患有遗传性和散发性神经退行性疾病的成年人的脑衰老恢复因子。
Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease.
作者信息
Casaletto Kaitlin B, Saloner Rowan, Kornak John, Staffaroni Adam M, Villeda Saul, Paolillo Emily, VandeBunte Anna M, Cadwallader Claire J, Lario Lago Argentina, Webb Julia, Chen Coty, Rascovsky Katya, Miyagawa Toji, Ramos Eliana Marisa, Masdeu Joseph C, Pantelyat Alexander, Tartaglia Maria Carmela, Bozoki Andrea, Pressman Peter S, Rademakers Rosa, Kremers Walter, Darby Ryan, Younes Kyan, Pascual Belen, Ghoshal Nupur, Lapid Maria, Mackenzie Ian R A, Li Jingyao, Hsiung Ging-Yuek Robin, Hall Jacob N, Yutsis Maya V, Litvan Irene, Henderson Victor W, Sivasankaran Rajeev, Worringer Katie, Domoto-Reilly Kimiko, Synder Allison, Loureiro Joseph, Kramer Joel H, Heuer Hilary, Forsberg Leah K, Rosen Howard J, Boeve Bradley, Rojas Julio C, Boxer Adam L
机构信息
Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA.
出版信息
Brain Commun. 2025 Jan 15;7(1):fcae432. doi: 10.1093/braincomms/fcae432. eCollection 2025.
The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate 'pro-aging' or 'pro-youthful' effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer's disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (M = 49.6; 50% female; 43% , 24% , 33% ) and 62 non-carriers (M = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (M = 3 years, range 1-7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer's disease cohort included 35 adults with sporadic Alzheimer's disease (M = 69.4; 60% female) and 56 controls (M = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting 'pro-youthful' levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer's disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer's disease and related dementias and warrant further investigation.
痴呆症最大的风险因素是年龄。异时血液交换研究发现了与年龄相关的血液因子，这些因子对小鼠大脑具有“促衰老”或“促年轻化”作用。这些因子对人类的临床相关性和综合影响尚不清楚。我们检测了患有常染色体显性额颞叶痴呆和散发性阿尔茨海默病的成年人脑脊液中的五种先前确定的脑年轻化因子。我们的额颞叶痴呆队列包括100名携带常染色体显性额颞叶痴呆突变的成年人（平均年龄49.6岁；50%为女性；43%、24%、33%），他们接受了观察性随访，还有62名非携带者（平均年龄52.6岁；45%为女性），对其脑脊液进行了Somascan分析，并进行了纵向（平均3年，范围1至7年）神经心理学和功能评估以及血浆神经丝轻链检测。我们的阿尔茨海默病队列包括35名散发性阿尔茨海默病成年人（平均年龄69.4岁；60%为女性）和56名对照者（平均年龄68.8岁，50%为女性），他们横断面完成了相同的脑脊液和临床结局测量。脑脊液中的C-C基序趋化因子配体11、C-C基序趋化因子配体2、β-2-微球蛋白、骨γ-羧基谷氨酸蛋白（又名骨钙素）和集落刺激因子2水平被线性组合成一个综合评分，分数越高反映“促年轻化”水平越高。在遗传性额颞叶痴呆中，较高的基线脑脊液年轻化蛋白预测认知、功能和神经丝轻链轨迹的下降速度较慢；不同基因型的估计结果相似。在跨诊断分析中，脑脊液年轻化蛋白水平较高与散发性阿尔茨海默病成年人更好的功能、认知和神经丝轻链结局相关。有临床前证据表明具有脑年轻化作用的蛋白质在患有阿尔茨海默病及相关痴呆症的成年人中显示出转化临床相关性，值得进一步研究。
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