Shana E. McCormack MD, MTR, David R. Weber MD, MSCE, David R. Lynch MD, PhD
<p>We read with interest the recent open label trial (n = 20) of 0.25 mcg/24 h of oral calcitriol in individuals 16 to 65 years old with genetically confirmed Friedreich Ataxia (FRDA).<span><sup>1</sup></span></p><p>The authors performed this trial to follow up on previous in vitro studies in which supplementation with calcitriol (eg, 20 nmol/L) in dorsal root ganglion neurons produced biochemical changes, including restoration of mitochondrial membrane potential, decrease in markers of apoptosis and degeneration, and cell survival.<span><sup>2</sup></span> Of note, the highest upper limit of the physiologic reference range for peripheral blood 1,25-dihydroxyvitamin D (eg, Mayo Clinic, females <16 years) is 86 pg/mL or 215 pmol/L or 0.2 nmol/L, two orders of magnitude below the values achieved in vitro with calcitriol supplementation. Therefore, dose selection becomes a highly relevant consideration for this translational study. Moreover, vitamin D metabolism is cell- and tissue-specific. Thus, it challenging to extrapolate from 1,25-dihydroxyvitamin D measurements made in vitro or even in vivo in peripheral blood to predict the effects of calcitriol supplementation in cardiac, musculoskeletal, or central nervous system in humans.<span><sup>3</sup></span></p><p>The dose of 0.25 mcg of calcitriol is cited as “low” by the group, but this designation is misleading, because calcitriol is most often prescribed to address hypocalcemia or secondary hyperparathyroidism in individuals with kidney disease or hypocalcemia in individuals with hypoparathyroidism. Individuals with FRDA do not have these disorders, nor is there clear evidence of overt deficiency in 1,25-OH-vitamin D in FRDA. Therefore, whereas this calcitriol dose might be considered “low” for individuals who meet typical indications, the dose is supra-physiologic for most others, including those with FRDA.</p><p>The most concerning claim of this study is that this regimen is safe. Of the 20 participants initially studied, five were withdrawn for what were indeed conservative stopping criteria for hypercalcemia; still, one quarter represents a sizeable proportion. Moreover, the study did not include additional safety assessments to support the safety claim, for example, measurement of urinary calcium excretion (a more sensitive measurement of excess 1,25-OH-vitamin D exposure depleting calcium stores from bone) or dual energy x-ray absorptiometry (to assess areal bone mineral density), which is relevant given many individuals with FRDA already have impaired bone health.<span><sup>4, 5</sup></span> Perhaps most relevant, participants were required to stop taking any supplemental calcium and/or vitamin D3 in the 30 days before enrollment. If these individuals were not consuming the typical recommended daily intake of calcium and vitamin D3, and given the established risk of vitamin D insufficiency in this population from previous studies, then such a decision is contrary to care guidelines tha
我们饶有兴趣地阅读了最近一项开放标签试验（n = 20），该试验针对 16 至 65 岁经基因确诊的弗里德里希共济失调症（FRDA）患者口服 0.25 微克/24 小时的降钙素三醇。1 作者进行这项试验是为了跟进之前的体外研究，在这些研究中，背根神经节神经元补充降钙素三醇（如 20 毫摩尔/升）可产生生化变化，包括线粒体膜电位恢复、细胞凋亡和变性标志物减少以及细胞存活。值得注意的是，外周血 1,25-二羟维生素 D 生理参考范围的最高上限（例如，梅奥诊所，女性<16 岁）为 86 pg/mL 或 215 pmol/L 或 0.2 nmol/L，比补充钙三醇在体外达到的值低两个数量级。因此，在这项转化研究中，剂量选择是一个非常重要的考虑因素。此外，维生素 D 的代谢具有细胞和组织特异性。因此，从体外甚至体内外周血中的 1,25-二羟维生素 D 测量值推断补充钙三醇对人体心脏、肌肉骨骼或中枢神经系统的影响具有挑战性。该研究小组称 0.25 微克的降钙素三醇剂量为 "低剂量"，但这种说法具有误导性，因为降钙素三醇最常被用于治疗肾病患者的低钙血症或继发性甲状旁腺功能亢进症，或甲状旁腺功能减退症患者的低钙血症。FRDA 患者没有这些疾病，也没有明确证据表明 FRDA 患者明显缺乏 1,25-OH-维生素 D。因此，对于符合典型适应症的人来说，降钙素三醇的剂量可能被认为是 "低 "的，但对于包括 FRDA 患者在内的大多数其他人来说，该剂量是超生理剂量。在最初接受研究的 20 名参与者中，有 5 人因高钙血症而退出研究，这确实是保守的停药标准；尽管如此，四分之一的参与者仍占了相当大的比例。此外，该研究并未包括额外的安全性评估来支持安全性声明，例如，尿钙排泄测量（一种更灵敏的测量过量 1,25-OH- 维生素 D 暴露消耗骨骼中钙储存的方法）或双能 X 射线吸收测量法（用于评估骨矿物质密度），鉴于许多 FRDA 患者的骨骼健康已经受损，这一点非常重要4，5。如果这些人没有摄入典型的钙和维生素 D3 推荐日摄入量，并考虑到以前的研究已经确定了这一人群维生素 D 不足的风险，那么这样的决定就违背了护理指南，该指南提倡确保所有人群摄入充足的钙和维生素 D，尤其是那些有骨骼脆弱风险的人群。作者建议对更高剂量的钙三醇进行研究，但在考虑和解决上述问题之前，似乎没有必要这样做。特别是考虑到降钙素三醇的随时可用性，FRDA 社区需要明确补充降钙素三醇的安全性和有效性。SEM、DRW、DRL：撰写和编辑手稿的最终版本。
{"title":"Calcitriol in Friedreich Ataxia","authors":"Shana E. McCormack MD, MTR, David R. Weber MD, MSCE, David R. Lynch MD, PhD","doi":"10.1002/mds.29970","DOIUrl":"10.1002/mds.29970","url":null,"abstract":"<p>We read with interest the recent open label trial (n = 20) of 0.25 mcg/24 h of oral calcitriol in individuals 16 to 65 years old with genetically confirmed Friedreich Ataxia (FRDA).<span><sup>1</sup></span></p><p>The authors performed this trial to follow up on previous in vitro studies in which supplementation with calcitriol (eg, 20 nmol/L) in dorsal root ganglion neurons produced biochemical changes, including restoration of mitochondrial membrane potential, decrease in markers of apoptosis and degeneration, and cell survival.<span><sup>2</sup></span> Of note, the highest upper limit of the physiologic reference range for peripheral blood 1,25-dihydroxyvitamin D (eg, Mayo Clinic, females <16 years) is 86 pg/mL or 215 pmol/L or 0.2 nmol/L, two orders of magnitude below the values achieved in vitro with calcitriol supplementation. Therefore, dose selection becomes a highly relevant consideration for this translational study. Moreover, vitamin D metabolism is cell- and tissue-specific. Thus, it challenging to extrapolate from 1,25-dihydroxyvitamin D measurements made in vitro or even in vivo in peripheral blood to predict the effects of calcitriol supplementation in cardiac, musculoskeletal, or central nervous system in humans.<span><sup>3</sup></span></p><p>The dose of 0.25 mcg of calcitriol is cited as “low” by the group, but this designation is misleading, because calcitriol is most often prescribed to address hypocalcemia or secondary hyperparathyroidism in individuals with kidney disease or hypocalcemia in individuals with hypoparathyroidism. Individuals with FRDA do not have these disorders, nor is there clear evidence of overt deficiency in 1,25-OH-vitamin D in FRDA. Therefore, whereas this calcitriol dose might be considered “low” for individuals who meet typical indications, the dose is supra-physiologic for most others, including those with FRDA.</p><p>The most concerning claim of this study is that this regimen is safe. Of the 20 participants initially studied, five were withdrawn for what were indeed conservative stopping criteria for hypercalcemia; still, one quarter represents a sizeable proportion. Moreover, the study did not include additional safety assessments to support the safety claim, for example, measurement of urinary calcium excretion (a more sensitive measurement of excess 1,25-OH-vitamin D exposure depleting calcium stores from bone) or dual energy x-ray absorptiometry (to assess areal bone mineral density), which is relevant given many individuals with FRDA already have impaired bone health.<span><sup>4, 5</sup></span> Perhaps most relevant, participants were required to stop taking any supplemental calcium and/or vitamin D3 in the 30 days before enrollment. If these individuals were not consuming the typical recommended daily intake of calcium and vitamin D3, and given the established risk of vitamin D insufficiency in this population from previous studies, then such a decision is contrary to care guidelines tha","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 9","pages":"1653-1654"},"PeriodicalIF":7.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29970","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CAG Repeat Expansion in THAP11 Is Not Detected in a Cohort with Spinocerebellar Ataxia from Hokkaido, the Northernmost Island of Japan","authors":"Shinichi Shirai MD, PhD, Keiichi Mizushima MD, Yuka Shibata MPH, PhD, Masaaki Matsushima MD, PhD, Ikuko Iwata MD, PhD, Hiroaki Yaguchi MD, PhD, Ichiro Yabe MD, PhD","doi":"10.1002/mds.29975","DOIUrl":"10.1002/mds.29975","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 9","pages":"1657-1658"},"PeriodicalIF":7.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Reply to: “CAG Repeat Expansion in THAP11 is Not Detected in a Cohort with Spinocerebellar Ataxia from Hokkaido, the Northernmost Island of Japan”","authors":"Cheng-Tsung Hsiao MD, PhD, Yi-Chu Liao MD, PhD, Yi-Chung Lee MD, PhD","doi":"10.1002/mds.29978","DOIUrl":"10.1002/mds.29978","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 9","pages":"1658-1659"},"PeriodicalIF":7.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marco Rosina, Federica Veltri, Valentina Nesci, Jacopo Bissacco, Roberta Bovenzi, Davide Mascioli, Clara Simonetta, Henri Zenuni, Daniela Maftei, Massimo Marano, Mariangela Pierantozzi, Alessandro Stefani, Valerio Chiurchiù, Patrizia Longone, Cristiana Valle, Nicola Biagio Mercuri, Alberto Ferri, Tommaso Schirinzi
Background: Peripheral immune cells critically contribute to the clinical-pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard.
Objective: Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort.
Methods: Seventy-one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil-to-lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase 1 (HO-1) pathway and the total tau (t-tau) and phosphorylated tau (p-tau) proteins. Case-control comparison and correlation analyses were performed.
Results: PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO-1 pathway activated in patients. P-tau, but not t-tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS.
Sara Bandres-Ciga PhD, Faraz Faghri PhD, Elisa Majounie PhD, Mathew J. Koretsky BSc, Jeffrey Kim BSc, Kristin S. Levine MSc, Hampton Leonard MSc, Mary B. Makarious PhD, Hirotaka Iwaki MD, Peter Wild Crea BSc, Dena G. Hernandez PhD, Sampath Arepalli BSc, Kimberley Billingsley PhD, Katja Lohmann PhD, Christine Klein MD, PhD, Steven J. Lubbe PhD, Edwin Jabbari MD, PhD, Paula Saffie-Awad MD, Derek Narendra MD, PhD, Armando Reyes-Palomares PhD, John P. Quinn PhD, Claudia Schulte PhD, Huw R. Morris MD, PhD, Bryan J. Traynor MD, PhD, Sonja W. Scholz MD, PhD, Henry Houlden MD, PhD, John Hardy PhD, Sonya Dumanis PhD, Ekemini Riley PhD, Cornelis Blauwendraat PhD, Andrew Singleton PhD, Mike Nalls PhD, Janina Jeff PhD, Dan Vitale MSc, the Global Parkinson's Genetics Program (GP2) and the Center for Alzheimer's and Related Dementias (CARD)
Background
Commercial genome-wide genotyping arrays have historically neglected coverage of genetic variation across populations.
Objective
We aimed to create a multi-ancestry genome-wide array that would include a wide range of neuro-specific genetic content to facilitate genetic research in neurological disorders across multiple ancestral groups, fostering diversity and inclusivity in research studies.
Methods
We developed the Illumina NeuroBooster Array (NBA), a custom high-throughput and cost-effective platform on a backbone of 1,914,934 variants from the Infinium Global Diversity Array and added custom content comprising 95,273 variants associated with more than 70 neurological conditions or traits, and we further tested its performance on more than 2000 patient samples. This novel platform includes approximately 10,000 tagging variants to facilitate imputation and analyses of neurodegenerative disease–related genome-wide association study loci across diverse populations.
Results
In this article, we describe NBA's potential as an efficient means for researchers to assess known and novel disease genetic associations in a multi-ancestry framework. The NBA can identify rare genetic variants and accurately impute more than 15 million common variants across populations. Apart from enabling sample prioritization for further whole-genome sequencing studies, we envisage that NBA will play a pivotal role in recruitment for interventional studies in the precision medicine space.
Sophia R.L. Vieira, Roxana Mezabrovschi, Marco Toffoli, Sara Lucas Del Pozo, Elisa Menozzi, Stephen Mullin, Selen Yalkic, Naomi Limbachiya, Sofia Koletsi, Nadine Loefflad, Grisel J. Lopez, Ziv Gan‐Or, Roy N. Alcalay, Ellen Sidransky, Anthony H.V. Schapira
Lorraine V. Kalia MD, PhD, FRCPC, Daniela Berg MD, Jeffery H. Kordower PhD, Kathleen M. Shannon MD, John-Paul Taylor MRCPsych, PhD, Francisco Cardoso MD, PhD, FAAN, Jennifer G. Goldman MD, MS, FAAN, Beomseok Jeon MD, PhD, Wassilos G. Meissner MD, PhD, Marina A.J. Tijssen MD, PhD, David J. Burn FMedSci, MD, FRCP, Victor S.C. Fung PhD, FRACP
<p>Parkinson's disease (PD) is a neurodegenerative disorder that, in the majority of patients, is associated with intraneuronal inclusions of aggregated fibrillar forms of α-synuclein, termed Lewy pathology. Although many questions regarding the link between α-synuclein and neurodegeneration in PD remain unanswered,<span><sup>1</sup></span> data generally indicate that α-synuclein aggregation can be accompanied by a decline in the health and function of neurons. Further, multiple lines of evidence support the hypothesis that Lewy pathology can occur before motor symptoms in PD and may spread across the neuroaxis via a prion-like mechanism.<span><sup>2-5</sup></span> Based on these pathobiological underpinnings of the disease, two novel frameworks regarding PD ontology were published in early 2024: Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS)<span><sup>6</sup></span> and Synucleinopathy-Neurodegeneration-Genetic research diagnostic criteria for PD (SynNeurGe).<span><sup>7</sup></span> Both propose a new research definition of PD that, unlike prior definitions of the disease, from James Parkinson's initial description to the International Parkinson and Movement Disorders Society (MDS) diagnostic criteria for PD,<span><sup>8</sup></span> are not anchored to the presence of the clinical syndrome of motor parkinsonism (ie, bradykinesia, rigidity, rest tremor). Instead, these two frameworks propose to redefine PD based on biological markers that can occur in the absence of signs or symptoms currently required for a clinical diagnosis of PD.</p><p>Many in the field view this as an opportune time to introduce such a paradigm shift, given recent advances in the development of high-performance biomarkers of disease-associated α-synuclein aggregates, particularly α-synuclein seed amplification assays (SAA) and α-synuclein immunostaining using skin biopsies. Relying on these biomarkers, NSD-ISS and SynNeurGe define α-synuclein biomarker positivity alone as the earliest time point of disease detection (with exceptions made only for disease associated with pathogenic/risk gene variants). Both frameworks therefore do not make a distinction between prodromal and manifest PD (ie, presence of disease before versus after fulfilling current clinical diagnostic criteria, respectively). Further, they integrate PD and dementia with Lewy bodies (DLB) into a unified entity based on their shared association with Lewy pathology.</p><p>These proposed frameworks offer opportunities to propel scientific inquiry and development of therapies targeting α-synuclein-related pathology in its early stages. Nevertheless, they pose several challenges and considerations. The MDS, which serves as a voice for the international community of PD care providers and researchers, previously provided a statement outlining the foundational principles for the development of a biological definition and any classification or staging system for PD.<span><sup>9</sup></span> The cu
{"title":"International Parkinson and Movement Disorder Society Viewpoint on Biological Frameworks of Parkinson's Disease: Current Status and Future Directions","authors":"Lorraine V. Kalia MD, PhD, FRCPC, Daniela Berg MD, Jeffery H. Kordower PhD, Kathleen M. Shannon MD, John-Paul Taylor MRCPsych, PhD, Francisco Cardoso MD, PhD, FAAN, Jennifer G. Goldman MD, MS, FAAN, Beomseok Jeon MD, PhD, Wassilos G. Meissner MD, PhD, Marina A.J. Tijssen MD, PhD, David J. Burn FMedSci, MD, FRCP, Victor S.C. Fung PhD, FRACP","doi":"10.1002/mds.30007","DOIUrl":"10.1002/mds.30007","url":null,"abstract":"<p>Parkinson's disease (PD) is a neurodegenerative disorder that, in the majority of patients, is associated with intraneuronal inclusions of aggregated fibrillar forms of α-synuclein, termed Lewy pathology. Although many questions regarding the link between α-synuclein and neurodegeneration in PD remain unanswered,<span><sup>1</sup></span> data generally indicate that α-synuclein aggregation can be accompanied by a decline in the health and function of neurons. Further, multiple lines of evidence support the hypothesis that Lewy pathology can occur before motor symptoms in PD and may spread across the neuroaxis via a prion-like mechanism.<span><sup>2-5</sup></span> Based on these pathobiological underpinnings of the disease, two novel frameworks regarding PD ontology were published in early 2024: Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS)<span><sup>6</sup></span> and Synucleinopathy-Neurodegeneration-Genetic research diagnostic criteria for PD (SynNeurGe).<span><sup>7</sup></span> Both propose a new research definition of PD that, unlike prior definitions of the disease, from James Parkinson's initial description to the International Parkinson and Movement Disorders Society (MDS) diagnostic criteria for PD,<span><sup>8</sup></span> are not anchored to the presence of the clinical syndrome of motor parkinsonism (ie, bradykinesia, rigidity, rest tremor). Instead, these two frameworks propose to redefine PD based on biological markers that can occur in the absence of signs or symptoms currently required for a clinical diagnosis of PD.</p><p>Many in the field view this as an opportune time to introduce such a paradigm shift, given recent advances in the development of high-performance biomarkers of disease-associated α-synuclein aggregates, particularly α-synuclein seed amplification assays (SAA) and α-synuclein immunostaining using skin biopsies. Relying on these biomarkers, NSD-ISS and SynNeurGe define α-synuclein biomarker positivity alone as the earliest time point of disease detection (with exceptions made only for disease associated with pathogenic/risk gene variants). Both frameworks therefore do not make a distinction between prodromal and manifest PD (ie, presence of disease before versus after fulfilling current clinical diagnostic criteria, respectively). Further, they integrate PD and dementia with Lewy bodies (DLB) into a unified entity based on their shared association with Lewy pathology.</p><p>These proposed frameworks offer opportunities to propel scientific inquiry and development of therapies targeting α-synuclein-related pathology in its early stages. Nevertheless, they pose several challenges and considerations. The MDS, which serves as a voice for the international community of PD care providers and researchers, previously provided a statement outlining the foundational principles for the development of a biological definition and any classification or staging system for PD.<span><sup>9</sup></span> The cu","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 10","pages":"1710-1715"},"PeriodicalIF":7.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.30007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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