effectively matched with the specific pathologies that are typically addressed by neurorehabilitation teams. OBJECTIVES: To extensively assess the available evidence which supports the use of psychological therapies for pain reduction in neurological diseases. METHODS: A systematic review of the studies evaluating the effect of psychotherapies on pain intensity in neurological disorders was performed through an electronic search using PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews. Based on the level of evidence of the included studies, recommendations were outlined separately for the different conditions. RESULTS: The literature search yielded 2352 results and the final database included 400 articles. The overall strength of the recommendations was medium/low. The different forms of psychological interventions, including Cognitive-Behavioral Therapy, cognitive or behavioral techniques, Mindfulness, hypnosis, Acceptance and Commitment Therapy (ACT), Brief Interpersonal Therapy, virtual reality interventions, various forms of biofeedback and mirror therapy were found to be effective for pain reduction in pathologies such as musculoskeletal pain, fibromyalgia, Complex Regional Pain Syndrome, Central Post-Stroke pain, Phantom Limb Pain, pain secondary to Spinal Cord Injury, multiple sclerosis and other debilitating syndromes, diabetic neuropathy, Medically Unexplained Symptoms, migraine and headache. CONCLUSIONS: Psychological interventions and psychotherapies are safe and effective treatments that can be used within an integrated approach for patients undergoing neurological rehabilitation for pain. The different interventions can be specifically selected depending on the disease being treated. A table of evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation is also provided in the final part of the pape

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian consensus conference on pain in neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

CLINICAL AND BIOCHEMICAL SIGNATURES OF GBA-RELATED PARKINSON DISEASE

Background: Parkinson’s disease (PD) is a common neurodegenerative disorder mainly characterized by dopaminergic neuronal loss in the substantia nigra and α-synuclein protein aggregation. Genetic factors are well known to contribute to PD susceptibility. Mutations in the glucocerebrosidase (GBA) gene are the commonest genetic risk factor for PD and also impact on disease development and progression. A better clinical and genetic classification of patients, as well as the identification of clinical and biochemical markers are therefore of utmost importance for multifold reasons: - to improve the characterization of patient's clinical phenotype of different forms of PD; - to identify reliable biomarkers for genetic subtypes of PD in order to obtain and early diagnosis and monitor disease progression; - to include patients with specific mutations in ad hoc clinical trials aiming to tailor medical treatment. Objective: The present project aims at exploring the bases of PD phenotype through the correlation of specific genetic and biochemical findings with the clinical picture, in subjects with GBA-related PD (GBA-PD) and subjects affected by idiopathic PD (non-mutated PD – NM-PD). We divided the investigation in three studies: i) definition of a clinical and biochemical profile which could distinguish GBA-PD from non-mutated PD (NM-PD) (study I); ii) longitudinal evaluation of the disease course of GBA-PD compared to NM-PD along 2-year follow-up, with a focus on clinical and biochemical parameters (study II); iii) definition of a biochemical prodomal profile in the asymptomatic GBA carriers that could differentiate subjects more at risk to develop PD. Methods: a comprehensive clinical assessment of motor and non-motor symptoms alongside the analysis of α-synuclein levels, glucocerebrosidase (GCase) enzymatic activity and main GCase-related lysosomal proteins in peripheral blood mononuclear cells (PBMCs) were performed in all the three studies. Results: At baseline, GBA-PD showed a worse clinical outcome both on motor and non-motor features compared to NM-PD, as well a distinctive biochemical profile in PBMCs showing significantly higher α –synuclein levels, lower GCase activity, higher LIMP-2 and lower Saposin C levels. Over time, both the GBA-PD and the NM-PD groups separately displayed a significant deterioration in dysautonomic functions, motor performance, cognitive functions and mood disorder compared to baseline, while GBA-PD had a more severe motor progression with a higher disease severity compared to NM-PD. At 2-year follow-up, the level of α-synuclein in PBMCs was able to differentiate GBA-PD from NM-PD and HC. Finally, a unique biochemical profile was observed also in the asymptomatic GBA mutation carriers, in which the combination of higher level of α-synuclein with lower Gcase activity was able to define a malignant prodromal profile. Conclusion: These studies contribute to our current understanding of the role of GBA mutations in the development and progression of PD. We confirm the biological effect of GBA mutations in determining clinical and biochemical distinctive profile of PD. We propose essays in PBMCs as an easily accessible and manageable model to provide a characteristic biochemical profile of GBA carriers, potentially useful for patient stratification or selection in clinical trials.Background: Parkinson’s disease (PD) is a common neurodegenerative disorder mainly characterized by dopaminergic neuronal loss in the substantia nigra and α-synuclein protein aggregation. Genetic factors are well known to contribute to PD susceptibility. Mutations in the glucocerebrosidase (GBA) gene are the commonest genetic risk factor for PD and also impact on disease development and progression. A better clinical and genetic classification of patients, as well as the identification of clinical and biochemical markers are therefore of utmost importance for multifold reasons: - to improve the characterization of patient's clinical phenotype of different forms of PD; - to identify reliable biomarkers for genetic subtypes of PD in order to obtain and early diagnosis and monitor disease progression; - to include patients with specific mutations in ad hoc clinical trials aiming to tailor medical treatment. Objective: The present project aims at exploring the bases of PD phenotype through the correlation of specific genetic and biochemical findings with the clinical picture, in subjects with GBA-related PD (GBA-PD) and subjects affected by idiopathic PD (non-mutated PD – NM-PD). We divided the investigation in three studies: i) definition of a clinical and biochemical profile which could distinguish GBA-PD from non-mutated PD (NM-PD) (study I); ii) longitudinal evaluation of the disease course of GBA-PD compared to NM-PD along 2-year follow-up, with a focus on clinical and biochemical parameters (study II); iii) definition of a biochemical prodomal profile in the asymptomatic GBA carriers that could differentiate subjects more at risk to develop PD. Methods: a comprehensive clinical assessment of motor and non-motor symptoms alongside the analysis of α-synuclein levels, glucocerebrosidase (GCase) enzymatic activity and main GCase-related lysosomal proteins in peripheral blood mononuclear cells (PBMCs) were performed in all the three studies. Results: At baseline, GBA-PD showed a worse clinical outcome both on motor and non-motor features compared to NM-PD, as well a distinctive biochemical profile in PBMCs showing significantly higher α –synuclein levels, lower GCase activity, higher LIMP-2 and lower Saposin C levels. Over time, both the GBA-PD and the NM-PD groups separately displayed a significant deterioration in dysautonomic functions, motor performance, cognitive functions and mood disorder compared to baseline, while GBA-PD had a more severe motor progression with a higher disease severity compared to NM-PD. At 2-year follow-up, the level of α-synuclein in PBMCs was able to differentiate GBA-PD from NM-PD and HC. Finally, a unique biochemical profile was observed also in the asymptomatic GBA mutation carriers, in which the combination of higher level of α-synuclein with lower Gcase activity was able to define a malignant prodromal profile. Conclusion: These studies contribute to our current understanding of the role of GBA mutations in the development and progression of PD. We confirm the biological effect of GBA mutations in determining clinical and biochemical distinctive profile of PD. We propose essays in PBMCs as an easily accessible and manageable model to provide a characteristic biochemical profile of GBA carriers, potentially useful for patient stratification or selection in clinical trials