Targeting alpha-synuclein or tau for treating neurodegenerative movement disorders.

The two commonest groups of neurodegenerative disorders causing movement disorders are synucleinopathies and tauopathies. These disorders are characterised by the accumulation of abnormally misfolded forms of α-synuclein and tau proteins. Our current understanding of their pathogenesis suggests that extracellular forms of these proteins are of major relevance to the mechanism of pathology propagation throughout the brain and disease progression. The most novel approaches to find disease-modifying therapies aim to reduce or block these forms of tau and α-synuclein. This article reviews therapeutic strategies targeting α-synuclein and tau protein which have entered clinical development.

The late stage of Parkinson's -results of a large multinational study on motor and non-motor complications.

INTRODUCTION: There is little information on the late stages of parkinsonism. METHODS: We conducted a multicentre study in 692 patients with late stage parkinsonism in six European countries. Inclusion criteria were disease duration of ≥7 years and either Hoehn and Yahr stage ≥4 or Schwab and England score of 50 or less. RESULTS: Average disease duration was 15.4 (SD 7.7) years and mean total UPDRS score was 82.7 (SD 22.4). Dementia according to MDS-criteria was present in 37% of patients. Mean levodopa equivalence dose was 874.1 (SD 591.1) mg/d. Eighty two percent of patients reported falls, related to freezing (16%) or unrelated to freezing (21% of patients) or occurring both related and unrelated to freezing (45%), and were frequent in 26%. Moderate-severe difficulties were reported for turning in bed by 51%, speech by 43%, swallowing by 16% and tremor by 11%. Off-periods occurred in 68% and were present at least 50% of the day in 13%, with morning dystonia occurring in 35%. Dyskinesias were reported by 45% but were moderate or severe only in 7%. Moderate-severe fatigue, constipation, urinary symptoms and nocturia, concentration and memory problems were encountered by more than half of participants. Hallucinations (44%) or delusions (25%) were present in 63% and were moderate-severe in 15%. The association with overall disability was strongest for severity of falls/postural instability, bradykinesia, cognitive score and speech impairment. CONCLUSION: These data suggest that current treatment of late stage parkinsonism in the community remains insufficiently effective to alleviate disabling symptoms in many patients.

Management of rare movement disorders in Europe: outcome of surveys of the European Reference Network for Rare Neurological Diseases.

BACKGROUND AND PURPOSE: The diagnosis of rare movement disorders is difficult and specific management programmes are not well defined. Thus, in order to capture and assess care needs, the European Reference Network for Rare Neurological Diseases has performed an explorative care need survey across all European Union (EU) countries. METHODS: This is a multicentre, cross-sectional study. A survey about the management of different rare movement disorders (group 1, dystonia, paroxysmal dyskinesia and neurodegeneration with brain iron accumulation; group 2, ataxias and hereditary spastic paraparesis; group 3, atypical parkinsonism; group 4, choreas) was sent to an expert in each group of disorders from each EU country. RESULTS: Some EU countries claimed for an increase of teaching courses. Genetic testing was not readily available in a significant number of countries. Regarding management, patients' accessibility to tertiary hospitals, to experts and to multidisciplinary teams was unequal between countries and groups of diseases. The availability of therapeutic options, such as botulinum toxin or more invasive treatments like deep brain stimulation, was limited in some countries. CONCLUSIONS: The management of these conditions in EU countries is unequal. The survey provides evidence that a European care-focused network that is able to address the unmet rare neurological disease care needs and inequalities is highly warranted.

A totally data-driven whole-brain multimodal pipeline for the discrimination of Parkinson's disease, multiple system atrophy and healthy control.

Parkinson's Disease (PD) and Multiple System Atrophy (MSA) are two parkinsonian syndromes that share many symptoms, albeit having very different prognosis. Although previous studies have proposed multimodal MRI protocols combined with multivariate analysis to discriminate between these two populations and healthy controls, studies combining all MRI indexes relevant for these disorders (i.e. grey matter volume, fractional anisotropy, mean diffusivity, iron deposition, brain activity at rest and brain connectivity) with a completely data-driven voxelwise analysis for discrimination are still lacking. In this study, we used such a complete MRI protocol and adapted a fully-data driven analysis pipeline to discriminate between these populations and a healthy controls (HC) group. The pipeline combined several feature selection and reduction steps to obtain interpretable models with a low number of discriminant features that can shed light onto the brain pathology of PD and MSA. Using this pipeline, we could discriminate between PD and HC (best accuracy = 0.78), MSA and HC (best accuracy = 0.94) and PD and MSA (best accuracy = 0.88). Moreover, we showed that indexes derived from resting-state fMRI alone could discriminate between PD and HC, while mean diffusivity in the cerebellum and the putamen alone could discriminate between MSA and HC. On the other hand, a more diverse set of indexes derived by multiple modalities was needed to discriminate between the two disorders. We showed that our pipeline was able to discriminate between distinct pathological populations while delivering sparse model that could be used to better understand the neural underpinning of the pathologies.

Factors associated with spousal burden in Parkinson's disease.

Parkinson's disease is characterized by motor and non-motor symptoms, which can lead to progressive disability that, in turn, can lead to a burden on caregivers. Thus, the objective of this study was to determine correlations between intensity of disease burden and characteristics of patients and their spouses. The study included 38couples (patients and spouses) living at home with no severe comorbidities. The following patients' characteristics were measured: disease severity (MDS-UPDRS); cognitive status (MoCA); non-motor signs (NMSS); quality of life (PDQ-8); anxiety and depression (HADS); and levodopa equivalent dose. The Zarit Burden Interview, quality of life questionnaire (EQ-5D-VAS) and HADS were administered to spouses. The average caregiver burden score was 14.4±12.7, and correlated (in descending order) with severity of non-motor signs (R2=0.46, P<0.0001), anxiety and depression in caregivers and patients (R2=0.35, P<0.0001 and R2=0.26, P<0.0001, respectively), motor severity (R2=0.3, P<0.0001), patients' quality of life (R2=0.27, P=0.0125), levodopa equivalent dose (R2=0.13, P=0.0261) and duration of illness (R2=0.12, P=0.0307). The severity of non-motor signs, patients' and caregivers' mood, and motor disease severity are the main determinants of caregiver burden, making them important targets in the management of Parkinson's disease.

L-DOPA-induced dyskinesias, motor fluctuations and health-related quality of life: the COPARK survey.

BACKGROUND AND PURPOSE: Studies assessing the correlations between L-DOPA-induced dyskinesias (LIDs) and motor fluctuations with health-related quality of life (HRQoL) in Parkinson's disease (PD) have yielded conflicting results. This study aimed to assess the relationship between LIDs and motor fluctuations with HRQoL in patients with PD, and to assess the relative contribution of their severity and duration in a large sample of patients with PD. METHODS: A total of 683 patients with PD from the COPARK survey were evaluated. HRQoL was assessed using the 39-Item Parkinson's Disease Questionnaire (PDQ-39) (primary outcome) and 36-Item Short Form Survey (SF-36). The daily duration and severity of LIDs were obtained from Unified Parkinson's Disease Rating Scale (UPDRS) IV items 32 and 33, respectively. The daily duration of motor fluctuations was obtained from UPDRS IV item 36 and severity was estimated as the difference between the UPDRS 2 (Activities of Daily Living) score in 'OFF' versus 'ON' condition. RESULTS: A total of 235 patients with PD (35%) experienced motor fluctuations and 182 (27%) experienced LIDs. The PDQ-39 total and SF-36 physical scores were significantly worse in patients with LIDs, after adjusting for the presence of motor fluctuations. The PDQ-39 total score and SF-36 physical and mental score were significantly worse in patients with motor fluctuations, after adjusting for the presence of LIDs. The severity of LIDs and the duration of motor fluctuations significantly and independently affected PDQ-39 scores. The SF-36 physical score was affected only by the severity of motor fluctuations, whereas the mental score was not affected by any of the aforementioned variables. CONCLUSION: Our findings suggest that LIDs (mainly their severity) and motor fluctuations (mainly their duration) correlate independently with HRQoL in patients with PD.

New insights into orthostatic hypotension in multiple system atrophy: a European multicentre cohort study.

OBJECTIVES: Orthostatic hypotension (OH) is a key feature of multiple system atrophy (MSA), a fatal progressive neurodegenerative disorder associated with autonomic failure, parkinsonism and ataxia. This study aims (1) to determine the clinical spectrum of OH in a large European cohort of patients with MSA and (2) to investigate whether a prolonged postural challenge increases the sensitivity to detect OH in MSA. METHODS: Assessment of OH during a 10 min orthostatic test in 349 patients with MSA from seven centres of the European MSA-Study Group (age: 63.6 ± 8.8 years; disease duration: 4.2 ± 2.6 years). Assessment of a possible relationship between OH and MSA subtype (P with predominant parkinsonism or C with predominant cerebellar ataxia), Unified MSA Rating Scale (UMSARS) scores and drug intake. RESULTS: 187 patients (54%) had moderate (> 20 mm Hg (systolic blood pressure (SBP)) and/or > 10 mm Hg (diastolic blood pressure (DBP)) or severe OH (> 30 mm Hg (SBP) and/or > 15 mm Hg (DBP)) within 3 min and 250 patients (72%) within 10 min. OH magnitude was significantly associated with disease severity (UMSARS I, II and IV), orthostatic symptoms (UMSARS I) and supine hypertension. OH severity was not associated with MSA subtype. Drug intake did not differ according to OH magnitude except for antihypertensive drugs being less frequently, and antihypotensive drugs more frequently, prescribed in severe OH. CONCLUSIONS: This is the largest study of OH in patients with MSA. Our data suggest that the sensitivity to pick up OH increases substantially by a prolonged 10 min orthostatic challenge. These results will help to improve OH management and the design of future clinical trials.

Age-related motor dysfunction and neuropathology in a transgenic mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a progressive degeneration of the striatonigral, olivo-ponto-cerebellar, and autonomic systems. Glial cytoplasmic inclusions (GCIs) containing alpha-synuclein represent the hallmark of MSA and are recapitulated in mice expressing alpha-synuclein in oligodendrocytes. To assess if oligodendroglial expression of human wild-type alpha-synuclein in mice (proteolipid promoter, PLP-SYN) could be associated with age-related deficits, PLP-SYN and wild-type mice were assessed for motor function, brain morphometry, striatal levels of dopamine and metabolites, dopaminergic loss, and distribution of GCIs. PLP-SYN displayed age-related impairments on a beam-traversing task. MRI revealed a significantly smaller brain volume in PLP-SYN mice at 12 months, which further decreased at 18 months together with increased volume of ventricles and cortical atrophy. The distribution of GCIs was reminiscent of MSA with a high burden in the basal ganglia. Mild dopaminergic cell loss was associated with decreased dopamine turnover at 18 months. These data indicate that PLP-SYN mice may recapitulate some of the progressive features of MSA and deliver endpoints for the evaluation of therapeutic strategies.

Validation of the French version of the MSA health-related Quality of Life scale (MSA-QoL).

INTRODUCTION: Multiple system atrophy (MSA) has considerable impact on health-related quality of life. The MSA health-related Quality of Life scale (MSA-QoL) is a patient-reported questionnaire, which has been recently designed to evaluate the quality of life in MSA. The objective of the present study was to validate the French version of the MSA-QoL questionnaire. METHODS: One hundred and thirty-six consecutive MSA patients were included in the study. Four patients with more than 10% missing responses were excluded from the final analysis. Data quality, scaling assumptions, acceptability, reliability and validity were assessed similar to the original validation of the English version. RESULTS: Missing responses were low, item and subscale scores were evenly distributed and floor and ceiling effects were negligible. Item-total correlations were higher than the recommended greater than 0.30 and internal consistency was high for all subscales. Test-retest reliability was good for all subscales. Validity was supported by moderate interscale correlations between the subscales and the predicted correlations with other scales assessing motor disability, activities of daily living, quality of life and mood. DISCUSSION: The French version of the MSA-QoL displays robust psychometric properties similar to the English version. CONCLUSION: The French version of MSA-QoL seems suitable for assessing quality of life in French speaking MSA patients.

When does Parkinson's disease begin? From prodromal disease to motor signs.

Cardinal motor features of Parkinson's disease (PD) appear when about half of the nigral dopamine neurons have disappeared. Based on extrapolations from post-mortem and imaging studies, the delay between the onset of dopamine denervation and the appearance of motor signs ranges from 5 to 20years. According to Braak and co-workers, motor symptoms only appear at stage III of PD, while the neurodegenerative process begins earlier in the olfactory bulb and lower brain stem. In addition to the cardinal motor features, non-motor signs are increasingly being recognized in PD. Some of them, mainly olfactory disturbances, rapid-eye-movement sleep behaviour disorder and autonomic dysfunction, are already present in the early disease stages and may precede the onset of motor signs by up to four decades. These non-motor signs are related to widespread extranigral and even extracerebral degeneration, and have been considered risk factors for many years. Indeed, recent evidence suggests that they may be prodromal manifestations of PD. From the perspective of future disease-modifying or neuroprotective treatments, combining prodromal non-motor signs and paraclinical investigations may help to further develop reliable tools for early diagnosis of PD before the onset of its cardinal motor features.