Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Clinical trials in REM sleep behavioural disorder: challenges and opportunities.

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

Comparison of tractography-assisted to atlas-based targeting for deep brain stimulation in essential tremor.

BACKGROUND: Direct targeting of the dentato-rubro-thalamic tract is efficacious in DBS for tremor suppression. OBJECTIVES: We sought to compare outcomes and optimal stimulation parameters for tremor control using the technique of directly targeting the dentato-rubro-thalamic tract to those who underwent indirect targeting of the ventral intermediate nucleus thalamus. METHODS: Twenty consecutive essential tremor patients obtained preoperative diffusion MRIs, where the dentato-rubro-thalamic tract was individually drawn and used to directly target the ventral intermediate nucleus of the thalamus during surgery. These patients were compared to an earlier cohort of 20 consecutive patients who underwent surgery using atlas-based coordinates. Baseline and 1-year postsurgery tremor amplitude using The Essential Tremor Rating Assessment Scale was recorded, as were the parameters needed for successful tremor control. RESULTS: The indirectly targeted group had greater baseline and postop tremor severity relative to those directly targeted (baseline, 2.9 vs. 2.6; P = 0.02; postop, 1.1 vs. 0.8; P = 0.03). Mean voltage, pulse width, and frequency for optimal tremor control in the directly targeted group (38 electrodes) = 2.8 V, 80 µs, 153 Hz; the parameters for the indirectly targeted group (38 electrodes) = 2.9 V, 86 µs, 179 Hz (significantly greater, P < 0.001). Both groups had significant improvement in arm tremor amplitude from baseline (P < 0.001) without sustained side effects. CONCLUSION: Direct targeting of the dentato-rubro-thalamic tract provides excellent tremor control, comparable to indirectly targeting the ventral intermediate nucleus of the thalamus. Use of lower stimulation parameters, especially frequency, to control tremor in the directly targeted group suggests that it is a more efficient targeting methodology, which may minimize battery depletion. © 2018 International Parkinson and Movement Disorder Society.

Acute and Subacute Presentations of Cerebral Edema following Deep Brain Stimulation Lead Implantation.

BACKGROUND/AIMS: Postoperative cerebral edema around a deep brain stimulation (DBS) electrode is an uncommon reported complication. The goal of this study was to identify instances of postoperative edema based on clinical presentation, and to remark on their management. METHODS: A retrospective chart review was performed on all patients who underwent DBS electrode implantation over a 3-year period. Routine CT imaging on postoperative day (POD) 1 was negative. Patients were identified based on clinical neurological changes, leading to imaging and subsequent diagnosis. RESULTS: Five of 145 patients (3.4%) presented with new neurological symptoms from POD 1 to 14, which were confirmed by CT imaging to show perilead and/or subcortical edema around 6 of 281 electrodes (2.1%). Four of 5 patients had unilateral edema despite bilateral implantation. Clinical presentations varied widely. Two patients presenting on POD 1 with deteriorating conditions required longer inpatient stays with supportive measures than those presenting later (p = 0.0002). All patients were treated with corticosteroids and returned to baseline by 3 months after surgery. CONCLUSIONS: Acute instances of DBS lead edema may occur as early as POD 1 and can rapidly progress into profound deficits. Treatment with supportive care and corticosteroids is otherwise identical to those cases presenting later.

Deep Brain Stimulation of the Dentato-Rubro-Thalamic Tract: Outcomes of Direct Targeting for Tremor.

OBJECTIVES: Targeting the dentato-rubro-thalamic tract (DRTt) has been suggested to be efficacious in deep brain stimulation (DBS) for tremor suppression, both in case reports and post-hoc analyses. This prospective observational study sought to analyze outcomes after directly targeting the DRTt in tremor patients. METHODS: 20 consecutively enrolled intention tremor patients obtained pre-operative MRI with diffusion tensor (dTi) sequences. Mean baseline tremor amplitude based on The Essential Tremor Rating Assessment Scale was recorded. The DRTt was drawn for each individual on StealthViz software (Medtronic) using the dentate nucleus as the seed region and the ipsilateral pre-central gyrus as the end region and then directly targeted during surgery. Intraoperative testing confirmed successful tremor control. Post-operative analysis of electrode position relative to the DRTt was performed, as was post-operative assessment of tremor improvement. RESULTS: The mean age of patients was 66.8 years; mean duration of tremor was 16 years. Mean voltage for the L electrode = 3.4 V; R = 2.6 V. Mean distance from the center of the active electrode contact to the DRTt was 0.9 mm on the L, and 0.8 mm on the R. Improvement in arm tremor amplitude from baseline after DBS was significant (P < 0.001). CONCLUSION: Direct targeting of the DRTt in DBS is an effective strategy for tremor suppression. Accounting for hardware, software, and model limitations, depiction of the DRTt allows for placement of electrode contacts directly within the fiber tract for modulation despite any anatomical variation, which reproducibly resulted in good tremor control.

Spasticity and intrathecal baclofen.

Severe spastic tone and/or spastic hypertonia can be the most disabling consequences of a neurologic insult, resulting from an excess of muscle tone. Baclofen, a GABA-B agonist, is one of the most widely used drugs in treating abnormal or disabling spastic tone. However, the effectiveness of baclofen taken orally is often limited by its systemic side effects, including sedation, confusion, and lethargy. Intrathecal baclofen (ITB) delivered by an implanted catheter can work directly at the spinal cord level to reduce spastic tone through presynaptic inhibition. Several decades after Penn and Kroin (1984) proved that continuous infusion of intrathecal baclofen reduced spinal cord spasticity, numerous studies have demonstrated the benefits of ITB therapy and proven its effectiveness in modulating and reducing spastic tone. In this article the authors review current methods of management with ITB therapy; summarize the current knowledge, controversies, and available scientific literature; illustrate through different clinical cases treatment strategies and their outcomes; and lastly, provide a synopsis of current clinical practice in ITB therapy with insights into new therapeutic developments.

Updated Parkinson's disease motor subtypes classification and correlation to cerebrospinal homovanillic acid and 5-hydroxyindoleacetic acid levels.

Introduction: Motor classifications of Parkinson's Disease (PD) have been widely used. This paper aims to update a subtype classification using the MDS-UPDRS-III and determine if cerebrospinal neurotransmitter profiles (HVA and 5-HIAA) differ between these subtypes in a cohort from the Parkinson's Progression Marker Initiative (PPMI). Methods: UPDRS and MDS-UPDRS scores were collected for 20 PD patients. Akinetic-rigid (AR), Tremor-dominant (TD), and Mixed (MX) subtypes were calculated using a formula derived from UPDRS, and a new ratio was developed for subtyping patients with the MDS-UPDRS. This new formula was subsequently applied to 95 PD patients from the PPMI dataset, and subtyping was correlated to neurotransmitter levels. Data were analyzed using receiver operating characteristic models and ANOVA. Results: Compared to previous UPDRS classifications, the new MDS-UPDRS TD/AR ratios produced significant areas under the curve (AUC) for each subtype. The optimal sensitivity and specificity cutoff scores were ≥0.82 for TD, ≤0.71 for AR, and >0.71 and <0.82 for Mixed. Analysis of variance showed that the AR group had significantly lower HVA and 5-HIAA levels than the TD and HC groups. A logistic model using neurotransmitter levels and MDS-UPDRS-III could predict the subtype classification. Conclusions: This MDS-UPDRS motor classification system provides a method to transition from the original UPDRS to the new MDS-UPDRS. It is a reliable and quantifiable subtyping tool for monitoring disease progression. The TD subtype is associated with lower motor scores and higher HVA levels, while the AR subtype is associated with higher motor scores and lower 5-HIAA levels.

Identifying the white matter pathways involved in multiple sclerosis-related tremor using diffusion tensor imaging.

Background: Tremor affects up to 45% of patients with Multiple Sclerosis (PwMS). Current understanding is based on insights from other neurological disorders, thus, not fully addressing the distinctive aspects of MS pathology. Objective: To characterize the brain white matter (WM) correlates of MS-related tremor using diffusion tensor imaging (DTI). Methods: In a prospective case-control study, PwMS with tremor were assessed for tremor severity and underwent MRI scans including DTI. PwMS without tremor served as matched controls. After tract selection and segmentation, the resulting diffusivity measures were used to calculate group differences and correlations with tremor severity. Results: This study included 72 PwMS. The tremor group (n = 36) exhibited significant changes in several pathways, notably in the right inferior longitudinal fasciculus (Cohen's d = 1.53, q < 0.001) and left corticospinal tract (d = 1.32, q < 0.001), compared to controls (n = 36). Furthermore, specific tracts showed a significant correlation with tremor severity, notably in the left medial lemniscus (Spearman's coefficient [rsp] = -0.56, p < 0.001), and forceps minor of corpus callosum (rsp = -0.45, p < 0.01). Conclusion: MS-related tremor is associated with widespread diffusivity changes in WM pathways and its severity correlates with commissural and sensory projection pathways, which suggests a role for proprioception or involvement of the dentato-rubro-olivary circuit.

IgA-Biome Profiles Correlate with Clinical Parkinson's Disease Subtypes.

BACKGROUND: Parkinson's disease is a heterogeneous neurodegenerative disorder with distinctive gut microbiome patterns suggesting that interventions targeting the gut microbiota may prevent, slow, or reverse disease progression and severity. OBJECTIVE: Because secretory IgA (SIgA) plays a key role in shaping the gut microbiota, characterization of the IgA-Biome of individuals classified into either the akinetic rigid (AR) or tremor dominant (TD) Parkinson's disease clinical subtypes was used to further define taxa unique to these distinct clinical phenotypes. METHODS: Flow cytometry was used to separate IgA-coated and -uncoated bacteria from stool samples obtained from AR and TD patients followed by amplification and sequencing of the V4 region of the 16 S rDNA gene on the MiSeq platform (Illumina). RESULTS: IgA-Biome analyses identified significant alpha and beta diversity differences between the Parkinson's disease phenotypes and the Firmicutes/Bacteroides ratio was significantly higher in those with TD compared to those with AR. In addition, discriminant taxa analyses identified a more pro-inflammatory bacterial profile in the IgA+ fraction of those with the AR clinical subclass compared to IgA-Biome analyses of those with the TD subclass and with the taxa identified in the unsorted control samples. CONCLUSION: IgA-Biome analyses underscores the importance of the host immune response in shaping the gut microbiome potentially affecting disease progression and presentation. In the present study, IgA-Biome analyses identified a unique proinflammatory microbial signature in the IgA+ fraction of those with AR that would have otherwise been undetected using conventional microbiome analysis approaches.