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Background and purposeDespite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing may be limited in clinical practice. The objective of this study was to assess worldwide access to genetic tests for movement disorders and factors impacting their utilization.MethodsThe Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society designed an online survey electronically mailed to all 7815 members.ResultsSurvey data completed by 1269 participants from 109 countries were analysed. Limited access to geneticists and genetic counsellors was reported in many world regions compared to Europe and North America. Availability of genetic testing was limited, with rates of access lower than 50%. Genetic testing for chorea was the most commonly available. For parkinsonism, dystonia, ataxia, hereditary spastic paraplegias and metabolic disorders, there was limited access to genetic testing in all countries compared to Europe and North America, with significant differences found for Africa, Central/South America, Asia. In many regions, genetic testing was supported by either private or public funding. Genetic testing was free of charge in Europe according to 63.5% of respondents. In North America, Africa, Central/South America, Asia and the Middle East access to free of charge genetic testing was by far significantly lower compared to Europe.ConclusionsThis survey highlights difficulties in accessing genetic testing and individuals with expertise in genetics at the worldwide level. In addition, major disparities in genetic testing amongst world regions are highlighted, probably due to a variety of factors including financial barriers.

Background and Objective: Early‐onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next‐generation sequencing (NGS) of PD‐associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far. Methods: We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD‐related genes, as well as PD‐multiplex ligation‐dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD‐associated GBA1 variants were considered diagnostic. Results: In 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive. Conclusions: This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS‐multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Parkinsonian features have been described in patients harboring variants in nuclear genes encoding for proteins involved in mitochondrial DNA maintenance, such as TWNK.Objectives: The aim was to screen for TWNK variants in an Italian cohort of Parkinson's disease (PD) patients and to assess the occurrence of parkinsonism in patients presenting with TWNK-related autosomal dominant progressive external ophthalmoplegia (TWNK-adPEO).Methods: Genomic DNA of 263 consecutively collected PD patients who underwent diagnostic genetic testing was analyzed with a targeted custom gene panel including TWNK, as well as genes causative of monogenic PD. Genetic and clinical data of 18 TWNK-adPEO patients with parkinsonism were retrospectively analyzed.Results: Six of 263 PD patients (2%), presenting either with isolated PD (n = 4) or in combination with bilateral ptosis (n = 2), carried TWNK likely pathogenic variants. Among 18 TWNK-adPEO patients, 5 (28%) had parkinsonism.Conclusions: We show candidate TWNK variants occurring in PD without PEO. This finding will require further confirmatory studies. © 2022 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. [ABSTRACT FROM AUTHOR]

• COVID-19 has significant impact on PD research and education activities. • Country-specific restrictions may pose challenges to PD research and require careful adaptations. • Neurological Symptoms of COVID-19 may overlap with PD. [ABSTRACT FROM AUTHOR]

Background: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear. Objectives: We determined the frequency of GBA‐related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time. Methods: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. β‐glucocerebrosidase activity was measured. The Kaplan‐Meier method and Cox proportional hazard regression models were performed. Results: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA‐PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA‐PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA‐PD had the lowest β‐glucocerebrosidase activity. Conclusions: GBA‐PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is one of the most common chronic neurological conditions leading to disability and social burden. According to the 2016 Italian National Plan on Chronic Diseases, regional health authorities are implementing dedicated networks to manage neurological diseases, including PD. Methods: A panel of experts representing health-care providers in Lombardy reached consensus on the organization of a patient-centered regional PD healthcare network. Results: The panel proposed a structure and organization implementing a hub-and-spoke PD network model. Three levels of neurological services were identified: General Neurologist, PD Clinic, PD Center. This model was applied to health service providers currently accredited in Lombardy, yielding 12 candidate PD Centers, each serving an area of ~1,000–2,000 km2, and not less than 27 PD Clinics. The panel agreed on uniform diagnostic and staging criteria for PD, and on a minimum common clinical data set, on PD patient management by the network at initial and follow-up assessments, on the cadence of follow-up visits, on patient referrals, and on outcome measures for the assessment of network activities. Conclusions: The implementation of disease-centered networks for chronic neurological diseases provides an innovative opportunity to improve patient management, facilitate research and education. [ABSTRACT FROM AUTHOR]

Several symptomatic treatments for Parkinson's disease (PD) are currently available. Still, the challenge today is to find a therapy that might reduce degeneration and slow down disease progression. The identification of pathogenic mutations in familial Parkinsonism (fPD) associated to the monogenic forms of PD provided pathophysiological insights and highlighted novel targets for therapeutic intervention. Mutations in the VPS35 gene have been associated with autosomal dominant fPD and a clinical phenotype indistinguishable from idiopathic PD. Although VPS35 mutations are relatively rare causes of PD, their study may help understanding specific cellular and molecular alterations that lead to accumulation α-synuclein in neurons of PD patients. Interacting with such mechanisms may provide innovative therapeutic approaches. We review here the evidence on the physiological role of VPS35 as a key intracellular trafficking protein controlling relevant neuronal functions. We further analyze VPS35 activity on α-synuclein degradation pathways that control the equilibrium between α-synuclein clearance and accumulation. Finally, we highlight the strategies for increasing VPS35 levels as a potential tool to treat PD. [ABSTRACT FROM AUTHOR]

An editorial is presented which discusses article on identification of Parkinson's Disease using global team science. It mentions that using genetic Parkinson disease (PD) as an example and illustrating the magnitude of the issue, up to 300,000 patients worldwide are estimated to have hereditary forms of PD, representing 5 percent of total of 6 million patients with PD in 2018; and highlights that neurologists commonly lack reliable reference data to be able to offer tailored counseling.

Introduction: Parkin disease (PARK2, OMIM 602544) is an autosomal-recessive early-onset parkinsonism characterized by an early occurrence of lower limb dystonia. The aim of this study was to analyze spatiotemporal, kinematic, and kinetic gait parameters in patients with parkin disease in the OFF and ON conditions compared to healthy age-matched controls.Methods: Fifteen patients with parkin disease and 15 healthy age-matched controls were studied in a gait analysis laboratory with an integrated optoelectronic system. Spatiotemporal, kinematic, and kinetic gait parameters at a self-selected speed were recorded in the OFF and ON conditions. A jerk index was computed to quantify the possible reduction of smoothness of joint movements.Results: Compared to controls, parkin patients had, either in the OFF or in the ON conditions, significant reduction of walking velocity, increased step width, and decreased percentage of double support. Kinematic analysis in both conditions showed: increased ankle dorsiflexion and knee flexion at the initial contact; maximal flexion and increased range of motion in mid stance; increased hip flexion and max extension in stance at pelvis; and increased mean tilt antiversion. Kinetics showed increased hip and knee power generation in stance in either condition. The jerk index was increased at all joints both in OFF and ON. There were no correlations between individual gait parameters and clinical ratings.Conclusion: Parkin patients have an abnormal gait pattern that does not vary between the OFF and the ON conditions. Variations recorded with instrumented analysis are more evident for kinematic than kinetic parameters at lower limbs. Severity of dystonia does not correlate with any individual kinematic parameter. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

This study focused on the substantia nigra (SN) in Parkinson's disease (PD). We measured its area and volume, mean diffusivity (MD), fractional anisotropy (FA) and iron concentration in early and late PD and correlated the values with clinical scores. Twenty-two early PD (EPD), 20 late PD (LPD) and 20 healthy subjects (age 64.7 ± 4.9, 60.5 ± 6.1, and 61 ± 7.2 years, respectively) underwent 1.5 T MR imaging with double-TI-IR T1-weighted, T2*-weighted and diffusion tensor imaging scans. Relative SN area, MD, FA and R2* were measured in ROIs traced on SN. Correlation with Unified Parkinson Disease Rating Scale (UPDRS) scores was assessed. In LPD, the SN area was significantly reduced with respect to EPD ( p = 0.04) and control subjects ( p < 0.001). In EPD, the SN area was also significantly smaller than in controls ( p = 0.006). Similarly, the SN volume significantly differed between LPD and controls ( p = 0.001) and between EPD and LPD ( p = 0.049), while no significant differences were found between controls and EPD. Both SN area ( r = 0.47, p = 0.004) and volume ( r = 0.46, p = 0.005) correlated with UPDRS scores. At 1.5 T, SN morphological measurements were sensitive to early PD changes and able to track the disease progression, while MD and FA measures and relaxometry did not provide significant results. [ABSTRACT FROM AUTHOR]

Patients affected by Parkinson's disease (PD) can provide crucial information about the involvement of the motor system and prefrontal cortex in processing idioms including action verbs, since dopamine modulates the activity of these structures, and, consequently, different levels of this neurotransmitter can induce different cognitive impairments. In order to investigate the ability to process ambiguous idioms containing an action verb in patients, we asked 15 PD patients, in both OFF- and ON-phases, and 15 healthy matched participants to judge the plausibility of literal and idiomatic sentences, each presented at a self-paced rate. Patients in OFF-phase were faster in reading idiomatic than literal sentences, supporting the view that the motor system is not involved in online idiom processing. However, patients during OFF-phase were impaired in judging the plausibility of idiomatic ambiguous sentences, possibly due to the reduction of dopamine in prefrontal regions. The involvement of the motor system was evident in the ON-phase for literal sentences, suggesting that motor activation is strictly dependent on the context. [ABSTRACT FROM PUBLISHER]

ABSTRACT Background Multiplications of the SNCA gene that encodes alpha-synuclein are a rare cause of autosomal dominant Parkinson's disease (PD). Methods Here, we describe 2 novel families in which there is autosomal dominant PD associated with SNCA duplication, and we compare the clinical features of all known patients carrying 3 or 4 SNCA copies. Results Affected members in family A presented with early onset PD that was variably associated with nonmotor features, such as dysautonomia, cognitive deficits, and psychiatric disturbances. In family B, the clinical presentation ranged from early onset PD-dementia with psychiatric disturbances to late onset PD with mild cognitive impairment. Conclusions The presence of 4 SNCA copies is associated with a rich phenotype, characterized by earlier onset of motor and nonmotor features compared with patients who bear 3 SNCA copies. The clinical spectrum associated with SNCA duplications is wide, even within a single family, suggesting a role for as yet unidentified genetic or environmental modifiers. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the efficacy and safety of epidural premotor stimulation in patients with primary focal dystonia. Seven patients were selected: 6 had cervical dystonia and 1 had right upper limb dystonia. In 2 patients, sustained muscle contractions led to a prevalently fixed head posture. Patients with cervical dystonia received a bilateral implant, whereas the patient with hand dystonia received a unilateral implant. Neurological and neuropsychological evaluations were performed before surgery (baseline), and 1, 3, 6, and 12 months afterward. The Burke-Fahn-Marsden scale (BFMS) and the Toronto Western spasmodic torticollis rating scale (TWSTRS) were administered at the same time points. Patients underwent resting 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans, before and 12 months after surgery. No adverse events occurred. An overall improvement was observed on the BFMS and TWSTRS after surgery. Patients with prevalently fixed cervical dystonia had a reduced benefit. Presurgical neuroimaging revealed a significant bilateral metabolic increase in the sensorimotor areas, which was reduced after surgery. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The links between Stn DBS and advanced Parkinson disease, and between GPi DBS and dystonia are nearly universally accepted by the neurologists and neurosurgeons. Nevertheless, in some conditions, targets such as the ventral thalamus and the Zona Incerta may be considered to optimize the results and avoid the side effects. Positive and negative aspects of current DBS treatments justify the research of new targets, new stimulation programs and new hardware. Since 1993, at the Istituto Nazionale Neurologico 'Carlo Besta' in Milan, 580 deep brain electrodes were implanted in 332 patients. 276 patients were affected by movement disorders. The DBS targets included Stn, GPi, Voa, Vop, Vim, CM-pf, cZi, IC. The long-term follow-up is reported and related to the chosen target. DBS gave a new therapeutic option to patients affected by severe movement disorders, and in some cases resolved life-threatening pathological conditions that would otherwise result in the death of the patient, such as in status dystonicus, and post-stroke hemiballismus. Nevertheless, the potential occurrence of severe complications still limit a wider use of DBS. At today, the use of DBS in severe movement disorders is strongly positive even if further investigations and studies are needed to unveil potential new applications, and to refine the selection criteria for the actual indications and targets. The experience of different targets may be useful to guide and tailor the target choice to the individual clinical condition. [ABSTRACT FROM AUTHOR]

Deep brain stimulation of the subthalamic nucleus represents the most important innovation for treatment of advanced Parkinson’s disease. Prospective studies have shown that although the beneficial effects of this procedure are maintained at 5 years, axial motor features and cognitive decline may occur in the long term after the implants. In order to address some unsolved questions raised by previous studies, we evaluated a series of 20 consecutive patients who received continuous stimulation for 8 years. The overall motor improvement reported at 5 years (55.5% at Unified Parkinson’s Disease Rating Scale—motor part, P < 0.001 compared with baseline) was only partly retained 3 years later (39%, P < 0.001, compared with baseline; −16.5%, P < 0.01, compared with 5 years), with differential effects on motor features: speech did not improve and postural stability worsened (P < 0.05). The preoperative levodopa equivalent daily dose was reduced by 58.2% at 5 years and by 60.3% at 8 years. In spite of subtle worsening of motor features, a dramatic impairment in functional state (−56.6% at Unified Parkinson’s Disease Rating Scale—Activities of Daily Living, P < 0.01) emerged after the fifth year of stimulation. The present study did not reveal a predictive value of preoperative levodopa response, whereas few single features at baseline (such as gait and postural stability motor scores and the preoperative levodopa equivalent daily dose) could predict long-term motor outcome. A decline in verbal fluency (slightly more pronounced than after 5 years) was detected after 8 years. A significant but slight decline in tasks of abstract reasoning, episodic memory and executive function was also found. One patient had developed dementia at 5 years with further progression at 8 years. Executive dysfunction correlated significantly with postural stability, suggesting interplay between axial motor deterioration and cognition. Eight years after surgery, no significant change was observed on scales assessing depression or anxiety when compared with baseline. At 8 years, there was no significant increase of side-effects when compared with 5-year follow-up. In conclusion, deep brain stimulation of the subthalamic nucleus is a safe procedure with regard to cognitive and behavioural morbidity over long-term follow-up. However, the global benefit partly decreases later in the course of the disease, due to progression of Parkinson’s disease and the appearance of medication- and stimulation-resistant symptoms. [ABSTRACT FROM PUBLISHER]

Dementia associated with Parkinson's disease (PD) ultimately develops in approximately 70% of patients with PD older than 80 years of age. The neuropathology of PD dementia (PDD) is likely multifactorial and affects several neuronal populations. These is evidence that PDD is associated with a cholinergic deficit, supporting the therapeutic role of cholinesterase inhibitors, which are already first-line agents in the treatment of Alzheimer's disease. Open-label and small controlled studies suggested a clinical efficacy of chilinesterase inhibitors in PDD. One large randomized placebo-controlled trial of 541 patients demonstrated that oral rivastigmine improve cognition, attention and executive functions, activities of daily living and behavioral symptoms after 6 months of treatment. Rivastigmine is a dual cholinesterase inhibitor, being effective on both acetylcholinesterase and butyrylcholinesterase. This paper reviews the pharmacokinetic and pharmacodynamic properties of rivastigmine (oral and transdermal administration). It also reviews evidence on clinical efficacy, safety and tolerability of the administration in PDD patients at doses of 3-12 mg/day. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of different parkinsonian syndromes and the ability to predict long-term drug efficacy constitute important clinical issues. Design: Motor responses to the acute administration of levodopa and apomorphine were analyzed in a series of 134 parkinsonian patients, including 83 patients with a clinical diagnosis of idiopathic Parkinson’s disease (PD), 28 patients with multiple-system atrophy (MSA), 6 with progressive supranuclear palsy, and 17 with an unclassified parkinsonian syndrome. Methods: The patients received oral levodopa/carbidopa (250/25 mg) and subcutaneous apomorphine (1.5, 3 and 4.5 mg). Clinical variations of the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score were evaluated 1 h following levodopa administration or 20 min following apomorphine. The motor improvement produced by each acute challenge was matched with the clinical diagnosis and with the response to chronic levodopa treatment. The diagnosis was verified by repeated clinical assessments or by autopsy in 2 cases. A receiver operating characteristics curve was plotted comparing PD vs. non-PD, PD vs. MSA and chronic responders vs. nonresponders. Cutoff threshold improvement was defined as the value closest to the crossing point for 80% sensitivity and 80% specificity, corresponding to the best trade-off for a predictive evaluation. Results: UPDRS motor score improvement was on average higher in PD than in non-PD patients (levodopa: 29.8 vs. 12.2%; apomorphine 1.5 mg: 27.1 vs. 10.5%; apomorphine 3 mg: 27.7 vs. 9.7%; apomorphine 4.5 mg: 28.8 vs. 11.8%; p < 0.01 with Student’s t test). When PD patients were compared to non-PD patients, levodopa challenge had the best diagnostic accuracy with a threshold improvement of 16%. Apomorphine had the best diagnostic accuracy with a threshold improvement of 13.5% for 1.5 mg, 13% for 3 mg, and 16% for 4.5 mg. This meant that patients improving at least 16% in all tests had the highest probability of having PD. When PD patients were compared to MSA patients, levodopa acute challenge had the best diagnostic accuracy with a threshold improvement of 17%. Apomorphine had the best diagnostic accuracy with an improvement of 13% for 1.5 mg, 15% for 3 mg, and 18% for 4.5 mg. This meant that patients improving at least 18% in all tests had the highest probability of having PD rather than MSA. When patients who responded to chronic levodopa treatment were compared to those who did not, acute challenge with levodopa had the best predictive accuracy with a threshold improvement of 14.5%. Apomorphine had the best predictive accuracy with an improvement of 13% for 1.5 mg, and 14% for 3 and 4.5 mg. This meant that patients improving at least 14.5% in all tests had the highest probability of responding to chronic treatment. Conclusion: A good agreement was found between acute challenges with levodopa/carbidopa and apomorphine, and the use of both improved the reliability of the test. Different threshold improvements after acute challenges would support a diagnosis of PD or the exclusion of MSA, and would have a predictive value for subsequent response to chronic levodopa therapy.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Few cases of frontotemporal dementia parkinsonism (FTDP-17) have been described in the literature. To our knowledge, this is the first Italian case. Objective: To report a case of FTDP linked to chromosome 17, exhibiting progressive supranuclear palsy on initial examination. Patient: A 50-year-old woman had a 4-year history of behavior changes associated with slowly progressive mental decay and parkinsonism, with poor balance, supranuclear vertical gaze palsy, and bradykinesia. The symptoms were not responsive to dopaminergic therapy. Her father had died at age 46 years after a 7-year history of parkinsonism, and her brother, diagnosed as having progressive supranuclear palsy, died at age 45 years. Results: Magnetic resonance imaging showed mild midbrain atrophy, results of an electroencephalogram were normal, and cognitive evaluation showed moderate cognitive impairment, especially evident in the executive and attentional functions. Genetic testing revealed a tau gene mutation at codon 279 (AAT→AAG) of exon 10. Conclusion: Exon 10 mutations (including the N279K mutation) that result in overproduction of the tau isoform with 4 microtubule binding motifs seem to be associated with a mainly parkinsonian phenotype at disease onset. [ABSTRACT FROM AUTHOR]

The clinical features and outcomes of post-COVID parkinsonism have not been organized systematically, and the possible correlations between COVID-19 and parkinsonism have not been elucidated. This scoping review addresses these two unmet needs. We searched two databases (Pubmed, Embase) for all published cases of post-COVID parkinsonism. Data were extracted from eligible studies using standardized forms and predefined inclusion and exclusion criteria. The patients' clinical features, their diagnosis and outcomes were assessed objectively. Twenty-six cases of post-COVID parkinsonism were reported in 17 publications. Their presenting features were grouped into three clinical syndromes: typical parkinsonian motor syndrome (12 patients), parkinsonism with postural instability and gait disorder (three), or encephalopathy with parkinsonism (10). Patients had the following diagnoses: clinically established Parkinson's disease (PD, three cases), clinically probable PD (eight), clinically probable multiple system atrophy (one), acquired parkinsonism (six), unclassified parkinsonism (eight). Isolated parkinsonian motor syndromes typically followed uncomplicated COVID-19 illness or pneumonia; instead, encephalopathy with parkinsonism was observed following a wide spectrum of COVID-19-related presentations, including severe forms. PD cases mainly occurred following uncomplicated COVID-19, whereas acquired or unclassified parkinsonism were reported following different COVID-19 presentations. Patients with uncomplicated COVID-19 are more likely to present PD and no signs of encephalopathy. There is no demonstration of a causative role of COVID-19, which can be coincidental in several cases. Patients with encephalopathy and parkinsonism constitute a distinct subset, suggesting a potentially different pathogenic role of SARS-CoV-2 infection. These findings provide a basis for further studies in the post-pandemic phase. • Several observations during pandemic have evidenced a possible relationship between COVID-19 and incident parkinsonism. • Patients with uncomplicated COVID-19 had mostly PD, whereas severe COVID-19 was followed by encephalopathy and parkinsonism. • This scoping review provides guidance for future prospective epidemiological studies on PD in the post-pandemic era. [ABSTRACT FROM AUTHOR]

Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa–carbidopa solution) compared with oral immediate-release levodopa–carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa–carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa–carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa–carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa–carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , NCT04006210 , and is complete. Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa–carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa–carbidopa (change from baseline of –0·48 h [–0·94 to –0·02] with subcutaneous ND0612 vs –2·20 h [–2·65 to –1·74] with oral levodopa–carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (–1·40 h [95% CI –1·99 to –0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (–3·05 [–4·28 to –1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa–carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa–carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa–carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit–risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. NeuroDerm. [ABSTRACT FROM AUTHOR]

Background: Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease.Methods: In this randomised, double-blind study eligible patients were aged 36-70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3-4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38-70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325,000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687.Findings: Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (-10.5 [SD 10.26] for transplantation vs -10.1 [SD 12.26] for sham surgery, p=0.9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells.Interpretation: Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery.Funding: Bayer HealthCare AG. [ABSTRACT FROM AUTHOR]

Summary: Pain and fatigue are part of the phenomenological spectrum of Parkinson''s disease (PD). These non-motor symptoms can be as troublesome as motor symptoms, impact activities of daily living, and are often underdiagnosed. The recognition of pain and fatigue requires a high degree of clinical suspicion and is facilitated by the use of specific questionnaires and ancillary tests. This workup is highly valuable particularly considering that pain and fatigue in PD may be treatable. We review here the clinical manifestations and management of these non-motor symptoms. Their resolution can be challenging, as there is insufficient evidence concerning effective treatment options. [Copyright &y& Elsevier]

Objective. To describe functioning and disability of patients with Parkinson's Disease (PD) according to the model endorsed by the International Classification of Functioning Disability and Health (ICF). Design. Adult PD patients were consecutively enrolled. The ICF checklist and the WHO Disability Assessment Schedule II (WHO-DAS II) were administered in individual sessions. Hoehn and Yahr Staging (HY) was used to define PD severity. Descriptive analyses have been performed to report on HY and WHO-DAS II scores. ICF categories reported as a problem by more than 20% of patients are described in detail. Results. Ninety-six patients with PD (mean age 64.1, 33.3% females) were enrolled, 48.4% of them were in HY class 2. WHO-DAS II mean score was 18.1 and the most severe limitations are reported in getting around and in participation to social situations. A total of 71 ICF categories reached the threshold of 20%, mostly derived from Activities and Participation domain. Conclusions. We reported information on a broad set of domains, expanding those PD-specific, such as reduced mobility. Our results are useful to define what dimensions have to be considered to expand disability assessment in patients with PD, considering both symptoms, activities and the role of environmental factors. [ABSTRACT FROM AUTHOR]

The article comments on the effectiveness regarding the use of a personalized exercise program designed to help patients with Parkinson's disease (PD) avoid falls and maintain mobility. The author explained that the exercises may help patients learn to adopt simpler motor strategies. It may also implement compensatory strategies that patients lose during the advance stages of the disease.

Summary: Deep brain stimulation (DBS) is an established procedure for the symptomatic treatment of Parkinson''s disease. Several deep brain nuclei have been stimulated, producing a wide range of effects on the motor and non-motor symptoms of Parkinson''s disease. Long-term, high-quality evidence is available for stimulation of the subthalamic nucleus and globus pallidus internus, both of which uniformly improve motor features, and for stimulation of the thalamic ventralis intermedius, which improves tremor. Short-term data are available for stimulation of other deep brain targets, such as the pedunculopontine nucleus and the centremedian/parafascicular thalamic complex. Some non-motor symptoms improve after DBS, partly because of motor benefit or reduction of drug treatment, and partly as a direct effect of stimulation. More evidence on the effects of DBS on non-motor symptoms is needed and specifically designed studies are warranted. [Copyright &y& Elsevier]

Abstract Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts' primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning. Fibroblasts' analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p < 0.05), and a reduction of complex II steady-state level (p < 0.01); a reduction of Coenzyme Q10 level (p < 0.001) and an up-regulation of some CoQ10 biosynthesis enzymes, namely COQ5 and COQ7; an impairment of mitophagy, demonstrated by a decreased reduction of mitochondrial markers after mitochondrial inner membrane depolarization (p < 0.05); a reduced basal autophagic activity, shown by a decreased level of LC3 II (p < 0.05); an increased mitochondrial mass in MSA-C, demonstrated by higher TOMM20 levels (p < 0.05) and suggested by a wide analysis of mitochondrial DNA content in blood of large cohorts of patients. The present study contributes to understand the causative mechanisms of Multiple System Atrophy. In particular, the observed impairment of respiratory chain activity, mitophagy and Coenzyme Q10 biosynthesis suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of the disease. Furthermore, these findings will hopefully contribute to identify novel therapeutic targets for this still incurable disorder. Highlights • Patient-derived fibroblasts were used to investigate the pathogenesis of MSA. • Mitochondrial respiratory chain, particularly complex II, was impaired in patients. • Increased mitochondrial mass was detected in the cerebellar subtype of the disease. • Reduced basal autophagy and impaired mitophagic machinery were observed in patients. • Reduced CoQ10 level and up-regulated CoQ10 biosynthesis were detected in patients. [ABSTRACT FROM AUTHOR]

Abstract: An impairment for verbs has been described in patients with Parkinson''s disease (PD), suggesting that a disruption of frontal–subcortical circuits may result in dysfunction of the neural systems involved in action–verb processing. A previous study suggested that deep brain stimulation (DBS) of the subthalamic nucleus (STN) during verb generation may affect the ability to select from many competing lexical alternatives. In this study, 12 PD patients who had undergone bilateral STN DBS and completed an 8-year follow-up and 14 matched normal controls were administered action and object naming tasks and verb and noun reading tasks. Their responses were recorded using a microphone, resulting in a signal that marked the onset of the verbal response and allowed to measure response times (RTs). Accuracy was scored manually. Results: Overall performance in naming (independently of stimulation): In naming task controls were faster and more accurate than PD patients. In both groups, performance (accuracy and RTs) was worse on action naming than object naming. PD patients were significantly slower than controls in naming actions. Effect of stimulation: Compared with the OFF stimulation condition, in ON stimulation condition PD patients showed improved performance on object and action naming tasks (increased accuracy, faster RTs), with a decreased number of semantic errors. Some evidence also emerged that action naming in the ON stimulation condition improved more than object naming. On noun and verb reading tasks, although accuracy was at ceiling in both groups and no significant difference was observed in RTs for nouns and verbs, PD patients were slower than controls. Conclusions: Our findings suggest that STN DBS may improve lexical search in PD patients. We hypothesize that STN stimulation may facilitate the motor components involved in naming and reading tasks (increased speed of speech onset), resulting in shorter RTs in both naming and reading and, to some extent, in increased accuracy in naming due to fewer omissions (no response within the 7500ms time limit). However, to account for greater accuracy in naming due to decreased number of semantic errors in the ON stimulation condition, we hypothesize that STN stimulation restores the activity of the corticostriatal circuits involved in selection processes of a target word among different alternatives. [Copyright &y& Elsevier]

Abstract: Patients with Parkinson’s disease suffer from a variety of motor and nonmotor symptoms (NMS), report reduced quality of life and increased disability. Aims of this study are to assess the impact of Parkinson’s disease on disability and quality of life, to evaluate the relationships between them and NMS prevalence. In this cross-sectional study, adult patients were consecutively enrolled and administered the World Health Organization Disability Assessment Schedule (WHO-DAS II), the 36-Item Short-Form Health Survey (SF-36) and the Non Motor Symptoms Questionnaire (NMSQuest). One-sample t-test was used to compare WHO-DAS II and SF-36 scores with normative value. Pearson’s correlation was performed between NMSQuest, WHO-DAS II and SF-36 summary scales. Independent-sample t-test was used to compare NMSQuest, WHO-DAS II and SF-36 scores in patients with Hoehn & Yahr stage <3 and ≥3. In total, 96 patients were enrolled. SF-36 and WHO-DAS II scores were significantly worse than the normative values. Correlation coefficients between NMSQuest, WHO-DAS II and SF-36’s mental score were moderate, and were high between WHO-DAS II and and SF-36’s physical score. Patients with Hoehn & Yahr stage ≥ 3 reported reduced quality of life, higher disability and more NMS. Parkinson’s disease severity is strongly associated with reduced quality of life, increased disability and NMS prevalence. Disability and quality of life assessment tools measure psychosocial facets that are similar specifically with regard to physical health component of health-related quality of life, are sensitive enough to capture differences related to disease’s progression and increased prevalence of NMS. [Copyright &y& Elsevier]

To assess the prevalence and phenomenology of Impulse control behavior (ICB) in Parkinson's disease (PD) patients carrying mutations in the β-glucocerebrosidase (GBA) gene. GBA mutations are a common genetic factor predisposing to PD. ICB is among the most disabling non-motor complications of PD. The occurrence of ICB in PD patients carrying GBA gene mutations (GBA-PD) has not been yet established. Forty-six patients with clinically definite PD (23 GBA-PD and 23 non-mutated patients, NM-PD) were screened for ICB. Diagnosis was clinically and rating based on a specific questionnaire (QUIP-RS). Other demographic and clinical variables did not differ between groups. ICB occurred more frequently in GBA-PD patients (52.2%) compared to NM-PD (13%) and the total QUIP-RS score was higher in the GBA-PD group. Hypersexuality and compulsive shopping were the most prevalent ICB types occurring in GBA patients. ICB occurred only in one GBA-PD patient on levodopa monotherapy and in 11 patients taking dopamine agonists, either monotherapy or combined with levodopa (the corresponding figures in NM-PD patients were 0 and 3). Most GBA-PD patients were heterozygous for two common genetic variants, without appreciable difference in their ICB profile. ICB is more common in GBA-PD patients compared to NM-PD. Dopamine agonist therapy may be synergic to GBA carrier status for ICB occurrence. • ICB is among the most disabling behavioral complications of PD. • ICB was more frequent in PD patients with GBA gene mutations compared to non-mutated patients. • PD patients with GBA mutations on dopamine agonist treatment were more prone to ICB. • This suggests caution when managing GBA-mutated patients treated with dopamine agonists. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD. [ABSTRACT FROM AUTHOR]