Modeling Accuracy and Variability of Motor Timing in Treated and Untreated Parkinson’s Disease and Healthy Controls

Parkinson’s disease (PD) is characterized by difficulty with the timing of movements. Data collected using the synchronization–continuation paradigm, an established motor timing paradigm, have produced varying results but with most studies finding impairment. Some of this inconsistency comes from variation in the medication state tested, in the inter-stimulus intervals (ISI) selected, and in changeable focus on either the synchronization (tapping in time with a tone) or continuation (maintaining the rhythm in the absence of the tone) phase. We sought to re-visit the paradigm by testing across four groups of participants: healthy controls, medication naïve de novo PD patients, and treated PD patients both “on” and “off” dopaminergic medication. Four finger tapping intervals (ISI) were used: 250, 500, 1000, and 2000 ms. Categorical predictors (group, ISI, and phase) were used to predict accuracy and variability using a linear mixed model. Accuracy was defined as the relative error of a tap, and variability as the deviation of the participant’s tap from group predicted relative error. Our primary finding is that the treated PD group (PD patients “on” and “off” dopaminergic therapy) showed a significantly different pattern of accuracy compared to the de novo group and the healthy controls at the 250-ms interval. At this interval, the treated PD patients performed “ahead” of the beat whilst the other groups performed “behind” the beat. We speculate that this “hastening” relates to the clinical phenomenon of motor festination. Across all groups, variability was smallest for both phases at the 500-ms interval, suggesting an innate preference for finger tapping within this range. Tapping variability for the two phases became increasingly divergent at the longer intervals, with worse performance in the continuation phase. The data suggest that patients with PD can be best discriminated from healthy controls on measures of motor timing accuracy, rather than variability

Impact of Chorea on Self-care Activity, Employment, and Health-care Resource Use in Patients with Huntington’s Disease

**Background:** Chorea is recognized as a prototypic motor feature of Huntington’s disease (HD), but its effect on health-related quality of life (HRQoL) has not been fully explored. This study describes the impact of chorea on HRQoL in patients with HD. **Objective:** To determine the impact of HD-related chorea on employment, self-care activities, activities of daily living, and health-care resource utilization (HCRU). **Methods:** Data were drawn from the Adelphi HD Disease Specific Programme, a real-world point-in-time survey of 144 neurologists and 427 patients in the United States between July and October 2017. HD patients with and without chorea were identified and examined for differences in employment status, reasons for employment changes, self-care activities, and modifications to cope with involuntary movements. Bivariate tests and inverse probability weighted regression adjustment methods were used to determine differences in outcomes between patients with and without chorea. **Results:** HD patients with (n=287) and without (n=140) chorea were identified. Patients with chorea were less likely to be employed full-time (16.7% vs 25.7%; _P_<0.04) and more likely to be on long-term sick leave (17.4% vs 5.0%; _P_<0.01). The onset of motor symptoms in HD-related chorea patients coincided with a change in employment status (42.7% vs 20.8%; _P_<0.01). Among those still working (n=145), more than two-fifths of patients with chorea required changes to their workplace and required these changes more frequently (45% vs 17%; _P_<0.001). HD patients with chorea required aid to help them get around significantly more frequently than those without chorea (55% vs 34%; _P_<0.001). **Discussion:** These results demonstrate that HD patients with chorea experienced greater negative impact to employment, self-care activities, and HCRU than patients without chorea experienced. These patients were more likely to stop working due to motor, cognitive, and behavioral symptoms; require modifications in the home and workplace; and need more assistance from caregivers than patients without chorea. **Conclusions:** Patients with HD-related chorea have greater detriments to emotional, interpersonal, and professional functioning that could be improved by reducing chorea

Impact of Chorea on Self-care Activity, Employment, and Health-care Resource Use in Patients with Huntington’s Disease

**Background:** Chorea is recognized as a prototypic motor feature of Huntington’s disease (HD), but its effect on health-related quality of life (HRQoL) has not been fully explored. This study describes the impact of chorea on HRQoL in patients with HD. **Objective:** To determine the impact of HD-related chorea on employment, self-care activities, activities of daily living, and health-care resource utilization (HCRU). **Methods:** Data were drawn from the Adelphi HD Disease Specific Programme, a real-world point-in-time survey of 144 neurologists and 427 patients in the United States between July and October 2017. HD patients with and without chorea were identified and examined for differences in employment status, reasons for employment changes, self-care activities, and modifications to cope with involuntary movements. Bivariate tests and inverse probability weighted regression adjustment methods were used to determine differences in outcomes between patients with and without chorea. **Results:** HD patients with (n=287) and without (n=140) chorea were identified. Patients with chorea were less likely to be employed full-time (16.7% vs 25.7%; _P_<0.04) and more likely to be on long-term sick leave (17.4% vs 5.0%; _P_<0.01). The onset of motor symptoms in HD-related chorea patients coincided with a change in employment status (42.7% vs 20.8%; _P_<0.01). Among those still working (n=145), more than two-fifths of patients with chorea required changes to their workplace and required these changes more frequently (45% vs 17%; _P_<0.001). HD patients with chorea required aid to help them get around significantly more frequently than those without chorea (55% vs 34%; _P_<0.001). **Discussion:** These results demonstrate that HD patients with chorea experienced greater negative impact to employment, self-care activities, and HCRU than patients without chorea experienced. These patients were more likely to stop working due to motor, cognitive, and behavioral symptoms; require modifications in the home and workplace; and need more assistance from caregivers than patients without chorea. **Conclusions:** Patients with HD-related chorea have greater detriments to emotional, interpersonal, and professional functioning that could be improved by reducing chorea

Predictors of persistence and adherence to deutetrabenazine among patients with Huntington disease or tardive dyskinesia

Introduction Deutetrabenazine is approved for treatment of Huntington disease (HD)-related chorea and tardive dyskinesia (TD) in adults. Factors associated with deutetrabenazine persistence and adherence are not well understood. Methods Claims data from the Symphony Health Solutions Integrated Dataverse (2017-2019) were analyzed to identify real-world predictors of deutetrabenazine persistence and adherence in adults with HD or TD in the United States. Predictive models for persistence and adherence that considered patient demographics, payer type, comorbidities, treatment history, and health care resource use were developed. Results In HD, use of anticonvulsants (HR = 2.00 [95% CI = 1.03, 3.85]; P < .05), lipid-lowering agents (2.22 [1.03, 4.76]; P < .05), and Medicaid versus Medicare insurance (2.27 [1.03, 5.00]; P < .05) predicted persistence, whereas only comorbid anxiety disorders predicted discontinuation (0.46 [0.23, 0.93]; P < .05). Of these patients, 62.5% were adherent at 6 months. Use of 22642 treatments for chronic diseases (OR = 0.18 [95% CI = 0.04, 0.81]; P < .05) and Medicaid versus Medicare insurance (0.27 [0.09, 0.75]; P < .05) was associated with lower odds of adherence. In TD, use of lipid-lowering agents (HR = 4.76 [95% CI = 1.02, 20.00]; P < .05) predicted persistence, while comorbid schizoaffective disorder and/or schizophrenia (0.16 [0.14, 0.69]; P < .05) and sleep-wake disorders (0.18 [0.04, 0.82]; P < .05) predicted discontinuation. Of these patients, 46.7% were adherent at 6 months. Comorbid schizoaffective disorder and/or schizophrenia was associated with lower odds of adherence (OR = 0.26 [0.07, 0.91]; P < .05). Discussion Identifying factors predictive of discontinuation and/or nonadherence to deutetrabenazine may facilitate the development of personalized support programs that seek to improve outcomes in patients with HD or TD

Anatomical texture patterns identify cerebellar distinctions between essential tremor and Parkinson&apos;s disease

Voxel-based morphometry is an established technique to study focal structural brain differences in neurologic disease. More recently, texture-based analysis methods have enabled a pattern-based assessment of group differences, at the patch level rather than at the voxel level, allowing a more sensitive localization of structural differences between patient populations. In this study, we propose a texture-based approach to identify structural differences between the cerebellum of patients with Parkinson&apos;s disease (n =???280) and essential tremor (n =???109). We analyzed anatomical differences of the cerebellum among patients using two features: T1-weighted MRI intensity, and a texture-based similarity feature. Our results show anatomical differences between groups that are localized to the inferior part of the cerebellar cortex. Both the T1-weighted intensity and texture showed differences in lobules VIII and IX, vermis VIII and IX, and middle peduncle, but the texture analysis revealed additional differences in the dentate nucleus, lobules VI and VII, vermis VI and VII. This comparison emphasizes how T1-weighted intensity and texture-based methods can provide a complementary anatomical structure analysis. While texture-based similarity shows high sensitivity for gray matter differences, T1-weighted intensity shows sensitivity for the detection of white matter differences

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial

Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Altres ajuts: European Alzheimer DNA BioBank, EADB; EU Joint Programme, Neurodegenerative Disease Research (JPND); Neurodegeneration research program of Amsterdam Neuroscience; Stichting Alzheimer Nederland; Stichting VUmc fonds; Stichting Dioraphte; JPco-fuND FP-829-029 (ZonMW projectnumber 733051061); Dutch Federation of University Medical Centers; Dutch Government (from 2007-2011); JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A); German Research Foundation (DFG RA 1971/6-1, RA1971/7-1, RA 1971/8-1); Grifols SA; Fundación bancaria 'La Caixa'; Fundació ACE; CIBERNED; Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'); NIH (P30AG066444, P01AG003991); Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund; Siemens Healthineers; Valdecilla Biobank (PT17/0015/0019); Academy of Finland (338182); German Center for Neurodegenerative Diseases (DZNE); German Federal Ministry of Education and Research (BMBF 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711); ZonMW (#73305095007); Health~Holland, Topsector Life Sciences & Health (PPP-allowance #LSHM20106); Hersenstichting; Edwin Bouw Fonds; Gieskes-Strijbisfonds; NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012); Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361); Dementia Foundation (2020-04-13, 2021-04-17); Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALF 716681); Swedish Research Council (11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096); Swedish Research Council for Health, Working Life and Welfare (2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496); Swedish Brain Power, Hjärnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163); Alzheimer's Association Zenith Award (ZEN-01-3151); Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); Alzheimer's Association (IIRG-03-6168, IIRG-09-131338); Bank of Sweden Tercentenary Foundation; Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALFGBG-771071); Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825); Swedish Research Council (2019-02075); Swedish Research Council (2016-01590); BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (024.004.012); Swedish Research Council (2018-02532); Swedish State Support for Clinical Research (ALFGBG-720931); Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862); UK Dementia Research Institute at UCL; Swedish Research Council (#2017-00915); Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); National Institute of Health (NIH), USA, (#1R01AG068398-01); Alzheimer's Association 2021 Zenith Award (ZEN-21-848495); National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614); Chuck Zuckerberg Initiative (CZI).Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume

Managing travel fatigue and jet lag in athletes : a review and consensus statement

Athletes are increasingly required to travel domestically and internationally, often resulting in travel fatigue and jet lag. Despite considerable agreement that travel fatigue and jet lag can be a real and impactful issue for athletes regarding performance and risk of illness and injury, evidence on optimal assessment and management is lacking. Therefore 26 researchers and/or clinicians with knowledge in travel fatigue, jet lag and sleep in the sports setting, formed an expert panel to formalise a review and consensus document. This manuscript includes definitions of terminology commonly used in the field of circadian physiology, outlines basic information on the human circadian system and how it is affected by time-givers, discusses the causes and consequences of travel fatigue and jet lag, and provides consensus on recommendations for managing travel fatigue and jet lag in athletes. The lack of evidence restricts the strength of recommendations that are possible but the consensus group identified the fundamental principles and interventions to consider for both the assessment and management of travel fatigue and jet lag. These are summarised in travel toolboxes including strategies for pre-flight, during flight and post-flight. The consensus group also outlined specific steps to advance theory and practice in these areas.https://www.springer.com/journal/402792022-07-14hj2021Sports MedicineStatistic

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.Peer reviewe

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele