Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Progressive Brain Atrophy in Multiple System Atrophy: A Longitudinal, Multicenter, Magnetic Resonance Imaging Study.

OBJECTIVE: To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA). BACKGROUND: Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion. METHODS: Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion. RESULTS: Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively. CONCLUSIONS: Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Sex-related differences in the clinical presentation of multiple system atrophy.

PURPOSE: To investigate sex-related differences in the clinical presentation of multiple system atrophy (MSA) through a literature review and an analysis of a retrospective cohort. METHODS: The PubMed database was searched for articles including sex-related information in MSA. In a retrospective Innsbruck cohort, we investigated the baseline to last available follow-up clinical-demographic differences between men and women with MSA in a univariate fashion, followed by multivariable binary regression analysis. RESULTS: The literature search yielded 46 publications with sex-related information in MSA. Most studies found comparable survival rates between the sexes, while some recent reports suggested a potential survival benefit for women, possibly due to initial motor onset and overall less severe autonomic failure compared to men. The retrospective Innsbruck MSA cohort comprised 56 female and 60 male individuals with a comparable median follow-up of 27 months. At baseline, female sex was independently associated with depression (odds ratio [OR] 4.7; p = 0.007) and male sex with severe orthostatic hypotension (OR 5.5; p = 0.016). In addition, at last follow-up, female sex was associated with the intake of central nervous system-active drugs (OR 4.1; p = 0.029), whereas male sex was associated with the presence of supine hypertension (OR 3.0; p = 0.020) and the intake of antihypertensive medications (OR 8.7; p = 0.001). Male sex was also associated with initiation of antihypertensive medications over the observation period (OR 12.4; p = 0.004). CONCLUSION: The available literature and findings of the present study indicate sex-related differences in the clinical presentation of MSA and its evolution over time, highlighting the importance of considering sex in symptom exploration, therapeutic decision-making, and future clinical trial design.

The Emergence and Progression of Motor Dysfunction in Individuals at Risk of Parkinson's Disease.

BACKGROUND: PREDICT-PD is a United Kingdom population-based study aiming to stratify individuals for future Parkinson's disease (PD) using a risk algorithm. METHODS: A randomly selected, representative sample of participants in PREDICT-PD were examined using several motor assessments, including the motor section of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III, at baseline (2012) and after an average of 6 years of follow-up. We checked for new PD diagnoses in participants seen at baseline and examined the association between risk scores and incident sub-threshold parkinsonism, motor decline (increasing ≥5 points in MDS-UPDRS-III) and single motor domains in the MDS-UPDRS-III. We replicated analyses in two independent datasets (Bruneck and Parkinson's Progression Markers Initiative [PPMI]). RESULTS: After 6 years of follow-up, the PREDICT-PD higher-risk group (n = 33) had a greater motor decline compared with the lower-risk group (n = 95) (30% vs. 12.5%, P = 0.031). Two participants (both considered higher risk at baseline) were given a diagnosis of PD during follow-up, with motor signs emerging between 2 and 5 years before diagnosis. A meta-analysis of data from PREDICT-PD, Bruneck, and PPMI showed an association between PD risk estimates and incident sub-threshold parkinsonism (odds ratio [OR], 2.01 [95% confidence interval (CI), 1.55-2.61]), as well as new onset bradykinesia (OR, 1.69 [95% CI, 1.33-2.16]) and action tremor (OR, 1.61 [95% CI, 1.30-1.98]). CONCLUSIONS: Risk estimates using the PREDICT-PD algorithm were associated with the occurrence of sub-threshold parkinsonism, including bradykinesia and action tremor. The algorithm could also identify individuals whose motor examination experience a decline over time. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Symptomatic Care in Multiple System Atrophy: State of the Art.

Without any disease-modifying treatment strategy for multiple system atrophy (MSA), the therapeutic management of MSA patients focuses on a multidisciplinary strategy of symptom control. In the present review, we will focus on state of the art treatment in MSA and additionally give a short overview about ongoing randomized controlled trials in this field.

Comparison of different risk scores for Parkinson disease in a population-based 10-year study.

BACKGROUND AND PURPOSE: Different algorithms aiming to identify individuals at risk of Parkinson disease (PD) have been proposed. Comparative studies of these scores and their recent updates in the general elder population are needed. METHODS: We have previously applied the "basic" PREDICT-PD algorithm, designed for remote screening, and the original and updated Movement Disorder Society (MDS) criteria for prodromal PD to the longitudinal population-based Bruneck study cohort. We have now additionally employed the "enhanced" PREDICT-PD algorithm (which includes motor assessment, olfaction, probable rapid eye movement sleep behaviour disorder status, pesticide exposure, and diabetes as additional factors). Risk scores were calculated based on comprehensive baseline assessments (2005) in 574 subjects aged 55-94 years (290 females), and cases of incident PD were identified at 5-year (n = 11) and 10-year follow-up (n = 9). We analysed the association of the different log-transformed risk scores with incident PD at follow-up (calculated per 1-SD unit change). RESULTS: The enhanced PREDICT-PD algorithm was associated with incident PD over 10-years of follow-up, yielding higher odds for incident PD (odds ratio [OR] = 4.61, 95% confidence interval [CI] = 2.68-7.93, p < 0.001) compared with the basic PREDICT-PD score (OR = 2.38, 95% CI = 1.49-3.79, p < 0.001). The updated MDS prodromal criteria yielded a numerically higher OR of 7.13 (95% CI = 3.49-14.54, p < 0.001) in comparison with the original criteria as well as the enhanced PREDICT-PD algorithm, with overlapping 95% CIs. CONCLUSIONS: The enhanced PREDICT-PD algorithm was significantly associated with incident PD. The consistent performance of both the enhanced PREDICT-PD algorithm and the updated MDS prodromal criteria compared to their original versions supports their use in PD risk screening.

Distinct smell and taste disorder phenotype of post-acute COVID-19 sequelae.

PURPOSE: Olfactory dysfunction (OD) commonly accompanies coronavirus disease 2019 (COVID-19). We investigated the kinetics of OD resolution following SARS-CoV-2 infection (wild-type and alpha variant) and its impact on quality of life, physical and mental health. METHODS: OD prevalence was assessed in an ambulatory COVID-19 survey (n = 906, ≥ 90 days follow-up) and an observational cohort of ambulatory and hospitalized individuals (n = 108, 360 days follow-up). Co-occurrence of OD with other symptoms and effects on quality of life, physical and mental health were analyzed by multi-dimensional scaling, association rule mining and semi-supervised clustering. RESULTS: Both in the ambulatory COVID-19 survey study (72%) and the observational ambulatory and hospitalized cohort (41%) self-reported OD was frequent during acute COVID-19. Recovery from self-reported OD was slow (survey: median 28 days, observational cohort: 90 days). By clustering of the survey data, we identified a predominantly young, female, comorbidity-free group of convalescents with persistent OD and taste disorders (median recovery: 90 days) but low frequency of post-acute fatigue, respiratory or neurocognitive symptoms. This smell and taste disorder cluster was characterized by a high rating of physical performance, mental health, and quality of life as compared with convalescents affected by prolonged fatigue or neurocognitive complaints. CONCLUSION: Our results underline the heterogeneity of post-acute COVID-19 sequelae calling for tailored management strategies. The persistent smell and taste disorder phenotype is characterized by good clinical, physical, and mental recovery and may pose a minor challenge for public health. STUDY REGISTRATION: ClinicalTrials.gov: NCT04661462 (survey study), NCT04416100 (observational cohort).

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

OBJECTIVE: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD). METHODS: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. RESULTS: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. INTERPRETATION: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.

Sensitivity to Change and Patient-Centricity of the Unified Multiple System Atrophy Rating Scale Items: A Data-Driven Analysis.

BACKGROUND: The Unified Multiple System Atrophy Rating Scale (UMSARS) is a commonly used semiquantitative rating scale to assess symptoms and measure disease progression in multiple system atrophy (MSA). However, it is currently incompletely understood which UMSARS items are the most sensitive to change and most relevant to the patient. OBJECTIVE: The objective of this study was to assess sensitivity to change and patient-centricity of single UMSARS items. METHODS: Data were taken from the European Multiple System Atrophy Study Group Natural History Study and the Rasagiline for Multiple System Atrophy trial. Sensitivity of change of an item of the UMSARS was assessed by calculation of a sensitivity-to-change ratio using its mean slope of progression divided by the standard deviation of the slope when modeling its progression over time. Patient-centricity was assessed through correlation of UMSARS items with quality-of-life measures. RESULTS: Progression rates above the mean in at least one of the two studies examined here were seen for seven items of UMSARS I and 11 items of UMSARS II. These items related to key motor functions such as swallowing, speech, handwriting, cutting food, hygiene, and dressing or walking, whereas items related to autonomic dysfunction were generally less sensitive to change in either data set. More UMSARS I items were identified as patient-centric compared with UMSARS II items, and items most strongly impacting patients' quality of life were those affecting verbal communication skills, personal hygiene, and walking. CONCLUSION: The present results illustrate the potential to optimize the UMSARS to enhance sensitivity to change and patient centricity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Disease Progression in Multiple System Atrophy-Novel Modeling Framework and Predictive Factors.

BACKGROUND: Multiple system atrophy (MSA) is a rare and aggressive neurodegenerative disease that typically leads to death 6 to 10 years after symptom onset. The rapid evolution renders it crucial to understand the general disease progression and factors affecting the disease course. OBJECTIVES: The aims of this study were to develop a novel disease-progression model to estimate a population-level MSA progression trajectory and predict patient-specific continuous disease stages describing the degree of progress into the disease. METHODS: The disease-progression model estimated a population-level progression trajectory of subscales of the Unified MSA Rating Scale and the Unified Parkinson's Disease Rating Scale using patients in the European MSA natural history study. The predicted disease continuum was validated via multiple analyses based on reported anchor points, and the effect of MSA subtype on the rate of disease progression was evaluated. RESULTS: The predicted disease continuum spanned approximately 6 years, with an estimated average duration of 51 months for a patient with global disability score 0 to reach the highest level of 4. The predicted continuous disease stages were shown to be correlated with time of symptom onset and predictive of survival time. MSA motor subtype was found to significantly affect disease progression, with MSA-parkinsonian (MSA-P) type patients having an accelerated rate of progression. CONCLUSIONS: The proposed modeling framework introduces a new method of analyzing and interpreting the progression of MSA. It can provide new insights and opportunities for investigating covariate effects on the rate of progression and provide well-founded predictions of patient-level future progressions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

European Academy of Neurology/Movement Disorder Society-European Section Guideline on the Treatment of Parkinson's Disease: I. Invasive Therapies.

BACKGROUND AND PURPOSE: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist should know the therapies and their place in the treatment pathway. METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered. RESULTS: Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended. CONCLUSIONS: Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [11 C]PBR28 and Machine Learning Analysis.

BACKGROUND: The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. OBJECTIVE: In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA. METHODS: We analyzed [11 C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. RESULTS: We observed a conspicuous pattern of elevated regional [11 C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. CONCLUSIONS: We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy.

BACKGROUND: The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. OBJECTIVE: To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology. METHODS: We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. RESULTS: The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. CONCLUSIONS: This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Development and Validation of Automated Magnetic Resonance Parkinsonism Index 2.0 to Distinguish Progressive Supranuclear Palsy-Parkinsonism From Parkinson's Disease.

BACKGROUND: Differentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging. OBJECTIVE: This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts. METHODS: We enrolled 676 participants: a training cohort (n = 346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n = 330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves. RESULTS: The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC] = 0.93 [95% confidence interval, 0.89-0.98] and AUC = 0.97 [0.93-1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC = 0.92 [0.87-0.97]; PSP-P versus controls, AUC = 0.94 [0.90-0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC = 0.91 [0.84-0.97]). A strong correlation (r = 0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. CONCLUSIONS: Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Factors associated with augmentation in patients with restless legs syndrome.

BACKGROUND AND PURPOSE: Augmentation is a paradoxical reaction mainly to dopaminergic medication in patients with restless legs syndrome (RLS), but the exact pathomechanism remains unclear. The aim of this study was to identify factors associated with augmentation in RLS patients. METHODS: RLS patients with and without current or previous augmentation were recruited. Demographic characteristics, history of smoking, questionnaires for depression, alexithymia, and impulsivity, and RLS severity were obtained. RESULTS: We included 122 patients, of whom half had a history of augmentation. Patients with augmentation had a longer disease duration (p = 0.001), had higher RLS severity scores (p = 0.013), had higher levodopa equivalent doses (p < 0.001), had higher scores for alexithymia (p = 0.028), had higher prevalence of impulse control disorders (p < 0.001), more often had a history of smoking (p = 0.039), were more often currently smoking (p = 0.015), and had more average pack-years (p = 0.016). CONCLUSIONS: Here, we describe several factors commonly associated with augmentation in RLS. These may help clinicians to screen and treat patients carefully to avoid the challenging side effect of augmentation.

European Academy of Neurology/Movement Disorder Society - European Section guideline on the treatment of Parkinson's disease: I. Invasive therapies.

BACKGROUND AND PURPOSE: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway. METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered. RESULTS: Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended. CONCLUSIONS: Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups.

Neurological outcomes 1 year after COVID-19 diagnosis: A prospective longitudinal cohort study.

BACKGROUND AND PURPOSE: Neurological sequelae from coronavirus disease 2019 (COVID-19) may persist after recovery from acute infection. Here, the aim was to describe the natural history of neurological manifestations over 1 year after COVID-19. METHODS: A prospective, multicentre, longitudinal cohort study in COVID-19 survivors was performed. At a 3-month and 1-year follow-up, patients were assessed for neurological impairments by a neurological examination and a standardized test battery including the assessment of hyposmia (16-item Sniffin' Sticks test), cognitive deficits (Montreal Cognitive Assessment < 26) and mental health (Hospital Anxiety and Depression Scale and Post-traumatic Stress Disorder Checklist 5). RESULTS: Eighty-one patients were evaluated 1 year after COVID-19, out of which 76 (94%) patients completed a 3-month and 1-year follow-up. Patients were 54 (47-64) years old and 59% were male. New and persistent neurological disorders were found in 15% (3 months) and 12% (10/81; 1 year). Symptoms at 1-year follow-up were reported by 48/81 (59%) patients, including fatigue (38%), concentration difficulties (25%), forgetfulness (25%), sleep disturbances (22%), myalgia (17%), limb weakness (17%), headache (16%), impaired sensation (16%) and hyposmia (15%). Neurological examination revealed findings in 52/81 (64%) patients without improvement over time (3 months, 61%, p = 0.230) including objective hyposmia (Sniffin' Sticks test <13; 51%). Cognitive deficits were apparent in 18%, whereas signs of depression, anxiety and post-traumatic stress disorders were found in 6%, 29% and 10% respectively 1 year after infection. These mental and cognitive disorders had not improved after the 3-month follow-up (all p > 0.05). CONCLUSION: Our data indicate that a significant patient number still suffer from neurological sequelae including neuropsychiatric symptoms 1 year after COVID-19 calling for interdisciplinary management of these patients.

Intercountry comparisons of advanced Parkinson's disease symptoms and management: Analysis from the OBSERVE-PD observational study.

OBJECTIVES: In the absence of widely accepted criteria, determining when a patient with Parkinson's disease (PD) may benefit from more advanced treatments such as device-aided therapy (DAT) so far remains a matter of physician judgment. This analysis investigates how classification of PD varies across countries relative to measures of disease severity. MATERIALS AND METHODS: The OBSERVational, cross-sEctional PD (OBSERVE-PD) study included consecutive patients with PD at centers that offer DATs in 18 countries. In this subgroup analysis, we explore intercountry differences in identification of advanced versus non-advanced PD based on physician's clinical judgment, symptoms assessed using Delphi consensus criteria, use of DAT, motor and non-motor symptoms, and caregiver support. Demographic and clinical characteristics were obtained through review of medical records. RESULTS: Overall, 1342 of 2615 patients (51.3%) were assessed by physicians as having advanced PD. The proportion of patients in different countries identified as having advanced PD (24.4-82.2%) varied. In 15 of 18 countries, a greater proportion of patients with advanced PD, according to select Delphi criteria, were identified by physicians as having advanced PD than with non-advanced PD. There was a wide variability across countries in the proportion of patients with no dyskinesia, disabling dyskinesia, dyskinesia pain, and non-motor symptoms who were identified by physicians as having advanced versus non-advanced PD. CONCLUSIONS: The proportion of patients identified with advanced PD symptoms varies widely across countries, despite differences on the patients' profiles, indicating a need for objective diagnostic criteria to help identify patients who may benefit from DAT.

Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.