Gut Microbiota in Monozygotic Twins Discordant for Parkinson's Disease.

Differences in gut microbiota between Parkinson's disease patients and controls seem to depend on multiple-frequently unmeasured-confounders. Monozygotic twins offer a unique model for controlling several factors responsible for interpersonal variation in gut microbiota. Fecal samples from 20 monozygotic twin pairs (n = 40) discordant for Parkinson's disease were studied (metagenomic shotgun analysis). Paired data analysis detected minimal differences in bacterial taxa abundance at species level (Bacteroides pectinophilus [p = 0.037], Bifidobacterium pseudocatenulatum [p = 0.050], and Bifidobacterium catenulatum [p = 0.025]) and in predicted metabolic pathways (primary bile acid biosynthesis [p = 0.037]). Additional studies are warranted to understand the role of gut microbiota in the pathogenesis of Parkinson's disease. ANN NEUROL 2022;92:631-636.

Therapeutic advances in dystonia.

Knowledge on dystonia has greatly improved recently, because of a renewed effort in understanding its cause, pathophysiology, and clinical characterization. Different drug classes traditionally have been used for the symptomatic treatment of dystonia, more recently surpassed by the introduction of botulinum neurotoxins and deep brain stimulation. No curative or disease-modifying treatments are available. Recent knowledge regarding the pathophysiology of inherited dystonias is highlighting new potential treatment strategies. We review therapeutic advances in dystonia that have been published over the last 3 years, particularly regarding oral medications, local injections of botulinum neurotoxins, deep brain stimulation, and transcranial or epidural brain stimulations. We discuss evidence of efficacy, highlight recent advances, and focus on key areas under development.

EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease.

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open-label, prospective, observational, 6-month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3-4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3-4). Cohen's effect sizes (≥0.8 considered as large) were "large" with both therapies with respect to total motor, nonmotor, and quality-of-life scores. The Non-Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy-five percent on IJLI improved in their quality-of-life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open-label, nonrandomized, comparative study, we report that, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life, and some NMS. Controlled, randomized studies are required.

Metformin use is associated with reduced mortality risk in diabetic patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) and type-2 diabetes (T2D) arguably share pathophysiologic mechanisms, resulting in a more severe phenotype and progression and diabetes is currently considered a risk factor of PD. Besides, research suggests antidiabetic therapies as potential disease-modifying strategies. The main aim was to assess the impact of a metformin-inclusive antidiabetic treatment on patient all-cause mortality. METHODS: A nested case-control prospective study including newly diagnosed PD patients reporting the onset of T2D within ±2 years from the onset of PD (n = 159) and matched (1:5; gender, year of PD onset and age at PD onset) non-diabetic cases (n = 795) followed until death or censoring. Patients on a metformin-inclusive treatment regimen were compared to those receiving other oral anti-diabetics (OADs). RESULTS: Among patients with T2D, 123 were treated with a drug regimen containing metformin (alone [65.0%] or in combination with other drugs [35.0%]) and 36 were prescribed other OADs. During a median PD duration of 96 months [IQR, 60-144], 171 patients died. Diabetes was not associated with reduced survival: fully-adjusted HR = 1.19 [95%CI, 0.81-1.76] (P = 0.37). After stratifying for T2D treatment, a metformin-inclusive regimen was not associated with increased risk of death (HR = 1.06 [95%CI, 0.61-1.84]; P = 0.83), while patients receiving other OADs had reduced survival (HR = 1.83 [95%CI, 1.01-3.32]; P = 0.034). CONCLUSIONS: Metformin use was not associated with increased risk of death in diabetic patients with PD reporting concomitant onset of the two diseases. Metformin appears to be a promising disease-modifying therapy given also the preclinical background, low cost and satisfactory safety and tolerability. Further studies are warranted to investigate its impact on disease progression.

Onset and mortality of Parkinson's disease in relation to type II diabetes.

OBJECTIVES: There is growing evidence that Parkinson's disease and diabetes are partially related diseases; however, the association between the two, and the impact of specific treatments, are still unclear. We evaluated the effect of T2D and antidiabetic treatment on age at PD onset and on all-cause mortality. RESEARCH DESIGN AND METHODS: The standardized rate of T2D was calculated for PD patients using the direct method and compared with subjects with essential tremor (ET) and the general Italian population. Age at onset and survival were also compared between patients without T2D (PD-noT2D), patients who developed T2D before PD onset (PD-preT2D) and patients who developed T2D after PD onset (PD-postT2D). RESULTS: We designed a retrospective and prospective study. The T2D standardized ratio of PD (N = 8380) and ET (N = 1032) patients was 3.8% and 6.1%, respectively, while in the Italian general population, the overall prevalence was 5.3%. In PD-preT2D patients, on antidiabetic treatment, the onset of PD was associated with a + 6.2 year delay (p < 0.001) while no difference was observed in PD-postT2D. Occurrence of T2D before PD onset negatively affected prognosis (adjusted hazard ratio = 1.64 [95% CI 1.33-2.02]; p < 0.001), while no effect on survival was found in PD-postT2D subjects (hazard ratio = 0.86, [95% CI 0.53-1.39]; p = 0.54). CONCLUSIONS: T2D, treated with any antidiabetic therapy before PD, is associated with a delay in its onset. Duration of diabetes increases mortality in PD-preT2D, but not in PD-postT2D. These findings prompt further studies on antidiabetic drugs as a potential disease-modifying therapy for PD.

Vitamin D Status and Parkinson's Disease.

Parkinson's disease (PD) is a complex and progressive neurodegenerative disease, characterized by resting tremor, rigidity, slowness of movement, and postural instability. Furthermore, PD is associated with a wide spectrum of non-motor symptoms that add to overall disability. In recent years, some investigations, from basic science to clinical applications, have focused on the role of vitamin D in PD, often with controversial findings. Vitamin D has widespread effects on several biological processes in the central nervous system, including neurotransmission in dopaminergic neural circuits. Various studies have recorded lower levels of vitamin D in PD patients than in healthy controls. Low vitamin D status has also been correlated with the risk for PD and motor severity, whereas less is known about the effects vitamin D has on cognitive function and other non-motor symptoms. This review aims to better characterize the correlation between vitamin D and PD, clarify the role of vitamin D in PD prevention and treatment, and discuss avenues for future research in this field.

Long-term safety, discontinuation and mortality in an Italian cohort with advanced Parkinson's disease on levodopa/carbidopa intestinal gel infusion.

INTRODUCTION: Levodopa/carbidopa intestinal gel (LCIG) is an effective treatment in patients with advanced Parkinson's disease (PD) with consolidated evidence of clinical efficacy. However, only few studies have assessed long-term safety, causes of discontinuation, mortality, and relative predictors. METHODS: We conducted a retrospective analysis of 79 PD patients treated with LCIG between 2005 and 2020 in two Italian Neurological Centers, recording all adverse events (AEs), including weight loss (WL). Kaplan-Meier curve was used to estimate the time to discontinuation and survival. Cox proportional hazard model was employed to identify predictors of discontinuation and mortality, while Pearson's correlation was used to analyze predictors of WL. RESULTS: The average follow-up was 47.7 ± 40.5 months and the median survival from disease onset was 25 years. There were three cases of polyradiculoneuropathy Guillain-Barre syndrome-like, all occurred in the early years of LCIG treatment. Twenty-five patients died (32%), 18 on LCIG (including one suicide) and seven after discontinuation. The mean WL was 3.62 ± 7.5 kg, which correlated with levodopa dose at baseline (p = 0.002), levodopa equivalent daily dose (LEDD) baseline (p = 0.017) and off-duration (p = 0.0014), but not dyskinesia. Peristomal complications emerged as a negative predictor of discontinuation (p = 0.008). CONCLUSIONS: LCIG has a relatively satisfactory long-term safety profile and efficacy and a relatively low rate of discontinuation. Peristomal complications may represent a predictor of longer duration of therapy. According to the mortality analysis, LCIG patients show a long lifespan. Delaying the initiation of LCIG does not affect the sustainability of LCIG therapy.

Rotigotine transdermal patch in the management of Parkinson's disease (PD) and its night-time use for PD-related sleep disorders.

Rotigotine (Neupro) is a non-ergolinic dopamine agonist available as a transdermal patch that can be applied once daily. To date, it is approved as monotherapy for the treatment of early Parkinson's disease (PD), and as adjunctive therapy to levodopa in the treatment of PD, including the advanced stage of the disease, when the efficacy of levodopa is reduced or becomes inconsistent and there are fluctuations in the therapeutic effect (end-dose, 'ON-OFF' phenomenon). The potential advantages of the rotigotine patch include immediacy of effect onset as intestinal absorption is not needed, constant drug delivery, and ease of use. This review provides an overview of several aspects of the use of the rotigotine transdermal patch, including the important issue of the management of sleep disorders in advanced PD patients, as well as the chemistry, preclinical and clinical pharmacology, efficacy, safety and tolerability of the drug. Furthermore, the rationale for the treatment of PD with the rotigotine transdermal patch is discussed, focusing in particular on the related sleep disorders.

Case Report: Efficacy of Rituximab in a Patient With Familial Mediterranean Fever and Multiple Sclerosis.

Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disease characterized by recurrent episodes of fever and serositis caused by mutations in the MEFV gene, while Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the CNS with genetic and environmental etiology. The two diseases rarely occur in association with relevant implications for clinical management and drug choice. In this paper, we present the case of a 53-year-old male with an autosomal dominant FMF since childhood who presented acute paresthesia at the right part of the body. He performed a brain and spinal cord MRI, which showed multiple brain lesions and a gd-enhancing lesion in the cervical spinal cord, and then received a diagnosis of MS. He then started Interferonß-1a which was effective but not tolerated and caused hepatotoxicity, and then shifted to Rituximab with 3-month clinical and neuroradiological efficacy.

Design and Operation of the Lombardy Parkinson's Disease Network.

Background: Parkinson's disease (PD) is one of the most common chronic neurological conditions leading to disability and social burden. According to the 2016 Italian National Plan on Chronic Diseases, regional health authorities are implementing dedicated networks to manage neurological diseases, including PD. Methods: A panel of experts representing health-care providers in Lombardy reached consensus on the organization of a patient-centered regional PD healthcare network. Results: The panel proposed a structure and organization implementing a hub-and-spoke PD network model. Three levels of neurological services were identified: General Neurologist, PD Clinic, PD Center. This model was applied to health service providers currently accredited in Lombardy, yielding 12 candidate PD Centers, each serving an area of ~1,000-2,000 km2, and not less than 27 PD Clinics. The panel agreed on uniform diagnostic and staging criteria for PD, and on a minimum common clinical data set, on PD patient management by the network at initial and follow-up assessments, on the cadence of follow-up visits, on patient referrals, and on outcome measures for the assessment of network activities. Conclusions: The implementation of disease-centered networks for chronic neurological diseases provides an innovative opportunity to improve patient management, facilitate research and education.

Botulinum neurotoxins for post-stroke spasticity in adults: a systematic review.

The aim of this systematic review was to determine whether botulinum neurotoxin (BoNT) reduce spasticity or improve function in adult patients after stroke. Eleven double-blind randomized placebo-controlled trials met inclusion criteria. They encompassed 782 patients, 767 (98%) of whom received BoNT/A, and 15 (2%) BoNT/B. Most studies used the Ashworth scale as primary outcome measure. Differences between treated and control groups were assessed as categorical or continuous comparisons. The overall effect on upper limb spasticity was in favor of BoNT/A. A significantly higher number of patients had a reduction of upper limb spasticity at 4-week and 8-week evaluations in the treatment group compared with placebo. Mean changes in joint spasticity revealed improvement 3 to 6 weeks and 9 to 12 weeks after treatment. There were insufficient data to establish BoNT/A efficacy on lower limb spasticity or the effect of BoNT/B on the upper and lower limbs. Because of inconsistency and heterogeneity of the available data, it was not possible to perform a meta-analysis on disability and patients' reported outcomes. There was an overlapping safety profile between the treatment and the placebo groups. BoNT/A reduces upper limb spasticity in patients post-stroke, but the improvement in functional ability remains to be established. This gap needs to be filled by new studies to assess the effect of BoNT in the context of multidisciplinary patient management.

Deep brain stimulation for dystonia due to cerebral palsy: A review.

Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest available studies.

Macrogol for the treatment of constipation in Parkinson's disease. A randomized placebo-controlled study.

Chronic constipation is the most frequent symptom of autonomic system involvement in Parkinson's disease (PD). Quite often the symptom is severe and impairs patients' quality of life. The objective of this study is to determine the efficacy and safety of an isosmotic macrogol solution for the treatment of constipation in PD patients, in a double-blind, placebo-controlled study. A total of 57 PD patients with constipation were randomly assigned to receive an isosmotic macrogol electrolyte solution (MC-ES; 29 patients) or placebo (28 patients) for 8 weeks. Treatment efficacy was defined as complete relief of the symptom or a marked improvement of two of the following indicators: stool frequency, straining, stool consistency, use of rectal laxatives as a rescue therapy. The responder rates were significantly higher in the MC-ES group both at the first (4 weeks; P < 0.0003) and at the final evaluation (8 weeks; P < 0.0012). The frequency of bowel movements (P < 0.002) and stool consistency (P < 0.006) were significantly changed in the MC-ES group compared to the placebo group. At the final evaluation, a rectal laxative was used by 2 (12.5%) patients on placebo, whereas no use was recorded in the MC-ES group. Responder rate for straining showed a favorable trend in patients treated with macrogol versus placebo. Unified Parkinson's Disease Rating Scale Part III and Parkinson's Disease Questionnaire (PDQ-39) did not show any significant modification in either group during the 8-week treatment period. The results of this placebo-controlled study show the efficacy of MC-ES in the treatment of constipation in PD. MC-ES was well-tolerated and did not affect the course of PD.

Medical healthcare use in Parkinson's disease: survey in a cohort of ambulatory patients in Italy.

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disease which at present has no cure, and it usually results in severe disability. The burden of PD increases as the illness progresses, resulting in the extensive utilisation of both health and community services. Knowledge of healthcare use patterns and of their determinants may greatly contribute to improve patient care, however few studies have examined this issue in PD. The present study was devised to describe the type of and reasons for medical healthcare resource use in persons with PD attending a Centre for PD and Movement Disorders, and to examine drug prescriptions issued on such occasions. METHODS: The study was a retrospective, cross-sectional survey in a cohort of ambulatory patients with PD, conducted by means of standard interviews. RESULTS: In the year before the study, 92 (70.8%) of 130 patients used medical healthcare resources: 1/5 of the patients was admitted to hospital, 1/5 to emergency room, 2/5 were visited by a non-neurology specialist, and 1/4 by the GP. Reasons were: nearly 20% programmed hospital admissions and visits, and more than 25% injuries and musculo-skeletal diseases. Other conditions typically occurring in PD (e.g. dementia, diabetes and cardio- and cerebro-vascular disease) were less frequently involved. On such occasions, drugs for PD were occasionally changed, however drug prescriptions for other indications were issued to more than 66% of the patients. CONCLUSION: Several physicians other than the neurologist may take care of PD patients on different occasions, thus emphasising the need for communication between the reference neurologist and other physicians who from time to time may visit the patient.

Causes of withdrawal of duodenal levodopa infusion in advanced Parkinson disease.

OBJECTIVE: We performed a real-life observation of patients with Parkinson disease (PD) who received duodenal levodopa infusion (DLI) to determine which adverse events caused treatment discontinuation and when such events occurred. METHODS: All consecutive patients with PD treated at the Carlo Besta Neurological Institute were included. The patients were evaluated at baseline and after DLI at regular intervals. Their motor condition was assessed and adverse events were recorded. RESULTS: Thirty-five patients with PD (15 men and 20 women) were included. They received DLI implants between October 2007 and September 2013. Four patients died of causes unrelated to the procedure. At the end of the study, 21 patients (60%) were still on treatment. DLI provided efficacious motor control in all patients. Discontinuation was most frequently caused by device- or infusion-related adverse events. Ten patients of the remaining 31 discontinued DLI. There were 2 main causes of withdrawal: stoma infection (4 patients), and worsening of dyskinesias not manageable with infusion reduction (3 patients). In most patients, discontinuations occurred during the first year after implant. Risk of discontinuation was related to age at implant, but no other demographic or clinical variables. CONCLUSIONS: We identified 2 main causes leading to DLI withdrawal during the first year postimplant and suggest adopting measures to prevent such occurrences. Elderly patients are at higher risk of treatment discontinuation.

Caribbean parkinsonism and other atypical parkinsonian disorders.

Atypical parkinsonism (AP) is a term applied to disorders characterized by parkinsonism that evolves rapidly, with poor or transient response to levodopa, or has other associated features such as early falls and postural instability, early autonomic failure, supranuclear gaze palsy, pyramidal or cerebellar signs, alien hand syndrome or severe ideomotor apraxia. The most common AP are multiple system atrophy, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Other APs include Caribbean parkinsonism (CP) and parkinsonism-dementia complex of Guam (PDC). In this review we provide an update in etiology, neuropathology, diagnosis and treatment of atypical parkinsonian disorders associated with protein tau deposit, also known as tauopathies.

Reproductive life milestones in women with Parkinson's disease.

Reproductive life milestones were studied in 150 unselected women with idiopathic Parkinson's disease (PD) and in 300 postmenopausal healthy women (PM). Duration of reproductive life was found to be similar in the two groups. The women with PD reported significantly more premenstrual symptoms, fewer deliveries and abortions, and less use of contraception. Time and mode of menopause onset were similar in PD and PM, but the PD women reported significantly more hot flushes, less insomnia, depression, urinary incontinence and dyspareunia, and less recourse to hormone replacement therapy than the PM women. Women diagnosed with PD before the menopause reported more premenstrual symptoms and contraceptive use compared with those with postmenopausal PD onset, as well as a premenstrual worsening of PD symptoms in more than 50% of cases. Our data indicate poor adaptation of neuronal pathways to the hormonal fluctuations of reproductive life in women with PD, supporting the existence of a qualitative relationship between PD and reproductive events.