Acetyl-L-carnitine

Findings may explain why women are at higher risk NEW YORK, Jan. 8, 2025 /PRNewswire/ -- Declining blood levels of two molecules that occur naturally in the body track closely with worsening Alzheimer's disease, particularly in women. Levels were found to drop gradually, from women with no signs of memory, disorientation, and slowed thinking to those with early signs of mild cognitive impairment. Decreases were more prominent in women with moderate or severe stages of the disease. Declines in men were evident in only one molecule, revealing a disease-specific difference between the sexes. Six million Americans, most over the age of 65 and predominantly women, are currently estimated to have some form of Alzheimer's disease. Led by neuroscientists at NYU Langone Health, in collaboration with other researchers in the U.S. and Brazil, the new study showed that blood levels of the protein acetyl-L-carnitine were lower in both women and men with mild cognitive impairment and Alzheimer's disease. Blood levels of free carnitine, the main byproduct of acetyl-L-carnitine in reactions essential to brain function, steadily declined in women in amounts related to the severity of their cognitive decline. In men, significant declines were seen only in acetyl-L-carnitine, not free carnitine. Published in the journal Molecular Psychiatry online Jan. 7, the study results suggest that declines in these two brain chemicals could indicate the presence and degree of Alzheimer's disease, and that this difference might offer an explanation as to why women are at higher risk of the disease than men. Additional computer testing showed that blood levels of acetyl-L-carnitine and free carnitine aligned in direct proportion in study participants to increased amyloid beta and tangled tau protein levels, long considered markers of progressive severity in Alzheimer's disease. Indeed, the research team's accuracy in diagnosing the severity of Alzheimer's disease rose from more than 80% – when using either amyloid beta and tangled tau protein levels collected from cerebrospinal fluid or the two blood molecules – to 93% when using both. "Our findings offer the strongest evidence to date that decreased blood levels of acetyl-L-carnitine and free carnitine could act as blood biomarkers for identifying those who have Alzheimer's disease, and potentially those who are at greater risk of developing early dementia," said study lead investigator Betty Bigio, PhD. "The results also might explain the differences by sex in Alzheimer's disease, with more women than men having dementia," said Bigio, a research assistant professor in the Department of Psychiatry at NYU Grossman School of Medicine. Bigio is also affiliated with the Nathan Kline Institute for Psychiatric Research. "Because declines in acetyl-L-carnitine and free carnitine tracked closely with the severity of Alzheimer's disease, the molecular pathways involved in their production offer other possible therapeutic targets for getting at the root cause of the disease and potentially intervening before permanent brain damage occurs," said senior study investigator Carla Nasca, PhD. Nasca is an assistant professor in the Departments of Psychiatry and Neuroscience at NYU Grossman School of Medicine. Nasca is also affiliated with the Nathan Kline Institute for Psychiatric Research. The study involved data on two separate groups of men and women in Brazil and California, in which the researchers measured blood levels of the two molecules. A total of 93 study volunteers diagnosed with varying degrees of cognitive impairment were involved, along with 32 cognitively healthy men and women of similar age, weight, and education. Results in the Californian group were used to confirm what was found in the Brazilian group. Moving forward, Nasca says more research is needed into the root sources of acetyl-L-carnitine and the molecular pathways that control its production and into tracking how the molecule affects brain chemistry as it is contained in brain vesicle stores released into the blood. The team's goal is to define other biomarkers in the brain that track closely with Alzheimer's disease progression. If further studies confirm their latest findings, Nasca says the team's research could be used to develop a blood test for dementia and for tracking the progression of Alzheimer's disease in an easier and noninvasive way. Currently, searching for biomarkers of disease progression can involve serial spinal taps that pose risks of pain and infection. A blood test might also be useful to support or add a more objective, quantitative measure of disease severity than existing questionnaires that test memory or thinking skills. A blood test, Nasca says, could also help predict the effectiveness, or lack thereof, of potential new drug treatments designed to delay or prevent the onset of Alzheimer's disease. Both acetyl-L-carnitine and free carnitine are essential for healthy brain function and regulating cell energy metabolism. Past research by Nasca's team showed that acetyl-L-carnitine also shuttles molecules from a cell's powerhouse mitochondria to a cell's controlling nucleus, allowing genes to open and become activated. This shuttling action is key in regulating genes that produce the neurotransmitter glutamate, another chemical involved in most brain activities, including nerve cell repair (plasticity). This matters in the hippocampus region of the brain, which helps regulate memory and where initial damage from Alzheimer's diseases is known to appear. Nasca says that excessive levels of glutamate have also been tied to mood disorders and severe cases of depression in humans, disorders closely tied to Alzheimer's disease. Her team has also linked deficiencies in acetyl-L-carnitine, but not free carnitine, to depression and childhood trauma. Future investigations are planned about how to prevent the progression of depression to Alzheimer's disease. Funding support for the study was provided by National Institutes of Health grants R24AG06517, P50AG16573, and P30AG066519. Additional funding support came from the Robertson Therapeutic Development Fund, D'Or Institute for Research and Education, Rede D'Or Sao Luiz Hospital Network, International Society for Neurochemistry, Fundacao Carlos Chagas Filho de Ampara a Pesquisa do Estado do Rio Janeiro, Serrapilheira Institute, and Alzheimer's Association grant AARG-D-61541. Besides Bigio and Nasca, other NYU Langone researchers involved in the study are co-investigators Aryeh Korman and Drew Jones. Other study co-investigators are Ricardo Lima-Filho, Felipe Sudo, Claudia Drummond, Naima Assuncao, Bart Vanderborght, Sergio Ferreira, Paulo Mattos, Fernanda Tovar-Moll, Fernanda De Felice, and Mychael Lourenco, at the Federal University of Rio de Janeiro and the D'Or Institute for Research and Education, also in Brazil; Olivia Barnhill, at Rockefeller University in New York City; James Beasley and Sarah Young, at Duke University in Durham, N.C.; and David Sultzer and Elizabeth Head, at the University of California Irvine. About NYU Langone Health NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient, Inc., has ranked NYU Langone the No. 1 comprehensive academic medical center in the country for three years in a row, and U.S. News & World Report recently placed nine of its clinical specialties among the top five in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across six inpatient locations, its Perlmutter Cancer Center, and more than 300 outpatient locations in the New York area and Florida. With $14.2 billion in revenue this year, the system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise with over $1 billion in active awards from the National Institutes of Health. Media Inquiries: David March 212-404-3528 [email protected] STUDY LINK SOURCE NYU Langone Health System WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

7月28日是“世界肝炎日”，今年的宣传主题是“消除肝炎，积极行动”。 近年来，我国病毒性肝炎发病率呈下降趋势，但非病毒性肝炎发病率明显升高，主要包括脂肪型肝炎、酒精性肝炎、药物性肝损伤（DILI）等。 其中，药物性肝损伤是当前急性肝损伤最为常见的病因之一，正成为全球急性肝衰竭的主要病因，其占比正在逐渐增加。根据2014年发布的国内迄今最大规模的药物性肝损伤流行病学研究成果——《中国大陆药物性肝损伤发生率及病因学》显示，我国药物性肝损伤的年发病率为23.8/10万人，远高于法国、美国、西班牙、瑞士等欧美国家，其中急性药物性肝损伤占87%。 目前已知全球有超出1100种上市药物具有潜在肝毒性。在欧美国家，非甾体抗炎药、抗感染药物是引起药物性肝损伤的常见药物。在我国，传统中草药和膳食补充剂、抗结核药、抗肿瘤药、免疫调节剂是引起肝损伤的主要可疑药物。 在亚洲，传统治疗药物具有悠久的应用历史并广泛用于各类疾病的预防和治疗。由于很多患者存在草药“天然无毒”的错误认识，对草药的肝损伤风险常缺乏警惕，我国多数研究报道的 DILI 患者由草药引起占比约为 20% ～ 30% 。在我国，据报道可能引起肝损伤的有何首乌、雷公藤、黄药子、补骨脂、千里光、淫羊藿、菊三七等 HMs 及其汤剂或成药。 1、根据发病机制，DILI 分为固有型、特异质型和间接型： 2、根据生物化学异常模式，DILI分为肝细胞损伤型、胆汁淤积型和混合型： （1）肝细胞损伤型：R ≥ 5； 轻者可无任何症状 ；重者则可出现黄疸，如全身皮肤和 / 或巩膜黄染、尿色加深等，伴或不伴不同程度的乏力、食欲减退、厌油、肝区胀痛及上腹不适等非特异性消化道症状。 （2）胆汁淤积型：R ≤ 2； 明显者可出现黄疸、大便颜色变浅和瘙痒等表现。进展为 ALF/SALF 者则可出现黄疸、凝血功能障碍、腹水、肝性脑病等相关症状。 （3）混合型：2 ＜ R ＜ 5。 R 值＝ [ 丙氨酸转氨酶（ALT）实测值 /ALT 的正常值上限（ULN）] / [ 碱性磷酸酶（ALP）实测值/ALP的ULN]。ALT缺失时，可用天冬氨酸转氨酶（AST）取代进行计算。 R值计算通常是基于首次可获得的异常肝脏生物化学检查结果，可大致反映肝损伤时的生物化学异常模式。 发病起始时的 R 值可随着肝损伤的演变而发生变化，病程中动态监测 R 值，有助于更全面地了解和判断肝损伤的演变过程。 3、特殊表型 7% ～ 13% 的患者在急性 DILI 事件后的 6 个月或 1 年，肝脏生物化学指标仍未恢复至正常或基线水平，提示急性肝损伤可能转化为慢性或肝损伤延迟恢复。 1、病史采集： 详细、完整的包括可疑药物应用史在内的病史采集对评估因果关系，最终建立 DILI 诊断至关重要。 疑似 DILI 患者，建立诊断或进行因果关系评估至少需采集的病史信息包括： （1）可疑药物信息及开始和停止用药时间； （2）可疑药物和/或同类药物的既往暴露史及反应； （3）其他合并用药信息及反应； （4）疑似 DILI 事件的起病时间、预后、去激发的反应等； （5）伴随疾病和基础肝病或既往肝损伤史； （6）排除肝损伤其他病因。 2、实验室检查： 诊断急性 DILI 时肝脏生物化学阈值需达到下述标准之一 ： （1）ALT ≥ 5×ULN ； （2）ALP ≥ 2×ULN（尤其是伴随 GGT 升高且排除骨骼疾病引起的 ALP 水平升高）； （3）ALT ≥ 3×ULN 同时 TBil ≥ 2×ULN。 未达上述阈值标准而因果关系评估为药物引起者，可界定为药物性肝脏生物化学异常。 需提醒的是，上述肝脏生物化学阈值标准仅适用于急性 DILI 时的诊断，不适用于慢性和特殊表型 DILI 的临床诊断。 3、组织学检查 DILI 的组织学表现复杂多样，几乎涵盖了肝脏病理改变的全部范畴。 由于缺乏特异性的诊断生物标志物，DILI 的诊断目前仍是基于详细病史采集、临床症状和体征、血清生物化学、影像学和组织学等的排他性策略。根据药品不良反应 / 事件关联性评价的原则，建立诊断最终很大程度上依赖于 ： （1）药物暴露或停药与肝脏生物化学的改变有明确、合理的时效关系； （2）肝损伤的临床和/或病理表现（型）与可疑药物已知的肝毒性一致； （3）停药或减少剂量后肝损伤显著改善或恢复正常； （4）再次用药后肝损伤再次出现； （5）排除了肝损伤的其他病因和基础肝病的活动或复发，且无法用其他合并用药/治疗手段、原发疾病进展来解释。 急性 DILI 诊断建立后，需对其严重程度进行评估，可按以下国际 DILI 专家工作组标准 ： 1级（轻度）：ALT ≥ 5×ULN 或 ALP ≥ 2×ULN 且 TBil ＜ 2×ULN； 2级（中度）：ALT ≥ 5×ULN 或 ALP ≥ 2×ULN 且 TBil ≥ 2×ULN，或有症状性肝炎； 3级（重度）：ALT ≥ 5×ULN 或 ALP ≥ 2×ULN 且 TBil ≥ 2×ULN，或有症状性肝炎并达到下述任何 1 项： ①INR ≥ 1.5， ②腹水和/或肝性脑病，病程 < 26 周，且无肝硬化， ③DILI 导致的其他器官功能衰竭 ； 4级（致命）：因 DILI 死亡，或需接受肝移植才能生存。 除了及时停用可疑肝损伤药物，尽量避免再次使用可疑或同类药物外，还可以结合目前循证医学证据，合理选择治疗药物。 除了上述比较常用的药物外，临床可以根据患者的具体情况酌情使用多烯磷脂酰胆碱、熊去氧胆酸、腺苷蛋氨酸、左旋肉碱和谷胱甘肽等。 1、鹅膏毒素引起的 DILI——水飞蓟素（宾）类 多项临床研究证实水飞蓟素（宾）类能够有效治疗鹅膏毒素中毒所致肝损伤。一项收集20年2000例毒蕈导致肝损伤患者的回顾性研究发现，应用水飞蓟素（宾）类的病死率为5.8%，而未使用水飞蓟素（宾）类的病死率高达14.1%。此外，还有临床研究证实水飞蓟素（宾）类治疗毒蕈中毒时安全性良好，可用于中位数年龄为5岁的儿童患者。 2、胆汁淤积型DILI——熊去氧胆酸/S-腺苷蛋氨酸： 胆汁淤积型DILI患者，尤其是严重或恢复缓慢的胆汁淤积型或混合型DILI患者中可使用熊去氧胆酸或S-腺苷蛋氨酸，用以降低ALP水平。 3、对乙酰氨基酚（APAP）引起的固有型DILI——N-乙酰半胱氨酸（NAC）： NAC是被FDA批准用来治疗APAP引起的固有型DILI的唯一解毒药物。 4、急性DILI——异甘草酸镁： 异甘草酸镁是目前唯一具有急性DILI适应证的药物。 5、DRESS综合征、DI-ALH、ICIs肝毒性——糖皮质激素： 对于伴随超敏或自身免疫征象的免疫介导的DILI是糖皮质激素应用的指征，如DRESS综合征、DI-ALH、ICIs肝毒性。 参考文献： [1]中国医药生物技术协会药物性肝损伤防治技术专业委员会, 中华医学会肝病学分会药物性肝病学组. 中国药物性肝损伤诊治指南（2023 年版）[J]. 中华肝脏病杂志,2023,31(4):355-384. [3]水飞蓟制剂肝病临床应用专家委员会. 水飞蓟制剂肝病临床应用专家共识 [J]. 中华实验和临床感染病杂志（电子版）,2016,10(5):517-521. 内容来源于网络，如有侵权，请联系删除。