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.

阿尔茨海默氏病（AD）和其他神经退行性，神经和精神病的生物标志物 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).迄今为止，我们已经进行了大量案例对照研究，以测量AD和对照对象在AD和对照对象中测量了外泌体β-淀粉样蛋白，TAU/P-TAU，SER和TYR磷酸化的IRS-1，突触标记，补体，线粒体蛋白和其他信号介质。我们发现了多种与疾病相关的差异，对于某些蛋白质，可以准确区分两组。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病障碍中的使用，证明了他们识别帕金森氏病（PD）患者（PD），多发性硬化症，创伤性脑损伤，腿部不安综合征，COVID-19感染 /长相和神经学异常，双极性疾病，以及动物模型（以及动物模型）的能力。 此外，我们已经证明了外泌体生物标志物评估涉及AD，PD和双相情感障碍患者的临床试验中对目标参与和对实验治疗的反应的能力。我们最近表明，外部生物标志物可以预测巴尔的摩纵向衰老纵向研究，威斯康星州阿尔茨海默氏症预防的登记处以及社区动脉粥样硬化风险的大型临床前同类群体的未来认知下降和未来的AD诊断。此外，我们表明外泌体生物标志物可以预测治疗反应，并在AD（鼻内胰岛素）和PD（艾烯肽）以及双相情感障碍中的抗炎治疗柔糖苷的临床试验中显示目标参与。 来年的主要目标是进行研究，以证明大型临床前/早期临床人群中的外泌体标记与AD（PET，CSF）的其他生物标志物之间的关系。需要这些研究来评估外泌体标志物的纵向变化及其在临床前阶段预测AD的潜力，跟踪疾病的进展并预测MCI从MCI到AD的转化。 我们正在分析女性健康计划记忆研究中大量参与者的样本 - 长寿研究，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（哈佛大学衰老脑研究和战车）进一步验证外泌体生物标志物，以防止认知性能，淀粉样蛋白和tau宠物沉积。 除了主要关注AD外，我们还在血管认知障碍/血管性痴呆，帕金森氏病，Lewy身体疾病，多个系统萎缩，脑损伤，脑损伤，躁动不安的腿综合症，多发性硬化症，多发性硬化症，长凝聚，近红，抑郁症，抑郁症和双色极性疾病中进行外oS盐生物标志物研究。 此外，我们在NIA 3T MRI设备上采用了一种新型的磁共振光谱（MRS）方法，该方法使我们能够在脑代谢产物（葡萄糖，乳酸，酮体）和神经递质（谷氨酸和GABA）（谷氨酸和GABA）上获得对体内的体内测量。以前，与对照组相比，我们在患者中显示出更高的葡萄糖和乳酸，以及较低的谷氨酸和GABA，这表明这些MRS标记物可以用作AD的诊断生物标志物。葡萄糖浓度与年龄正相关。 认知衰老/预防认知能力下降的临床研究 我们完成了实施5-2 CR的间歇性热量限制（CR）的研究（定期摄入的5天和2天的CR）。这是一项为期8周的超重中年受试者的5-2个CR研究，以评估对胰岛素抵抗，脑代谢，认知性能，fMRI活性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是中年临时预防AD和认知衰老的候选干预措施。此外，我们正在对中年代谢综合征的中年个体的口服酮酯进行随机对照研究。使用认知测试以及MRS和外泌体生物标志物，我们旨在证明脑酮浓度的升高以及脑代谢向酮利用率的转化，以及认知性能的改善。 我们已经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间开始对鼻内胰岛素进行临床试验，以防止术后认知能力下降。我们的主要目的是进行外泌体生物标志物分析，以显示靶向核心胰岛素的靶标参与和药效反应。该项目已从阿尔茨海默氏症的药物发现基金会获得资金。 与法国里尔大学的Mohamad El Haj博士合作，我们参与了关于阿尔茨海默氏病认知特征的临床研究的设计和分析。例如，与对照组相比，我们研究了AD患者队列中过去和未来事件的自传。我们发现，与对照组相比，患者的未来和过去事件更相似，并且产生未来事件的能力与患者的情节记忆密切相关。此外，生成未来事件的能力与额叶功能有关。这些发现表明，记住过去并想象未来依赖于广泛的大脑结构，这两者在AD中都受到损害。我们还一直在研究Covid-19对AD，其家人和医疗保健提供者和老年设施人员的心理影响。

项目成果

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

• 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

"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

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

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

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