Clinical and biomarker studies in Alzheimer's disease and related disorders

阿尔茨海默病及相关疾病的临床和生物标志物研究

• 批准号: 10913184
• 负责人: Dimitrios Kapogiannis
• 金额: $ 558.77万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913184
• 关键词: Age; Aging; Agonist; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Astrocytes; Autobiography; Baltimore; Biological Markers; Bipolar Disorder; Blood; Brain; COVID-19 impact; COVID-19 pandemic; Caloric Restriction; Calories; Canada; Cardiac Surgery procedures; Case/Control Studies; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Cognitive; Cognitive aging; Collaborations; Communities; Complement; Conduct Clinical Trials; Consumption; Data; Deposition; Diagnosis; Disease; Disease Progression; Drug Targeting; Elderly; Energy Metabolism; Episodic memory; Esters; Event; Family; Foundations; France; Functional Magnetic Resonance Imaging; Funding; Future; GLAST Protein; Generations; Genotype; Glucose; Glutamates; Goals; Health Personnel; Human; Human Resources; Impaired cognition; Impairment; Individual; Inflammatory; Insulin; Insulin Resistance; Intake; Intervention; Investigational Therapies; Ketone Bodies; Ketones; Lewy Body Disease; Life; Long COVID; Longitudinal Studies; Longitudinal cohort; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediator; Memory; Mental Depression; Mental disorders; Metabolic; Metabolic syndrome; Metabolism; Methodology; Mitochondria; Mitochondrial Proteins; Multiple Sclerosis; Multiple System Atrophy; Nerve Degeneration; Nerve Regeneration; Neural Cell Adhesion Molecule L1; Neurodegenerative Disorders; Neurologic; Neurologic Symptoms; Neurons; Neurosciences; Neurotransmitters; Oral; Outcome; Overweight; Parkinson Disease; Participant; Pathogenesis; Pathogenicity; Patients; Perioperative; Pharmacodynamics; Phosphorylation; Plasma; Positron-Emission Tomography; Postoperative Period; Prediction of Response to Therapy; Prevention; Primary Prevention; Process; Prognostic Marker; Proteins; Psychological Impact; Registries; Research Personnel; Restless Legs Syndrome; SARS-CoV-2 infection; Sampling; Schizophrenia; Signal Transduction; Source; Sphingomyelinase; Structure; Surface; Synapses; Syndrome; Translational Research; Traumatic Brain Injury; Universities; Vascular Cognitive Impairment; Vascular Dementia; Wisconsin; Women' s Health; aging brain; apolipoprotein E-4; atherosclerosis risk; brain health; brain metabolism; cognitive performance; cognitive testing; cohort; comparison control; design; diagnostic biomarker; drug discovery; exenatide; exosome; extracellular vesicles; frontal lobe function; gamma-Aminobutyric Acid; glucagon-like peptide 1; human disease; improved; in vivo; infliximab; insulin sensitivity; middle age; nervous system disorder; neuroimaging; neurotransmission; novel; pre-clinical; predictive marker; prevent; randomized, controlled study; resilience; response; response biomarker; synaptic function; tau Proteins; tau-1; treatment response; validation studies

Biomarkers for Alzheimer's Disease (AD) and other neurodegenerative, neurological and psychiatric diseases The Human Neuroscience Section pioneered biomarker studies using blood Extracellular Vesicles (EVs, aka exosomes) enriched for neuronal origin (isolated by immunoaffinity capture targeting neuronal surface markers, such as L1CAM), or astrocytic origin (isolated by immunoaffinity capture tarheting astrocytic surface marker GLAST). To date, we have conducted scores of case control studies measuring exosomal beta-amyloid, tau/p-tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, complement, mitochondrial proteins and other signaling mediators, in AD and control subjects. We have found multiple disease-associated differences that, for some proteins, may accurately discriminate between the two groups. In addition, biomarker abnormalities may be present at the preclinical stage and may predict AD and related dementias (ADRD). We have expanded the use of exosome biomarkers in other neurological and psychiatric disorders, demonstrating their ability to identify patients with Parkinson's disease (PD), Multiple Sclerosis, Traumatic Brain Injury, Restless Legs Syndrome, Covid-19 infection / long COVID and neurological abnormalities, Bipolar Disorder, and Schizophrenia (and also animal models of AD). Moreover, we have demonstrated the ability of exosome biomarkers to assess target engagement and response to experimental therapeutics in clinical trials involving patients with AD, PD, and bipolar disorder. We recently showed that exosome biomarkers predict future cognitive decline and future AD diagnosis in large preclinical cohorts from the Baltimore Longitudinal Study on Aging, the Wisconsin Registry for Alzheimer's Prevention, and Atherosclerotic Risk in Communities. In addition, we showed that exosome biomarkers predict treatment response and show target engagement in clinical trials of metabolic interventions in AD (intranasal insulin) and PD (exenatide), as well as anti-inflammatory treatment infliximab in Bipolar Disorder. One major goal for the coming year is to conduct studies seeking to demonstrate the relationship between exosomal markers and other biomarkers for AD (PET, CSF) in large preclinical/early clinical cohorts. These studies are needed to assess longitudinal changes in exosome markers and their potential to predict AD at the preclinical stage, track disease progression and predict conversion from MCI to AD. We are in the process of analyzing samples from a large cohort of participants in the Women's Health Initiative Memory Study - Long Life Study to assess the relationship of exosome biomarkers with cognitive resilience and APOE e4 genotype. In addition we intend to further validate exosome biomarkers against cognitive performance, amyloid and tau PET deposition using longitudinal cohorts (Harvard Aging Brain Study and CHARIOT-PRO). In addition to a main focus on AD, we are conducting exosome biomarker studies in vascular cognitive impairment/vascular dementia, Parkinson's disease, Lewy Body disease, Multiple Systems Atrophy, Traumatic Brain Injury, Restless Legs Syndrome, Multiple Sclerosis, long COVID, Schizophrenia, Depression, and Bipolar Disorder. In addition, we have employed a novel Magnetic Resonance Spectroscopy (MRS) methodology at the NIA 3T MRI facility, which allows us to obtain in vivo measures on brain metabolites (glucose, lactate, ketone bodies) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. Previously, we showed higher glucose and lactate, and lower glutamate and GABA in patients compared to controls, suggesting that these MRS markers may be used as diagnostic biomarkers for AD. Glucose concentration is positively correlated with age. Clinical studies in cognitive aging/prevention of cognitive decline We completed a study of Intermittent caloric restriction (CR)implementing 5-2 CR (alternating 5 days of regular calorie intake and 2 days of CR). This is a 8-week study of 5-2 CR in overweight middle aged subjects to assess potential beneficial effects on insulin resistance, brain metabolism, cognitive performance, fMRI activity and biomarkers. We are currently analyzing outcomes. 5-2 CR is a candidate intervention for primary prevention of AD and cognitive aging at midlife. Moreover, we are conducting a randomized controlled study of an oral ketone ester in middle aged individuals with metabolic syndrome. Using cognitive testing, as well as MRS and exosome biomarkers, we aim to demonstrate an increase in brain ketone concentration and a switch of brain metabolism towards ketone utilization, alongside improvements in cognitive performance. We have formed a collaboration with Investigators at McGill University, Canada, who plan to start a clinical trial of intranasal insulin in the peri-operative period of heart surgery patients to prevent post-operative cognitive decline. Our main goal is to conduct exosome biomarker analysis showing target engagement and pharmacodynamic response to intranasal insulin. The project has received funding from the Alzheimer's Drug Discovery Foundation. In collaboration with Dr. Mohamad El Haj from University of Lille, France, we have been involved in the design and analysis of clinical studies on cognitive features of Alzheimer's disease. For instance, we looked at autobiographical generation of past and future events in a cohort of AD patients compared to controls. We found that future and past events are more similar in patients compared to controls and that the ability to generate future events is closely related with the patient's episodic memory. In addition, the ability to generate future events was associated with Frontal Lobe functions. These findings suggest that remembering the past and imagining the future rely on common brain structures, which are both impaired in AD. We have also been studying the psychological impact of COVID-19 on patients with AD, their families and healthcare providers and geriatric facility personnel.

阿尔茨海默病 (AD) 和其他神经退行性疾病、神经系统疾病和精神疾病的生物标志物 人类神经科学部分率先使用血液细胞外囊泡（EV，又名外泌体）进行生物标志物研究，该血液细胞外囊泡（EV，又名外泌体）富含神经元来源（通过针对神经元表面标记物的免疫亲和捕获分离，例如 L1CAM）或星形细胞来源（通过针对星形细胞表面标记物 GLAST 的免疫亲和捕获分离）。迄今为止，我们已经开展了数十项病例对照研究，测量 AD 和对照受试者的外泌体 β-淀粉样蛋白、tau/p-tau、Ser 和 Tyr 磷酸化 IRS-1、突触标记物、补体、线粒体蛋白和其他信号传导介质。我们发现了多种与疾病相关的差异，对于某些蛋白质来说，这些差异可以准确地区分两组。此外，生物标志物异常可能存在于临床前阶段，并且可以预测 AD 和相关痴呆症 (ADRD)。我们扩大了外泌体生物标志物在其他神经和精神疾病中的使用，证明了它们识别帕金森病 (PD)、多发性硬化症、创伤性脑损伤、不宁腿综合症、Covid-19 感染/长期新冠和神经系统异常、双相情感障碍和精神分裂症（以及 AD 动物模型）患者的能力。 此外，我们已经证明外泌体生物标志物能够在涉及 AD、PD 和双相情感障碍患者的临床试验中评估靶点参与和对实验治疗的反应。我们最近在巴尔的摩老龄化纵向研究、威斯康星州阿尔茨海默病预防登记处和社区动脉粥样硬化风险登记处的大型临床前队列中表明，外泌体生物标志物可以预测未来的认知能力下降和未来的 AD 诊断。此外，我们在AD（鼻内胰岛素）和PD（艾塞那肽）的代谢干预以及双向情感障碍的抗炎治疗英夫利昔单抗的临床试验中表明，外泌体生物标志物可以预测治疗反应并显示出目标参与。 来年的一个主要目标是开展研究，试图在大型临床前/早期临床队列中证明外泌体标志物与 AD 的其他生物标志物（PET、CSF）之间的关系。需要这些研究来评估外泌体标记物的纵向变化及其在临床前阶段预测 AD、跟踪疾病进展和预测从 MCI 向 AD 转化的潜力。 我们正在分析来自女性健康倡议记忆研究 - 长寿研究的大量参与者的样本，以评估外泌体生物标志物与认知弹性和 APOE e4 基因型的关系。此外，我们打算使用纵向队列（哈佛衰老大脑研究和 CHARIOT-PRO）进一步验证外泌体生物标志物对认知能力、淀粉样蛋白和 tau PET 沉积的影响。 除了主要关注 AD 外，我们还在血管性认知障碍/血管性痴呆、帕金森病、路易体病、多系统萎缩、创伤性脑损伤、不宁腿综合征、多发性硬化症、长期新冠肺炎、精神分裂症、抑郁症和双相情感障碍等领域进行外泌体生物标志物研究。 此外，我们在 NIA 3T MRI 设施中采用了一种新型磁共振波谱 (MRS) 方法，使我们能够获得与 AD 发病机制相关的脑代谢物（葡萄糖、乳酸、酮体）和神经递质（谷氨酸和 GABA）的体内测量结果。此前，我们发现与对照组相比，患者的葡萄糖和乳酸较高，而谷氨酸和 GABA 较低，这表明这些 MRS 标记物可用作 AD 的诊断生物标记物。血糖浓度与年龄呈正相关。 认知衰老/预防认知衰退的临床研究 我们完成了一项间歇性热量限制 (CR) 研究，实施 5-2 CR（交替 5 天常规热量摄入和 2 天 CR）。这是一项针对超重中年受试者的 5-2 CR 为期 8 周的研究，旨在评估对胰岛素抵抗、大脑代谢、认知能力、功能磁共振成像活动和生物标志物的潜在有益影响。我们目前正在分析结果。 5-2 CR 是 AD 和中年认知衰老一级预防的候选干预措施。此外，我们正在对患有代谢综合征的中年个体进行口服酮酯的随机对照研究。使用认知测试以及 MRS 和外泌体生物标志物，我们的目标是证明大脑酮浓度的增加和大脑代谢向酮利用的转变，同时认知能力的改善。 我们与加拿大麦吉尔大学的研究人员建立了合作，他们计划在心脏手术患者的围手术期启动鼻内胰岛素临床试验，以预防术后认知能力下降。我们的主要目标是进行外泌体生物标志物分析，显示对鼻内胰岛素的靶点参与和药效学反应。该项目已获得阿尔茨海默病药物发现基金会的资助。 我们与法国里尔大学的 Mohamad El Haj 博士合作，参与了阿尔茨海默病认知特征临床研究的设计和分析。例如，我们将一组 AD 患者与对照组的过去和未来事件的自传式生成进行了比较。我们发现，与对照组相比，患者未来和过去的事件更加相似，并且产生未来事件的能力与患者的情景记忆密切相关。此外，生成未来事件的能力与额叶功能相关。这些发现表明，记住过去和想象未来依赖于共同的大脑结构，而这些结构在 AD 中均受到损害。我们还一直在研究 COVID-19 对 AD 患者、其家人、医疗保健提供者和老年设施工作人员的心理影响。

项目成果

Clinical and neurocognitive aspects of hallucinations in Alzheimer's disease.

阿尔茨海默氏病幻觉的临床和神经认知方面。

• DOI: 10.1016/j.neubiorev.2017.02.021
• 发表时间: 2017-12
• 期刊: Neuroscience and biobehavioral reviews
• 影响因子: 8.2
• 作者: El Haj M;Roche J;Jardri R;Kapogiannis D;Gallouj K;Antoine P
• 通讯作者: Antoine P

Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.

使用神经元来源的细胞外囊泡探索患有双相抑郁症的成人的大脑胰岛素抵抗。

• DOI: 10.1016/j.jpsychires.2020.12.007
• 发表时间: 2021-01
• 期刊: Journal of psychiatric research
• 影响因子: 4.8
• 作者: Mansur RB;Delgado-Peraza F;Subramaniapillai M;Lee Y;Iacobucci M;Nasri F;Rodrigues N;Rosenblat JD;Brietzke E;Cosgrove VE;Kramer NE;Suppes T;Raison CL;Fagiolini A;Rasgon N;Chawla S;Nogueras-Ortiz C;Kapogiannis D;McIntyre RS
• 通讯作者: McIntyre RS

The subjective experience of recollection and familiarity in Alzheimer's disease.

阿尔茨海默病的记忆和熟悉的主观体验。

• DOI: 10.1017/s0140525x19001766
• 发表时间: 2020
• 期刊: The Behavioral and brain sciences
• 作者: Kapogiannis,Dimitrios;ElHaj,Mohamad
• 通讯作者: ElHaj,Mohamad

Synaptic proteins in neuron-derived extracellular vesicles as biomarkers for Alzheimer's disease: novel methodology and clinical proof of concept.

神经元衍生的细胞外囊泡中的突触蛋白作为阿尔茨海默病的生物标志物：新方法和临床概念证明。

• DOI: 10.20517/evcna.2023.13
• 发表时间: 2023
• 期刊: Extracellular vesicles and circulating nucleic acids
• 作者: Eitan,Erez;Thornton-Wells,Tricia;Elgart,Katya;Erden,Eren;Gershun,Eve;Levine,Amir;Volpert,Olga;Azadeh,Mitra;Smith,DanielG;Kapogiannis,Dimitrios
• 通讯作者: Kapogiannis,Dimitrios

"My sympathetic clinician": perception of sympathy by patients with Alzheimer's disease increases when asked to provide autobiographical memories.

• DOI: 10.1007/s40520-021-02056-x
• 发表时间: 2022-06
• 期刊: AGING CLINICAL AND EXPERIMENTAL RESEARCH
• 影响因子: 4
• 作者: El Haj, Mohamad;Allain, Philippe;Antoine, Pascal;Chapelet, Guillaume;Kapogiannis, Dimitrios;Boutoleau-Bretonniere, Claire;Gallouj, Karim
• 通讯作者: Gallouj, Karim