Long-Term Medication Profiles in Parkinson's Disease under Subthalamic Deep Brain Stimulation: A Controlled Study.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) reduces antiparkinsonian medications in Parkinson's disease (PD) compared with the preoperative state. Longitudinal and comparative studies on this effect are lacking. OBJECTIVE: To compare longitudinal trajectories of antiparkinsonian medication in STN-DBS treated patients to non-surgically treated control patients. METHODS: We collected retrospective information on antiparkinsonian medication from PD patients that underwent subthalamic DBS between 1999 and 2010 and control PD patients similar in age at onset and baseline, sex-distribution, and comorbidities. RESULTS: In 74 DBS patients levodopa-equivalent daily dose (LEDD) were reduced by 33.9-56.0% in relation to the preoperative baseline over the 14-year observational period. In 61 control patients LEDDs increased over approximately 10 years, causing a significant divergence between groups. The largest difference amongst single drug-classes was observed for dopamine agonists. CONCLUSION: In PD patients, chronic STN-DBS was associated with a lower LEDD compared with control patients over 14 years.

Long-term safety and efficacy of open-label nabilone on sleep and pain in Parkinson´s Disease.

The synthetic tetrahydrocannabinol-analog nabilone improved non-motor symptoms (NMS) in Parkinson's disease (PD) patients in a placebo-controlled, double-blind, parallel-group, randomized withdrawal trial with enriched enrollment (NMS-Nab-study). This was a single-center open-label extension study to assess the long-term safety and efficacy of nabilone for NMS in PD. To be eligible for this study, patients had to be treatment responders during the previous NMS-Nab-trial and complete its double-blind phase without experiencing a drug-related serious/severe/moderate adverse event (AE). Patients were re-introduced to nabilone during an up-titration phase until their overall NMS burden improved. Nabilone was continued for six months with clinic visits every 3 months. Evaluation of AEs was based on self-report and clinical assessment. Twenty-two patients participated in the NMS-Nab2-study (age-median 68.33 y, 52% females, disease duration-median 7.42 y). Nabilone was well tolerated with concentration difficulties as the most common treatment-related AE (possibly/not related n = 1 each). One in two drop-outs discontinued because of an AE for which a prohibited concomitant medication needed to be introduced (night-time sleep problems). Efficacy evaluation showed a significant and lasting improvement in NMS burden according to the CGI-I (79% at V3). Nabilone improved overall sleep (NMSS Domain-2: -8.26 points; 95%CI -13.82 to -2.71; p = 0.004; ES = -0.72), night-time sleep problems (MDS-UPDRS-1.7: -1.42 points; 95 CI -2.16 to -0.68; p = 0.002; ES = -0.92), and overall pain (KPPS Total Score: -8.00 points; 95%CI -15.05 to -0.95; p = 0.046; ES -0.55 and MDS-UPDRS-1.9: -0.74 points; 95%CI -1.21 to -0.26; p = 0.008; ES = -0.74). This study demonstrates continuous long-term safety and efficacy in PD patients responding early to nabilone without intolerable side effects.

A Blinded Evaluation of Brain Morphometry for Differential Diagnosis of Atypical Parkinsonism.

BACKGROUND: Advanced imaging techniques have been studied for differential diagnosis between PD, MSA, and PSP. OBJECTIVES: This study aims to validate the utility of individual voxel-based morphometry techniques for atypical parkinsonism in a blinded fashion. METHODS: Forty-eight healthy controls (HC) T1-WI were used to develop a referential dataset and fit a general linear model after segmentation into gray matter (GM) and white matter (WM) compartments. Segmented GM and WM with PD (n = 96), MSA (n = 18), and PSP (n = 20) were transformed into z-scores using the statistics of referential HC and individual voxel-based z-score maps were generated. An imaging diagnosis was assigned by two independent raters (trained and untrained) blinded to clinical information and final diagnosis. Furthermore, we developed an observer-independent index for ROI-based automated differentiation. RESULTS: The diagnostic performance using voxel-based z-score maps by rater 1 and rater 2 for MSA yielded sensitivities: 0.89, 0.94 (95% CI: 0.74-1.00, 0.84-1.00), specificities: 0.94, 0.80 (0.90-0.98, 0.73-0.87); for PSP, sensitivities: 0.85, 0.90 (0.69-1.00, 0.77-1.00), specificities: 0.98, 0.94 (0.96-1.00, 0.90-0.98). Interrater agreement was good for MSA (Cohen's kappa: 0.61), and excellent for PSP (0.84). Receiver operating characteristic analysis using the ROI-based new index showed an area under the curve (AUC): 0.89 (0.77-1.00) for MSA, and 0.99 (0.98-1.00) for PSP. CONCLUSIONS: These evaluations provide support for the utility of this imaging technique in the differential diagnosis of atypical parkinsonism demonstrating a remarkably high differentiation accuracy for PSP, suggesting potential use in clinical settings in the future.

Body Composition and Physical Performance 1 Year After COVID-19.

OBJECTIVE: Long-term consequences after COVID-19 include physical complaints, which may impair physical recovery and quality of life. DESIGN: We assessed body composition and physical ability in patients 12 months after COVID-19. Consecutively recruited patients recovering from mild to severe COVID-19 were assessed using bioelectrical impedance analysis, 6-min-walk test, additional scales for physical performance and health-related quality of life. RESULTS: Overall physical recovery was good (i.e., Glasgow Outcome Scale-Extended ≥7 in 96%, Modified Rankin Scale ≤1 in 87%, Eastern Cooperative Oncology Group ≤1 in 99%). Forty-four percent of the 69 patients experienced a significant body mass index increase in the year after COVID-19 (≥1 kg/m 2 ), whereas skeletal muscle mass index was reduced in only 12%. Patients requiring intensive care treatment ( n = 15, 22%) during acute COVID-19 more often had a body mass index increase ( P = 0.002), worse 6-min-walk test-performance ( P = 0.044), and higher body fat mass ( P = 0.030) at the 1-yr follow-up when compared with patients with mild ( n = 22, 32%) and moderate ( n = 32, 46%) acute COVID-19. Body mass index increase was also more frequent in patients who had no professional rehabilitation ( P = 0.014). CONCLUSIONS: Although patients with severe COVID-19 had increased body mass index and body fat and performed worse in physical outcome measures 1 yr after COVID-19, overall physical recovery was satisfying. Translating these findings to variants beyond the Alpha strain of severe acute respiratory syndrome coronavirus 2 virus needs further studies.

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.

OBJECTIVE: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years. RESULTS: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17). INTERPRETATION: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543.

Distinct smell and taste disorder phenotype of post-acute COVID-19 sequelae.

PURPOSE: Olfactory dysfunction (OD) commonly accompanies coronavirus disease 2019 (COVID-19). We investigated the kinetics of OD resolution following SARS-CoV-2 infection (wild-type and alpha variant) and its impact on quality of life, physical and mental health. METHODS: OD prevalence was assessed in an ambulatory COVID-19 survey (n = 906, ≥ 90 days follow-up) and an observational cohort of ambulatory and hospitalized individuals (n = 108, 360 days follow-up). Co-occurrence of OD with other symptoms and effects on quality of life, physical and mental health were analyzed by multi-dimensional scaling, association rule mining and semi-supervised clustering. RESULTS: Both in the ambulatory COVID-19 survey study (72%) and the observational ambulatory and hospitalized cohort (41%) self-reported OD was frequent during acute COVID-19. Recovery from self-reported OD was slow (survey: median 28 days, observational cohort: 90 days). By clustering of the survey data, we identified a predominantly young, female, comorbidity-free group of convalescents with persistent OD and taste disorders (median recovery: 90 days) but low frequency of post-acute fatigue, respiratory or neurocognitive symptoms. This smell and taste disorder cluster was characterized by a high rating of physical performance, mental health, and quality of life as compared with convalescents affected by prolonged fatigue or neurocognitive complaints. CONCLUSION: Our results underline the heterogeneity of post-acute COVID-19 sequelae calling for tailored management strategies. The persistent smell and taste disorder phenotype is characterized by good clinical, physical, and mental recovery and may pose a minor challenge for public health. STUDY REGISTRATION: ClinicalTrials.gov: NCT04661462 (survey study), NCT04416100 (observational cohort).

Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.

Dorsolateral Nigral Hyperintensity on 1.5 T Versus 3 T Susceptibility-Weighted Magnetic Resonance Imaging in Neurodegenerative Parkinsonism.

Background: An absent dorsolateral nigral hyperintensity (DNH) is a common finding in patients with neurodegenerative parkinsonism at high or ultra-high field susceptibility-weighted magnetic resonance imaging (SWI). Objective: Despite increasing use of high field magnetic resonance imaging (MRI) in specialized centers, these scanners are still frequently unavailable in primary care or outpatient facilities and underdeveloped or emerging countries. Therefore, the aim of the present study was to evaluate the diagnostic utility of DNH assessment at 1.5 versus 3 T MRI to distinguish patients with neurodegenerative parkinsonism, including Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), from healthy controls (HC). Methods: Absence of DNH was assessed on visual inspection of anonymized 1.5 T and 3.0 T SWI scans in a case-control study including 86 patients with neurodegenerative parkinsonism and 33 healthy controls (HC). All study participants were consecutively recruited to undergo 1.5 and 3 T MRI. Results: Overall correct classification was 81.7% (95% CI, 72.6-88.4%) for 1.5 T and 95.7% (95% CI, 89.1-98.7%) for 3 T MRI in discriminating neurodegenerative parkinsonism from controls. However, while DNH was bilaterally present in all but one of the HC at 3 T MRI, it was rated as abnormal (at least unilateral absence) in 15 of 22 HC at 1.5 T MRI, resulting in a specificity of 31.8%. Conclusions: The results of the present study demonstrate an insufficient specificity of visual assessment of DNH at 1.5 T MRI for the diagnosis of neurodegenerative parkinsonism.

Pimavanserin: A Truly Effective Treatment for Parkinson's Disease Psychosis? A Review of Interventions.

Parkinson's disease (PD) is the second-most common neurodegenerative disorder with a long-term 60% cumulative prevalence of PD psychosis. Medical treatment is limited to few atypical antipsychotic drugs with low affinity to dopamine D2 receptors. In 2016, pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved by the US Food and Drug Administration (FDA) as the only treatment for PD psychosis (PDP). This article provides an overview of the epidemiology, pathophysiology, and treatment options for PDP and illuminates the mode of action and therapy options with pimavanserin and the current study data.

α-Synuclein Seed Amplification Assays in the Diagnosis of Synucleinopathies Using Cerebrospinal Fluid-A Systematic Review and Meta-Analysis.

Background: Real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) have been developed to detect minute amounts of amyloidogenic proteins via amplification techniques and have been used to detect misfolded α-synuclein (αSyn) aggregates in the cerebrospinal fluid (CSF) and other source materials of patients with Parkinson's Disease and other synucleinopathies. Objectives: The aim of this systematic review and meta-analysis was to evaluate the diagnostic accuracy of αSyn seed amplification assays (αSyn-SAAs), including RT-QuIC and PMCA, using CSF as source material to differentiate synucleinopathies from controls. Methods: The electronic MEDLINE database PubMed was searched for relevant articles published until June 30, 2022. Study quality assessment was performed using the QUADAS-2 toolbox. A random effects bivariate model was exploited for data synthesis. Results: Our systematic review identified 27 eligible studies according to the predefined inclusion criteria, of which 22 were included in the final analysis. Overall, 1855 patients with synucleinopathies and 1378 non-synucleinopathies as control subjects were included in the meta-analysis. The pooled sensitivity and specificity to differentiate synucleinopathies from controls with αSyn-SAA were 0.88 (95% CI, 0.82-0.93) and 0.95 (95% CI, 0.92-0.97), respectively. Evaluating the diagnostic performance of RT-QuIC in a subgroup analysis for the detection of patients with multiple system atrophy the pooled sensitivity decreased to 0.30 (95% CI, 0.11-0.59). Conclusions: While our study clearly demonstrated a high diagnostic performance of RT-QuIC and PMCA for differentiating synucleinopathies with Lewy bodies from controls, results for the diagnosis of multiple system atrophy were less robust.

Temporal Muscle Thickness Correlates with Sarcopenia in Parkinson's Disease.

BACKGROUND: Sarcopenia is characterized by a progressive loss of muscle mass, strength, and function resulting in adverse health outcomes. Current assessment strategies are bothersome and means to simplify the diagnosis are an unmet medical need in Parkinson's disease (PD). OBJECTIVE: To evaluate temporal muscle thickness (TMT) obtained on routine cranial MRI as a surrogate marker of sarcopenia in PD patients. METHODS: We correlated TMT from axial non-contrast-enhanced T1-weighted sequences of MRI close (±12 months) to an outpatient visit including sarcopenia (EWGSOP1, EWGSOP2, SARC-F), frailty (Fried's criteria, clinical frailty scale), and disease characteristics of Parkinson's patients (Hoehn and Yahr-scale, Movement Disorder Society-Unified Parkinson's Disease Rating Scale, quality of life with the Parkinson's Disease Questionnaire-8) assessments. RESULTS: Cranial MRI was available in 32 patients with a mean age of 73.56±5.14 years, mean disease duration of 11.46±5.66 years, and median Hoehn and Yahr stage of 2.5. The mean TMT was 7.49±2.76 (7.15) mm. Mean TMT was significantly associated with sarcopenia (EWGSOP2, p = 0.018; EWGSOP1, p = 0.023) and frailty status (physical phenotype; p = 0.045). Moreover, there were significant moderate to strong correlations between TMT measurement and appendicular skeletal muscle mass index (r: 0.437, p = 0.012), as well as handgrip strength (r: 0.561, p < 0.001). CONCLUSION: Reduced TMT seems to be a promising surrogate marker for sarcopenia (EWGSOP2) and muscle strength in this pilot study in PD patients.

Anti-IgLON5 Disease with Isolated Hemichorea: A Case Report and Review of the Literature.

Background: Anti-IgLON5 disease is an autoimmune encephalopathy with sleep disturbances as a hallmark in the majority of reported cases. Additional clinical symptoms are heterogenous and include movement disorders, bulbar dysfunction, autonomic disorders, and neurocognitive impairment. Case: Here, we report the case of an 87-year-old woman presenting with isolated progressive hemichorea. An extensive diagnostic work-up revealed antibodies against IgLON5 in the serum. Neither history nor polysomnography (PSG) unveiled signs and features of sleep dysfunction typically reported in anti-IgLON5 disease. Literature Review: In an extensive literature review we identified twelve other studies reporting about patients with confirmed anti-IgLON5 disease and chorea as extrapyramidal movement disorder in their clinical phenotype. Subsequently, clinical characteristics of these patients were carefully evaluated. Conclusions: Our results support the diversity of clinical phenotypes in anti-IgLON5 disease, adding isolated hemichorea to the spectrum of presenting symptoms. As sleep-related disorders are often not the leading reason for consultation and only revealed by PSG examination, we suggest that screening for antibodies against IgLON5 should be considered in patients presenting with unexplained movement disorders, including isolated hemichorea.

Symptomatic Care in Multiple System Atrophy: State of the Art.

Without any disease-modifying treatment strategy for multiple system atrophy (MSA), the therapeutic management of MSA patients focuses on a multidisciplinary strategy of symptom control. In the present review, we will focus on state of the art treatment in MSA and additionally give a short overview about ongoing randomized controlled trials in this field.

Nomogram to Predict the Probability of Functional Dependence in Early Parkinson's Disease.

BACKGROUND: Early identification of Parkinson's disease (PD) patients at risk for becoming functionally dependent is important for patient counseling. Several models describing the relationship between predictors and outcome have been reported, however, most of these require computer software for practical use. OBJECTIVE: Here we report the development of a risk nomogram allowing an approximate graphical computation of the risk of becoming functionally dependent in early PD. METHODS: We analyzed data form the Parkinson's Progression Markers Initiative cohort of newly diagnosed PD patients from baseline through the first 5 years of follow-up. Functional dependence was defined as a score < 80 on the Schwab & England Activities of Daily Living scale. A binary logistic model was developed to estimate the risk of functional dependence and based on the results, a nomogram for the prediction of functional dependence was drawn in order to provide an easy-to-use tool in clinical and academic settings as a part of personalized medicine approach to PD treatment. RESULTS: At baseline, three patients and over the five-year follow-up, 85 (22%) out of 395 patients were functionally dependent as scored by the Schwab & England Activities of Daily Living rating scale. The binary logistic model showed that clinical parameters such as MDS-UPDRS I (rater part), MDS-UPDRS II, and MDS-UPDRS axial motor score were significant predictors for functional dependence within 5 years. CONCLUSION: We here provide an easy-to-use tool to estimate the risk of functional dependence in PD patients based on the MDS-UPDRS part I, II and axial motor score.

Cognitive dysfunction 1 year after COVID-19: evidence from eye tracking.

Increasing evidence suggests persistent cognitive dysfunction after COVID-19. In this cross-sectional study, frontal lobe function was assessed 12 months after the acute phase of the disease, using tailored eye tracking assessments. Individuals who recovered from COVID-19 made significantly more errors in all eye tracking tasks compared to age/sex-matched healthy controls. Furthermore, patients who were treated as inpatients performed worse compared to outpatients and controls. Our results show impaired inhibitory cortical control in individuals who recovered from COVID-19. The association between disease severity and its sequelae may contribute to a better understanding of post-COVID-19 cognitive function.

Effects of Nabilone on Sleep Outcomes in Patients with Parkinson's Disease: A Post-hoc Analysis of NMS-Nab Study.

Background: The synthetic tetrahydrocannabinol analogue nabilone improved overall non-motor symptom (NMS) burden in Parkinson's disease (PD) patients in comparison to placebo. Objectives: To characterize the effects of nabilone on different sleep outcomes in PD patients. Methods: We performed a post-hoc analysis of the controlled, double-blind, enriched enrollment randomized withdrawal NMS-Nab study to assess the effects of nabilone on sleep outcomes in study participants who reported clinically-relevant sleep problems (MDS-UPDRS-1.7 ≥ 2 points). Results: After open-label nabilone administration, 77.4% reported no relevant sleep problem. In the withdrawal phase of the trial, the MDS-UPDRS-1.7. and the NMS-Scale Domain 2 (i.e., Sleep/Fatigue) significantly worsened only in PD patients in the placebo group, which was mostly driven by a significant worsening of insomnia (question 5 of the NMS-Scale Domain 2). Conclusions: This post-hoc analysis of the NMS-Nab trial suggests that nabilone has beneficial effects on sleep outcomes in PD patients experiencing sleep problems at baseline.The original trial was registered with ClinicalTrials.gov (NCT03769896, https://clinicaltrials.gov/ct2/show/NCT03769896) and EudraCT (2017-000192-86).

Hospital Admissions of Huntington's Disease Patients in a Huntington's Disease Centre Between 2011 and 2016: A Retrospective Analysis.

Background: Huntington's Disease (HD) is a relentlessly progressive genetic neurodegenerative disorder with characteristic motor, psychiatric, and behavioral abnormalities that inevitably results in severe disability and death. Many patients have multiple hospital admissions during the disease course, but there is limited information which problems lead to hospitalization. Objectives: To assess acute reasons for hospital admissions, discharge routes, and clinical characteristics of HD patients in a retrospective analysis. Methods: We reviewed all medical records of patients with an established diagnosis of Huntington's Disease and hospital admissions between 2011 and 2016 in our local hospital-based database. Results: There were 135 hospital admissions in 53 HD patients during the review period, representing a median of two admissions per patient. Median duration of hospitalization was seven days. The most frequent reason for admission was a worsening of HD motor symptoms (n = 77, 57.0%) such as chorea, parkinsonism, gait problems, falls, and dysphagia. Psychiatric symptoms related to HD were the second most common reason for admission (n = 58, 43.0%). Infections (including aspiration pneumonia) and traumas/surgical procedures were only responsible for 6.7% and 5.9% of admissions, respectively. Emergency admissions were not common (42.2%), and the majority of patients were able to return to their previous residency upon discharge (85.2%, home or nursing home). Recurrent admissions were associated with worse motor function and functional capacity. Conclusions: Worsening of motor and psychiatric symptoms associated with Huntington's Disease were the most common reasons for hospital admissions. Therefore, our data highlight the importance of optimal symptom control in HD patients.

Eye Tracking in Patients with Parkinson's Disease Treated with Nabilone-Results of a Phase II, Placebo-Controlled, Double-Blind, Parallel-Group Pilot Study.

The topic of the therapeutic use of cannabinoids in Parkinson's disease (PD) is broadly discussed and frequently comes up in the outpatient clinic. So far, there are only a few randomized clinical trials assessing the effects of cannabinoids in PD. We are able to demonstrate a reduction in non-motor symptom (NMS) burden after the administration of nabilone. As impairment of attention and working memory have been described earlier as possible side effects, we assess cognitive performance using saccadic paradigms measured by an eye tracker. We do not observe a significant difference in any of the saccadic paradigms between PD patients on placebo versus those treated with nabilone. We, therefore, conclude that top-down inhibitory control is not affected by the tetrahydrocannabinol analogue. Nabilone did not significantly worsen cognitive performance and appears to be safe to use in selected PD patients who suffer from disabling NMS.