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PurposeHuntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content.MethodsNew item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD.ResultsModerate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose.ConclusionsHDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

Classical accounts of the pathophysiology of Parkinson's disease have emphasized degeneration of dopaminergic nigrostriatal neurons with consequent dysfunction of cortico-striatal-thalamic loops. In contrast, post-mortem studies indicate that pathological changes in Parkinson's disease (Lewy neurites and Lewy bodies) first appear primarily in the lower brainstem with subsequent progression to more rostral parts of the neuraxis. The nigrostriatal and histological perspectives are not incompatible, but they do emphasize different anatomical structures. To address the question of which brain structures are functionally most affected by Parkinson's disease, we performed a resting-state functional magnetic resonance imaging study focused on striatal functional connectivity. We contrasted 13 patients with advanced Parkinson's disease versus 19 age-matched control subjects, using methodology incorporating scrupulous attention to minimizing the effects of head motion during scanning. The principal finding in the Parkinson's disease group was markedly lower striatal correlations with thalamus, midbrain, pons and cerebellum. This result reinforces the importance of the brainstem in the pathophysiology of Parkinson's disease. Focally altered functional connectivity also was observed in sensori-motor and visual areas of the cerebral cortex, as well the supramarginal gyrus. Striatal functional connectivity with the brainstem was graded (posterior putamen > anterior putamen > caudate), in both patients with Parkinson's disease and control subjects, in a manner that corresponds to well-documented gradient of striatal dopaminergic function loss in Parkinson's disease. We hypothesize that this gradient provides a clue to the pathogenesis of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Sequence variants in coding and noncoding regions of THAP1 have been associated with primary dystonia.Methods: In this study, 1,446 Caucasian subjects with mainly adult-onset primary dystonia and 1,520 controls were genotyped for a variant located in the 5'-untranslated region of THAP1 (c.-237_236GA>TT).Results: Minor allele frequencies were 62/2892 (2.14%) and 55/3040 (1.81%) in subjects with dystonia and controls, respectively (P=0.202). Subgroup analyses by gender and anatomical distribution also failed to attain statistical significance. In addition, there was no effect of the TT variant on expression levels of THAP1 transcript or protein.Discussion: Our findings indicate that the c.-237_236GA>TT THAP1 sequence variant does not increase risk for adult-onset primary dystonia in Caucasians. [ABSTRACT FROM AUTHOR]

The basal ganglia are thought to be important in the selection of wanted and the suppression of unwanted motor patterns according to explicit rules (i.e. response inhibition). The subthalamic nucleus has been hypothesized to play a particularly critical role in this function. Deep brain stimulation of the subthalamic nucleus in individuals with Parkinson's disease has been used to test this hypothesis, but results have been variable. Based on current knowledge of the anatomical organization of the subthalamic nucleus, we propose that the location of the contacts used in deep brain stimulation could explain variability in the effects of deep brain stimulation of the subthalamic nucleus on response inhibition tasks. We hypothesized that stimulation affecting the dorsal subthalamic nucleus (connected to the motor cortex) would be more likely to affect motor symptoms of Parkinson's disease, and stimulation affecting the ventral subthalamic nucleus (connected to higher order cortical regions) would be more likely to affect performance on a response inhibition task. We recruited 10 individuals with Parkinson's disease and bilateral deep brain stimulation of the subthalamic nucleus with one contact in the dorsal and another in the ventral subthalamic region on one side of the brain. Patients were tested with a Go-No-Go task and a motor rating scale in three conditions: stimulation off, unilateral dorsal stimulation and unilateral ventral stimulation. Both dorsal and ventral stimulation improved motor symptoms, but only ventral subthalamic stimulation affected Go-No-Go performance, decreasing hits and increasing false alarms, but not altering reaction times. These results suggest that the ventral subthalamic nucleus is involved in the balance between appropriate selection and inhibition of prepotent responses in cognitive paradigms, but that a wide area of the subthalamic nucleus region is involved in the motor symptoms of Parkinson's disease. This finding has implications for resolving inconsistencies in previous research, highlights the role of the ventral subthalamic nucleus region in response inhibition and suggests an approach for the clinical optimization of deep brain stimulation of the subthalamic nucleus for both motor and cognitive functions. [ABSTRACT FROM AUTHOR]

Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia., Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia., Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation., Results: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small., Conclusions: Moderate single-nucleotide polymorphism-based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson's disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue. NEW & NOTEWORTHY In this study, we examined different components of bradykinesia in patients with Parkinson's disease (PD). We identified different components through signal processing techniques and their response to deep brain stimulation (DBS). We found that some components of bradykinesia respond to stimulation, whereas others do not. This knowledge advances our understanding of brain mechanisms that control movement speed and amplitude.

Background: Prior studies have indicated that female individuals outnumber male individuals for certain types of dystonia. Few studies have addressed factors impacting these sex differences or their potential biological mechanisms., Objectives: To evaluate factors underlying sex differences in the dystonias and explore potential mechanisms for these differences., Methods: Data from individuals with various types of dystonia were analyzed in relation to sex. Data came from two different sources. One source was the Dystonia Coalition database, which contains predominantly idiopathic adult-onset focal and segmental dystonias. The second source was the MDSGene database, which contains predominantly early-onset monogenic dystonias., Results: The 3222 individuals from the Dystonia Coalition included 71% female participants and 29% male participants for an overall female-to-male ratio (F:M) of 2.4. This ratio varied according to body region affected and whether dystonia was task-specific. The female predominance was age-dependent. Sex did not have a significant impact on co-existing tremor, geste antagoniste, depression or anxiety. In the 1377 individuals from the MDSGene database, female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A)., Conclusions: These results are in keeping with prior studies that have indicated female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic dystonias. These results extend prior observations by revealing that sex ratios depend on the type of dystonia, age, and underlying genetics., (© 2024 International Parkinson and Movement Disorder Society.)

Laryngeal dystonia is a potentially disabling task specific dystonia primarily affecting speech. The evaluation and diagnosis of laryngeal dystonia remain challenging, and often require a multi-disciplinary approach, involving collaboration among speech language pathologists, neurologists and laryngologists (1-5). It is crucial to correctly differentiate between the types of laryngeal dystonia due to the distinct therapeutic approaches and responses to botulinum toxin therapy or speech therapy. For educational purposes, we have divided laryngeal dystonia into two main types: adductor and abductor dystonia. In this article, we describe a series of examination techniques that can assist movement disorders neurologists diagnosing this condition, and appropriately differentiating the most common forms of laryngeal dystonia., (© 2024 International Parkinson and Movement Disorder Society.)

Here we report our design and synthesis of 28 new fluorine-containing compounds as potential F-18 radiotracers for CNS imaging of sphingosine-1-phosphate receptor 1 (S1PR1), and determination of their in vitro binding potency and selectivity toward S1PR1 over other S1PR subtypes. Nine potent and selective compounds, 7c&d, 9a&c, 12b, 15b, and 18a-c with IC 50 values ranging from 0.6-12.3 nM for S1PR1 and weak binding toward S1PR2, 3, 4, and 5, were further 18 F-radiolabeled to produce [ 18 F]7c&d, [ 18 F]9a&c, [ 18 F]12b, [ 18 F]15b, and [ 18 F]18a-c. Multi-step F-18 radiochemistry procedures were investigated for radiosynthesis of [ 18 F]7c&d and [ 18 F]9a&c, and the presumed intermediates were synthesized and authenticated by analytic HPLC. We then performed nonhuman primate (NHP) PET brain imaging studies for eight radiotracers: [ 18 F]7c&d, [ 18 F]9a, [ 18 F]12b, [ 18 F]15b, and [ 18 F]18a-c. Three radiotracers, [ 18 F]7c, [ 18 F]7d, and [ 18 F]15b, had high NHP brain uptake with standardized uptake values (SUVs) at 2 h post-injection of 2.42, 2.84, and 2.00, respectively, and good brain retention. Our ex vivo biodistribution study in rats confirmed [ 18 F]7d had a high brain uptake with no in vivo defluorination. Radiometabolic analysis of [ 18 F]7c and [ 18 F]7d in rat plasma and brain samples found that [ 18 F]7c has a more favorable metabolic profile than [ 18 F]7d. However, the trend of increased brain uptake precludes [ 18 F]7c as a suitable PET radiotracer for imaging S1PR1 in the brain. Further structural optmization is warranted to identify a highly S1PR1-specific radiotracer with rapid brain uptake kinetics.

Background: We recently identified three distinct Parkinson's disease subtypes: "motor only" (predominant motor deficits with intact cognition and psychiatric function); "psychiatric & motor" (prominent psychiatric symptoms and moderate motor deficits); "cognitive & motor" (cognitive and motor deficits)., Objective: We used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes., Methods: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function. Next, we combined the original (N = 162) and replication (N = 100) datasets to test the classification model with the full combined dataset (N = 262). We also generated 10 random split-half samples of the combined dataset to establish the reliability of the subtype classifications. Latent class analyses were applied to the replication, combined, and split-half samples to determine subtype classification., Results: First, LCA supported the three-class solution - Motor Only, Psychiatric & Motor, and Cognitive & Motor- in the replication sample. Next, using the larger, combined sample, LCA again supported the three subtype groups, with the emergence of a potential fourth group defined by more severe motor deficits. Finally, split-half analyses showed that the three-class model also had the best fit in 13/20 (65%) split-half samples; two-class and four-class solutions provided the best model fit in five (25%) and two (10%) split-half replications, respectively., Conclusions: These results support the reproducibility and reliability of the Parkinson's disease behavioral subtypes of motor only, psychiatric & motor, and cognitive & motor groups., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Therese Cash received support from NIH (NS097437, NS075321, NS097799, NS124738, NS118146, AT011015). Christina N. Lessov-Schlaggar received support from NINDS NS097437. Erin R. Foster is funded by the National Institutes of Health (NIA R21AG063974, NIA R01AG065214, NIDDK R01DK126826, R01DK064832), the American Parkinson Disease Association (APDA) (ID# 971,949), and the APDA Advanced Parkinson Disease Research Center at Washington University in St Louis, and the Missouri Chapter of the APDA. Peter S. Myers received support from NINDS NS097437. Joshua J. Jackson received support from NINDS NS097437, NIMH AG061162-01, NIDCD DC017522-02S1. Baijayanta Maiti received funding from NINDS K23 NS125107, National Center for Advancing Translational Sciences of the National Institute of Health KL2 TR002346, American Academy of Neurology and American Brain Foundation Clinical Research Training Fellowship in Parkinson's disease, Parkinson Study Group/Parkinson's Disease Foundation Mentored Clinical Research Award, Missouri Chapter of American Parkinson Disease Association, and the Jo Oertli fund and has received honoraria for reviewing grants as a member of the Parkinson Study Group mentoring committee and from the American Academy of Neurology for authorship. Paul T. Kotzbauer received funding from National Institutes of Health NS110436, NS097799, NS075321, NS110456, AG071754, NS123860, NS097437, and from Biogen and has received previous funding and honoraria from AbbVie. Joel S. Perlmutter has received research funding from National Institutes of Health NS075321, NS103957, NS107281, NS092865, U10NS077384, NS097437, U54NS116025, U19 NS110456, AG050263, AG-64937, NS097799, NS075527, ES029524, NS109487, R61 AT010753, (NCATS, NINDS, NIA), R01NS118146, R01AG065214, Department of Defense (DOD W81XWH-217-1-0393), Michael J FoxFoundation, Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson disease research fund), American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, Missouri Chapter of the APDA, Paula and Rodger Riney Fund, Jo Oertli Fund, Huntington Disease Society of America, Murphy Fund, N. Grant Williams Fund and CHDI. He co-directs the Dystonia Coalition, which received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke, TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). Dr. Perlmutter has provided medical legal consultation to Wood, Cooper and Peterson, LLC and to Simmons and Simmons LLP. He serves as Director of Medical and Scientific Advisory Committee of the Dystonia Medical Research Foundation, Chair of the Scientific Advisory Committee of the Parkinson Study Group, Chair of the Standards Committee of the Huntington Study Group (honoraria for this one), member of the Scientific Advisory Board of the APDA, Chair of the Scientific and Publication Committee for ENROLL-HD (honoraria from this one), and member of the Education Committee of the Huntington Study Group (honoraria from this one). Dr. Perlmutter has received honoraria from CHDI, Huntington Disease Study Group, Parkinson Study Group, Beth Israel Hospital (Harvard group), U Pennsylvania, Stanford U. Boston University. Meghan C. Campbell receives research support from NIH (NS097437, NS075321, NS097799, NS124378, AG063974, AT010753, AT010753-S1), the McDonnell Center for Systems Neuroscience, the Mallinckrodt Institute of Radiology at WUSTL, the Neurimaging Labs Innovation Award and has received honoraria from the Parkinson Foundation., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Molecular imaging of brain vesicular acetylcholine transporter provides a biomarker to explore cholinergic systems in humans. We aimed to characterize the distribution of, and optimize methods to quantify, the vesicular acetylcholine transporter-specific tracer (-)-(1-(8-(2-[ 18 F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([ 18 F]VAT) in the brain using PET. Methods: Fifty-two healthy participants aged 21-97 y had brain PET with [ 18 F]VAT. [ 3 H]VAT autoradiography identified brain areas devoid of specific binding in cortical white matter. PET image-based white matter reference region size, model start time, and duration were optimized for calculations of Logan nondisplaceable binding potential (BP ND ). Ten participants had 2 scans to determine test-retest variability. Finally, we analyzed age-dependent differences in participants. Results: [ 18 F]VAT was widely distributed in the brain, with high striatal, thalamic, amygdala, hippocampal, cerebellar vermis, and regionally specific uptake in the cerebral cortex. [ 3 H]VAT autoradiography-specific binding and PET [ 18 F]VAT uptake were low in white matter. [ 18 F]VAT SUVs in the white matter reference region correlated with age, requiring stringent erosion parameters. Logan BP ND estimates stabilized using at least 40 min of data starting 25 min after injection. Test-retest variability had excellent reproducibility and reliability in repeat BP ND calculations for 10 participants (putamen, 6.8%; r > 0.93). We observed age-dependent decreases in the caudate and putamen (multiple comparisons corrected) and in numerous cortical regions. Finally, we provide power tables to indicate potential mean differences that can be detected between 2 groups of participants. Conclusion: These results validate a reference region for BP ND calculations and demonstrate the viability, reproducibility, and utility of using the [ 18 F]VAT tracer in humans to quantify cholinergic pathways., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The sphingosine-1-phosphate receptor 1 (S1PR1) radiotracer [ 11 C] CS1P1 has shown promise in proof-of-concept PET imaging of neuroinflammation in multiple sclerosis (MS). Our HPLC radiometabolite analysis of human plasma samples collected during PET scans with [ 11 C] CS1P1 detected a radiometabolite peak that is more lipophilic than [ 11 C] CS1P1 . Radiolabeled metabolites that cross the blood-brain barrier complicate quantitative modeling of neuroimaging tracers; thus, characterizing such radiometabolites is important. Here, we report our detailed investigation of the metabolite profile of [ 11 C] CS1P1 in rats, nonhuman primates, and humans. CS1P1 is a fluorine-containing ligand that we labeled with C-11 or F-18 for preclinical studies; the brain uptake was similar for both radiotracers. The same lipophilic radiometabolite found in human studies also was observed in plasma samples of rats and NHPs for CS1P1 labeled with either C-11 or F-18. We characterized the metabolite in detail using rats after injection of the nonradioactive CS1P1 . To authenticate the molecular structure of this radiometabolite, we injected rats with 8 mg/kg of CS1P1 to collect plasma for solvent extraction and HPLC injection, followed by LC/MS analysis of the same metabolite. The LC/MS data indicated in vivo mono-oxidation of CS1P1 produces the metabolite. Subsequently, we synthesized three different mono-oxidized derivatives of CS1P1 for further investigation. Comparing the retention times of the mono-oxidized derivatives with the metabolite observed in rats injected with CS1P1 identified the metabolite as N -oxide 1 , also named TZ82121 . The MS fragmentation pattern of N -oxide 1 also matched that of the major metabolite in rat plasma. To confirm that metabolite TZ82121 does not enter the brain, we radiosynthesized [ 18 F] TZ82121 by the oxidation of [ 18 F] FS1P1 . Radio-HPLC analysis confirmed that [ 18 F] TZ82121 matched the radiometabolite observed in rat plasma post injection of [ 18 F] FS1P1 . Furthermore, the acute biodistribution study in SD rats and PET brain imaging in a nonhuman primate showed that [ 18 F] TZ82121 does not enter the rat or nonhuman primate brain. Consequently, we concluded that the major lipophilic radiometabolite N -oxide [ 11 C] TZ82121 , detected in human plasma post injection of [ 11 C] CS1P1 , does not enter the brain to confound quantitative PET data analysis. [ 11 C] CS1P1 is a promising S1PR1 radiotracer for detecting S1PR1 expression in the CNS.

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn., (© 2024. The Author(s).)

Objectives: Characterize the presentation, workup, and management of SGCE myoclonus-dystonia, a rare genetic condition, in a patient with atypical presenting symptoms and no family history of movement abnormalities., Methods: A woman with myoclonus and dystonia was identified based on clinical history and physical examination. Workup was conducted to determine the cause of her symptoms, including whole-exome sequencing. Myoclonus-dystonia is associated with more than 100 distinct mutations in MYC/DYT -SGCE that account for only half of the total myoclonus-dystonia patients. As such, this case required intensive genetic analyses rather than screening only for a small subset of well-characterized mutations., Results: Childhood onset myoclonus and worsening dystonia with age were identified in a young woman. She underwent screening for common causes of twitching movements, followed by whole-exome sequencing which identified a de novo novel variant in the SGCE gene, resulting in a diagnosis of SGCE myoclonus-dystonia., Discussion: Myoclonus-dystonia should be considered in patients with symptoms of head and upper extremity myoclonus early in life, especially with co-occurring dystonia, even in the absence of a family history of similar symptoms. Diagnosis of this condition should take place using sequencing, as new mutations continue to be discovered., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine longitudinal predictors of health-related quality of life (HR-QoL) in an international multicenter cohort of patients with isolated dystonia., Methods: Out of 603 dystonia patients prospectively enrolled in the Natural History Dystonia Coalition study, 155 were assessed three times within 2 years for HR-QoL, symptoms of depression, generalized anxiety disorder (GAD), and social anxiety disorder (SAD), as well as dystonia severity and dystonic tremor. In addition, the impact of botulinum neurotoxin (BoNT) injections on HR-QoL was evaluated after 1 year., Results: Depressive symptoms at baseline predicted lower HR-QoL on all subscales after 2 years (all p ≤ 0.001). Higher GAD scores at baseline predicted lower HR-QoL related to general health, pain and emotional well-being, whereas higher SAD scores predicted higher pain-related QoL after 2 years (all p ≤ 0.006). Dystonia severity at baseline predicted social functioning (p = 0.002). Neither dystonic tremor, age, or sex predicted HR-QoL at 2 years. Two latent categories were revealed across the three-time points: Category 1 with higher total HR-QoL scores (mean HR-QoL = 74.4% ± 16.1), susceptible to symptoms of depression and SAD, and Category 2 with lower total HR-QoL scores (mean HR-QoL = 45.5% ± 17.6), susceptible to symptoms of GAD. HR-QoL improved over the course of 1 year irrespective of the use of BoNT., Conclusion: The longitudinal impact of psychiatric symptoms on HR-QoL emphasizes the importance of incorporating mental health treatment, in particular also the therapy of anxiety disorders, into treatment regimens for dystonia., (© 2023. The Author(s).)

There is a need for affordable, scalable, and specific blood-based biomarkers for Alzheimer's disease that can be applied to a population level. We have developed and validated disease-specific cell-free transcriptomic blood-based biomarkers composed by a scalable number of transcripts that capture AD pathobiology even in the presymptomatic stages of the disease. Accuracies are in the range of the current CSF and plasma biomarkers, and specificities are high against other neurodegenerative diseases., Competing Interests: The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid Genetics, Halia Therapeutics, and ADx Healthcare and has received research support from Biogen, EISAI, Alector and Parabon. The rest of the authors report no conflict of interest. Patent Pending., (© 2023 The Author(s).)

Multiple sclerosis (MS) is an immune-mediated disease that is characterized by demyelination and inflammation in the central nervous system (CNS). Previous studies demonstrated that sphingosine-1-phosphate receptor (S1PR) modulators effectively inhibit S1PR1 in immune cell trafficking and reduce entry of pathogenic cells into the CNS. Studies have also implicated a nonimmune, inflammatory role of S1PR1 within the CNS in MS. In this study, we explored the expression of S1PR1 in the development and progression of demyelinating pathology of MS by quantitative assessment of S1PR1 expression using our S1PR1-specific radioligand, [ 3 H]CS1P1, in the postmortem human CNS tissues including cortex, cerebellum, and spinal cord of MS cases and age- and sex-matched healthy cases. Immunohistochemistry with whole slide scanning for S1PR1 and various myelin proteins was also performed. Autoradiographic analysis using [ 3 H]CS1P1 showed that the expression of S1PR1 was statistically significantly elevated in lesions compared to nonlesion regions in the MS cases, as well as normal healthy controls. The uptake of [ 3 H]CS1P1 in the gray matter and nonlesion white matter did not significantly differ between healthy and MS CNS tissues. Saturation autoradiography analysis showed an increased binding affinity ( K d ) of [ 3 H]CS1P1 to S1PR1 in both gray matter and white matter of MS brains compared to healthy brains. Our blocking study using NIBR-0213, a S1PR1 antagonist, indicated [ 3 H]CS1P1 is highly specific to S1PR1. Our findings demonstrated the activation of S1PR1 and an increased uptake of [ 3 H]CS1P1 in the lesions of MS CNS. In summary, our quantitative autoradiography analysis using [ 3 H]CS1P1 on human postmortem tissues shows the feasibility of novel imaging strategies for MS by targeting S1PR1.

Background: There are several widely used clinical rating scales for documenting the severity and distribution of various types of dystonia., Objectives: The goal of this study was to evaluate the performance of the most commonly used scales in a large group of adults with the most common types of isolated dystonia., Methods: Global Dystonia Rating Scale (GDRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFM) scores were obtained for 3067 participants. Most had focal or segmental dystonia, with smaller numbers of multifocal or generalized dystonia. These scales were also compared for 209 adults with cervical dystonia that had Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores and 210 adults with blepharospasm that had Blepharospasm Severity Scale (BSRS) scores., Results: There were strong correlations between the GDRS and BFM total scores ( r  = 0.79) and moderate correlations for their sub scores ( r  > 0.5). Scores for both scales showed positive skew, with an overabundance of low scores. BFM sub-scores were not normally distributed, due to artifacts caused by the provoking factor. Relevant sub-scores of the GDRS and BFM also showed moderate correlations with the TWSTRS ( r  > 0.5) for cervical dystonia and the BSRS ( r  > 0.5) for blepharospasm., Conclusions: The BFM is more widely used than the GDRS, but these results suggest the GDRS may be preferable for focal and segmental dystonias. The overabundance of very low scores for both scales highlights challenges associated with discriminating very mild dystonia from other abnormal movements or variants of normal behavior., (© 2023 International Parkinson and Movement Disorder Society.)

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants' motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee's scale), clinical grading of spasm intensity (Chen's scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc's scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from "poor" to "moderate"; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee's, Chen's, and Tunc's scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc's scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc's scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training., (© 2023. The Author(s).)

Background: Assessing disease severity can be performed using either clinician-rated scales (CRS) or patient-rated outcome (PRO) tools. These two measures frequently demonstrate poor correlations., Objectives: To determine if the correlation between a CRS and PRO for motor features of cervical dystonia (CD) improves by accounting for non-motor features., Methods: Subjects with CD (N = 209) were evaluated using a CRS (Toronto Western Spasmodic Torticollis Rating Scale, TWSTRS) and a PRO (Cervical Dystonia Impact Profile, CDIP-58)., Results: Linear regression revealed a weak correlation between the two measures, even when considering only the motor subscales of each. The strength of this relationship improved with a regression model that included non-motor symptoms of pain, depression, and disability., Conclusions: These results argue that the results of motor assessments in a PRO for CD cannot be fully appreciated without simultaneous assessment of non-motor co-morbidities. This conclusion might apply to other disorders, especially those with frequent non-motor co-morbidities., (© 2023 International Parkinson and Movement Disorder Society.)

Common and rare variants in the LRRK2 locus are associated with Parkinson's disease (PD) risk, but the downstream effects of these variants on protein levels remain unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7006 aptamers (6138 unique proteins) in 3107 individuals). The dataset comprised six different and independent cohorts (five using the SomaScan7K (ADNI, DIAN, MAP, Barcelona-1 (Pau), and Fundació ACE (Ruiz)) and the PPMI cohort using the SomaScan5K panel). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 25 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk, and seven were validated in the PPMI cohort. Mendelian randomization analyses identified GPNMB, LCT, and CD68 causal for PD and nominate one more (ITGB2). These 25 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also that LRRK2 is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways., (© 2023. The Author(s).)

Aim: To determine the movement features governing expert assessment of gait dystonia severity in individuals with cerebral palsy (CP)., Method: In this prospective cohort study, three movement disorder neurologists graded lower extremity dystonia severity in gait videos of individuals with CP using a 10-point Likert-like scale. Using conventional content analysis, we determined the features experts cited when grading dystonia severity. Then, using open-source pose estimation techniques, we determined gait variable analogs of these expert-cited features correlating with their assessments of dystonia severity., Results: Experts assessed videos from 116 participants (46 with dystonia aged 15 years [SD 3] and 70 without dystonia aged 15 years [SD 2], both groups ranging 10-20 years old and 50% male). Variable limb adduction was most commonly cited by experts when identifying dystonia, comprising 60% of expert statements. Effect on gait (regularity, stability, trajectory, speed) and dystonia amplitude were common features experts used to determine dystonia severity, comprising 19% and 13% of statements respectively. Gait variables assessing adduction variability and amplitude (inter-ankle distance variance and foot adduction amplitude) were significantly correlated with expert assessment of dystonia severity (multiple linear regression, p < 0.001)., Interpretation: Adduction variability and amplitude are quantifiable gait features that correlate with expert-determined gait dystonia severity in individuals with CP. Consideration of these features could help optimize and standardize the clinical assessment of gait dystonia severity in individuals with CP., (© 2023 Mac Keith Press.)

Objective: Death anxiety, represented by the HDQLIFE™ Concern with Death and Dying (CwDD) patient-reported outcome (PRO) questionnaire, captures a person's worry about the death and dying process. Previous work suggests that death anxiety remains an unremitting burden throughout all stages of Huntington disease (HD). Although palliative interventions have lessened death anxiety among people with advanced cancer, none has yet to undergo testing in the HD population. An account of how death anxiety is associated with longitudinal changes to aspects of health-related quality of life (HRQoL) would help optimize neuropalliative interventions for people with HD. Methods: HDQLIFE collected PROs concerning physical, mental, social, and cognitive HRQoL domains and clinician-rated assessments from people with HD at baseline and 12 and 24 months. Linear mixed-effects models were created to determine how baseline death anxiety was associated with follow-up changes in HRQoL PROs after controlling for baseline death anxiety and other disease and sociodemographic covariates. Results: Higher baseline HDQLIFE CwDD is associated with 12- and 24-month declines in HDQLIFE Speech Difficulties, neurology quality of life (NeuroQoL) Depression, Suicidality, HDQLIFE Meaning and Purpose, and NeuroQoL Positive Affect and Well-being. Interpretation: Death anxiety may be a risk factor for worsening mental health and speech difficulty. A further prospective study is required to evaluate whether interventions on death anxiety or mental health generally can reduce declines in HRQoL for people with HD over time.

Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [ 11 C] CS1P1 into clinical investigation for multiple sclerosis. Herein, we reported the design, synthesis and evaluation of novel F-18 S1PR1 radioligands. We combined the structural advantages of our two lead S1PR1 radioligands and synthesized 14 new S1PR1 compounds, then performed F-18 radiochemistry on the most promising compounds. Compound 6h is potent (IC 50 = 8.7 nM) and selective for S1PR1. [ 18 F] 6h exhibited a high uptake in macaque brain (SUV > 3.0) and favorable brain washout pharmacokinetics in positron emission tomography (PET) study. PET blocking and displacement studies confirmed the specificity of [ 18 F] 6h in vivo . Radiometabolite analysis confirmed no radiometabolite of [ 18 F] 6h entered into the brain to confound the PET measurement. In summary, [ 18 F] 6h is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.

Purpose: TRPC5 belongs to the mammalian superfamily of transient receptor potential (TRP) Ca 2+ -permeable cationic channels and it has been implicated in various CNS disorders. As part of our ongoing interest in the development of a PET radiotracer for imaging TRPC5, herein, we explored the radiosynthesis, and in vitro and in vivo evaluation of a new C-11 radiotracer [ 11 C]HC070 in rodents and nonhuman primates., Procedures: [ 11 C]HC070 was radiolabeled utilizing the corresponding precursor and [ 11 C]CH 3 I via N-methylation protocol. Ex vivo biodistribution study of [ 11 C]HC070 was performed in Sprague-Dawley rats. In vitro autoradiography study was conducted for the rat brain sections to characterize the radiotracer distribution in the brain regionals. MicroPET brain imaging studies of [ 11 C]HC070 were done for 129S1/SvImJ wild-type mice and 129S1/SvImJ TRPC5 knockout mice for 0-60-min dynamic data acquisition after intravenous administration of the radiotracer. Dynamic PET scans (0-120 min) for the brain of cynomolgus male macaques were performed after the radiotracer injection., Results: [ 11 C]HC070 was efficiently prepared with good radiochemical yield (45 ± 5%, n = 15), high chemical and radiochemical purity (> 99%), and high molar activity (320.6 ± 7.4 GBq/μmol, 8.6 ± 0.2 Ci/μmol) at the end of bombardment (EOB). Radiotracer [ 11 C]HC070 has good solubility in the aqueous dose solution. The ex vivo biodistribution study showed that [ 11 C]HC070 had a quick rat brain clearance. Autoradiography demonstrated that [ 11 C]HC070 specifically binds to TRPC5-enriched regions in rat brain. MicroPET study showed the peak brain uptake (SUV value) was 0.63 in 129S1/SvImJ TRPC5 knockout mice compared to 1.13 in 129S1/SvImJ wild-type mice. PET study showed that [ 11 C]HC070 has good brain uptake with maximum SUV of ~ 2.2 in the macaque brain, followed by rapid clearance., Conclusions: Our data showed that [ 11 C]HC070 is a TRPC5-specific radiotracer with high brain uptake and good brain washout pharmacokinetics in both rodents and nonhuman primates. The radiotracer is worth further investigating of its suitability to be a PET radiotracer for imaging TRPC5 in animals and human subjects in vivo., (© 2022. The Author(s), under exclusive licence to World Molecular Imaging Society.)