Validation of a non-motor fluctuations questionnaire in Parkinson's disease.

INTRODUCTION: Non-motor fluctuations (NMF) in Parkinson's disease (PD) remain poorly recognized but have a high impact on patients' quality of life. The lack of assessment tools limits our understanding of NMF, compromising appropriate management. Our objective was to validate a hetero-questionnaire for NMF in PD patients at different stages of the disease: without treatment, without motor fluctuations, with motor fluctuations. METHODS: We included patients in 15 centers in France. Our questionnaire, NMF-Park, resulted from previous studies, allowing us to identify the more pertinent NMF for evaluation. Patients reported the presence (yes or no) of 22 selected NMF, and their link with dopaminergic medications. The assessment was repeated at one and two years to study the progression of NMF. We performed a metrological validation of our questionnaire. RESULTS: We included 255 patients (42 without treatment, 88 without motor fluctuations and 125 with motor fluctuations). After metrological validation, three dimensions of NMF were found: dysautonomic; cognitive; psychiatric. The sensory/pain dimension described in the literature was not statistically confirmed by our study. DISCUSSION: Our questionnaire was validated according to clinimetric standards, for different stages of PD. It was clinically coherent with three homogeneous dimensions. It highlighted a link between fatigue, visual accommodation disorder, and cognitive fluctuations; and the integration of sensory/pain fluctuations as part of dysautonomic fluctuations. It focused exclusively on NMF, which is interesting considering the described differences between non-motor and motor fluctuations. CONCLUSION: Our study validated a hetero-questionnaire of diagnosis for NMF for different stages of PD.

Pathophysiology of Parkinson's disease: Mitochondria, alpha-synuclein and much more .

Parkinson's disease (PD) is a complex, age-related, neurodegenerative disease whose pathogenesis remains incompletely understood. Here, we give an overview of the progress that has been made over the past four decades in our understanding of this disorder. We review the role of mitochondria, environmental toxicants, alpha-synuclein and neuroinflammation in the development of PD. We also discuss more recent data from genetics, which strongly support the endosomal-lysosomal pathways and mitophagy as being central to PD. Finally, we discuss the emerging role of the gut-brain axis as a modulator of PD progression. This article is intended to provide a comprehensive, general and practical review of PD pathogenesis for the general neurologist.

STW5 (Iberogast®) for constipation in Parkinson's disease.

BACKGROUND: Chronic constipation is one of the most frequent non-motor symptoms in Parkinson's disease (PD), and impairs patients' quality of life. OBJECTIVE: The aim of this pilot study was to assess the efficacy and the tolerability of STW5, a phytotherapeutic agent composed of nine plant extracts, for the treatment of constipation in patients with PD. METHODS: We carried out an open monocentric study of STW5 in the treatment of constipation in parkinsonian patients. Forty-four PD patients with a mean age of 66.4±7.3 years (range, 35-78), a mean disease duration of 12.6±5.4 years (range, 3-27) and with constipation defined by Rome III criteria for functional constipation were included. Following a two-week laxative-free baseline period, all the patients were treated with 20 drops STW5 t.i.d for 28 days, after a seven-day titration period. Treatment efficacy was defined as marked improvement of stool frequency with an increase of three exonerations during the last week of treatment when compared to the week before the initiation of treatment. Responder rate for stool frequency was estimated at 29/45 patients. RESULTS: An increase of stool frequency≥three eliminations/week was observed in only four out of 44 patients (9.0%) at the end of the study. The only significant difference observed before and after treatment was a decrease in stool consistency (P=0.0272). CONCLUSIONS: Our results suggest that STW5 has a safety profile but is not effective as a phytotherapeutic agent in constipation related to Parkinson's disease.

Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates.

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates [termed "Lewy bodies" (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.

Parkinson's disease polygenic risk score is not associated with impulse control disorders: A longitudinal study.

OBJECTIVE: To examine the relationship between a Parkinson's disease (PD) polygenic risk score (PRS) and impulse control disorders (ICDs) in PD. BACKGROUND: Genome wide association studies (GWAS) have brought forth a PRS associated with increased risk of PD and younger disease onset. ICDs are frequent adverse effects of dopaminergic drugs and are also more frequent in patients with younger disease onset. It is unknown whether ICDs and PD share genetic susceptibility. METHODS: We used data from a multicenter longitudinal cohort of PD patients with annual visits up to 6 years (DIG-PD). At each visit ICDs, defined as compulsive gambling, buying, eating, or sexual behavior were evaluated by movement disorders specialists. We genotyped DNAs using the Megachip assay (Illumina) and calculated a weighted PRS based on 90 SNPs associated with PD. We estimated the association between PRS and prevalence of ICDs at each visit using Poisson generalized estimating equations, adjusted for dopaminergic treatment and other known risk factors for ICDs. RESULTS: Of 403 patients, 185 developed ICDs. Patients with younger age at onset had a higher prevalence of ICDs (p < 0.001) as well as higher PRS values (p = 0.06). At baseline, there was no association between the PRS and ICDs (overall, p = 0.84). The prevalence of ICDs increased over time similarly across the quartiles of the PRS (overall, p = 0.88; DA users, p = 0.99). CONCLUSION: Despite younger disease onset being associated with both higher PRS and ICD prevalence, our findings are not in favor of common susceptibility genes for PD and ICDs.

Could it be that neurodegenerative diseases are infectious?

The cell-to-cell transmission of the major pathogenic proteins of Parkinson's disease and Alzheimer's disease is reminiscent of the prion protein, which is defined as a proteinaceous infectious particle that causes human and animal transmissible spongiform encephalopathies. The possibility has raised that the pathogenic proteins of Parkinson's and Alzheimer's disease are infectious, i.e. that they can transmit disease from human to human. In this review, we address this question by comparing the similarities and differences between Alzheimer's disease/Parkinson's disease pathological proteins and prions and by discussing the possible consequences for disease transmission risk.

Inaugural tumor-like multiple sclerosis: clinical presentation and medium-term outcome in 87 patients.

BACKGROUND: Tumefactive demyelinating lesions of the central nervous system can be the initial presentation in various pathological entities [multiple sclerosis (the most common), Balo's concentric sclerosis, Schilder's disease and acute disseminated encephalomyelitis] with overlapping clinical presentation. The aim of our study was to better characterize these patients. METHODS: Eighty-seven patients (62 women and 25 men) from different MS centers in France were studied retrospectively. Inclusion criteria were (1) a first clinical event (2) MRI showing one or more large demyelinating lesions (20 mm or more in diameter) with mass-like features. Patients with a previous demyelinating event (i.e. confirmed multiple sclerosis) were excluded. RESULTS: Mean age at onset was 26 years. The most common initial symptoms (67% of the patients) were hemiparesis or hemiplegia. Aphasia, headache and cognitive disturbances (i.e. atypical symptoms for demyelinating diseases) were observed in 15, 18 and 15% of patients, respectively. The mean largest diameter of the tumefactive lesions was 26.9 mm, with gadolinium enhancement in 66 patients (81%). Twenty-one patients (24%) had a single tumefactive lesion. During follow-up (median time 5.7 years) 4 patients died, 70 patients improved or remained stable and 12 worsened. 86% of patients received initial corticosteroid treatment, and 73% received disease-modifying therapy subsequently. EDSS at the end of the follow-up was 2.4 ± 2.6 (mean ± SD). CONCLUSION: This study provides further evidence that the clinical course of MS presenting with large focal tumor-like lesions does not differ from that of classical relapsing-remitting MS, once the noisy first relapsing occurred.

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.

Enteric neurons from Parkinson's disease patients display ex vivo aberrations in mitochondrial structure.

Based on autopsy material mitochondrial dysfunction has been proposed being part of the pathophysiological cascade of Parkinson's disease (PD). However, in living patients, evidence for such dysfunction is scarce. As the disease presumably starts at the enteric level, we studied ganglionic and mitochondrial morphometrics of enteric neurons. We compared 65 ganglia from 11 PD patients without intestinal symptoms and 41 ganglia from 4 age-matched control subjects. We found that colon ganglia from PD patients had smaller volume, contained significantly more mitochondria per ganglion volume, and displayed a higher total mitochondrial mass relative to controls. This suggests involvement of mitochondrial dysfunction in PD at the enteric level. Moreover, in PD patients the mean mitochondrial volume declined in parallel with motor performance. Ganglionic shrinking was evident in the right but not in the left colon. In contrast, mitochondrial changes prevailed in the left colon suggesting that a compensatory increase in mitochondrial mass might counterbalance mitochondrial dysfunction in the left colon but not in the right colon. Reduction in ganglia volume and combined mitochondrial morphometrics had both predictive power to discriminate between PD patients and control subjects, suggesting that both parameters could be used for early discrimination between PD patients and healthy individuals.

What a gastrointestinal biopsy can tell us about Parkinson's disease?

BACKGROUND: The intraneuronal inclusions called Lewy bodies and neurites, which represent the characteristic pathological changes in Parkinson's disease, are found in the enteric neurons in the great majority of parkinsonian patients. This observation led to a substantial amount of research over the last few years in order to develop a minimally invasive diagnostic procedure in living patients based on gastrointestinal (GI) biopsies. PURPOSE: In this review, we will begin by discussing the studies that focused on the detection of Lewy bodies and neurites in GI biopsies, then broaden the discussion to the pathological changes that also occur in the enteric glial cells and intestinal epithelial cells. We conclude by proposing that a GI biopsy could represent a unique window to assess the whole pathological process of the brain in Parkinson's disease.

[Is Parkinson's disease a prion disease?]. / La maladie de Parkinson est-elle une maladie à prion?

The accumulation of a specific protein in aggregated form is a common phenomenon in human neurodegenerative diseases. In Parkinson's disease, this protein is α-synuclein which is a neuronal protein of 143 amino acids. With a monomeric conformation in solution, it also has a natural capacity to aggregate into amyloid structures (dimers, oligomers, fibrils and Lewy bodies or neurites). It therefore fulfils the characteristics of a prion protein (different conformations, seeding and spreading). In vitro and in vivo experimental evidence in transgenic and wild animals indicates a prion-like propagation of Parkinson's disease. The sequential and predictive distribution of α-synuclein demonstrated by Braak et al. and its correlation with non-motor signs are consistent with the prion-like progression. Although the triggering factor causing the misfolding and aggregation of the target protein is unknown, Parkinson's disease is a highly relevant model for the study of these mechanisms and also to test specific treatments targeting the assemblies of α-synuclein and propagation from pre-motor phase of the disease. Despite this prion-like progression, there is currently no argument indicating a risk of human transmission of Parkinson's disease.

[Dementia: Where are the Lewy bodies?]. / Démences : où sont les corps de Lewy ?

Dementia with Lewy bodies (DLB) is the second cause of degenerative dementia in autopsy studies. In clinical pratice however, the prevalence of DLB is much lower with important intercenter variations. Among the reasons for this low sensitivity of DLB diagnosis are (1) the imprecision and subjectivity of the diagnostic criteria; (2) the underestimation of non-motor symptoms (REM-sleep behavior disorder, dysautonomia, anosmia); mostly (3) the nearly constant association of Lewy bodies with Alzheimer's disease pathology, which dominates the clinical phenotype. With the avenue of targeted therapies against the protein agregates, new clinical scales able to apprehend the coexistence of Lewy pathology in Alzheimer's disease are expected.

Effects of oral administration of rotenone on gastrointestinal functions in mice.

BACKGROUND: The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD, especially neurodegeneration of the substantia nigra and lesions in the enteric nervous system (ENS). Nevertheless, the precise effects of oral rotenone on the ENS have not been addressed yet. This study was therefore designed to assess the effects of a chronic oral treatment by rotenone on enteric neurochemical phenotype, gastrointestinal (GI) motility, and intestinal epithelial barrier permeability. METHODS: Male C57BL6N mice received once daily oral rotenone administration for 28 days. GI functions were analyzed 4 weeks after rotenone treatment. Gastrointestinal motility was assessed by measuring gastric emptying, total transit time, fecal pellet output, and bead latency. Intestinal barrier permeability was evaluated both in vivo and ex vivo. The number of enteric neurons and the enteric neurochemical phenotype were analyzed by immunohistochemistry. Tyrosine hydroxylase (TH) immunostaining of dopaminergic neurons of the substantia nigra was performed in a subset of animals. KEY RESULTS: Mice treated orally with rotenone had a decrease in fecal pellet output and in jejunal alpha-synuclein expression as compared with control animals. This was associated with a significant decrease in TH-immunoreactive neurons in the substantia nigra. No change in gastric emptying, total transit time, intestinal epithelial barrier permeability, and enteric neurochemical phenotype was observed. CONCLUSIONS & INFERENCES: Chronic oral treatment with rotenone only induced minor changes in the ENS and did not recapitulate the GI abnormalities seen in PD, while it replicates neurodegeneration of the substantia nigra.

A comparison between colonic submucosa and mucosa to detect Lewy pathology in Parkinson's disease.

BACKGROUND: Lewy bodies and neurites (LN), the two pathological hallmarks of Parkinson's disease (PD), are found in the enteric nervous system (ENS). Previously, we have shown that whole mounts of submucosa obtained after microdissection of colonic biopsies can be used for the detection of LN in the submucosal plexus (SMP) of PD patients. Recent reports suggest that Lewy pathology may extend beyond the submucosa to involve the digestive mucosa. The aim of the present research was to determine whether the analysis of the mucosa obtained after microdissection may help improve the sensitivity of colonic biopsies to detect Lewy pathology in the colon of PD patients. METHODS: Nine PD patients and 10 controls were included. Four biopsies were taken from the sigmoid/descending colon junction during the course of a rectosigmoidoscopy (short colonoscopy) in PD patients and during a total colonoscopy for colorectal screening in controls. Biopsies were microdissected, the mucosa was separated from the submucosa and both structures were analyzed by immunohistochemistry. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha-synuclein to detect LN and neurofilaments NF200 kDa to label the neuronal structures. KEY RESULTS: Lewy neurites were present in the SMP of four patients and in the mucosa of three patients. Remarkably, among the patients who displayed LN within their mucosa, one was devoid of Lewy pathology in his SMP. No LN were observed in the mucosa and the SMP of controls. CONCLUSIONS & INFERENCES: The parallel analysis of colonic mucosa, along with the SMP, can help detect Lewy pathology in PD.

[Enteric nervous system and Parkinson's disease]. / Système nerveux entérique et maladie de Parkinson.

It has become increasingly evident over the last years that Parkinson's disease is a multicentric neurodegenerative disease that affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. The aims of the present article are to discuss the role of the enteric nervous system lesions in pathology spreading (Braak's hypothesis) and in the gastrointestinal dysfunction encountered in Parkinson's disease. Owing to its accessibility to biopsies, we further discuss the use of the enteric nervous system as an original source of biomarker in Parkinson's disease.

Parkinson disease: the enteric nervous system spills its guts.

Lewy pathology in Parkinson disease (PD) extends well beyond the CNS, also affecting peripheral autonomic neuronal circuits, especially the enteric nervous system (ENS). The ENS is an integrative neuronal network also referred to as "the brain in the gut" because of its similarities to the CNS. We have recently shown that the ENS can be readily analyzed using routine colonic biopsies. This led us to propose that the ENS could represent a unique window to assess the neuropathology in living patients with PD. In this perspective, we discuss current evidence which indicates that the presence of ENS pathology may by exploited to improve our understanding and management of PD and likely other neurodegenerative disorders.

[Non-dopaminergic treatments for Parkinson's disease]. / Quelles pistes pharmacologiques non-dopaminergiques pour le traitement de la maladie de Parkinson ?

It has become increasingly evident over the past years that the pathological process in Parkinson's disease extends well beyond the substantia nigra and involves non-dopaminergic neurotransmitter systems that mediate motor and non-motor symptoms. In this article, both the pathophysiology and the pharmacological management of these non-dopaminergic symptoms are discussed.

Routine colonic biopsies as a new tool to study the enteric nervous system in living patients.

Better characterization of enteric neuropathies during the course of gastrointestinal diseases could be of great diagnostic and/or therapeutic interest. However, studies using whole mounts of the enteric nervous system (ENS) are restricted to specific diseases requiring surgery and are also limited by the small number of specimens available. Therefore, we here describe a novel method to obtain whole mounts of submucosal plexus in routine colonic biopsies. We show that a single biopsy displays a substantial number of submucosal ganglia and neurons and that it can be reliably used to perform morphometric and neurochemical analysis and Western Blots quantification of neuronal or glial markers. This method of analysis of the human ENS will enable us to gain better insight into the characterization of enteric neuropathies in living patients.

Risk factors for progressive supranuclear palsy: a case-control study in France.

BACKGROUND: The risk factors of progressive supranuclear palsy (PSP), a rare but severe Parkinsonian syndrome, are poorly known. OBJECTIVE: To study the risk factors of PSP in a case control study among French patients. METHOD: The study was conducted between April 2000 and December 2003. Cases were in- or outpatients of five large hospitals and fulfilled the Golbe criteria. Controls were relatives of patients from the same hospitals, free of Parkinsonian syndrome and dementia, and matched to cases for age, gender and living area. Data on demographic characteristics, occupation history, diet habits, anti-inflammatory drugs use, alcohol consumption, smoking habits, gardening and leisure activities, and exposure to pesticides were collected through a face-to-face questionnaire. A conditional logistic regression was used to analyse matched data and estimate OR. RESULTS: 79 cases and 79 controls were included. Only a few comparisons were significant. Cases reached a lower education attainment than controls (odds ratio (OR) = 2.6 (1.3 to 5.3), p = 0.01). Analysis of diet habits did not show any major difference although cases ate meat or poultry more frequently. Conversely, controls ate fruits more frequently than did cases. No association was found between PSP and occupation, use of pesticides, gardening, alcohol consumption, smoking habits and anti-inflammatory agent use. CONCLUSION: In this case-control study, we did not find any strong environmental risk factors for PSP.

Neurochemical plasticity in the enteric nervous system of a primate animal model of experimental Parkinsonism.

Emerging evidences suggest that the enteric nervous system (ENS) is affected by the degenerative process in Parkinson's disease (PD). In addition lesions in the ENS could be associated with gastrointestinal (GI) dysfunctions, in particular constipation, observed in PD. However, the precise alterations of the ENS and especially the changes in the neurochemical phenotype remain largely unknown both in PD and experimental Parkinsonism. The aim of our study was thus to characterize the neurochemical coding of the ENS in the colon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, a well-characterized model of PD. In the myenteric plexus, there was a significant increase in the number of neurons per ganglia (identified with Hu), especially nitric oxide synthase immunoreactives (IR) neurons in MPTP-treated monkeys compared to controls. A concomitant 72% decrease in the number of tyrosine hydroxylase-IR neurons was observed in MPTP-treated monkeys compared to controls. In contrast no change in the cholinergic or vasoactive intestinal peptide-IR population was observed. In addition, the density of enteric glial cells was not modified in MPTP-treated monkeys. Our results demonstrate that MPTP induces major changes in the myenteric plexus and to a lesser extent in the submucosal plexus of monkeys. They further reinforce the observation that lesions of the ENS occur in the course of PD that might be related to the GI dysfunction observed in this pathology.