Search

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 [ r s p ] = -0.56, p  < 0.001), and forceps minor of corpus callosum ( r s p  = -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., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: The intestinal microbiome plays a primary role in the pathogenesis of neurodegenerative disorders and may provide an opportunity for disease modification. We performed a pilot clinical study looking at the safety of fecal microbiota transplantation (FMT), its effect on the microbiome, and improvement of symptoms in Parkinson's disease., Methods: This was a randomized, double-blind placebo-controlled pilot study, wherein orally administered lyophilized FMT product or matching placebo was given to 12 subjects with mild to moderate Parkinson's disease with constipation twice weekly for 12 weeks. Subjects were followed for safety and clinical improvement for 9 additional months (total study duration 12 months)., Results: Fecal microbiota transplantation caused non-severe transient upper gastrointestinal symptoms. One subject receiving FMT was diagnosed with unrelated metastatic cancer and was removed from the trial. Beta diversity (taxa) of the microbiome, was similar comparing placebo and FMT groups at baseline, however, for subjects randomized to FMT, it increased significantly at 6 weeks ( p = 0.008) and 13 weeks ( p = 0.0008). After treatment with FMT, proportions of selective families within the phylum Firmicutes increased significantly, while proportion of microbiota belonging to Proteobacteria were significantly reduced. Objective motor findings showed only temporary improvement while subjective symptom improvements were reported compared to baseline in the group receiving FMT. Constipation, gut transient times (NS), and gut motility index ( p = 0.0374) were improved in the FMT group., Conclusions: Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms., Clinical Trial Registration: ClinicalTrial.gov, identifier: NCT03671785., Competing Interests: HD and Z-DJ have applied for a patent for the FMT product used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 DuPont, Suescun, Jiang, Brown, Essigmann, Alexander, DuPont, Iqbal, Utay, Newmark and Schiess.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

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.

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.

Our objective is to derive a sequential decision-making rule on the combination of medications to minimize motor symptoms using reinforcement learning (RL). Using an observational longitudinal cohort of Parkinson's disease patients, the Parkinson's Progression Markers Initiative database, we derived clinically relevant disease states and an optimal combination of medications for each of them by using policy iteration of the Markov decision process (MDP). We focused on 8 combinations of medications, i.e., Levodopa, a dopamine agonist, and other PD medications, as possible actions and motor symptom severity, based on the Unified Parkinson Disease Rating Scale (UPDRS) section III, as reward/penalty of decision. We analyzed a total of 5077 visits from 431 PD patients with 55.5 months follow-up. We excluded patients without UPDRS III scores or medication records. We derived a medication regimen that is comparable to a clinician's decision. The RL model achieved a lower level of motor symptom severity scores than what clinicians did, whereas the clinicians' medication rules were more consistent than the RL model. The RL model followed the clinician's medication rules in most cases but also suggested some changes, which leads to the difference in lowering symptoms severity. This is the first study to investigate RL to improve the pharmacological approach of PD patients. Our results contribute to the development of an interactive machine-physician ecosystem that relies on evidence-based medicine and can potentially enhance PD management.

Background: There is considerable debate regarding the use of intraoperative microelectrode recording (MER) in deep brain stimulation (DBS)., Objective: To determine if the use of intraoperative MER impacts the final position of the lead implant in DBS of the subthalamic nucleus (STN) and globus pallidus (GPi) and to evaluate the incidence of complications., Methods: The authors conducted a retrospective chart review of all patients who underwent STN and GPi DBS with MER, at the University of Texas Health Science Center in Houston from June 1, 2009 to October 1, 2013 to compare initial and final coordinates. Hemorrhagic and infectious complications were reviewed., Results: A total of 90 lead implants on 46 patients implanted at the center during this time period were reviewed and included in the study. A statistically significant difference between the initial and final coordinates was observed in the superior-inferior direction with a mean difference of 0.40 mm inferiorly (±0.96 mm, P<0.05) and 0.96 mm inferiorly (±1.32 mm, P<0.05) in the STN and GPi locations, respectively. A nonstatistically significant difference was also observed in the anterior-posterior direction in both locations. There were no intraparenchymal hemorrhages on postoperative computed tomography. Two patients developed postoperative seizures (7.4%). One STN electrode (1.1%) required revision because of a suboptimal response., Conclusions: Intraoperative MER in STN and GPi DBS implant does not seem to have a higher rate of surgical complications compared with historical series not using MER and might also be useful in determining the final lead location.

Objective: To assist in the assessment of intrathecal baclofen (ITB) therapy risks and benefits by providing surgical intervention rate, safety, and elective device replacement rate data., Materials and Methods: An ongoing prospective, long-term, multicenter Product Surveillance Registry (PSR) (NCT01524276) enrolled consented patients implanted with the SynchroMed II infusion system. Pump and catheter performance data were collected, with patients followed prospectively for events related to the device, procedure, and therapy. Investigators provided event descriptions, patient symptoms, and patient outcomes., Results: We analyzed registry data from 1743 patients (77% adult, 46.8% female) treated with ITB for severe spasticity at 53 registry sites between August 2003 and October 2017, for an accumulated 6481 patient-years. Discontinuation from the registry was largely (58.6% of discontinued patients) due to study site closure and patient relocation; exit due to an adverse event was limited to 0.3%. After 10 years, 87.2% of adult and 76.3% of pediatric patients continued with ITB. Overall, 99.1% of pumps reaching end of battery life were replaced at the time of explant., Conclusions: ITB therapy for the treatment of severe spasticity requires surgical implantation of a programmable infusion system for chronic drug delivery. If complications arise, many necessitate surgical intervention for correction. For spinal and cerebral spasticity in pediatric and adult patients, discontinuation rates due to an adverse event were low (0.3%), and there was high acceptance (99.1%) of surgical intervention for therapy continuation. Patient/caregiver willingness to accept surgical and other risks for therapy continuation was extremely high., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals, Inc. on behalf of International Neuromodulation Society.)

Low levels of the natural antioxidant uric acid (UA) and the presence of REM sleep behavior disorder (RBD) are both associated with an increased likelihood of developing Parkinson's disease (PD). RBD and PD are also accompanied by basal ganglia dysfunction including decreased nigrostriatal and nigrocortical resting state functional connectivity. Despite these independent findings, the relationship between UA and substantia nigra (SN) functional connectivity remains unknown. In the present study, voxelwise analysis of covariance was used in a cross-sectional design to explore the relationship between UA and whole-brain SN functional connectivity using the eyes-open resting state fMRI method in controls without RBD, patients with idiopathic RBD, and PD patients with and without RBD. The results showed that controls exhibited a positive relationship between UA and SN functional connectivity with left lingual gyrus. The positive relationship was reduced in patients with RBD and PD with RBD, and the relationship was found to be negative in PD patients. These results are the first to show differential relationships between UA and SN functional connectivity among controls, prodromal, and diagnosed PD patients in a ventral occipital region previously documented to be metabolically and structurally altered in RBD and PD. More investigation, including replication in longitudinal designs with larger samples, is needed to understand the pathophysiological significance of these changes., (Copyright © 2020 Ellmore, Suescun, Castriotta and Schiess.)

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., Competing Interests: Competing interests: AV reports personnel fees from Acorda, Acadia, Pfizer, Theranexus, Jazz and Wilson Therapeutics. IA reports personal fees from Roche Pharma and UCB Pharma. BH reports personal fees from Jazz, Ono, Axovant, Benevolent Bio, Mundipharma, Roche, Takeda, AoP Orphan, Jazz, Abbvie, AoP, Lundbeck, Eli Lilly, Otsuka, Janssen Cilag, Inspire and Habel Medizintechnik. FP reports personal fees from Vanda Pharmaceutical, Sanofi, Zambon, Fidia, Bial, Eisai Japan and Italfarmaco. CHS reports personal fees from Axovant. CT reports personal fees from Britannia, Roche, UCB, Gruenenthal and Otsuka., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and is one of the leading sources of morbidity and mortality in the aging population. There is a long preclinical period followed by mild cognitive impairment (MCI). Clinical diagnosis and the rate of decline is variable. Progression monitoring remains a challenge in AD, and it is imperative to create better tools to quantify this progression. Brain magnetic resonance imaging (MRI) is commonly used for patient assessment. However, current approaches for analysis require strong a priori assumptions about regions of interest used and complex preprocessing pipelines including computationally expensive non-linear registrations and iterative surface deformations. These preprocessing steps are composed of many stacked processing layers. Any error or bias in an upstream layer will be propagated throughout the pipeline. Failures or biases in the non-linear subject registration and the subjective choice of atlases of specific regions are common in medical neuroimaging analysis and may hinder the translation of many approaches to the clinical practice. Here we propose a data-driven method based on an extension of a deep learning architecture, DeepSymNet, that identifies longitudinal changes without relying on prior brain regions of interest, an atlas, or non-linear registration steps. Our approach is trained end-to-end and learns how a patient's brain structure dynamically changes between two-time points directly from the raw voxels. We compare our approach with Freesurfer longitudinal pipelines and voxel-based methods using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our model can identify AD progression with comparable results to existing Freesurfer longitudinal pipelines without the need of predefined regions of interest, non-rigid registration algorithms, or iterative surface deformation at a fraction of the processing time. When compared to other voxel-based methods which share some of the same benefits, our model showed a statistically significant performance improvement. Additionally, we show that our model can differentiate between healthy subjects and patients with MCI. The model's decision was investigated using the epsilon layer-wise propagation algorithm. We found that the predictions were driven by the pallidum, putamen, and the superior temporal gyrus. Our novel longitudinal based, deep learning approach has the potential to diagnose patients earlier and enable new computational tools to monitor neurodegeneration in clinical practice., (Copyright © 2019 Pena, Barman, Suescun, Jiang, Schiess, Giancardo and the Alzheimer's Disease Neuroimaging Initiative.)

Parkinson's disease is the second most prevalent neurodegenerative disorder in the Western world. It is estimated that the neuronal loss related to Parkinson's disease precedes the clinical diagnosis by more than 10 years (prodromal phase) which leads to a subtle decline that translates into non-specific clinical signs and symptoms. By leveraging diffusion magnetic resonance imaging brain (MRI) data evaluated longitudinally, at least at two different time points, we have the opportunity of detecting and measuring brain changes early on in the neurodegenerative process, thereby allowing early detection and monitoring that can enable development and testing of disease modifying therapies. In this study, we were able to define a longitudinal degenerative Parkinson's disease progression pattern using diffusion magnetic resonance imaging connectivity information. Such pattern was discovered using a de novo early Parkinson's disease cohort ( n = 21), and a cohort of Controls ( n = 30). Afterward, it was tested in a cohort at high risk of being in the Parkinson's disease prodromal phase ( n = 16). This progression pattern was numerically quantified with a longitudinal brain connectome progression score. This score is generated by an interpretable machine learning (ML) algorithm trained, with cross-validation, on the longitudinal connectivity information of Parkinson's disease and Control groups computed on a nigrostriatal pathway-specific parcellation atlas. Experiments indicated that the longitudinal brain connectome progression score was able to discriminate between the progression of Parkinson's disease and Control groups with an area under the receiver operating curve of 0.89 [confidence interval (CI): 0.81-0.96] and discriminate the progression of the High Risk Prodromal and Control groups with an area under the curve of 0.76 [CI: 0.66-0.92]. In these same subjects, common motor and cognitive clinical scores used in Parkinson's disease research showed little or no discriminative ability when evaluated longitudinally. Results suggest that it is possible to quantify neurodegenerative patterns of progression in the prodromal phase with longitudinal diffusion magnetic resonance imaging connectivity data and use these image-based patterns as progression markers for neurodegeneration.

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., (© 2018 International Parkinson and Movement Disorder Society.)

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., (© 2017 International Neuromodulation Society.)

Current clinical diagnostic tools are limited in their ability to accurately differentiate idiopathic Parkinson's disease (PD) from multiple system atrophy (MSA) and other parkinsonian disorders early in the disease course, but eye movements may stand as objective and sensitive markers of disease differentiation and progression. To assess the use of eye movement performance for uniquely characterizing PD and MSA, subjects diagnosed with PD ( N  = 21), MSA ( N  = 11), and age-matched controls (C, N  = 20) were tested on the prosaccade and antisaccade tasks using an infrared eye tracker. Twenty of these subjects were retested ~7 months later. Saccade latencies, error rates, and longitudinal changes in saccade latencies were measured. Both PD and MSA patients had greater antisaccade error rates than C subjects, but MSA patients exhibited longer prosaccade latencies than both PD and C patients. With repeated testing, antisaccade latencies improved over time, with benefits in C and PD but not MSA patients. In the prosaccade task, the normal latencies of the PD group show that basic sensorimotor oculomotor function remain intact in mid-stage PD, whereas the impaired latencies of the MSA group suggest additional degeneration earlier in the disease course. Changes in antisaccade latency appeared most sensitive to differences between MSA and PD across short time intervals. Therefore, in these mid-stage patients, increased antisaccade errors combined with slowed prosaccade latencies might serve as a useful marker for early differentiation between PD and MSA, and, antisaccade performance, a measure of MSA progression. Together, our findings suggest that eye movements are promising biomarkers for early differentiation and progression of parkinsonian disorders.

OBJECTIVE Patients with Parkinson disease (PD) who undergo subthalamic nucleus (STN) deep brain stimulation (DBS) often develop a deterioration in speech performance, but there is no clear consensus on the specific effects seen or the mechanism involved and little description of the impact of DBS on conversational speech. Furthermore, there has been no fiber tract connectivity analysis to identify the structures potentially modulated by DBS to cause such deficits. The main objective of this study was to quantify spontaneous speech performance and identify potential involvement of the dentatorubrothalamic tract (DRTt) in patients who underwent STN DBS, because this tract has been implicated in speech deterioration. METHODS Spontaneous speech samples were obtained with STN DBS in both on and off modes in 35 patients with PD and assessed across multiple domains. Diffusion tensor imaging tractography seeded from the therapeutic DBS contacts was performed to identify the fiber tracts involved and, specifically, the DRTt. The position of active electrode contacts was assessed relative to that of the STN. RESULTS Fifteen patients with akinetic-rigid (AR) PD and 20 with tremor-dominant (TD) PD subtypes were identified. In the AR-PD subgroup of patients, in whom there was DRTt involvement, 71% demonstrated much better overall speech and largely improved or unchanged fluency in the DBS-off condition. In patients with TD PD with DRTt involvement, 50% demonstrated better overall speech in the off condition, and equivocal results regarding improved or worsened fluency were found. When there was minimal DRTt involvement, 75% of patients with AR PD had better overall speech in the DBS-on condition and better or minimal fluency changes. Similarly, 83% of patients with TD PD with minimal DRTt involvement had better or minimal overall speech and fluency changes in the on condition. More medially placed left electrode contacts were associated with more DRTt involvement in 77% of patients (10 of 13). CONCLUSIONS To the authors' knowledge, this is the first study to have investigated a specific fiber tract involved in STN DBS in different subtypes of PD relative to its impact on spontaneous speech. At optimal therapeutic programming of STN DBS, overall spontaneous speech and fluency were affected more negatively in patients with AR PD than in those with TD PD when there was DRTt involvement. After fiber tract analysis and modeling, it was found that medially positioned left electrode contacts more often involved fibers of the DRTt. If possible, avoidance of the DRTt by using active electrode contacts that are positioned less medially, specifically in patients with AR PD, might result in less speech deterioration.

Neuromodulation of subcortical areas of the brain as therapy to reduce Parkinsonian motor symptoms was developed in the mid-twentieth century and went through many technical and scientific advances that established specific targets and stimulation parameters. Deep Brain Stimulation (DBS) was approved by the FDA in 2002 as neuromodulation therapy for advanced Parkinson's disease, prompting several randomized controlled trials that confirmed its safety and effectiveness. The implantation of tens of thousands of patients in North America and Europe ignited research into its potential role in early disease stages and the therapeutic benefit of DBS compared to best medical therapy. In 2013 the EARLY-STIM trial provided Class I evidence for the use of DBS earlier in Parkinson's disease. This finding led to the most recent FDA approval in patients with at least 4 years of disease duration and 4 months of motor complications as an adjunct therapy for patients not adequately controlled with medications. This following review highlights the historical development and advances made overtime in DBS implantation, the current application, and the challenges that come with it.

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., (© 2017 S. Karger AG, Basel.)

Background: Specific factors in Parkinson's disease have become targets as to their protective and degenerative effects. We have demonstrated that cytokines and PD-CSF detrimentally affect microglia and astrocyte growth. While glial cell-derived neurotrophic factor (GDNF) has been recognized as a possible neuron-rescue agent, nitric oxide synthase (NOS) has been implicated in neurodegenerative processes., Objective: To demonstrate that glial cell activation, cytokine production, and NOS induction, play an intimate role in the loss of dopaminergic signaling, via mechanisms that are a result of inflammation and inflammatory stimuli., Methods: Study animals were sacrificed following endotoxin treatment and tissue sections were harvested and probed for GDNF and NOS isomers by fluorescence deconvolution microscopy. Fluorescence was mapped and quantified for each probe., Results: An immune cell influx into 'vulnerable' areas of the brain was seen, and three NOS isomers, inducible (iNOS), neuronal (nNOS) and endothelial (eNOS), were synthesized in the brains, a finding which suggests that each isomer has a role in neurodegeneration. eNOS was found associated with blood vessels, while iNOS was associated with glial and matrix cells and nNOS was located with both glia and neurons. Following endotoxin treatment, serum levels of nitric oxide were higher at 6-8 hours, while tissue levels of NOS were elevated for much longer. Thus, induction of NOS occurred earlier than the induction of GDNF., Conclusion: Our findings suggest that the protective abilities of GDNF to combat neural destruction are not available rapidly enough, and do not remain at sufficiently high levels long enough to assert its protective effects. (250).

In 2005, a European expert panel developed and validated an electronic tool to support the appropriate referral of patients with Parkinson's disease (PD) for the consideration of deep brain stimulation (DBS). Since new evidence has become available over the last decade an update of the tool is necessary. A world-wide expert panel (71 neurologists and 11 neurosurgeons) used the RAND/UCLA Appropriateness Method to assess the appropriateness of referral for 1296 scenarios (9-point scale). Scenarios were permutations of 8 clinical variables relevant to the decision of referral. Appropriateness of referral was calculated on the basis of the median score and the extent of agreement. Compared to 2005, the impact of clinical variables on the appropriateness of referral was similar for severity of on-off fluctuations, dyskinesias and refractory tremor (positive association, p < 0.001), and cognitive impairment (negative association, p < 0.001). A relatively stronger negative impact was seen for levodopa-unresponsive gait and balance disturbances as well as older age, the latter most likely due to a higher cut-off value (75 versus 70 years in the previous study). The impact of PD duration on the appropriateness of referral was less pronounced than in 2005. The contribution of the newly included variable 'non-motor side effects of anti-PD medication' was very modest. Based on these results the panel produced new recommendations on the appropriateness of referral for the evaluation of DBS in PD patients. Differences from the previous study reflect the new clinical evidence, particularly related to the use of DBS in an earlier stage of PD. The validation of the updated recommendations is in progress.

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., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Diffusion tensor imaging (DTI) is a form of MRI that has been used extensively to map in vivo the white matter architecture of the human brain. It is also used for mapping subcortical nuclei because of its general sensitivity to tissue orientation differences and effects of iron accumulation on the diffusion signal. While DTI provides excellent spatial resolution in individual subjects, a challenge is visualizing consistent patterns of diffusion orientation across subjects. Here we present a simple method for averaging direction-encoded color anisotropy maps in standard space, explore this technique for visualizing the substantia nigra (SN) in relation to other midbrain structures, and show with signal-to-noise analysis that averaging improves the direction-encoded color signature. SN is distinguished on averaged maps from neighboring structures, including red nucleus (RN) and cerebral crus, and is proximal to SN location from existing brain atlases and volume of interest (VOI) delineation on individual scans using two blinded raters., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Study Objectives: Rapid eye movement sleep behavior disorder (RBD) is a condition closely associated with Parkinson disease (PD). RBD is a sleep disturbance that frequently manifests early in the development of PD, likely reflecting disruption in normal functioning of anatomical areas affected by neurodegenerative processes. Although specific neuropathological aspects shared by RBD and PD have yet to be fully documented, further characterization is critical to discovering reliable biomarkers that predict PD onset. In the current study, we tested the hypothesis of altered functional connections of the substantia nigra (SN) in patients in whom RBD was diagnosed., Design: Between-groups, single time point imaging., Setting: UTHSC-H 3 telsa MRI center., Participants: Ten patients with RBD, 11 patients with PD, and 10 age-matched controls., Interventions: NA., Measurements and Results: We measured correlations of SN time series using resting state blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) in patients with idiopathic RBD who were at risk for developing PD, patients in whom PD was diagnosed, and age-matched controls. Using voxelwise analysis of variance, different correlations (P < 0.01, whole-brain corrected) between left SN and left putamen were found in patients with RBD compared with controls and patients with PD. SN correlations with right cuneus/precuneus and superior occipital gyrus were significantly different for patients with RBD compared with both controls and patients with PD., Conclusions: The results suggest that altered nigrostriatal and nigrocortical connectivity characterizes rapid eye movement sleep behavior disorder before onset of obvious motor impairment. The functional changes are discussed in the context of degeneration in dopaminergic and cognition-related networks.

This study examined inflammatory cell and cytokine production in brain tissue from a lipopolysaccharide (LPS)-treated rat model that mimics many of the neuropathologic changes associated with neurodegenerative diseases We also monitored the appearance of a glial cell line-derived neurotrophic factor (GDNF) and circulating nitric oxide (NO) levels, as well as an immune system-associated cells in a selected area of the brain, the olfactory lobe. The studies were based on the hypothesis that LPS treatment stimulates temporal changes within the brain and that these responses include immune cell recruitment, increased tissue levels of immune modulating cytokines and NO, as well as greater glial cell activation resulting in increased production of GDNF. As previously reported by other investigators, our animal model of systemic LPS treatment leads to an increase in the concentrations of circulating cytokines, including TNF-α, IL-Iβ, and IL-6, with a maximum response 6 h post LPS administration. Concomitant with cytokine elevations, circulating NO levels were elevated for several hours post LPS administration. The brain content of the GDNF was also elevated over a similar time frame. Lymphocytes, neutrophils, macrophages, plasma cells, and cytokines were all seen in various areas of LPS-treated brains, often around blood vessels associated with the meninges, with these localizations possibly indicating involvement of both the blood-brain and blood-cerebral spinal fluid barriers in these inflammatory episodes. Our results suggest an involvement of both the peripheral and the central nervous system immune components in response to inflammation and inflammatory episodes. This leads us to propose that inflammation initiates an immune response by activating both microglia and astrocytes and that the presence of continuing and increasing proinflammatory mechanisms results in a situation, where cellular protective mechanisms are overcome and the more susceptible cells enter into cell death pathways, initiating a train of events that is a major part of neurodegeneration.

Importance: Histoplasmosis, a systemic mycosis caused by the fungus Histoplasma capsulatum, primarily affects immune-suppressed patients and commonly involves the lung and rarely the central nervous system (CNS). Herein, we report a case of isolated CNS histoplasmosis presenting with pontine stroke and meningitis., Observations: A 35-year-old, white, immune-competent man was transferred from an outside facility with worsening dysarthria and confusion after having presented 4 weeks prior with dysarthria, gait ataxia, and bilateral upper extremity weakness. Brain magnetic resonance imaging revealed bilateral pontine strokes, and the working diagnosis was ischemic infarctions, presumed secondary to small vessel vasculitis. Cerebral spinal fluid (CSF) examination showed marked abnormalities including an elevated protein level (320 mg/dL), low glucose level (2 mg/dL), and high white blood cell count (330/mm(3); 28% lymphocytes, 56% neutrophils, and 16% monocytes) suggestive of a bacterial, fungal, or tuberculosis meningitis. Empirical antibiotics and a second trial of intravenous steroids were started before infectious etiologies of meningitis were ultimately ruled out. Repeated magnetic resonance imaging of the brain revealed no evidence of new ischemic lesions. On hospital day 11, results of his CSF Histoplasma antigen and urine antigen tests were positive. His CSF culture also was positive for H capsulatum. The patient was treated initially with liposomal amphotericin B, 430 mg daily, but changed to voriconazole, 300 mg twice daily, secondary to renal insufficiency and eventually continued treatment with itraconazole cyclodextrin, 100 mg twice daily. Computed tomographic imaging revealed obstructive hydrocephalus, and a ventriculoperitoneal shunt was placed that successfully decompressed the ventricles. At 1 year, the patient demonstrated good clinical improvement and results of follow-up CSF cultures were negative., Conclusions and Relevance: While pulmonary involvement of histoplasmosis in immune-suppressed patients is common, systemic presentation of this fungal infection in immune-competent patients is rare and self-limiting. Isolated CNS histoplasmosis is exceedingly rare. Clinicians should consider CNS histoplasmosis in the differential diagnosis in atypical stroke cases, particularly those presenting with meningitis.

Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson's disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129 together with total α-synuclein in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total α-synuclein concentrations in CSF, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether the concentration of PS-129 in CSF will be useful for diagnosing PD and for monitoring PD severity and progression.

α-synuclein is thought to play a key role in Parkinson's disease (PD) because it is the major protein in Lewy bodies, and because its gene mutations, duplication, and triplication are associated with early-onset PD. There are conflicting reports as to whether serum and plasma concentrations of α-synuclein and anti-α-synuclein antibodies differ between PD and control subjects. The objectives of this study were to compare the levels of α-synuclein and its antibodies between individuals with typical PD (n=14), atypical Parkinson syndromes (n=11), idiopathic rapid eye movement sleep behavior disorder (n=10), and healthy controls (n=9), to assess the strength of association between these serum proteins, and to determine group sizes needed for a high probability (80% power) of detecting statistical significance for 25% or 50% differences between typical PD and control subjects for these measurements. Analysis of log-transformed data found no statistically significant differences between groups for either α-synuclein or its antibodies. The concentrations of these proteins were weakly correlated (Spearman rho=0.16). In subjects with typical PD and atypical Parkinson syndromes, anti-α-synuclein antibody levels above 1.5 µg/ml were detected only in subjects with no more than four years of clinical disease. Power analysis indicated that 236 and 73 samples per group would be required for an 80% probability that 25% and 50% differences, respectively, in mean α-synuclein levels between typical PD and control subjects would be statistically significant; for anti-α-synuclein antibodies, 283 and 87 samples per group would be required. Our findings are consistent with those previous studies which suggested that serum concentrations of α-synuclein and its antibodies are not significantly altered in PD.

Objectives: Evaluate the benefit of intrathecal baclofen (ITB) therapy on function, quality of life, and progression in patients with multiple system atrophy (MSA)., Methods: We report on three MSA patients at different stages treated with ITB therapy. MSA patients were staged using Watanabe et al. ADL milestones for disease progression and by scales for tone (modified Ashworth scale) ambulation (Hauser ambulation index) and disability (expanded disability status scale), Results: All three patients had an improvement in the modified Ashworth scale and none had progression in their disability or ambulatory outcomes and did not progress as predicted by Watanabe et al., Conclusions: Our results suggest that ITB can maintain (or improve function) and maintain quality of life in patients with MSA. ITB is currently not indicated for patients with MSA but should be studied further for the quality of life benefits and delay in disease progression it potentially provides., (© 2011 International Neuromodulation Society.)

Objectives: To assess the effects of intrathecal baclofen (ITB) therapy for the treatment of poststroke spastic hemiparesis on quality of life, functional independence, and upper, lower extremity (UE, LE) motor functions., Materials and Methods: Prospective observational study of adult men and women with a minimum 6-month stroke-related spastic hemiparesis graded as ≥2 in UE and LE on Modified Ashworth Scale (MAS). Patients served as their own controls with measures compared pre-implant with 12 months post ITB including: MAS, manual muscle test (MMT), gait distance/velocity, Functional Independence Measures (FIM), stroke-specific quality of life scale (SSQL), and upper extremity manual activity log., Results: After 12-month ITB therapy, 26 patients (poststroke=6.4±9 years) demonstrated 1) reduced MAS/increased MMT for most LE muscle groups (p≤0.0001); 2) reduced MAS/increased MMT most UE muscle groups (p≤0.01); 3) FIM scores improved (p≤0.05) except bed mobility and lower body dressing; 4) gait distance and velocity improved (p≤0.05); 5) SSQL domains of family roles, mobility, personality, self-care, social roles, thinking, UE function, and work/productivity improved (p≤0.05); 6) amount of use and quality of movement of the spastic UE in performing common activities of daily living increased (p<0.0001)., Conclusions: Regardless of duration of spastic hemiparesis, a reduction in tone with ITB therapy facilitates motor strength improvement and is associated with clinically significant improvements in functional independence and quality of life., (© 2010 International Neuromodulation Society.)

Objective: The purpose of this study was to quantify volumes of specific subcortical gray matter nuclei implicated in Parkinson's disease (PD) as a preliminary step for identifying a non-invasive clinical biomarker for PD. We hypothesized that REM sleep behavior disorder (RBD) patients, at risk for developing PD, will demonstrate a pattern of neuronal degeneration reflected in reduced striatal volumes on T1-weighted MRI., Methods: We compared measures of RBD patients confirmed by polysomnography (PSG) with groups of age/gender-matched Control subjects and early PD (EPD) patients (Hoehn & Yahr < 2). Clinical measurements included the Unified Parkinson's disease Rating Scales (UPDRS), timed gait and finger tapping tasks, the Parkinson's Disease Questionnaire (PDQ-39), and a time-synchronized video recorded single-night PSG. Volumetric measurements were derived from high-resolution T1-weighted 3 T MRI images., Results: The matched Control and EPD groups were statistically similar to the RBD group in age, gender, handedness, and total brain volumes. The RBD group had smaller bilateral putamen volumes (both raw and normalized by brain tissue volume), in addition to some clinical impairment on the UPDRS and PDQ-39., Conclusions: Reduced putamen volumes may be a structural marker for RBD and reflect a pattern of neurodegeneration that predicts the development of PD., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Excessive and abnormal accumulation of alpha-synuclein (α-synuclein) is a factor contributing to pathogenic cell death in Parkinson's disease. The purpose of this study, based on earlier observations of Parkinson's disease cerebrospinal fluid (PD-CSF) initiated cell death, was to determine the effects of CSF from PD patients on the functionally different microglia and astrocyte glial cell lines. Microglia cells from human glioblastoma and astrocytes from fetal brain tissue were cultured, grown to confluence, treated with fixed concentrations of PD-CSF, non-PD disease control CSF, or control no-CSF medium, then photographed and fluorescently probed for α-synuclein content by deconvolution fluorescence microscopy. Outcome measures included manually counted cell growth patterns from day 1-8; α-synuclein density and distribution by antibody tagged 3D model stacked deconvoluted fluorescent imaging., Results: After PD-CSF treatment, microglia growth was reduced extensively, and a non-confluent pattern with morphological changes developed, that was not evident in disease control CSF and no-CSF treated cultures. Astrocyte growth rates were similarly reduced by exposure to PD-CSF, but morphological changes were not consistently noted. PD-CSF treated microglia showed a significant increase in α-synuclein content by day 4 compared to other treatments (p ≤ 0.02). In microglia only, α-synuclein aggregated and redistributed to peri-nuclear locations., Conclusions: Cultured microglia and astrocytes are differentially affected by PD-CSF exposure compared to non-PD-CSF controls. PD-CSF dramatically impacts microglia cell growth, morphology, and α-synuclein deposition compared to astrocytes, supporting the hypothesis of cell specific susceptibility to PD-CSF toxicity.

Human derived glioblastoma cells were cultured and treated with cytokines interleukin-6 (IL6), tumor necrosis factor alpha (TNF) and interferon-gamma (IFN) and imaged by fluorescence deconvolution microscopy to localize alpha-synuclein, tau and ubiquitin. Exposures were for short (2 h) and prolonged times (up to 96 h), with doses at both low (10 ng/ml), and high (100 ng/ml) concentrations. Further experiments used additive doses up to 200 ng/ml (2 x 100 ng), mimicking a super-infection state. Single, low doses of the cytokines initiated changes in levels of intracellular proteins, but these changes, be they increases or decreases, were not sustained, so we added higher doses of cytokine to the culture medium or fresh aliquots of cytokines over time. Finally, we treated cells with high, single doses of cytokine (200 ng/ml), to try to sustain perturbations of the proteins with cytokines. IFN caused a disruption and reduction of peripheral synuclein, TNF treatment resulted in increased levels of ubiquitin and IL6 disrupted and appeared to fragment tau. Of note, each of the proteins was found in a specific locale, tau being perinuclear, ubiquitin residing in the cytoplasm, and alpha-synuclein occupying the tips of cellular processes, exhibiting the characteristics of an adhesion protein/molecule [Word count=198].

The purpose of this study was to determine the effects of specific proinflammatory cytokines interleukin-6 (Il-6), interleukin-1beta (Il-1beta), interferon-gamma (IFN), and tumor necrosis factor-alpha (TNFalpha), on content and distribution of alpha-synuclein (alpha-synuclein), tau and ubiquitin in human derived cultured glial cells. Exposure paradigms mimicked acute (2 h), intermediate (18 h) and prolonged time frames (96 h); consisting of single or repeated low doses (10 ng/ml) or high doses (50 ng/ml), consistent with either mild or serious systemic infectious/inflammatory responses. Images of intracellular protein content and distribution were reconstructed from emission patterns generated by fluorescence deconvolution microscopy. Minor alterations were seen in protein content with IFN; Il-1beta decreased alpha-synuclein and tau at 18 and 96 h; TNFalpha inversely reduced alpha-synuclein and increased ubiquitin content. Combinations of Il-1beta and IFN produced a robust increase of alpha-synuclein and tau at 2 h. Consecutive low doses of Il-6 produced only minor increases in alpha-synuclein and ubiquitin after 4 h, whereas a single high dose resulted in major increases for all three proteins over the first 18 h. Protein localization patterns were distinctly different and were altered dependent upon cytokine treatment. A high dose exposure (2 x 50 ng/ml) with Il-6 and IFN demonstrated that protein increases and dispersals could be sustained and that the normal perinuclear tau and peripheral alpha-synuclein patterns were disrupted. These results support the postulate that specific cytokines affect temporal protein changes with concomitant pattern disruptions, possibly reflecting a mechanism of cell dysfunction in Parkinson's degeneration.

Background: The integrity of frontal systems responsible for voluntary control and their interaction with subcortical regions involved in reflexive responses were studied in patients with Parkinson's disease (PD). Previous studies have shown that patients with PD have impaired executive function, including deficits in attention, motor planning and decision making., Methods: Executive function was measured through eye movements: reflexive (stimulus driven) prosaccades and voluntary (internally guided) antisaccades. Patients with advanced idiopathic PD, off and on their optimal levodopa therapy, were tested on a prosaccade and an antisaccade task and compared with matched controls., Results: Levodopa significantly increased response time for reflexive prosaccades and reduced error rate for voluntary antisaccades., Conclusions: Consistent with our proposed model, patients with PD in the medicated state are better able to plan and execute voluntary eye movements. These findings suggest levodopa improves function of the voluntary frontostriatal system, which is deficient in PD.

Intrathecal baclofen (ITB) therapy has been increasingly employed for the management of poststroke spastic hypertonia, a complication that can lead to deformity, discomfort, and exacerbation of motor impairments. Because its use in stroke is not as established as other indications, ITB therapy has not been subjected to rigorous investigation. There is limited evidence to guide clinicians regarding application of this therapy in this patient population. This article aims to review the available scientific literature and the opinion of several experts on the topic. It will also describe the recommendations of these experts with regard to addressing common clinical situations that may influence treatment decisions in the stroke population.

In an attempt to distinguish and define the altered cognitive processes associated with Parkinson's disease (PD), we examine and try to dissociate the components of an effective voluntary saccade: (1) the planning and execution of a voluntary saccade; (2) the suppression of reflexive eye movements; and (3) the working memory processes required. We tested 14 PD patients (off their medications) and 11 control subjects on antisaccade (AS), delayed antisaccade (DAS), and remembered antisaccade (RAS) paradigms. The three tasks required identical responses, each task only differing in a single manipulation for direct comparison--a delay period was added in the DAS, and the target was removed during the delay period of the RAS--allowing us to study the specific cognitive processes involved in the execution of a voluntary saccade. Voluntary saccade response times were longer in the PD group compared to controls on all three tasks, suggesting difficulties in voluntary saccade execution. Furthermore, PD patients showed difficulty suppressing reflexive saccades (increased number of errors in the AS task and increased number of disinhibitions in the DAS task). Finally, our study did not show significant differences in either response time or error rate between the RAS and the DAS tasks for either control subjects or PD patients. In sum, we report evidence for voluntary saccade execution deficits together with problems inhibiting reflexive saccades in Parkinson's disease patients. These findings were correlated with each other and disease severity, suggesting that eye movement measurement may be a useful tool for studying higher cognitive function.

The purpose of this study is to elucidate the mechanism of action and site of action of calcitonin gene-related peptide (CGRP) and its effects on calcium concentrations in two types of cardiomyocytes, neonatal and adult, by employing real-time fluorescence imaging. CGRP caused an increase in intramyocytic calcium with adult cells, but a decrease with neonates. Treatment of adult myocytes with ouabain and ryanodine yielded results suggesting that CGRP action is not at the ryanodine receptor (RyR) and does not involve Na+ +K+ ATPase. Furthermore, in neonatal cardiomyocytes CGRP caused a reduction in intramyocytic calcium levels, and challenges with ryanodine and ouabain gave results supporting the hypothesis that CGRP acts at the sarcolemmal L-type calcium channel. Employing real-time fluorescence measurements in cultured, dedifferentiated adult cardiomyocytes, which are known to express a fetal phenotype and exhibit neonatal-like calcium transients, our acquisitions demonstrated a major reduction in intracellular calcium levels. Finally, our collaborative studies in human myocardium using fluorescence deconvolution microscopy revealed that CGRP localization was found in a pattern similar to that of the sarcolemmal L-type calcium channel.

CGRP has potent cardiovascular effects but its role in heart failure is unclear. Effects of CGRP on calcium concentrations in fresh adult rat cardiomyocytes, cultured adult cardiomyocytes and neonatal cardiomyocytes were determined by real time fluorescence spectrophotometry. Treatment of cultured adult cardiomyocytes with CGRP resulted in a rapid cessation of beating and a reduction in intracellular calcium. Similar results were obtained in cultured neonatal myocytes. However, rod-shaped adult cardiomyocytes revealed a number of responses; (a) non-beating cells began to beat with increased intracellular calcium; (b) spontaneously beating cells exhibited increased intracellular calcium content and a faster beating rate or (c), myocytes increased their beating rate and became arrhythmic, suggesting that CGRP action on cultured dedifferentiated adult and neonatal myocytes depletes intracellular calcium, whereas in the rod-shaped mature myocytes calcium is retained, pointing to a different mode of action for CGRP on developing and dedifferentiating cardiomyocytes, compared to fully developed cardiomyocytes.

The purpose of this study was to localize sites of calcitonin gene-related peptide binding in neonatal, freshly isolated and dedifferentiated adult cardiac myocytes in order to help us elucidate the mechanisms of action of this neuropeptides. Previous work has shown that treatment with calcitonin gene-related peptide results in dramatic changes in calcium transients, so we carried out multi-channel acquisitions of fluorescently labeled images to reveal where calcitonin gene-related protein and the L-type calcium channel were localized. Calcitonin gene-related protein was sparse and randomly distributed in rod-like adult cardiomyocytes, found in abundance in areas of the cell where striations were apparent and not where adhesion proteins predominated in dedifferentiating adult myocytes, and in a large perinuclear concentration, with some spreading into the cytoplasm in neonatal cells. Subsequent modeling demonstrated that calcitonin gene-related peptide and the L-type calcium channel protein were closely associated in each of the three myocyte types, suggesting that while the peptide has dramatic and different effects on intracellular calcium levels of the various cardiomyocytes, the action is probably via diverse mechanisms as a result of effects on different channels or pump proteins due to alterations in intracellular calcium concentrations.

The current study presents preliminary data regarding the development and validation of a rating system designed to classify PD patients into clinical subgroups. Using portions of the Unified Parkinson's Disease Rating Scale, a ratio value was derived, yielding three patient subtypes: a tremor-dominant group (T), an akinetic-rigid group (AR), and a mixed group (MX). Validation of the schema was conducted by grouping PD surgical candidates into specific disease subtypes and evaluating differences in neurotransmitter profiles among disease subtypes and non-PD neurological controls. High pressure liquid chromatography analysis of ventricular cerebrospinal fluid indicated 5-hydroxyindoleacetic acid was significantly lower in the AR and MX groups compared to non-PD controls; whereas, glycine was significantly higher in the AR group compared to the T, MX, and control groups. The results suggest that an operational approach can be utilized to differentiate between PD subtypes with distinct neurochemical profiles.

Forty central amygdala neurons labelled with 2% Neurobiotin were categorized according to their distinctive bioelectrical membrane properties and classified physiologically by their hyperpolarized resting membrane potential (-74 mV), short duration medium afterhyperpolarization (239.2 ms), and non-accommodating response as Type A neurons (63%; N = 25/40), or as Type B neurons (37%; N = 15/40) by their depolarized resting membrane potential (-66 mV), long slow-afterhyperpolarization (1.8 s), and accommodation response. Visualized within subnuclei of the central amygdala, Neurobiotin-labelled Type A neurons were medium-size cells [16.5 +/- 3 x 10.7 +/- 2 mu m; length x width] with smooth, spine-free ovoid, pyramiform, and fusiform perikarya. Aspinous primary dendrites gave rise to distal dendrites covered with numerous small pedunculated spines; density of spines ranged from sparse to abundant. Type B central amygdala neurons were larger cells [23.9 +/- 5 x 14.9 +/- 4 mu m] with smooth, aspinous ovoid, polygonal, and pyramiform somata. Dendrites were aspinous and covered with variably sized varicosities. Two distinct populations of neurons exist within the central amygdaloid complex: the medium-size, spine-laden Type A defined neuron with its non-accommodating electrophysiological response and the larger aspinous, varicosity-laden Type B defined neuron with its accommodating response. In contrast to their neighboring "cortical-like" amygdala neurons, central amygdala neurons possess a "striatal-like" cytoarchitecture and electrophysiology., (Copyright 1999 Wiley-Liss, Inc.)