The Pain in Dystonia Scale (PIDS)—Development and Validation in Cervical Dystonia

BACKGROUND: A better understanding of pain in adult-onset idiopathic dystonia (AOID) is needed to implement effective therapeutic strategies. OBJECTIVE: To develop a new rating instrument for pain in AOID and validate it in cervical dystonia (CD). METHODS: Development and validation of the Pain in Dystonia Scale (PIDS) comprised three phases. In phase 1, international experts and participants with AOID generated and evaluated the preliminary items for content validity. In phase 2, the PIDS was drafted and revised by the experts, followed by cognitive interviews to ensure self-administration suitability. In phase 3, the PIDS psychometric properties were assessed in 85 participants with CD and retested in 40 participants. RESULTS: The final version of PIDS evaluates pain severity (by body-part), functional impact, and external modulating factors. Test-retest reliability showed a high-correlation coefficient for the total score (0.9, P < 0.001), and intraclass correlation coefficients were 0.7 or higher for all items in all body-parts subscores. The overall PIDS severity score showed high internal consistency (Cronbach's α, 0.9). Convergent validity analysis revealed a strong correlation between the PIDS severity score and the Toronto Western Spasmodic Torticollis Rating Scale pain subscale (0.8, P < 0.001) and the Brief Pain Inventory-short form items related to pain at time of the assessment (0.7, P < 0.001) and impact of pain on daily functioning (0.7, P < 0.001). CONCLUSION: The PIDS is the first specific questionnaire developed to evaluate pain in all patients with AOID, here, demonstrating high-level psychometric properties in people with CD. Future work will validate PIDS in other forms of AOID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.[Background] As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited.[Objective] The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.[Methods] We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.[Results] We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.[Conclusions] Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.This project was funded by The Michael J. Fox Foundation (ID 15015.02)Peer reviewe

p.Met233Val in a Complex Neurodegenerative Movement and Neuropsychiatric Disorder

Mutations in presenilin 1 (PSEN1) are the most common cause of autosomal dominant Alzheimer’s disease. Here, we report a Canadian-Vietnamese family carrying a PSEN1 p.Met233Val mutation with an exceptionally early and severe presentation that includes a wide range of atypical symptoms, including prominent ataxia, Parkinsonism, spasticity, dystonia, action tremor, myoclonus, bulbar symptoms, seizures, hallucinations and behavioral changes. Whole-exome sequencing (WES) was performed on the affected proband after many assessments over several years proved diagnostically inconclusive. The results were analyzed using the AnnEx “Annotated Exomes” browser (http://annex.can.ubc.ca), a web-based platform that facilitates WES variant annotation and interpretation. High-throughput sequencing can be especially informative for complex neurological disorders, and WES warrants consideration as a first-line clinical test. Data analyses facilitated by web-based bioinformatics tools have great potential for novel insight, although confirmatory, diagnostically accredited Sanger sequencing is recommended prior to reporting

Compulsive use of dopaminergic drug therapy in Parkinson's disease: Reward and anti-reward

A few Parkinson patients develop a disabling pattern of compulsive dopaminergic drug use ("dopamine dysregulation syndrome"-DDS). DDS patients commonly identify aversive dysphoric "OFF" mood-states as a primary motivation to compulsively use their drugs. We compared motoric, affective, non-motor symptoms and incentive arousal after overnight medication withdrawal and after levodopa in DDS and control PD patients. Twenty DDS patients were matched to 20 control PD patients for age, gender, and disease duration and underwent a standard levodopa challenge. Somatic symptomatology, positive and negative affective states, drug effects, reward responsivity, motor disability, and dyskinesias were tested in the "OFF"-state after overnight withdrawal of medications, and then after a challenge with a standard dose of levodopa, after a full "ON"-state was achieved. In the "OFF"-state, DDS patients reported lower positive affect, and more motor and non-motor disability. In the "ON"-state, DDS patients had higher expressions of drug "wanting," reward responsivity, and dyskinesias. Positive and negative affect, non-motor symptomatology, and motor disability were comparable. These findings suggest that affective, motivational, and motoric disturbances in PD are associated with the transition to compulsive drug use in individuals who inappropriately overuse their dopaminergic medication

The Role of Ultrasound for the Personalized Botulinum Toxin Treatment of Cervical Dystonia

The visualization of the human body has frequently been groundbreaking in medicine. In the last few years, the use of ultrasound (US) imaging has become a well-established procedure for botulinum toxin therapy in people with cervical dystonia (CD). It is now undisputed among experts that some of the most relevant muscles in this indication can be safely injected under visual US guidance. This review will explore the method from basic technical considerations, current evidence to conceptual developments of the phenomenology of cervical dystonia. We will review the implications of introducing US to our understanding of muscle function and anatomy of common cervical dystonic patterns. We suggest a flow chart for the use of US to achieve a personalized treatment of people with CD. Thus, we hope to contribute a resource that is useful in clinical practice and that stimulates the ongoing development of this valuable technique.Medicine, Faculty ofOther UBCNon UBCMedicine, Department ofNeurology, Division ofReviewedFacult

Medical Management of Parkinson's Disease after Initiation of Deep Brain Stimulation

In this review, we have gathered all the available evidence to guide medication management after deep brain stimulation (DBS) in Parkinson's disease (PD). Surprisingly, we found that almost no study addressed drug-based management in the postoperative period. Dopaminergic medications are usually reduced, but whether the levodopa or dopamine agonist is to be reduced is left to the personal preference of the treating physician. We have summarized the pros and cons of both approaches. No study on the management of cognitive problems after DBS has been done, and only a few studies have explored the pharmacological management of such DBS-resistant symptoms as voice (amantadine), balance (donepezil) or gait disorders (amantadine, methylphenidate). As for the psychiatric problems so frequently reported in PD patients, researchers have directed their attention to the complex interplay between stimulation and reduction of dopaminergic drugs only recently. In conclusion, studies addressing medical management following DBS are still needed and will certainly contribute to the ultimate success of DBS procedures

Structural Network Analysis Using Diffusion MRI Tractography in Parkinson's Disease and Correlations With Motor Impairment

Functional impairment of spatially distributed brain regions in Parkinson's disease (PD) suggests changes in integrative and segregative network characteristics, for which novel analysis methods are available. To assess underlying structural network differences between PD patients and controls, we employed MRI T1 gray matter segmentation and diffusion MRI tractography to construct connectivity matrices to compare patients and controls with data originating from two different centers. In the Dutch dataset (Data-NL), 14 PD patients, and 15 healthy controls were analyzed, while 19 patients and 18 controls were included in the Canadian dataset (Data-CA). All subjects underwent T1 and diffusion-weighted MRI. Patients were assessed with Part 3 of the Unified Parkinson's Disease Rating Scale (UPDRS). T1 images were segmented using FreeSurfer, while tractography was performed using ExploreDTI. The regions of interest from the FreeSurfer segmentation were combined with the white matter streamline sets resulting from the tractography, to construct connectivity matrices. From these matrices, both global and local efficiencies were calculated, which were compared between the PD and control groups and related to the UPDRS motor scores. The connectivity matrices showed consistent patterns among the four groups, without significant differences between PD patients and control subjects, either in Data-NL or in Data-CA. In Data-NL, however, global and local efficiencies correlated negatively with UPDRS scores at both the whole-brain and the nodal levels [false discovery rate (FDR) 0.05]. At the nodal level, particularly, the posterior parietal cortex showed a negative correlation between UPDRS and local efficiency, while global efficiency correlated negatively with the UPDRS in the sensorimotor cortex. The spatial patterns of negative correlations between UPDRS and parameters for network efficiency seen in Data-NL suggest subtle structural differences in PD that were below sensitivity thresholds in Data-CA. These correlations are in line with previously described functional differences. The methodological approaches to detect such differences are discussed

In vivo dopaminergic and serotonergic dysfunction inDCTN1gene mutation carriers

Photograph of a scene during a Kaw Nation Pow Wow