Learning Phenotypic Associations for Parkinson's Disease with Longitudinal Clinical Records.

Parkinson's disease (PD) is associated with multiple clinical motor and non-motor manifestations. Understanding of PD etiologies has been informed by a growing number of genetic mutations and various fluid-based and brain imaging biomarkers. However, the mechanisms underlying its varied phenotypic features remain elusive. The present work introduces a data-driven approach for generating phenotypic association graphs for PD cohorts. Data collected by the Parkinson's Progression Markers Initiative (PPMI), the Parkinson's Disease Biomarkers Program (PDBP), and the Fox Investigation for New Discovery of Biomarkers (BioFIND) were analyzed by this approach to identify heterogeneous and longitudinal phenotypic associations that may provide insight into the pathology of this complex disease. Findings based on the phenotypic association graphs could improve understanding of longitudinal PD pathologies and how these relate to patient symptomology.

Neurologic and psychiatric features of impending neurodegeneration in iRBD.

Introduction: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is linked to Parkinson's disease and other alpha-synucleinopathies, but various subsets of iRBD may not carry equal risk (i.e., those with depression are at higher risk than those without). Here, we prospectively focus on neurologic and psychiatric aspects of subjects with iRBD, in an attempt to determine what factors are prominent in those who undergo phenoconversion as opposed to those who do not. Methods: We analyzed data from the "REM Sleep Behavior Disorder Associations with Parkinson's Disease Study (RAPiDS)" cohort both at baseline and then at follow-up evaluations (1 to 3 years later) utilizing several neurologic batteries, including the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Montreal Cognitive Assessment (MoCA), the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP), the 10-M Walk Test (10MWT), and the Epworth Sleepiness Scale. Determination of phenoconversion was ascertained from physical examination and medical chart review from the initial evaluation onward. Results: Of those who completed both evaluations, there were 33 subjects with iRBD, with an average age of 63.1 ± 12.8 years, with 9 women and 24 men. Of these, 8 (24%) iRBD subjects developed neurodegenerative illness, and demonstrated multiple areas of neurologic and psychiatric signs and symptoms, such as speech and movement problems as well as anxiety and depression. Conclusions: Our data adds to the literature regarding risk of phenoconversion in those with iRBD. Further study will be needed, but it is clear that not all subjects with iRBD present the same risk for neurodegeneration.

Can google glass™ technology improve freezing of gait in parkinsonism? A pilot study.

PURPOSE: Freezing of gait (FOG) is a disabling phenomenon defined by the periodic absence or reduction of forward progression of the feet despite the intention to walk. We sought to understand whether Google Glass (GG), a lightweight wearable device that provides simultaneous visual-auditory cues, might improve FOG in parkinsonism. METHODS: Patients with parkinsonism and FOG utilized GG custom-made auditory-visual cue applications: "Walk With Me" and "Unfreeze Me" in a single session intervention. We recorded ambulation time with and without GG under multiple conditions including 25 feet straight walk, dual task of performing serial 7's while straight walking, 180 degree turn after walking 25 feet, and walking through a doorway. FOG and patient experience questionnaires were administered. RESULTS: Using the GG "Walk With Me" program, improvements were noted in the following: average 25 feet straight walk by 0.32 s (SD 2.12); average dual task of serial 7's and 25 feet straight walk by 1.79 s (SD 2.91); and average walk through doorway by 0.59 s (SD 0.81). Average 180 degree turn after 25 feet walk worsened by 1.89 s (SD 10.66). Using the "Unfreeze Me" program, only the average dual task of serial 7's and 25 feet straight walk improved (better by 0.82 s (SD 3.08 sec). All other tasks had worse performance in terms of speed of completion. CONCLUSION: This feasibility study provides preliminary data suggesting that some walking tasks may improve with GG, which uses various musical dance programs to provide visual and auditory cueing for patients with FOG.IMPLICATIONS FOR REHABILITATIONFreezing of gait in parkinsonian syndromes is a disabling motor block described by patients as having their feet stuck to the floor leading to difficulty in initiation of gait and increased risk for falls.Wearable assistive devices such as Google Glass™ use visual and auditory cueing that may improve gait pattern in patients with freezing of gait.Augmented reality programs using wearable assistive devices are a home-based therapy, with the potential for reinforcing physical therapy techniques; this is especially meaningful during the COVID-19 pandemic when access to both medical and rehabilitative care has been curtailed.

Tablet-based patient educational interventions in care and management of complex movement disorders.

BACKGROUND: Patient education is an essential part of management of complex, disabling neurological disorders. Mobile web-based educational materials provide a novel and potentially valuable means to communicate clinical information that can aid in both medical management and rehabilitation. AIMS: We, therefore, evaluated an educational tablet-based intervention in three patient cohorts regarding the following topics: Parkinson's disease (PD) medications, dystonia and botulinum toxin treatment. METHODS: A total of 50 subjects with PD, 32 with dystonia and 61 receiving botulinum toxin treatment for movement disorders or sialorrhoea were enrolled. Participants in each cohort completed a specific educational module at the time of their regularly scheduled clinic visit, comprising slides, in addition to pre- and post-module quizzes and a satisfaction survey. Additionally, participants in the dystonia and botulinum toxin modules were given a follow-up test at their 3- or 6-month clinical treatment visit. RESULTS: There were 143 participants with 50 completing the PD module, 32 completing the dystonia module and 61 completing the botulinum toxin module. All three groups demonstrated significant improvement in knowledge of module content between their pre- and post-module test scores (PD: p=.0001, dystonia: p<.0001 and botulinum toxin: p=.008), and those who took the dystonia module maintained significant improvement at either a 3- or 6-month follow up compared to pre-module (p <.0001). CONCLUSIONS: Tablet-based teaching modules are an effective means of communicating key concepts to patients. This study supports their use for improving patient understanding that can support lifelong approaches to managing disabling, neurological conditions.Implication for RehabilitationTablet-based modules are relatively easy to use for enhancing education during clinic visits and can possibly help reduce and maintain disability with chronic conditions like Parkinson's disease and dystonia.Improvements in post-test scores suggested that patient participants were able to retain information from the tablets about their complex and challenging conditions and treatments.Adding patients who are fluent in another language would have made this study more generalizable and future studies exploring educational interventions are warranted to help better tailor interventions to patients with chronic neurologic illnesses to help understand the complex aspects of their medical and rehabilitation therapy.The effect of cognitive changes in neurological conditions and understanding of educational information needs to be further tested.This positive result is especially meaningful during the COVID-19 pandemic when in-person access to both medical and rehabilitative care has been curtailed.

Clinical Review of Smartphone Applications in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is the second leading neurodegenerative disease worldwide. Important advances in monitoring and treatment have been made in recent years. This article reviews literature on utility of smartphone applications in monitoring PD symptoms that may ultimately facilitate improved patient care, and on movement modulation as a potential therapeutic. REVIEW SUMMARY: Novel mobile phone applications can provide one-time and/or continuous data to monitor PD motor symptoms in person or remotely, that may support precise therapeutic adjustments and management decisions. Apps have also been developed for medication management and treatment. CONCLUSIONS: Smartphone applications provide a wide array of platforms allowing for meaningful short-term and long-term data collection and are also being tested for intervention. However, the variability of the applications and the need to translate complicated sensor data may hinder immediate clinical applicability. Future studies should involve stake-holders early in the design process to promote usability and streamline the interface between patients, clinicians, and PD apps.

Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy.

Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget's disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group's conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.

Baseline Differences in Long-term Survivors and Nonsurvivors of the Colorado/Columbia Fetal Implant Trial.

OBJECTIVE: This study is based on long-term follow-up of participants in a randomized double-blind sham surgery-controlled trial (1995-1999) designed to determine the effectiveness of implantation of human embryonic mesencephalic tissue containing dopamine neuron precursors into the brains of patients with advanced Parkinson's disease (PD). We investigated differences between long-term survivors and nonsurvivors at baseline in order to contribute to information regarding optimal patient selection for upcoming stem cell trials. METHOD: Forty participants were randomly assigned to receive either neural implantation or sham surgery. Thirty-four patients who ultimately received the implant were followed periodically with the most recent assessment occurring in 2015-2016. Demographic information, neurological measures, positron emission tomography (PET) imaging, neuropsychological assessments, and a personality assessment were included in the current analyses. T-tests were used to compare survivors and nonsurvivors. Logistic regression analyses examined predictors of survivorship. RESULTS: Five of six survivors were female. They were younger than nonsurvivors (p = .03) and more neuropsychologically "intact" across a broad range of cognitive areas (significance levels ranged from <.001 to .045). There were no differences between survivors and nonsurvivors off medications at baseline on neurological or PET assessments. Survivors reported more "Openness to Experience" (p = .004) than nonsurvivors. Using empirically derived predictor variables, results of logistic regression analyses indicated that Animal Naming (cognitive task) and Openness to Experience (personality variable) were the strongest predictors of survivorship. CONCLUSIONS: Variables to consider when selecting participants for future cell-based therapies include being "intact" neuropsychologically, level of Openness to Experience, younger age, and inclusion of women.

Characteristics and Outcomes of Parkinson's Disease Individuals Hospitalized with COVID-19 in a New York City Hospital System.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused worse health outcomes among elderly populations with specific pre-existing medical conditions and chronic illnesses. There are limited data on health outcomes of hospitalized Parkinson's disease (PD) individuals infected with COVID-19. Objectives: To determine clinical characteristics and outcomes in hospitalized PD individuals infected with COVID-19. Methods: Individuals admitted to NewYork-Presbyterian with a diagnosis of PD were retrospectively identified using an electronic medical record system. Clinical characteristics and mortality were abstracted. Results: Twenty-five individuals with PD, mostly male (76%) with a median age of 82 years (IQR 73-88 years), were hospitalized for COVID-19 infection. A total of 80% of individuals had mid-stage to advanced PD (Hoehn and Yahr 3-5) and 80% were on symptomatic pharmacologic therapy, most commonly levodopa (72%). The most common comorbidities were hypertension (72%) and mild cognitive impairment or dementia (48%). A total of 44% and 12% of individuals presented with altered mental status and falls, respectively. Mortality rate was 32% compared to 26% for age-matched controls (P = 0.743). Individuals who died were more likely to have encephalopathy during their admission (88% vs. 35%; P < 0.03). Conclusion: PD individuals who require hospitalization for COVID-19 infection are likely to be elderly, have mid-stage to advanced disease, and be on pharmacologic therapy. Hypertension and cognitive impairment are common comorbidities in these individuals and encephalopathy during hospitalization is associated with risk of death. Altered mental status and falls are clinical presentations of COVID-19 infection in PD that clinicians should be aware of. A diagnosis of PD is not a risk factor for COVID-19 mortality.

Comprehensive subtyping of Parkinson's disease patients with similarity fusion: a case study with BioFIND data.

Parkinson's disease (PD) is a complex neurodegenerative disorder with diverse clinical manifestations. To better understand this disease, research has been done to categorize, or subtype, patients, using an array of criteria derived from clinical assessments and biospecimen analyses. In this study, using data from the BioFIND cohort, we aimed at identifying subtypes of moderate-to-advanced PD via comprehensively considering motor and non-motor manifestations. A total of 103 patients were included for analysis. Through the use of a patient-wise similarity matrix fusion technique and hierarchical agglomerative clustering analysis, three unique subtypes emerged from the clustering results. Subtype I, comprised of 60 patients (~58.3%), was characterized by mild symptoms, both motor and non-motor. Subtype II, comprised of 20 (~19.4%) patients, was characterized by an intermediate severity, with a high tremor score and mild non-motor symptoms. Subtype III, comprised of 23 (~22.3%) patients, was characterized by more severe motor and non-motor symptoms. These subtypes show statistically significant differences when looking at motor (on and off medication) clinical features and non-motor clinical features, while there was no clear difference in demographics, biomarker levels, and genetic risk scores.

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.

Contemporary Neuroscience Core Curriculum for Medical Schools.

Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also, because the nervous system plays such a critical role in the function of every organ system. Due to the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the pre-clerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are re-assessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the pre-clerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors.

Comparison of the Parkinson's KinetiGraph to off/on levodopa response testing: Single center experience.

BACKGROUND AND OBJECTIVE: Levodopa off/on testing is frequently performed to assess medication response in patients with Parkinson's disease (PD) as an aid in determining best medical management or potential surgical candidacy. The Parkinson's Kinetigraph (PKG) is a wearable device which generates tremor, bradykinesia (BKS) and dyskinesia (DKS) scores representing motor symptoms over a six-day period. In this study, we compared off/on testing with PKG motor scores. METHODS: Patients were enrolled as part of an observational study: Assessing the Longitudinal Signs in PD, a three-year study evaluating clinical and biomarker evolution in patients with PD taking levodopa. Patients underwent off/on testing at baseline and 6-month visits. A greater than 30% improvement between off and on MDS-Unified Parkinson's Disease Rating Scale scores was considered a robust response. After each visit, patients wore the PKG for 6 days. A bradykinesia score (BKS) greater than 26 and dyskinesia score (DKS) greater than 9 were considered poorly controlled bradykinesia and dyskinesia, respectively. RESULTS: The median BKS at the baseline and 6-month visits were 27.15 and 27.55, respectively, despite a robust median off/on improvement at both visits. In addition, 10/18 (66%) and 7/13 (53.8%) patients with robust off/on improvement at the baseline and 6-month visits, respectively, demonstrated a BKS > 26 or DKS > 9. CONCLUSION: A robust off/on response during a clinic visit does not necessarily reflect adequately controlled motor symptoms. The PKG, by virtue of its continuous recording of motor movements, may provide additional clinically relevant data on motor symptoms which may be useful for prospective observational studies.

Population-based input function for TSPO quantification and kinetic modeling with [11C]-DPA-713.

INTRODUCTION: Quantitative positron emission tomography (PET) studies of neurodegenerative diseases typically require the measurement of arterial input functions (AIF), an invasive and risky procedure. This study aims to assess the reproducibility of [11C]DPA-713 PET kinetic analysis using population-based input function (PBIF). The final goal is to possibly eliminate the need for AIF. MATERIALS AND METHODS: Eighteen subjects including six healthy volunteers (HV) and twelve Parkinson disease (PD) subjects from two [11C]-DPA-713 PET studies were included. Each subject underwent 90 min of dynamic PET imaging. Five healthy volunteers underwent a test-retest scan within the same day to assess the repeatability of the kinetic parameters. Kinetic modeling was carried out using the Logan total volume of distribution (VT) model. For each data set, kinetic analysis was performed using a patient-specific AIF (PSAIF, ground-truth standard) and then repeated using the PBIF. PBIF was generated using the leave-one-out method for each subject from the remaining 17 subjects and after normalizing the PSAIFs by 3 techniques: (a) Weightsubject×DoseInjected, (b) area under AIF curve (AUC), and (c) Weightsubject×AUC. The variability in the VT measured with PSAIF, in the test-retest study, was determined for selected brain regions (white matter, cerebellum, thalamus, caudate, putamen, pallidum, brainstem, hippocampus, and amygdala) using the Bland-Altman analysis and for each of the 3 normalization techniques. Similarly, for all subjects, the variabilities due to the use of PBIF were assessed. RESULTS: Bland-Altman analysis showed systematic bias between test and retest studies. The corresponding mean bias and 95% limits of agreement (LOA) for the studied brain regions were 30% and ± 70%. Comparing PBIF- and PSAIF-based VT estimate for all subjects and all brain regions, a significant difference between the results generated by the three normalization techniques existed for all brain structures except for the brainstem (P-value = 0.095). The mean % difference and 95% LOA is -10% and ±45% for Weightsubject×DoseInjected; +8% and ±50% for AUC; and +2% and ± 38% for Weightsubject×AUC. In all cases, normalizing by Weightsubject×AUC yielded the smallest % bias and variability (% bias = ±2%; LOA = ±38% for all brain regions). Estimating the reproducibility of PBIF-kinetics to PSAIF based on disease groups (HV/PD) and genotype (MAB/HAB), the average VT values for all regions obtained from PBIF is insignificantly higher than PSAIF (%difference = 4.53%, P-value = 0.73 for HAB; and %difference = 0.73%, P-value = 0.96 for MAB). PBIF also tends to overestimate the difference between PD and HV for HAB (% difference = 32.33% versus 13.28%) and underestimate it in MAB (%difference = 6.84% versus 20.92%). CONCLUSIONS: PSAIF kinetic results are reproducible with PBIF, with variability in VT within that obtained for the test-retest studies. Therefore, VT assessed using PBIF-based kinetic modeling is clinically feasible and can be an alternative to PSAIF.

Preclinical Efficacy and Safety of a Human Embryonic Stem Cell-Derived Midbrain Dopamine Progenitor Product, MSK-DA01.

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra leading to disabling deficits. Dopamine neuron grafts may provide a significant therapeutic advance over current therapies. We have generated midbrain dopamine neurons from human embryonic stem cells and manufactured large-scale cryopreserved dopamine progenitors for clinical use. After optimizing cell survival and phenotypes in short-term studies, the cell product, MSK-DA01, was subjected to an extensive set of biodistribution, toxicity, and tumorigenicity assessments in mice under GLP conditions. A large-scale efficacy study was also performed in rats with the same lot of cells intended for potential human use and demonstrated survival of the grafted cells and behavioral amelioration in 6-hydroxydopamine lesioned rats. There were no adverse effects attributable to the grafted cells, no obvious distribution outside the brain, and no cell overgrowth or tumor formation, thus paving the way for a future clinical trial.

Molecular Imaging of Striatal Dopaminergic Neuronal Loss and the Neurovascular Unit in Parkinson Disease.

Parkinson disease (PD) is the second most common neurodegenerative disorder, characterized by loss of nigrostriatal dopaminergic neurons. Impairment of the neurovascular unit (NVU) has been hypothesized to play a critical role in early PD pathophysiology, and to precede neurodegenerative mechanisms. [C-11]-PE2I (N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methyl-phenyl)nortropane) (PE2I) is a PET radiotracer targeting neuronal dopamine transporters (DaT) with high specificity, allowing for highly accurate and specific DaT quantification. We investigated NVU integrity using arterial spin labeling (ASL) MRI in a prospective cohort of 26 patients with PD, and correlated our findings with analysis of striatal DaT density using PE2I PET in a subcohort of 17 patients. Analysis was performed in FreeSurfer to obtain rCBF and mean standardized regional PET avidity. Pearson correlations and Mann-Whitney tests were performed. Significantly lower mean normalized striatal PE2I SUV values were seen in multiple regions in patients with greater disease duration (p < 0.05). PET uptake in the putamen correlated with disease duration independent of patient age. Stratifying patients based on Montreal Cognitive Assessment (MoCA) scores (stratified into ≥ 27 vs. < 27), there was statistically significantly lower PE2I PET avidity in the higher MoCA score group in both more and less affected sides of the caudate, putamen and pallidum (p < 0.05). A moderate negative correlation between MDS-UPDRS part 3 (motor) "off" and rCBF values was also seen in the L and R cerebellum WM (r = -0.43 and -0.47, p < 0.05). A statistically significant negative correlation was found between dominant hand pegboard test results and rCBF in the less affected pallidum (r = -0.41; p = 0.046). A statistically significant negative correlation of ASL MRI with [11C]-PE2I PET was also found (r = -0.53 to -0.58; p-value 0.017-0.033) between left cerebral WM rCBF and more and less affected striatal PET regions. Our ROI-based analyses suggest that longer disease duration is associated with lower rCBF and lower PE2I mean SUV, implying greater NVU dysfunction and dopaminergic neuronal loss, respectively. Combined ASL MRI and PE2I PET imaging could inform future prospective clinical trials providing an improved mechanistic understanding of the disease, laying the foundation for the development of early disease biomarkers and potential therapeutic targets.

A machine learning and network framework to discover new indications for small molecules.

Drug repurposing, identifying novel indications for drugs, bypasses common drug development pitfalls to ultimately deliver therapies to patients faster. However, most repurposing discoveries have been led by anecdotal observations (e.g. Viagra) or experimental-based repurposing screens, which are costly, time-consuming, and imprecise. Recently, more systematic computational approaches have been proposed, however these rely on utilizing the information from the diseases a drug is already approved to treat. This inherently limits the algorithms, making them unusable for investigational molecules. Here, we present a computational approach to drug repurposing, CATNIP, that requires only biological and chemical information of a molecule. CATNIP is trained with 2,576 diverse small molecules and uses 16 different drug similarity features, such as structural, target, or pathway based similarity. This model obtains significant predictive power (AUC = 0.841). Using our model, we created a repurposing network to identify broad scale repurposing opportunities between drug types. By exploiting this network, we identified literature-supported repurposing candidates, such as the use of systemic hormonal preparations for the treatment of respiratory illnesses. Furthermore, we demonstrated that we can use our approach to identify novel uses for defined drug classes. We found that adrenergic uptake inhibitors, specifically amitriptyline and trimipramine, could be potential therapies for Parkinson's disease. Additionally, using CATNIP, we predicted the kinase inhibitor, vandetanib, as a possible treatment for Type 2 Diabetes. Overall, this systematic approach to drug repurposing lays the groundwork to streamline future drug development efforts.

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

Restoring Function to Dopaminergic Neurons: Progress in the Development of Cell-Based Therapies for Parkinson's Disease.

There is escalating interest in cell-based therapies to restore lost dopamine inputs in Parkinson's disease. This is based upon the rationale that implanting dopamine progenitors into the striatum can potentially improve dopamine-responsive motor symptoms. A rich body of data describing clinical trials of previous cell transplantation exists. These have included multiple cell sources for transplantation including allogeneic (human embryonic mesencephalic tissue, retinal pigment epithelial cells) and autologous (carotid body, adrenal medullary tissue) cells, as well as xenotransplantation. However, there are multiple limitations related to these cell sources, including availability of adequate numbers of cells for transplant, heterogeneity within cells transplanted, imprecisely defined mechanisms of action, and poor cell survival after transplantation in some cases. Nonetheless, evidence has accrued from a subset of trials to support the rationale for such a regenerative approach. Recent rapid advances in stem cell technology may now overcome these prior limitations. For example, dopamine neuron precursor cells for transplant can be generated from induced pluripotent cells and human embryonic stem cells. The benefits of these innovative approaches include: the possibility of scalability; a high degree of quality control; and improved understanding of mechanisms of action with rigorous preclinical testing. In this review, we focus on the potential for cell-based therapies in Parkinson's disease to restore the function of dopaminergic neurons, we critically review previous attempts to harness such strategies, we discuss potential benefits and predicted limitations, and we address how previous roadblocks may be overcome to bring a cell-based approach to the clinic.

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

Neurophysiological Biomarkers of Parkinson's Disease.

BACKGROUND: There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics. OBJECTIVE: To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison's disease. METHODS: A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson's disease patients off medication and compared against age-matched controls. RESULTS: Qualitative and test/retest analysis of the EEG data demonstrated the reliability of the methods. Source localization using low resolution brain electromagnetic tomography identified significant differences in Parkinson's patients versus control subjects in the anterior cingulate and temporal lobe, areas with established association to Parkinson's disease pathology. Changes in cortico-cortical and cortico-thalamic coupling were observed as excessive EEG beta coherence in Parkinson's disease patients, and correlated with UPDRS scores and dopamine transporter activity, supporting the potential for cortical EEG coherence to serve as a reliable measure of disease severity. Using machine learning approaches, an EEG discriminant function analysis classifier was identified that parallels the loss of dopamine synapses as measured by dopamine transporter PET. CONCLUSION: Our results support the utility of EEG in characterizing alterations in neurophysiological oscillatory activity associated with Parkinson's disease and highlight potential as a reliable method for monitoring disease progression and as a pharmacodynamic endpoint for Parkinson's disease modification therapy.