Aron Emmi,Veronica Macchi,Elena Stocco,Aleksandar Tushevski,Angelo Antonini,Raffaele De Caro,Andrea Porzionato
{"title":"α-Synuclein Pathology in the Carotid Body: Experimental Evidence for a possible Contributor to Respiratory Impairment in Parkinson's Disease.","authors":"Aron Emmi,Veronica Macchi,Elena Stocco,Aleksandar Tushevski,Angelo Antonini,Raffaele De Caro,Andrea Porzionato","doi":"10.1002/mds.30036","DOIUrl":"https://doi.org/10.1002/mds.30036","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"125 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489724","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}
Riikka Ajalin, Haidar Al-Abdulrasul, Jouni M Tuisku, Jussi Hirvonen, Salla Lahdenpohja, Juha O Rinne, Anna Brück
Background: In Parkinson's disease (PD), postural instability and gait disorder (PIGD) symptoms are associated with a worse prognosis for an unknown reason.
Objective: The objective was to explore the relationship between cannabinoid receptor type 1 (CB1R) availability and motor symptoms in PD with [18F]FMPEP-d2 positron emission tomography (PET).
Methods: Fifteen individuals with PD underwent [18F]FMPEP-d2 PET to measure cerebral CB1R availability. The Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) was used to evaluate the motor symptoms.
Results: A negative correlation was observed between [18F]FMPEP-d2 VT and PIGD score (P = 0.002) as well as rigidity subscore (P < 0.001). Both clusters covered widespread areas of both hemispheres. In contrast, tremor or bradykinesia did not correlate to [18F]FMPEP-d2 VT.
<p>From a metabolic and basic science point of view, triheptanoin was an excellent therapeutic candidate for patients with Glut1DS. Earlier studies in humans were promising; however, these studies were open-label, observational studies with a small number of participants.<span><sup>1-4</sup></span> Two randomized placebo-controlled trials have failed to demonstrate triheptanoin efficacy to control seizure frequency and movement disorders in GLUT1DS.<span><sup>5, 6</sup></span> To our knowledge, no other double-blind, placebo-controlled trials have been conducted. Additionally, triheptanoin has been tested in many other metabolic and mitochondrial pathologies but has demonstrated efficacy in only one disease: long-chain fatty acid oxidation disorders (LC-FAOD).<span><sup>7, 8</sup></span></p><p>Dr. Mochel and colleagues<span><sup>9</sup></span> point out some limitations of our trial. These same limitations were described in detail in our article.<span><sup>5</sup></span> Briefly, the dietary restrictions, dietary instructions, and dosing schedules used in our study mimic those used in earlier studies by Dr. Mochel and others.<span><sup>1-4</sup></span> These earlier open-label studies did show a strong effect for triheptanoin, whereas in the more demanding clinical trials we did not. As these factors are similar among studies with different outcomes, it is unlikely that these factors are driving the differences.</p><p>Safflower oil was used as a placebo to match the appearance, taste, and smell of triheptanoin. This was necessary to maintain blinding, though as discussed in the article, “any oil, in a condition such as Glut1DS that may respond to additional dietary fat, may have a treatment effect, and therefore, may not function as a true placebo.”</p><p>Finally, treatment duration was 10–12 weeks of titration and 8 weeks of maintenance. This was followed by an open-label extension period of up to 3 years. No differences were seen during the double-blind portion of the study. No differences were seen during the open-label extension. Therefore, it seems unlikely that a longer duration of follow-up would reveal belated results.</p><p>In summary, triheptanoin failed to meet the primary endpoint, or any other endpoints in this clinical trial. While some patients may have benefited from triheptanoin, perhaps those with more subtle symptoms, these are single, anecdotal results that cannot be generalized without solid evidence of efficacy. The trial was, unfortunately, negative. We hope the details provided in our article<span><sup>5</sup></span> and in this discussion are helpful to patients, caregivers, and other researchers working on therapies for this challenging disease.</p><p>(1) Conception; (2) A. Writing of the First Draft, B. Review and Critique.</p><p>V.D.G.: 1, 2A, 2B</p><p>D.C.D.: 1, 2B</p><p>V.D.G. has received speaker honoraria from Nutricia, Vitaflo, Kanso; has served as advisor/consultant for Vitaflo and Longboard Pharmaceuticals; has
{"title":"Reply to: Comment on De Giorgis et al. “Randomized Phase 3 Study of Triheptanoin for Glut1 Deficiency Syndrome–Associated Paroxysmal Movement Disorders”","authors":"Valentina De Giorgis, Darryl C. De Vivo","doi":"10.1002/mds.29985","DOIUrl":"10.1002/mds.29985","url":null,"abstract":"<p>From a metabolic and basic science point of view, triheptanoin was an excellent therapeutic candidate for patients with Glut1DS. Earlier studies in humans were promising; however, these studies were open-label, observational studies with a small number of participants.<span><sup>1-4</sup></span> Two randomized placebo-controlled trials have failed to demonstrate triheptanoin efficacy to control seizure frequency and movement disorders in GLUT1DS.<span><sup>5, 6</sup></span> To our knowledge, no other double-blind, placebo-controlled trials have been conducted. Additionally, triheptanoin has been tested in many other metabolic and mitochondrial pathologies but has demonstrated efficacy in only one disease: long-chain fatty acid oxidation disorders (LC-FAOD).<span><sup>7, 8</sup></span></p><p>Dr. Mochel and colleagues<span><sup>9</sup></span> point out some limitations of our trial. These same limitations were described in detail in our article.<span><sup>5</sup></span> Briefly, the dietary restrictions, dietary instructions, and dosing schedules used in our study mimic those used in earlier studies by Dr. Mochel and others.<span><sup>1-4</sup></span> These earlier open-label studies did show a strong effect for triheptanoin, whereas in the more demanding clinical trials we did not. As these factors are similar among studies with different outcomes, it is unlikely that these factors are driving the differences.</p><p>Safflower oil was used as a placebo to match the appearance, taste, and smell of triheptanoin. This was necessary to maintain blinding, though as discussed in the article, “any oil, in a condition such as Glut1DS that may respond to additional dietary fat, may have a treatment effect, and therefore, may not function as a true placebo.”</p><p>Finally, treatment duration was 10–12 weeks of titration and 8 weeks of maintenance. This was followed by an open-label extension period of up to 3 years. No differences were seen during the double-blind portion of the study. No differences were seen during the open-label extension. Therefore, it seems unlikely that a longer duration of follow-up would reveal belated results.</p><p>In summary, triheptanoin failed to meet the primary endpoint, or any other endpoints in this clinical trial. While some patients may have benefited from triheptanoin, perhaps those with more subtle symptoms, these are single, anecdotal results that cannot be generalized without solid evidence of efficacy. The trial was, unfortunately, negative. We hope the details provided in our article<span><sup>5</sup></span> and in this discussion are helpful to patients, caregivers, and other researchers working on therapies for this challenging disease.</p><p>(1) Conception; (2) A. Writing of the First Draft, B. Review and Critique.</p><p>V.D.G.: 1, 2A, 2B</p><p>D.C.D.: 1, 2B</p><p>V.D.G. has received speaker honoraria from Nutricia, Vitaflo, Kanso; has served as advisor/consultant for Vitaflo and Longboard Pharmaceuticals; has ","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 10","pages":"1899-1900"},"PeriodicalIF":7.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29985","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451438","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}
<p>The Ultragenyx@-sponsored phase 3 randomized controlled study evaluating the effect of triheptanoin to treat paroxysmal episodes of movement disorders related to Glut1 deficiency syndrome (Glut1-DS) failed to demonstrate efficacy.<span><sup>1</sup></span> This was unexpected considering the rationale supporting the use of triheptanoin,<span><sup>2</sup></span> and the striking results of preliminary investigator-driven open-label studies that showed over 90% reduction of paroxysmal movement disorders in patients with Glut1-DS,<span><sup>3, 4</sup></span> a clinical benefit sustainable over years of treatment.<span><sup>5</sup></span></p><p>Triheptanoin is an odd medium C7 chain triglyceride that is metabolized into acetyl-CoA and propionyl-CoA, two key entries of the tricarboxylic acid cycle, making it a unique molecule to address defective brain energy metabolism.<span><sup>6</sup></span> Importantly, treatment of Glut1-DS with triheptanoin must comprise a restriction of dietary carbohydrates, especially those with a high glycemic index.<span><sup>7</sup></span> Indeed, the brain always prefers simple sugars to any alternative source of energy fuel,<span><sup>8</sup></span> and patients with Glut1-DS tend to spontaneously increase their sugar intakes when experiencing paroxysmal manifestations. We documented in two distinct patient populations that increased sugar intake in patients with Glut1-DS treated with triheptanoin led to a prompt recurrence of movement disorders.<span><sup>4, 5</sup></span> In the present Ultragenyx@-sponsored negative study, most patients did not follow this basic principle. In fact, De Giorgis et al<span><sup>1</sup></span> indicated that “patients/caregivers were instructed to avoid simple sugars at the end of the inclusion period (December 2017).” Given that almost all patients had by then completed the 8-week treatment periods, this is a major issue regarding the study conduct and the validity of the authors' conclusions. Other factors that may have affected the study results comprise short study periods in a highly fluctuating disease, absence of an optimal placebo, and lack of a tailored treatment schedule (ie, fixed daily pattern of drug administration despite variable energy needs depending on energy expenditure in patients with Glut1-DS).</p><p>There are several reasons for a potentially efficacious drug to fail to demonstrate efficacy such as flawed study designs, inappropriate statistical endpoints, or underpowered studies.<span><sup>9</sup></span> Pharmaceutical companies must deal with the high cost of clinical trials, but their desire to move experimental drugs forward into clinical applications may have deleterious consequences on important aspects of study design such as too short study periods or the lack of appropriate dietary instructions for a study drug that mainly consisted into a dietary intervention as it was the case in De Giorgis study.<span><sup>1</sup></span> Ultimately, this may hamper th
Ultragenyx@ 赞助的第三阶段随机对照研究评估了三庚酸治疗与 Glut1 缺乏综合征（Glut1-DS）相关的阵发性运动障碍的效果，但未能证明其疗效。1 考虑到支持使用三庚酸的理由，2 以及由研究者驱动的开放标签初步研究的惊人结果，即显示 Glut1-DS 患者阵发性运动障碍减少了 90% 以上，3、4 这种临床益处可持续数年的治疗，这种结果是出乎意料的。三庚酸是一种奇特的中C7链甘油三酯，可代谢为乙酰-CoA和丙酰-CoA，它们是三羧酸循环的两个关键入口，使其成为解决大脑能量代谢缺陷的独特分子。重要的是，用三七皂苷治疗 Glut1-DS 必须限制饮食中的碳水化合物，尤其是那些血糖生成指数较高的碳水化合物。7 事实上，大脑总是偏爱单糖而非其他能量燃料来源，8 而 Glut1-DS 患者在出现阵发性表现时往往会自发增加糖的摄入量。我们曾在两个不同的患者群体中发现，接受三七皂苷治疗的 Glut1-DS 患者增加糖分摄入会导致运动障碍迅速复发。事实上，De Giorgis 等人1 指出，"在纳入期结束时（2017 年 12 月），已指示患者/护理人员避免摄入单糖"。鉴于当时几乎所有患者都已完成了为期 8 周的治疗，这对研究的进行和作者结论的有效性是一个重大问题。可能影响研究结果的其他因素还包括：在一种波动性很大的疾病中研究时间短、缺乏最佳安慰剂、缺乏量身定制的治疗计划（即尽管 Glut1-DS 患者的能量消耗不同，对能量的需求也不同，但每天的给药模式却是固定的）。制药公司必须面对高昂的临床试验成本，但他们希望将实验药物推进到临床应用的愿望可能会对研究设计的重要方面产生有害影响，如研究时间过短，或对主要由饮食干预组成的研究药物缺乏适当的饮食指导，De Giorgis 的研究就是这种情况1 。最终，这可能会阻碍患者获得至少可以帮助其中一部分人的药物，尤其是在罕见病领域。我们怀疑这就是那里发生的情况。因此，我们主张从患者的角度出发，公开分析治疗试验领域的错误，而不是试图尽量减少错误，这一点至关重要。E.R.从Orkyn、Elivie、Merz-Pharma、Janssen和Teva获得了演讲酬金，并参加了Elivie、Merz-Pharma、Teva和BIAL的顾问委员会。他曾获得过 Elivie、Merz-Pharma、Orkyn、Ipsen、Everpharma、AMADYS、ADCY5.org、Fonds de dotation Patrick Brou de Laurière、Agence Nationale de la Recherche、肌张力障碍医学研究基金会、Hope for Annabel 和交替性偏瘫基金会的研究资助。A.M.从默沙东制药公司（Merz-Pharma）和梯瓦公司（Teva）获得演讲酬金，并从默沙东制药公司（Merz-Pharma）和埃利维公司（Elivie）获得旅费资助。E.H. 曾获得波士顿科学公司的演讲酬金以及波士顿科学公司和 Insightec 公司的差旅资助。F.M. 从 Minoryx Therapeutics 获得顾问费，并从 Minoryx Therapeutics 和 Vigil Neuroscience 获得参加顾问委员会的酬金。她曾获得 Minoryx Therapeutics、Vigil Neuroscience、Leadiant Biosciences、Agence Nationale de la Recherche 和巴黎脑研究所的研究支持：A.撰写初稿，B.审稿和批改.E.R.：1AA.M.：1BE.H.：1BF.M.：1B
{"title":"Comment to: “Randomized Phase 3 Study of Triheptanoin for Glut1 Deficiency Syndrome–Associated Paroxysmal Movement Disorders”","authors":"Emmanuel Roze MD, PhD, Aurélie Méneret MD, PhD, Elodie Hainque MD, PhD, Fanny Mochel MD, PhD","doi":"10.1002/mds.29983","DOIUrl":"10.1002/mds.29983","url":null,"abstract":"<p>The Ultragenyx@-sponsored phase 3 randomized controlled study evaluating the effect of triheptanoin to treat paroxysmal episodes of movement disorders related to Glut1 deficiency syndrome (Glut1-DS) failed to demonstrate efficacy.<span><sup>1</sup></span> This was unexpected considering the rationale supporting the use of triheptanoin,<span><sup>2</sup></span> and the striking results of preliminary investigator-driven open-label studies that showed over 90% reduction of paroxysmal movement disorders in patients with Glut1-DS,<span><sup>3, 4</sup></span> a clinical benefit sustainable over years of treatment.<span><sup>5</sup></span></p><p>Triheptanoin is an odd medium C7 chain triglyceride that is metabolized into acetyl-CoA and propionyl-CoA, two key entries of the tricarboxylic acid cycle, making it a unique molecule to address defective brain energy metabolism.<span><sup>6</sup></span> Importantly, treatment of Glut1-DS with triheptanoin must comprise a restriction of dietary carbohydrates, especially those with a high glycemic index.<span><sup>7</sup></span> Indeed, the brain always prefers simple sugars to any alternative source of energy fuel,<span><sup>8</sup></span> and patients with Glut1-DS tend to spontaneously increase their sugar intakes when experiencing paroxysmal manifestations. We documented in two distinct patient populations that increased sugar intake in patients with Glut1-DS treated with triheptanoin led to a prompt recurrence of movement disorders.<span><sup>4, 5</sup></span> In the present Ultragenyx@-sponsored negative study, most patients did not follow this basic principle. In fact, De Giorgis et al<span><sup>1</sup></span> indicated that “patients/caregivers were instructed to avoid simple sugars at the end of the inclusion period (December 2017).” Given that almost all patients had by then completed the 8-week treatment periods, this is a major issue regarding the study conduct and the validity of the authors' conclusions. Other factors that may have affected the study results comprise short study periods in a highly fluctuating disease, absence of an optimal placebo, and lack of a tailored treatment schedule (ie, fixed daily pattern of drug administration despite variable energy needs depending on energy expenditure in patients with Glut1-DS).</p><p>There are several reasons for a potentially efficacious drug to fail to demonstrate efficacy such as flawed study designs, inappropriate statistical endpoints, or underpowered studies.<span><sup>9</sup></span> Pharmaceutical companies must deal with the high cost of clinical trials, but their desire to move experimental drugs forward into clinical applications may have deleterious consequences on important aspects of study design such as too short study periods or the lack of appropriate dietary instructions for a study drug that mainly consisted into a dietary intervention as it was the case in De Giorgis study.<span><sup>1</sup></span> Ultimately, this may hamper th","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 10","pages":"1898-1899"},"PeriodicalIF":7.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29983","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451439","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":"Reply to: Comment on: Diagnostic Criteria for Primary Tic Disorders: Time for Reappraisal","authors":"Davide Martino MD, PhD, Tamara M. Pringsheim MD","doi":"10.1002/mds.30013","DOIUrl":"10.1002/mds.30013","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 10","pages":"1903-1904"},"PeriodicalIF":7.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451370","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}
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