Lessons from Green Lanes: Evaluating Protected Bike Lanes in the U.S.

This report presents finding from research evaluating U.S. protected bicycle lanes (cycle tracks) in terms of their use, perception, benefits, and impacts. This research examines protected bicycle lanes in five cities: Austin, TX; Chicago, IL; Portland, OR; San Francisco, CA; and Washington, D.C., using video, surveys of intercepted bicyclists and nearby residents, and count data. A total of 168 hours were analyzed in this report where 16,393 bicyclists and 19,724 turning and merging vehicles were observed. These data were analyzed to assess actual behavior of bicyclists and motor vehicle drivers to determine how well each user type understands the design of the facility and to identify potential conflicts between bicyclists, motor vehicles and pedestrians. City count data from before and after installation, along with counts from video observation, were used to analyze change in ridership. A resident survey (n=2,283 or 23% of those who received the survey in the mail) provided the perspective of people who live, drive, and walk near the new lanes, as well as residents who bike on the new lanes. A bicyclist intercept survey (n= 1,111; or 33% of those invited to participate) focused more on people's experiences riding in the protected lanes. A measured increase was observed in ridership on all facilities after the installation of the protected cycling facilities, ranging from +21% to +171%. Survey data indicates that 10% of current riders switched from other modes, and 24% shifted from other bicycle routes

Polyglutamine-expanded ataxin-3: a target engagement marker for spinocerebellar ataxia type 3 in peripheral blood

Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). Methods: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. Results: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. Conclusions: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyFunding agencies: This project is supported by the EU Joint Programme—Neurodegenerative Disease Research (JPND) through the following funding organizations under the aegis of JPND: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; Portugal, Foundation for Science and Technology (FCT, grant number JPCOFUND/0001/2015), and Regional Fund for Science and Technology of the Azores; and United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 643417. In addition, support has been received by the BIONIC project (number 733050822, which has been made possible by ZonMW as part of “Memorabel,” the research and innovation program for dementia, as part of the Dutch national “Deltaplan for Dementia”: zonmw.nl/dementiaresearch), the CAF[1]E project (the National Institutes of Health, USA, grant number 5R01NS104147-02), and a grant from the Selfridges Group Foundation (NR170024). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and Rhode Island University

The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors

BACKGOUND: Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS. OBJECTIVE: To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors. METHODS: In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity. RESULTS: Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant. CONCLUSION: This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3

Background: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity. Objective: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease. Methods: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels. Results: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume. Conclusion: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.Acknowledgements: This work was supported by the Horizon 2020 research and innovation programme (grant 779257 Solve-RD to MS and RS), the National Ataxia Foundation (grant to CW and MS), the Wilhelm Vaillant Stiftung (grant to CW), the EU Joint Programme—Neurodegenerative Disease Research (JPND) through participating national funding agencies, and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643417. BM was supported in part from the grant NKFIH 119540. HJ was funded by the Medical Faculty of the University of Heidelberg. CB was funded by the University of Basel (PhD Program in Health Sciences). The funding sources had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript

Solving unsolved rare neurological diseases-a Solve-RD viewpoint.

Funder: Durch Princess Beatrix Muscle Fund Durch Speeren voor Spieren Muscle FundFunder: University of Tübingen Medical Faculty PATE programFunder: European Reference Network for Rare Neurological Diseases | 739510Funder: European Joint Program on Rare Diseases (EJP-RD COFUND-EJP) | 44140962

Lessons from the Green Lanes: Evaluating Protected Bike Lanes in the U.S.

This report presents finding from research evaluating U.S. protected bicycle lanes (cycle tracks) in terms of their use, perception, benefits, and impacts. This research examines protected bicycle lanes in five cities: Austin, TX; Chicago, IL; Portland, OR; San Francisco, CA; and Washington, D.C., using video, surveys of intercepted bicyclists and nearby residents, and count data. A total of 168 hours were analyzed in this report where 16,393 bicyclists and 19,724 turning and merging vehicles were observed. These data were analyzed to assess actual behavior of bicyclists and motor vehicle drivers to determine how well each user type understands the design of the facility and to identify potential conflicts between bicyclists, motor vehicles and pedestrians. City count data from before and after installation, along with counts from video observation, were used to analyze change in ridership. A resident survey (n=2,283 or 23% of those who received the survey in the mail) provided the perspective of people who live, drive, and walk near the new lanes, as well as residents who bike on the new lanes. A bicyclist intercept survey (n= 1,111; or 33% of those invited to participate) focused more on people’s experiences riding in the protected lanes. A measured increase was observed in ridership on all facilities after the installation of the protected cycling facilities, ranging from +21% to +171%. Survey data indicates that 10% of current riders switched from other modes, and 24% shifted from other bicycle routes. Over a quarter of riders indicated they are riding more in general because of the protected bike lanes. A large majority of drivers and bicyclists stated that they understood the intent of the intersection designs and were observed to use them as intended, though specific designs perform better than others on certain tasks. No collisions or near-collisions were observed over 144 hours of video review for safety at intersections, including 12,900 bicyclists. Residents and bicyclists indicated that any type of buffer shows a considerable increase in self-reported comfort levels over a striped bike lane, though designs with more physical separation had the highest scores. Buffers with vertical physical objects (those that would be considered protected lanes - e.g. with flexposts, planters, curbs, or parked cars) all resulted in considerably higher comfort levels than buffers created only with paint. Flexpost buffers got very high ratings even though they provide little actual physical protection from vehicle intrusions— cyclists perceive them as an effective means of positive separation. Support for the protected lanes among residents was generally strong with 75% saying that they would support building more protected bike lanes at other locations, and 91% of surveyed residents agreed with the statement, I support separating bikes from cars. This agreement was high among primary users of all modes (driving, walking, transit, and bicycling), though motorists expressed concerns about the impacts of protected lanes on congestion and parking. Most residents also agreed with the statement I would be more likely to ride a bicycle if motor vehicles and bicycles were physically separated by a barrier, with Interested but Concerned residents expressing the highest level of agreement at 85%. Nearly three times as many residents felt that the protected bike lanes had led to an increase in the desirability of living in their neighborhood, as opposed to a decrease in desirability (43% vs 14%)

Blood transcriptome sequencing identifies biomarkers able to track disease stages in spinocerebellar ataxia type 3

Transcriptional dysregulation has been described in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), an autosomal dominant ataxia caused by a polyglutamine expansion in the ataxin-3 protein. As ataxin-3 is ubiquitously expressed, transcriptional alterations in blood may reflect early changes that start before clinical onset and might serve as peripheral biomarkers in clinical and research settings. Our goal was to describe enriched pathways and report dysregulated genes, which can track disease onset, severity or progression in carriers of the ATXN3 mutation (pre-ataxic subjects and patients). Global dysregulation patterns were identified by RNA sequencing of blood samples from 40 carriers of ATXN3 mutation and 20 controls and further compared with transcriptomic data from post-mortem cerebellum samples of MJD patients and controls. Ten genes - ABCA1, CEP72, PTGDS, SAFB2, SFSWAP, CCDC88C, SH2B1, LTBP4, MEG3 and TSPOAP1 - whose expression in blood was altered in the pre-ataxic stage and simultaneously, correlated with ataxia severity in the overt disease stage, were analysed by quantitative real-time PCR in blood samples from an independent set of 170 SCA3/MJD subjects and 57 controls. Pathway enrichment analysis indicated the Gαi signalling and the oestrogen receptor signalling to be similarly affected in blood and cerebellum. SAFB2, SFSWAP and LTBP4 were consistently dysregulated in pre-ataxic subjects compared to controls, displaying a combined discriminatory ability of 79%. In patients, ataxia severity was associated with higher levels of MEG3 and TSPOAP1. We propose expression levels of SAFB2, SFSWAP and LTBP4 as well as MEG3 and TSPOAP1 as stratification markers of SCA3/MJD progression, deserving further validation in longitudinal studies and in independent cohorts.</p

The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors

Background Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS. Objective To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors. Methods In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity. Results Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant. Conclusion This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle.Funding: Open Access funding enabled and organized by Projekt DEAL. This publication is an outcome of ESMI, an EU Joint Programme—Neurodegenerative Disease Research (JPND) project (seewww.jpnd.eu). The project was supported through the following funding organizations under the aegis of JPND: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; Portugal, Foundation for Science and Technology (FCT); United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 643417. H.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, HE 8803/1–1). At the US sites, this work was in part supported by the National Ataxia Foundation and the National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080816. Several authors are members of the European Reference Network for Rare Neurological Diseases—Project No 739510. Bart van de Warrenburg receives research support from ZonMw, Hersenstichting, Gossweiler Foundation, and Radboud university medical center, receives royalties from BSL – Springer Nature, and has served on scientifc advisory boards of uniQure and Servier. Jeremy D. Schmahmann is inventor of the CCAS/Schmahmann Scale, the PROM-Ataxia, Brief Ataxia Rating Scale, and Cerebellar Neuropsychiatric Rating Scale to which the General Hospital Corporation holds the copyright. He consults for Biogen and Medavante, receives support from Biohaven and the National Ataxia Foundation, is site PI for Biohaven NCT03952806 and NCT03701399, and receives royalties from Elsevier, MacKeith, Oxford, and Springer. Matthis Synofzik has received consultancy honoraria from Janssen Pharmaceuticals, Ionis Pharmaceuticals, Orphazyme Pharmaceuticals and AviadoBio, all unrelated to the present manuscript