Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment. METHODS: We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI). RESULTS: Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (ß-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory. CONCLUSIONS: iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Consensus practice recommendations for management of gastrointestinal dysfunction in Parkinson disease.

BACKGROUND: Gastrointestinal (GI) dysfunction is a common non-motor feature of Parkinson disease (PD). GI symptoms may start years before the onset of motor symptoms and impair quality of life. Robust clinical trial data is lacking to guide screening, diagnosis and treatment of GI dysfunction in PD. OBJECTIVE: To develop consensus statements on screening, diagnosis, and treatment of GI dysfunction in PD. METHODS: The application of a modified Delphi panel allowed for the synthesis of expert opinions into clinical statements. Consensus was predefined as a level of agreement of 100 % for each item. Five virtual Delphi rounds were held. Two movement disorders neurologists reviewed the literature on GI dysfunction in PD and developed draft statements based on the literature review. Draft statements were distributed among the panel that included five movement disorder neurologists and two gastroenterologists, both experts in GI dysmotility and its impact on PD symptoms. All members reviewed the statements and references in advance of the virtual meetings. In the virtual meetings, each statement was discussed, edited, and a vote was conducted. If there was not 100 % consensus, further discussions and modifications ensued until there was consensus. RESULTS: Statements were developed for screening, diagnosis, and treatment of common GI symptoms in PD and were organized by anatomic segments: oral cavity and esophagus, stomach, small intestine, and colon and anorectum. CONCLUSIONS: These consensus recommendations offer a practical framework for the diagnosis and treatment of GI dysfunction in PD.

Efficacy of the iron-chelating agent, deferiprone, in patients with Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: Several studies have reported iron accumulation in the basal ganglia to be associated with the development of Parkinson's Disease (PD). Recently, a few trials have examined the efficacy of using the iron-chelating agent Deferiprone (DFP) for patients with PD. We conducted this meta-analysis to summarize and synthesize evidence from published randomized controlled trials about the efficacy of DFP for PD patients. METHODS: A comprehensive literature search of four electronic databases was performed, spanning until February 2023. Relevant RCTs were selected, and their data were extracted and analyzed using the RevMan software. The primary outcome was the change in the Unified Parkinson's Disease Rating Scale (UPDRS-III). RESULTS: Three RCTs with 431 patients were included in this analysis. DFP did not significantly improve UPDRS-III score compared to placebo (Standardized mean difference -0.06, 95% CI [-0.69, 0.58], low certainty evidence). However, it significantly reduced iron accumulation in the substantia nigra, putamen, and caudate as measured by T2*-weighted MRI (with high certainty evidence). CONCLUSION: Current evidence does not support the use of DFP in PD patients. Future disease-modification trials with better population selection, adjustment for concomitant medications, and long-term follow up are recommended.

Seizures in juvenile Huntington's disease: frequency and characterization in a multicenter cohort.

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required.

Anticholinergic Medication Burden in Parkinson's Disease Outpatients.

BACKGROUND: Individuals with Parkinson's disease (PD) may be especially vulnerable to future cognitive decline from anticholinergic medications. OBJECTIVE: To characterize anticholinergic medication burden, determine the co-occurrence of anticholinergic and cholinesterase inhibitors, and to assess the correlations among anticholinergic burden scales in PD outpatients. METHODS: We studied 670 PD outpatients enrolled in a clinic registry between 2012 and 2020. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Drug Burden Index-Anticholinergic component (DBI-Ach). Correlations between scales were assessed with weighted kappa coefficients. RESULTS: Between 31.5 to 46.3% of PD patients were taking medications with anticholinergic properties. Among the scales applied, the ACB produced the highest prevalence of medications with anticholinergic properties (46.3%). Considering only medications with definite anticholinergic activity (scores of 2 or 3 on ACB, ADS, or ARS), the most common anticholinergic drug classes were antiparkinsonian (8.2%), antipsychotic (6.4%), and urological (3.3%) medications. Cholinesterase inhibitors and medications with anticholinergic properties were co-prescribed to 5.4% of the total cohort. The most highly correlated scales were ACB and ADS (κ= 0.71), ACB and ARS (κ= 0.67), and ADS and ARS (κ= 0.55). CONCLUSION: A high proportion of PD patients (20%) were either taking antiparkinsonian, urological, or antipsychotic anticholinergic medications or were co-prescribed anticholinergic medications and cholinesterase inhibitors. By virtue of its detection of a high prevalence of anticholinergic medication usage and its high correlation with other scales, our data support use of the ACB scale to assess anticholinergic burden in PD patients.

Gastrointestinal features of Parkinson's disease.

Gastrointestinal (GI) symptoms are among the most common nonmotor manifestations of Parkinson's disease (PD), and they have many important ramifications for patients. The purpose of this review is to raise awareness of the full spectrum of GI symptoms in PD which include weight loss, sialorrhea, dysphagia, nausea, constipation, and defecatory dysfunction. We will discuss their practical significance, and outline a clear approach to their evaluation and management. A brief discussion about the impacts of commonly used medical and surgical PD therapies on GI symptom manifestation is also included.

Tardive dyskinesia.

OPINION STATEMENT: Tardive dyskinesia (TD) is iatrogenic (drug-induced); hence the best strategy is prevention. Try to limit exposure to any dopamine receptor blocking agents (DRBAs) if possible. These agents may be unavoidable in some psychiatric conditions such as schizophrenia, but alternative therapies can be used in many situations, such as in the treatment of depression, anxiety, gastrointestinal conditions, and other neurologic conditions, including migraines and sleep disorders. When DRBAs are necessary, physicians should prescribe the smallest possible dose and try to taper and stop the drug at the earliest signs of TD. Abrupt cessation should be avoided, as this can worsen symptoms of TD. Always discuss and document the possibility of TD as an adverse effect when starting patients on DRBAs. If TD is mild and tolerable, the withdrawal of the offending agent is possible, and exposure to DRBAs was short, physicians should consider avoiding treatment and waiting for spontaneous recovery. When treatment is necessary, tetrabenazine (TBZ) is considered a potential first-line agent and is known to be one of the most effective drugs in treating TD, but it is expensive and adverse effects such as depression, akathisia and parkinsonism frequently occur. Therefore, second-line agents with better tolerability profiles are often tried first in practice. These include amantadine, benzodiazepines, beta-blockers, and levetiracetam. When using TBZ, adverse effects should be aggressively monitored. (Depression often can be managed with antidepressants, for instance). In patients with psychosis, withdrawal of the antipsychotic may not be possible. Switching to clozapine or quetiapine is one option to minimize TD. When these agents are contraindicated and the patient must continue using other atypical antipsychotic drugs, try to add dopamine-depleting agents such as TBZ or reserpine, but watch for the development of parkinsonism. When the symptoms are focal, such as tongue protrusion or blepharospasm, botulinum toxin injections can be very effective if spontaneous recovery does not occur. As a last resort, when disabling, life-threatening symptoms of TD persist despite all of the above-mentioned methods, some advocate resuming treatment with the DRBA to suppress symptoms of TD. This has the potential to worsen TD in the long run.

Therapeutic approaches to cholinergic deficiency in Lewy body diseases.

Introduction: Cortical cholinergic denervation resulting from degeneration of the nucleus basalis of Meynert (NBM) is a primary contributor to cognitive impairment and neuropsychiatric symptoms in the Lewy body diseases Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). Considering the morbidity associated with cognitive impairment and neuropsychiatric symptoms in these diseases, it is important to investigate all potential therapies to improve these symptoms.Areas covered: The authors review the current landscape of pharmacological and surgical therapies for mitigating the cortical cholinergic deficiency in PD, PDD, and DLB.Expert opinion: The cholinesterase inhibitors rivastigmine, donepezil, and galantamine are currently the primary pharmacological treatments available to improve cognition and associated neuropsychiatric symptoms in Lewy body diseases. Other possible pharmacological strategies include increasing acetylcholine release with 5-HT4 agonists or directly stimulating cholinergic receptors with muscarinic and nicotinic agonists. The side effect profile of muscarinic agonists is a deterrent to their future study, but 5-HT4 and nicotinic agonists deserve further investigation. Targeting the basal forebrain with either deep brain stimulation (DBS)- or cell-based therapies is another strategy to mitigate cortical cholinergic deficiency. Before NBM DBS studies continue, it will be important to resolve issues related to targeting, stimulation pattern, and duration.

Biobehavioral Framework of Symptom and Health Outcomes of Uncertainty and Psychological Stress in Parkinson Disease.

Parkinson disease (PD) is a debilitating, progressive neurodegenerative disorder characterized by complex motor and nonmotor symptoms that fluctuate in onset, severity, level of disability, and responsiveness to treatment. The unpredictable nature of PD and the inability to halt or slow disease progression may result in uncertainty and psychological stress. Uncertainty and psychological stress have important implications for symptom and health outcomes in PD. Uncertainty and psychological stress have been shown to worsen symptoms, functional capacity, and quality of life in chronic illnesses; however, the causal mechanisms have yet to be elucidated. We propose a biobehavioral framework for examining uncertainty and psychological stress in PD. The framework considers factors that may contribute to uncertainty and neuroendocrine-immune mechanisms of uncertainty and psychological stress that may influence symptom and health outcomes in PD, for the ultimate purpose of improving symptom and disease progression, functional capacity, and quality of life.

Control of arterial pressure by angiotensin II and nitric oxide at the onset of diabetes.

We have reported that the induction of diabetes in N(omega)-nitro-L-orginine methyl ester (L-NAME)-infused rats causes significant hypertension that is associated with increased plasma renin activity. This study tested the role of angiotensin II (Ang II) by clamping it chronically at baseline levels. The clamp consisted of an intravenous infusion of enalapril (10 mg/kg/d), which decreased mean arterial pressure (MAP) by approximately 20 mm Hg after 3 days, and adding chronic Ang II at 4 ng/kg/min, which restored MAP to normal. Chronic L-NAME infusion increased MAP to 127 +/- 1 and 132 +/- 2 mm Hg in normal and clamped rats, respectively, and induction of diabetes (streptozotocin) increased MAP progressively in normal rats to 161 +/- 8 mm Hg by day 12, whereas MAP in the clamped rats decreased progressively to 98 +/- 5 mm Hg by day 12. In non-L-NAME rats, MAP averaged 95 +/- 1 and 91 +/- 1 mm Hg for normal and clamped groups, respectively, before diabetes, and MAP was 10 to 13 mm Hg lower in the clamped versus normal rats midway through the diabetic period. This suggests that Ang II is important for maintaining blood pressure at the onset of diabetes, possibly to compensate for renal volume losses. Angiotensin II also is required for the hypertension caused by induction of diabetes in rats with chronic blockade of nitric oxide synthesis, but whether this is due to increased volume sensitivity in L-NAME-treated, vasoconstricted rats remains to be determined.

Tardive dyskinesia: therapeutic options for an increasingly common disorder.

Tardive dyskinesia (TD) is a serious, often disabling, movement disorder that is caused by medications that block dopamine receptors (i.e., neuroleptics, anti-emetics). There is currently no standard treatment approach for physicians confronted with such patients. This may be the result of notions that TD is disappearing because of the switch to second-generation antipsychotic agents and that it is largely reversible. In this article we demonstrate that second-generation antipsychotics do, indeed, cause TD and, in fact, the frequency is likely higher than expected because of growing off-label uses and a tripling of prescriptions written in the last 10 years. In addition, studies demonstrate that TD actually remits in only a minority of patients when these drugs are withdrawn. Furthermore, neuroleptic agents are often utilized to treat TD, despite prolonged exposure being a risk factor for irreversibility. The outcome of these trends is a growing population afflicted with TD. We review non-neuroleptic agents that have shown positive results in small, early-phase, blinded trials, including tetrabenazine, amantadine, levetiracetam, piracetam, clonazepam, propranolol, vitamin B6, and Ginkgo biloba. Other options, such as botulinum toxin and deep brain stimulation, will also be discussed, and a suggested treatment algorithm is provided. While these agents are reasonable treatment options at this time there is a need, with a concerted effort between neurology and psychiatry, for full-scale drug development, including multicenter, randomized, blinded trials to confirm the effectiveness of the agents that were positive in phase 2 trials and the development of newer ones.

Tardive Syndromes are Rarely Reversible after Discontinuing Dopamine Receptor Blocking Agents: Experience from a University-based Movement Disorder Clinic.

BACKGROUND: Several studies have examined reversibility of tardive syndromes (TS), primarily in psychotic patients who are maintained on dopamine receptor blocking drugs. The results have varied widely. However, few have assessed remission rates after discontinuing the offending agents. This study evaluated reversibility of TS in patients who permanently withdrew the causative agent(s). We also examined for any possible clinical predictors of reversibility. METHODS: A retrospective cohort of 108 TS patients was studied. Most of the patients were not psychotic; most patients were being treated either for a mood disorder with atypical antipsychotics or for a gastrointestinal disturbance with metoclopramide. Patients were stratified on the basis of reversibility, and statistical tests were used for subgroup comparisons of relevant clinical variables. Logistic regression was undertaken to identify clinical variables predictive of reversibility. RESULTS: Only 13% of the cohort experienced reversibility of the TS, 2% without medical intervention. When stratified by reversibility, there were no significant differences in any study variables between subgroups. None of the study variables predicted reversibility in the logistic regression. DISCUSSION: Our study demonstrated a low remission rate for TS in a cohort of psychiatric and non-psychiatric patients seen in a movement disorder clinic after the offending agents were completely withdrawn. Such a finding has significant prognostic implications. It is possible that limitations of the retrospective design may have resulted in an underestimation. There is a clear need for prospective, multicenter, clinical trials in populations that can be safely withdrawn from dopamine receptor blocking agents so that true remission rates can be measured.

Treatment strategies for dystonia.

IMPORTANCE OF THE FIELD: Dystonia is a neurological syndrome characterized by involuntary twisting movements and unnatural postures. It has many different manifestations and causes, and many different treatment options are available. These options include physical and occupational therapy, oral medications, intramuscular injection of botulinum toxins, and neurosurgical interventions. AREAS COVERED IN THIS REVIEW: In this review, we first summarize the treatment options available, then we provide suggestions from our own experience for how these can be applied in different types of dystonia. In preparing this review article, an extensive literature search was undertaken using PubMed. Only selected references from 1970 to 2008 are cited. WHAT THE READER WILL GAIN: This review is intended to provide the clinician with a practical guide to the treatment of dystonia. TAKE HOME MESSAGE: Treatment of dystonia begins with proper diagnosis and classification, followed by an appropriate search for underlying etiology, and an assessment of the functional impairment associated with the dystonia. The therapeutic approach, which is usually limited to symptomatic therapy, must then be tailored to the individual needs of the patient.