The pattern of cortical thickness associated with executive dysfunction in MCI and SCC: The MEMENTO cohort.

BACKGROUND: The association between the pattern of cortical thickness (CT) and executive dysfunction (ED) in mild cognitive impairment (MCI) and subjective cognitive complaints (SCC) is still poorly understood. We aimed to investigate the association between CT and ED in a large French cohort (MEMENTO) of 2323 participants with MCI or SCC. METHODS: All participants with available CT and executive function data (verbal fluency and Trail Making Test [TMT]) were selected (n=1924). Linear regressions were performed to determine relationships between executive performance and the brain parenchymal fraction (BPF) and CT using FreeSurfer. RESULTS: The global executive function score was related to the BPF (sß: 0.091, P<0.001) and CT in the right supramarginal (sß: 0.060, P=0.041) and right isthmus cingulate (sß: 0.062, P=0.011) regions. Literal verbal fluency was related to the BPF (sß: 0.125, P<0.001) and CT in the left parsorbitalis region (sß: 0.045, P=0.045). Semantic verbal fluency was related to the BPF (sß: 0.101, P<0.001) and CT in the right supramarginal region (sß: 0.061, P=0.042). The time difference between the TMT parts B and A was related to the BPF (sß: 0.048, P=0.045) and CT in the right precuneus (sß: 0.073, P=0.019) and right isthmus cingulate region (sß: 0.054, P=0.032). CONCLUSIONS: In a large clinically based cohort of participants presenting with either MCI or SCC (a potential early stage of Alzheimer's disease [AD]), ED was related to the BPF and CT in the left pars orbitalis, right precuneus, right supramarginal, and right isthmus cingulate regions. This pattern of lesions adds knowledge to the conventional anatomy of ED and could contribute to the early diagnosis of AD.

Mindfulness in Parkinson's disease: A French national survey and a pilot intervention feasibility trial using the MBSR program (M-Park).

BACKGROUND: Non-pharmacological complementary interventions, particularly mind-body practices, are of growing importance in the management of Parkinson's disease (PD). Among these, mindfulness meditation seems particularly effective, especially on anxiety and depression symptoms. However, current knowledge on mindfulness standardized programs in PD is still limited, particularly in France. Aiming at improving this knowledge we designed the M-PARK study in two phases. Phase 1 consisted in a French national survey to explore expectations, needs and initiatives for mindfulness meditation for PD patients. Phase 2 was a clinical trial with objectives to assess feasibility, acceptability and effects of a mindfulness (MBSR) program proposed to PD patients. METHODS: In phase 1, online questionnaires were addressed to members of a French PD patient's association (France Parkinson) and French MBSR qualified instructors. In Phase 2, a clinical trial involving 30 PD patients consisted of a standard MBSR program with two additional evaluation visits one month before and after the program. Data collection included a global clinical evaluation, assessment of depression and anxiety symptoms, sleep, pain and quality of life and a face-to-face interview for qualitative assessment of the acceptability and lived experience during the program. Three MBSR programs were proposed to three groups of ten patients: two were online due to the pandemic situation, one proposed to patients with no or minor fluctuations (group 1) and one for patients with slight to moderate fluctuations (group 2), and the last one face-to-face for patients with no or minor fluctuations (group 3). RESULTS: French survey: 209 responses were collected for the questionnaire sent to the members of the association France Parkinson; and 68 for the questionnaire sent to the instructors. Two-thirds of patients surveyed had heard of mindfulness meditation (66%), but were unaware of what this approach really consisted and how it could really help them. Few instructors (29%) had had to deal with patients with PD in their current practice. Yet 90% of patients surveyed indicated they were in favor of introducing this type of approach into their care. CLINICAL TRIAL: The results indicated that the program is feasible and acceptable both online and face-to-face for patients with PD. Among the 30 patients enrolled, 25 completed the program. No unwanted effects related to mindfulness meditation practice were observed. The results showed a statistically significant reduction in anxiety symptoms, depressive symptoms, and improvement in quality of life. Furthermore, no statistically significant change was measured for pain or sleep quality. There was no striking difference in results observed between the patient groups. For the qualitative analysis, major themes highlighted were in relation with: (i) the lived experience during program; (ii) changes in the daily life; and (iii) disease-related changes. A large majority of patients who completed the program (24/25) described their participation as positive or very positive. They reported better management of stress and emotions, as well as greater autonomy in implementing new behavioral strategies, particularly in terms of self-care, acceptance, and de-identification from the disease. CONCLUSION: Despite high expectations, PD patients are poorly informed about available mindfulness programs. This study however shows that these programs, whether offered online or face-to-face, are particularly beneficial, especially for anxiety and depressive symptoms, at least in mild-to-moderate stages of the 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.

French consensus procedure for assessing cognitive function in Parkinson's disease.

INTRODUCTION: One of the objectives of the French expert centers for Parkinson's disease (NS-Park) network was to determine a consensus procedure for assessing cognitive function in patients with Parkinson's. This article presents this procedure and briefly describes the selected tests. METHODS: A group of 13 experts used the Delphi method for consensus building to define the overall structure and components of the assessment procedure. For inclusion in the battery, tests had to be validated in the French language, require little motor participation, have normative data and be recognized by the international community. Experimental tasks and tests requiring specific devices were excluded. RESULTS: Two possibilities were identified, depending on whether an abbreviated or comprehensive assessment of cognitive function was necessary. For an abbreviated assessment, the experts recommended the Montreal Cognitive Assessment (MoCA) as a screening test for cognitive impairment or dementia. For a comprehensive neuropsychological assessment, the experts recommended assessing global efficiency plus the five main cognitive domains (attention and working memory, executive function, episodic memory, visuospatial function and language) that may be impaired in Parkinson's disease, using two tests for each domain. DISCUSSION AND CONCLUSION: A common procedure for assessing cognitive function is now available across the French network dedicated to Parkinson's disease, and is recommended for both research and clinical practice. It will also help to promote standardization of the neuropsychological assessment of Parkinson's disease.

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.

Oro-buccal symptoms (dysphagia, dysarthria, and sialorrhea) in patients with Parkinson's disease: preliminary analysis from the French COPARK cohort.

INTRODUCTION: Abnormal oro-buccal functions including dysarthria, sialorrhea and dysphagia commonly affect patients with Parkinson's disease (PD). OBJECTIVES: To estimate the prevalence of such oro-buccal symptoms at baseline in the first 419 patients with PD included in the COPARK cohort and to analyze their correlations with patients' demographics, clinical characteristics, and drugs consumption. METHODS: Patients were assessed using the Unified PD Rating Scale, the Hospital Anxiety and Depression Scale, and the PDQ-39. Dysarthria, sialorrhea, and dysphagia were defined as UPDRS items 5, 6, or 7 ≥ 1. RESULTS: Dysarthria, sialorrhea, or dysphagia were present in 51%, 37%, or 18% out of the 419 patients, respectively. At least one of these symptom was present in 267/419 patients (65%), whilst a combination of symptoms was present in 136/419 (33%). Logistic regression showed that the presence of each of the three oro-buccal symptoms was significantly correlated with that of the two others. Other correlations included male gender, hallucinations, disease severity, levodopa use and lack of opiates consumption for dysarthria; disease severity, orthostatic hypotension and absence of antidepressants consumption for sialorrhea; female gender, motor fluctuations, and depressive symptoms for dysphagia. None of the three oro-buccal symptoms were associated with a reduced PDQ-39 score. CONCLUSION: Oro-buccal symptoms were present in two of three patients with moderate PD, the presence of each symptoms being significantly correlated with that of the two others.

Animal models of multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disorder clinically characterized by a variable combination of dysautonomia, levodopa-unresponsive parkinsonian and cerebellar symptoms. Neurodegeneration in MSA occurs in the substantia nigra, putamen, inferior olive, pontine and brainstem nuclei, as well as intermediolateral cell column of the spinal cord. MSA is recognized as a synucleinopathy due to the accumulation of insoluble alpha-synuclein in oligodendroglial cytoplasmic inclusions. Several animal models have been developed in order to reproduce various clinical and pathological features of MSA. Using "double toxin-double lesion" or "single toxin-double lesion", neurotoxin-based models were designed in rats, mice and non-human primates to reproduce the neuropathology of MSA in the nigrostriatal system while gene-based models were developed in mice to reproduce the accumulation of insoluble alpha-synuclein in oligodendrocytes. Both approaches have then been merged to create optimized, dual-hit models. This review describes the different animal models of MSA, their respective advantages and limitations and their usefulness to decipher the pathophysiology of MSA then to define efficient symptomatic and disease-modifying therapies. This article is part of a Special Issue entitled: Neuroscience Disease Models.

A long-term follow-up of weight changes in subthalamic nucleus stimulated Parkinson's disease patients.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) constitutes the mainstay treatment in advanced Parkinson's disease (PD) with motor fluctuations. Despite its efficacy on motor signs and quality of life, emergent adverse events have been recently reported. Among them, weight gain (WG) is a recognized adverse event of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). Also, WG is poorly known at the long-term and predisposing factors have not yet been identified. We conducted a cross-sectional study of WG in 47 STN-DBS PD patients between 1999-2006. Data on disease history, motor status and dopaminergic drug treatment were retrospectively collected at surgery and 1 year post-surgery. Weight at disease diagnosis and at surgery, as well as the current weight and height were gathered by an autoquestionnaire. Moreover, the weight before surgery was obtained and verified in medical files in more than 90% of our patients. Sixty-six patients who underwent surgery between 1999-2006 were included, but six were deceased, four refused to participate and nine were lost for follow-up. So, 47 (71%) were retained in our analysis. A total of 78.7% of patients gained weight. On average 4.7 years follow up after surgery, the mean weight gain was +7.2±8.1kg compared to the preoperative assessment (p<0.001) and the mean BMI gain was +2.7±3.0kg/m(2) compared to pre-surgery values (p<0.001). The patients gained more weight after surgery than they had lost during disease evolution before surgery. Women and patients with a more severe UPDRS-III "off" drug score before surgery significantly gained more weight. Our study provides further evidence that the WG is a problem after STN-DBS and concerns a majority of patients at the long term. It may expose them to complications that should be considered for prevention and the patient's information before surgery.

["Red flags": when to be alerted and how to explore?]. / «Drapeaux rouges¼: quand s'alarmer, quel examens demander?

The diagnosis of Parkinson's disease (PD) requires ruling out other causes of parkinsonism. Among various "other" causes of parkinsonism, neurodegenerative causes or "atypical parkinsonism" are the most difficult to diagnose. Most common diseases are "synucleinopathies": multiple system atrophy and dementia with Lewy bodies and "tauopathies": progressive supranuclear palsy and corticobasal degeneration. Unexpected or atypical signs and symptoms for PD, also called "red flags" along with absent or poor or short-lived levodopa response may be a clue for the diagnosis. Some tests may also support the diagnosis, among them, structural (MRI) and functional brain imaging, autonomic function tests and urodynamics, oculographic recordings and neuropsychological work-up, are the most useful.

Motor activation in multiple system atrophy and Parkinson disease: a PET study.

BACKGROUND: Multiple system atrophy (MSA) is an atypical parkinsonian syndrome including cerebellar impairment and poor response to levodopa. We assessed right hand motor activation in patients with MSA before and after an acute levodopa challenge in comparison with patients with PD and healthy volunteers (HVs). METHODS: Eighteen patients with MSA, 8 patients with PD, and 10 age-matched HVs were included. Regional cerebral blood flow measurements with H(2)(15)O PET were performed at rest and during a right hand movement. Statistical parametric mapping was used to analyze motor vs rest in OFF and ON conditions and the effect of levodopa on motor activation. RESULTS: Before levodopa, patients with MSA activated most known cerebral motor areas. Compared with HVs, patients with MSA exhibited less bilateral cerebellar activation and greater left superior parietal activation. They also had less bilateral cerebellar and greater supplementary motor and left superior parietal activation than patients with PD. Conversely, patients with PD had greater activation than HVs in the right cerebellum and less in the supplementary motor cortex. After levodopa, patients with MSA exhibited reduced activation in anterior cingulate, whereas patients with PD had greater activation in the right cerebellum. CONCLUSION: Patients with MSA and patients with PD recruited different motor networks. Patients with PD preferentially activated cerebellar pathways, possibly to compensate for basal ganglia dysfunction. This was not observed in patients with MSA, probably because of cerebellar dysfunction; other frontoparietal cortical areas were recruited.

A 15-year population-based cohort study of the incidence of Parkinson's disease and dementia with Lewy bodies in an elderly French cohort.

OBJECTIVE: To provide global and age-related incidence over 65 years of Parkinsonian syndromes (PS), Parkinson's disease (PD) and suspected dementia with Lewy bodies (DLB). METHODS: A 15-year prospective population-based elderly cohort study in South-Western France (PAQUID). RESULTS: Incidences found were: 557.7/100,000 person-years for PS, 263 per 100 000 person-years for PD and 112 per 100,000 person-years for suspected DLB. The incidence of all PS, PD and suspected DLB was greater in men. The age-specific incidence of PD decreased over 85, while that of DLB continuously increased, even in the oldest individuals. CONCLUSIONS: The authors provide new data on PD and suspected DLB incidence in a large population-based French cohort of subjects aged over 65 and followed up for 15 years. PD incidence decreased in the oldest old contrary to that of suspected DLB cases and Alzheimer's disease.

Molecular analyses of the LRRK2 gene in European and North African autosomal dominant Parkinson's disease.

BACKGROUND: Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (ADPD), the most common of which is the p.G2019S substitution that has been found at varying frequencies worldwide. Because of the size of the LRRK2 gene, few studies have analysed the entire gene in large series of ADPD families. METHODS: We performed extensive mutation analyses of all 51 coding exons of the LRRK2 gene in index cases from 226 Parkinson's disease families compatible with autosomal dominant inheritance, mostly from France (n = 182) and North Africa (n = 14). RESULTS: We found 79 sequence variants, 29 of which were novel. Eight potentially or proven pathogenic mutations were found in 22 probands (9.7%). There were four novel amino acid substitutions that are potentially pathogenic (p.S52F, p.N363S, p.I810V, p.R1325Q) and two novel variants, p.H1216R and p.T1410M, that are probably not causative. The common p.G2019S mutation was identified in 13 probands (5.8%) including six from North Africa (43%). The known heterozygous p.R1441H and p.I1371V mutations were found in two probands each, and the p.E334K variant was identified in one single patient. Most potentially or proven pathogenic mutations were located in the functional domains of the Lrrk2 protein. CONCLUSION: This study leads us to conclude that LRRK2 mutations are a common cause of autosomal dominant Parkinson's disease in Europe and North Africa.

[Epidemiology of restless legs syndrome]. / Epidémiologie du syndrome des jambes sans repos.

INTRODUCTION: Restless legs syndrome (RLS) is a chronic sensorimotor disorder where patients complain of an almost irresistible urge to move their legs. This urge can often be accompanied by pain or other unpleasant sensations, it either occurs or worsens with rest particularly at night, and improves with activity. The International Restless Legs Syndrome Study Group has established four essential criteria for clinical diagnosis of RLS. STATE OF ART: Affecting an estimated 7.2 to 11.5% of the adult population, the symptoms of RLS may be associated with significant sleep disturbance and may have a negative impact on quality of life. The prevalence of RLS increases with age, and women are more frequently affected than men. In France, the estimated prevalence is 8.5%. Among sufferers, 4.4% complain of very severe symptoms. Although RLS is mainly idiopathic, several clinical conditions have been associated with it, especially iron deficiency with or without anemia, end-stage renal disease and pregnancy. These conditions may share a common pathophysiological mechanism involving a disorder of iron metabolism. By contrast, controversy persists as to whether polyneuropathy, particularly when associated with diabetes, is to be considered as an important cause of secondary RLS. This association is difficult to demonstrate as conventional electromyography is not adequate to detect small fiber neuropathy often associated with diabetes. CONCLUSION AND PERSPECTIVES: RLS is often underdiagnosed and few subjects receive recommended RLS drug treatment. There is a clear need for complementary education to improve the accurate diagnosis of RLS. Indeed, better knowledge of this syndrome is a prerequisite to prompt an appropriate therapeutic management.

[Deep-brain stimulation of the internal pallidum in multiple system atrophy]. / Stimulation cérébrale profonde du pallidum interne dans l'atrophie multisystématisée.

INTRODUCTION: The experience with deep-brain stimulation (DBS) in multiple-system atrophy (MSA) is sparse and generally disappointing. DBS is currently not recommended in MSA and its use is often related to a misdiagnosis. OBSERVATION: We describe the outcome of bilateral DBS of the internal pallidum in a 46-year-old woman suffering from MSA that initially resembled Parkinson's disease with prominent levodopa-induced dyskinesias. DBS of the left internal pallidum was performed in 1998 after a ten-year clinical course and improved dyskinesias. Six months later, the right side was implanted. A few months after the second surgery, the patient progressively developed signs of cerebellar and dysautonomic impairment and MSA was diagnosed. CONCLUSION: Our observation confirms the ineffectiveness of DBS of the internal pallidum in MSA and even suggests a harmful effect. DBS remains contra-indicated in atypical parkinsonism.

Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls.

BACKGROUND: Mutations in the parkin gene cause autosomal recessive early-onset parkinsonism. The effect of single heterozygous mutations in parkin is still unclear. The aim of this study was to evaluate the frequency of exonic parkin variants in a case-control study. METHODS: The parkin gene was screened for both point mutations and exon rearrangements in 172 French patients with Parkinson disease (PD) and 170 controls from the same population. Patients with single parkin variants were also screened for PINK1, DJ-1 and LRRK2 exon 41 mutations. RESULTS: 10 exonic sequence variations were identified, including 3 known polymorphisms and 7 rare heterozygous variants, 2 of which were novel. There were significantly more rare heterozygous variants in patients (n = 10) with early-onset PD than in controls (n = 2). Screening of PINK1, DJ-1 and LRRK2 exon 41 in the 10 patients heterozygous for parkin failed to identify a second causative mutation. CONCLUSION: These results suggest that single parkin mutations increase the risk of early-onset PD, but the possibility of a second parkin mutation cannot be excluded.