A Double-Blind, Randomized, Placebo-Controlled Trial of Bumetanide in Parkinson's Disease.

BACKGROUND: Acting on the main target of dopaminergic cells, the striatal γ-aminobutyric acid (GABA)-ergic cells, might be a new way to treat persons with Parkinson's disease (PD). OBJECTIVE: The objective of this study was to assess the efficacy of bumetanide, an Na-K-Cl cotransporter (NKCC1) inhibitor, to improve motor symptoms in PD. METHODS: This was a 4-month double-blind, randomized, parallel-group, placebo-controlled trial of 1.75 to 3 mg/day bumetanide as an adjunct to levodopa in 44 participants with PD and motor fluctuations. RESULTS: Compared to the baseline, the mean change in OFF Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score after 4 months of treatment (primary endpoint) did not improve significantly compared with placebo. No changes between participants treated with bumetanide and those treated with placebo were observed for most other outcome measures. Despite no relevant safety signals, bumetanide was poorly tolerated. CONCLUSIONS: There was no evidence in this study that bumetanide has efficacy in improving motor symptoms of PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Wake and non-rapid eye movement sleep dysfunction is associated with colonic neuropathology in Parkinson's disease.

STUDY OBJECTIVES: The body-first Parkinson's disease (PD) hypothesis suggests initial gut Lewy body pathology initially propagates to the pons before reaching the substantia nigra, and subsequently progresses to the diencephalic and cortical levels, a disease course presumed to likely occur in PD with rapid eye movement sleep behavior disorder (RBD). We aimed to explore the potential association between colonic phosphorylated alpha-synuclein histopathology (PASH) and diencephalic or cortical dysfunction evidenced by non-rapid eye movement (NREM) sleep and wakefulness polysomnographic markers. METHODS: In a study involving 43 patients with PD who underwent clinical examination, rectosigmoidoscopy, and polysomnography, we detected PASH on colonic biopsies using whole-mount immunostaining. We performed a visual semi-quantitative analysis of NREM sleep and wake electroencephalography (EEG), confirmed it with automated quantification of spindle and slow wave features of NREM sleep, and the wake dominant frequency, and then determined probable Arizona PD stage classifications based on sleep and wake EEG features. RESULTS: The visual analysis aligned with the automated quantified spindle characteristics and the wake dominant frequency. Altered NREM sleep and wake parameters correlated with markers of PD severity, colonic PASH, and RBD diagnosis. Colonic PASH frequency also increased in parallel to probable Arizona PD stage classifications. CONCLUSIONS: Colonic PASH is strongly associated with widespread brain sleep and wake dysfunction, suggesting an extensive diffusion of the pathologic process in PD. Visual and automated analyses of polysomnography signals provide useful markers to gauge covert brain dysfunction in PD. CLINICAL TRIAL: Name: SYNAPark, URL: https://clinicaltrials.gov/study/NCT01748409, registration: NCT01748409.

Wake and non-rapid eye movement sleep dysfunction is associated with colonic neuropathology in Parkinson's disease.

Study Objectives: The body-first Parkinson's disease (PD) hypothesis suggests initial gut Lewy body pathology that propagates to the pons before reaching the substantia nigra, and subsequently progresses to the diencephalic and cortical levels. This disease course may also be the most likely in PD with rapid eye movement sleep behavior disorder (RBD). Objectives: We aimed to explore the potential association between colonic phosphorylated alpha-synuclein histopathology (PASH) and diencephalic or cortical dysfunction evidenced by non-rapid eye movement (NREM) sleep and wakefulness polysomnographic markers. Methods: In a study involving 43 patients with PD who underwent clinical examination, rectosigmoidoscopy, and polysomnography, we detected PASH on colonic biopsies using whole-mount immunostaining. We performed a visual semi-quantitative and automated quantification of spindle and slow wave features of NREM sleep, and the wake dominant frequency, and then determined Braak and Arizona stage classifications for PD severity based on sleep and wake electroencephalographic features. Results: The visual analysis aligned with the automated quantified spindle characteristics and the wake dominant frequency. Altered NREM sleep and wake parameters correlated with markers of PD severity, colonic PASH, and RBD diagnosis. Colonic PASH frequency also increased in parallel to presumed PD Braak and Arizona stage classifications. Conclusions: Colonic PASH in PD is strongly associated with widespread brain sleep and wake dysfunction, pointing toward likely extensive diffusion of the pathological process in the presumptive body-first PD phenotype. Visual and automated analyses of polysomnography signals provide useful markers to gauge covert brain dysfunction in PD. Statement of Significance: The presence of gut synucleinopathy in Parkinson's disease can be linked to the body-first hypothesis in its pathophysiology. This study, performed in a cohort of 43 patients with Parkinson's disease that underwent clinical assessment, rectosigmoidoscopy and polysomnography, provides evidence that colonic neuropathology in Parkinson's disease is associated with widespread brain dysfunction, as evaluated by wake and non-rapid eye movement sleep polysomnographic markers. Our results support the assumption of an extensive diffusion of the pathological process to diencephalic and neocortical structures in the presumptive body-first phenotype. They also suggest the use of routine polysomnography in phenotyping patients with Parkinson's disease. Future studies should investigate the brain diffusion pattern and its sleep markers in the hypothesized brain-first phenotype of Parkinson's disease.

Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

LeSCoD: a new clinical scale for the detection of Lewy body disease in neurocognitive disorders.

BACKGROUND: Dementia with Lewy bodies remains underdiagnosed in clinical practice mainly because of the low sensitivity of existing diagnostic criteria and a strong overlap with Alzheimer's pathology that can mask the Lewy phenotype. OBJECTIVE: The objective of this study was therefore to develop and validate a new clinical scale designed to detect signs of Lewy body disease, called LeSCoD for Lewy body Screening scale in Cognitive Disorders. METHODS: 128 patients who fulfilled the clinical criteria of dementia with Lewy bodies (DLB; n = 32), Alzheimer's disease (AD; n = 77) or both (n = 19) was prospectively enrolled. 18F-DOPA PET imaging and/or CSF biomarkers were available in some patients. LeSCoD scale was systematically administered and the potential correlation with 18F-DOPA PET imaging was evaluated in a subgroup of patients. RESULTS: LeSCoD scale showed robust internal and external validity. We determined a cut-off of 10 above which the sensitivity and specificity for Lewy body disease diagnosis were 86% and 95%, respectively. The LeSCoD scale correlated with striatal dopamine uptake in 18F-DOPA PET. CONCLUSION: LeSCoD scale is a simple and reliable tool for the evaluation of Lewy body disease in routine clinical practice, with a higher sensitivity and specificity than the existing criteria. It might be an alternative to the use of dopamine-specific imaging.

Colonic neuropathology is not associated with autonomic dysfunction in Parkinson's disease.

INTRODUCTION: Dysautonomia in Parkinson's disease (PD) has been shown to be associated with disease severity and especially with the occurrence of dementia. One proposed explanation for this finding is that phosphorylated alpha-synuclein histopathology (PASH), the characteristic pathological feature of PD is more diffuse in dysautonomia-associated PD than in disease without dysautonomia, not only in the central nervous system but also in peripheral autonomic networks. The aim of this study was therefore to determine if colonic alpha-synuclein histopathology is associated with dysautonomia in PD. METHODS: A total of 43 PD patients participated in this study. For each patient, two biopsies were taken in the sigmoid colon and analyzed by immunohistochemistry with antibodies against phosphorylated alpha-synuclein and PGP 9.5. All patients had a complete neuropsychological and neurological assessment along with a comprehensive evaluation of dysautonomia with questionnaires (SCOPA-Aut, NMS-Quest, Rome III constipation criteria and dry eye symptoms) and functional tests (pupillometry, Saxon and Schirmer's tests, heart rate variability, orthostatic blood pressure measure and sympathetic skin response). RESULTS: Colonic PASH was observed in 20/43 PD patients. No differences were observed in autonomic symptoms and testing between patients with and without PASH. CONCLUSIONS: Although frequent in PD, autonomic dysfunction is not related to colonic PASH. In addition to the existing literature, our findings further suggest that each dysautonomic symptom in PD might not be associated with a more severe or diffuse PASH not only in the central nervous system but also in the peripheral autonomic nervous systems.

Heterogeneous pattern of autonomic dysfunction in Parkinson's disease.

Dysautonomic symptoms are frequent non-motor complaints in patients with Parkinson's disease. Numerous neuropathological studies have shown that Lewy bodies and neurites, the pathological hallmarks of Parkinson's disease, are widely distributed throughout the peripheral autonomic nervous systems and across end organs. However, few investigations integrally explored the symptoms and physiology of dysautonomia in Parkinson's disease. We, therefore, performed a comprehensive evaluation of the autonomic function in a prospective group of 45 patients with idiopathic Parkinson's disease. Autonomic components (pupillomotor, tear, salivary, cardiovascular, digestive, urinary, sexual, sudomotor functions and skin sensitivity) were evaluated using questionnaires and functional tests. Skin biopsy was performed for intraepidermal nerve fibre density quantification. In addition, all patients underwent polysomnography and a complete neuropsychological and neurological assessment. The analysis association of autonomic components showed that dysautonomic signs and symptoms were heterogeneously distributed among patients. Skin denervation as assessed by intraepidermal nerve fibre density quantification was only associated with quantitative thermal sensory testing (OR = 12.0, p = 0.02), constipation (OR = 5.5, p = 0.01) and ocular dryness symptoms (OR = 8.29, p = 0.04). Cognitive alteration was associated with cardiovascular symptoms (OR = 4.33, p = 0.03) and dysfunction (OR = 5.83, p = 0.02) as well as with constipation (OR = 5.38, p = 0.02). Axial motor impairment and rapid eye movement (REM) sleep behaviour disorder were not related to any of the autonomic complaint or dysfunction. Our results show that autonomic functions are affected in a heterogeneous pattern in Parkinson's disease, thereby suggesting that the progression of autonomic dysfunction follows an erratic rather than a stepwise progression.

REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease.

OBJECTIVE: To determine whether REM sleep behavior disorder (RBD) in Parkinson disease (PD) is associated with lesions and dysfunctions of the autonomic nervous system by evaluating enteric phosphorylated α-synuclein histopathology (PASH) and permeability. METHODS: A total of 45 patients with PD were included in this cross-sectional study. RBD was diagnosed on the basis of a standardized clinical interview and confirmed by polysomnography. For each patient, 5 biopsies were taken at the junction between the sigmoid and descending colon during the course of a rectosigmoidoscopy. For the detection of enteric PASH, 2 colonic biopsies were analyzed by immunohistochemistry with antibodies against phosphorylated α-synuclein and PGP9.5 in 43 patients (2 patients were excluded because only 1 biopsy was available). The paracellular permeability and transcellular permeability were evaluated by measuring sulfonic acid and horseradish peroxidase flux, respectively, in the 3 remaining biopsies mounted in Ussing chambers. RESULTS: Enteric PASH was more frequent in the subgroup of patients with PD with RBD compared to patients without RBD (18 of 28, 64.3%, vs 2 of 15, 13.3%, respectively, p < 0.01). No differences were observed in intestinal permeability between patients with PD with and without RBD. CONCLUSIONS: Patients with PD and RBD have a greater frequency of synuclein pathology in the enteric nervous system, suggesting that RBD is associated with widespread synuclein neuropathology.

Structural alterations of the intestinal epithelial barrier in Parkinson's disease.

Functional and morphological alterations of the intestinal epithelial barrier (IEB) have been consistently reported in digestive disorders such as irritable bowel syndrome and inflammatory bowel disease. There is mounting evidence that Parkinson's disease (PD) is not only a brain disease but also a digestive disorder. Gastrointestinal involvement is a frequent and early event in the course of PD, and it may be critically involved in the early development of the disease. We therefore undertook the present survey to investigate whether changes in the IEB function and/or morphology occur in PD. Colonic biopsies were performed in 31 PD patients and 11 age-matched healthy controls. The para- and transcellular permeability were evaluated by measuring sulfonic acid and horseradish peroxidase flux respectively, in colonic biopsies mounted in Ussing chambers. The expression and localization of the two tight junctions proteins ZO-1 and occludin were analyzed by Western blot and immunofluorescence, respectively. The para- and transcellular permeability were not different between PD patients and controls. The expression of occludin, but not ZO-1, was significantly lower in colonic samples from PD patients as compared to controls and the cellular distribution of both proteins was altered in colonic mucosal specimens from PD patients. Our findings provide evidence that the IEB is morphologically altered in PD and further reinforce the potential role of the gastrointestinal tract in the initiation and/or the progression of the disease.