Biomarkers of Parkinson Disease and Related Disorders

帕金森病及相关疾病的生物标志物

• 批准号: 9157529
• 负责人: David Goldstein
• 金额: $ 67.39万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 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/9157529
• 关键词: 3,4-Dihydroxyphenylacetic Acid; Accounting; Acids; Affect; Alzheimer' s Disease; Back; Behavior; Binding; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Brain; Cardiac; Catecholamines; Catechols; Cell membrane; Cessation of life; Characteristics; Chemicals; Chest; Clinical; Clinical Protocols; Cohort Studies; Collaborations; Confocal Microscopy; Data; Data Analyses; Defect; Denervation; Deposition; Desipramine; Development; Disease; Dopamine; Dopamine-beta-monooxygenase; Dreams; Early Diagnosis; Etiology; Extramural Activities; Family; Fiber; Heart; Heart Transplantation; Injection of therapeutic agent; Inpatients; Italy; Lesion; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Ligands; Link; Location; Measures; Methods; Motor; Multiple System Atrophy; Myocardial; Myocardium; National Institute of Neurological Disorders and Stroke; Nerve; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroglia; Neurology; Neurons; Norepinephrine; Occipital lobe; Orthostatic Hypotension; Parkinson Disease; Parkinsonian Disorders; Participant; Patients; Peripheral; Plasma; Play; Positron; Positron-Emission Tomography; Predisposition; Process; Production; Progressive Supranuclear Palsy; Protocols documentation; Publishing; Pure Autonomic Failures; Radioactivity; Recording of previous events; Reporting; Research Personnel; Residual state; Risk; Risk Factors; Role; Rome; Scanning; Secondary Parkinson Disease; Site; Skin; Smell Perception; Specificity; Sympathectomy; Testing; Time; Tissues; Tracer; Tyrosine 3-Monooxygenase; United States National Institutes of Health; Universities; Vesicle; Visit; Visual; aldehyde dehydrogenases; alpha synuclein; axonal degeneration; base; clinical Diagnosis; cooking; dihydroxyphenylethylene glycol; disorder control; disorder risk; follow-up; in vivo; indexing; nerve supply; neurochemistry; neuroimaging; nigrostriatal system; noradrenaline transporter; noradrenergic; novel; oxidation; prospective; protein aggregate; putamen; synucleinopathy; tv watching; web site

Vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines. A vesicular storage defect therefore could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of 18F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of 18F-DA-derived radioactivity and post-mortem by increased 3,4-dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen 18F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial 18F-DA-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons. (Goldstein DS, Holmes C, Mash D, Sidransky E, Stefani A, Kopin IJ, Sharabi Y. Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration. Parkinsonism Relat Disord 2015;21:1013-1022.) PD with orthostatic hypotension (PD+OH) can be difficult to distinguish clinically from parkinsonian form of MSA (MSA-P). Cardiac sympathetic neuroimaging by 18F-DAPET scanning efficiently separates these diseases, but this testing is not generally available. We assessed whether plasma biomarkers of a vesicular storage defect can separate PD+OH from MSA-P. After F-DA injection, augmented production of F-dihydroxyphenylacetic acid (F-DOPAC) indicates decreased vesicular storage, and we predicted that arterial plasma F-DOPAC would be elevated in PD+OH but not in MSA-P. We measured plasma F-DOPAC after 18F-DA administration in patients with PD+OH or MSA-P and in healthy control subjects. Peak F-DOPAC:DHPG was calculated, to adjust for effects of denervation on F-DOPAC production. All MSA-P patients had peak F-DOPAC:DHPG <60, in contrast with 9 of 12 PD+OH patients (p<0.0001). Adjustment of peak F-DOPAC for DHPG increased test sensitivity from 58% to 81% at similar high specificity. Thus, after F-DA injection plasma peak F-DOPAC:DHPG distinguishes PD+OH from MSA-P (Goldstein DS, Kopin IJ, Sharabi Y, Holmes C. Plasma biomarkers of decreased vesicular storage distinguish Parkinson disease with orthostatic hypotension from the Parkinsonian form of multiple system atrophy. Clin Auton Res 2015;25:61-67). About 1/3 of PD patients, most MSA patients, and all PAF patients have neurogenic orthostatic hypotension (OH). In a prospective cohort study we compared long-term survival in these synucleinopathies. We found that survival depends on the particular disease, with the risk of death greater in MSA than in PD+OH and in PD+OH than in PD without OH or in PAF. The analysis also demonstrated differential survivals based on 18F-DOPA putamen and 18F-DA cardiac neuroimaging data alone, regardless of the clinical diagnosis (Goldstein DS, Holmes C, Sharabi Y, Wu T. Long-term survival in synucleinopathies: A prospective cohort study of Parkinson disease, multiple system atrophy, and pure autonomic failure. Neurology 2015 (in press)). We recently published post-mortem neurochemical evidence for decreased putamen aldehyde dehydrogenase (ALDH) activity in both PD and MSA (Cook GA, Sullivan P, Holmes C, Goldstein DS. Cardiac sympathetic denervation without Lewy bodies in a case of multiple system atrophy. Park Rel Dis 2014;20:926-928; Goldstein DS, Sullivan P, Holmes C, Kopin IJ, Sharabi Y, Mash DC. Decreased vesicular storage and aldehyde dehydrogenase in multiple system atrophy. Park Rel Dis 2015;21:567-572). We have sought an in vivo biomarker of central ALDH activity. Decreased ALDH activity should increase CSF levels of indices of DA auto-oxidation with respect to indices of DA enzymatic oxidation. We published previously that PD and MSA involve decreased CSF levels of DOPAC, the main deaminated metabolite of DA. To assess DA auto-oxidation we developed and applied an assay method for measuring cysteinyl-DA (Cys-DA) simultaneously with DOPAC. Preliminarily, CSF Cys-DA:DOPAC is about twice as high in PD and MSA as in controls. Elevated CSF Cys-DA:DOPAC may provide an in vivo biomarker of decreased central ALDH activity in parkinsonian disorders. In a collaborative study with Dr. Alessandro Stefani (University of Tor Vergata, Rome, Italy) we have assayed catechols in CSF from patients with PD, progressive supranuclear palsy (PSP), Alzheimers disease (AD), and controls. Preliminarily, we have found decreased CSF DOPAC in PD and PSP and not in AD, replicating and extending on our previous report based on patients referred to the NIH. In parkinsonian disorders low CSF DOPAC seems to provide a biomarker of central dopaminergic deficiency regardless of the particular pathogenetic mechanism. We are using 11C-methylreboxetine (11C-MRB), a positron-emitting ligand for the cell membrane norepinephrine transporter (NET), as a biomarker to visualize sites of noradrenergic innervation by PET scanning. A potential limitation of 11C-MRB PET scanning is non-specific binding of the tracer. To assess non-specific binding, we are examining effects of NET blockade by desipramine on cardiac 11C-MRB-derived radioactivity and are studying patients who are status post cardiac transplantation and therefore have denervated hearts. In the NINDS PDRisk study (NIH Clinical Protocol 09-N-0010) we are following people with multiple PD risk factors (family history, loss of sense of smell, dream enactment behavior, orthostatic hypotension) to determine whether biomarkers of catecholamine deficiency predict later development of PD. The biomarkers we are focusing on are CSF DOPAC, the putamen:occipital cortex (PUT:OCC) ratio of 18F-DOPA-derived radioactivity assessed by brain PET scanning, and the interventricular septal myocardial concentration of 18F-DA-derived radioactivity assessed by thoracic PET scanning. As of this report, 131,084 people have visited the protocol-specific PDRisk website, 3,030 have entered their risk factor data, 371 have been flagged as eligible at the website, and 78 have come to the NIH Clinical Center and have been accrued. Of the 78 accrued at risk participants, 35 have had confirmation of all their risk factors. Of the 35, 3 already had PD at the time of screening and were not studied further, and 32 screened participants have been invited back for inpatient biomarkers testing. Of the 32, 29 have had data obtained for all three biomarkers. Of the 29, 16 (55%) have had at least one positive biomarker, and of these 4 (25%) so far have developed PD (Lewy body dementia in 1 patient). None of the 13 accrued subjects with confirmed risk factors but without positive biomarkers has developed PD. Under NIH Clinical Protocol 03-N-0004 we are obtaining skin biopsy specimens from patients with different forms of alpha-synucleinopathy. In collaboration with extramural Associate Investigators we are testing whether alpha-synuclein, tyrosine hydroxylase, or DA-beta-hydroxylase immunostaining provides pathophysiologically relevant biomarkers.

囊泡隔离限制了儿茶酚胺的酶促和自发氧化的有毒产物的积累。因此，囊泡储存缺陷可能在各种神经退行性疾病中的儿茶酚胺能神经元死亡中起致病作用。在pe虫中，由于组织多巴胺（DA）：dopa比率降低，在体内揭示了不足的囊泡储存。在心肌内体内，通过加速了18F-DA衍生的放射性损失，并通过增加3,4-二羟基苯基乙二醇：去甲肾上腺素（DHPG：NE）的比例增加。血浆F-二羟基苯甲酸（F-DOPAC）：DHPG比率增加，在交感神经中的总体体内总体上。我们回顾性地分析了来自20条条件下的数据，这些数据涉及不同的病因，致病机制和病变位置。涉及帕金森氏症的所有条件都加速了壳骨18f-dopa衍生的放射性的损失。在具有验尸后数据的人中，壳虫DA：DOPA比率也降低了。所有涉及心脏交感神经神经支配的条件都加速了心肌18F-DA衍生的放射性的损失。在具有验尸后数据的人中，心肌DHPG：NE比率增加。所有涉及儿茶酚胺能神经局部丧失的条件均具有在被取消的区域特别降低囊泡储存的证据。因此，在神经退行性疾病中，儿茶酚胺能神经元的丧失似乎与残留神经元中的水泡储存减少有关。 （Goldstein DS，Holmes C，Mash D，Sidransky E，Stefani A，Kopin IJ，Sharabi Y.缺乏囊泡储存：Catecholaminergic神经变性的常见主题。 具有体位性低血压（PD+OH）的PD很难与MSA（MSA-P）的临床区分开。通过18F-Wapet扫描有效地将这些疾病分开，但这种测试通常不可用。我们评估了囊泡存储缺陷的血浆生物标志物是否可以将PD+OH与MSA-P分开。注射F-DA后，F-二羟基苯基乙酸（F-DOPAC）的产生增强表明囊泡储存降低，我们预测动脉血浆F-DOPAC在PD+OH中会升高，但在MSA-P中不会升高。在PD+OH或MSA-P患者以及健康对照组患者的患者中，我们测量了18F-DA给药后的血浆F-DOPAC。 F-DOPAC峰值：DHPG计算，以调整去神经对F-DOPAC产生的影响。与12个PD+OH患者中的9例相比，所有MSA-P患者均具有F-DOPAC峰值：DHPG <60（P <0.0001）。在类似的高特异性下，对DHPG的峰值F-DOPAC的调整将测试灵敏度从58％提高到81％。因此，在F-DA注射血浆峰F-DOPAC之后：DHPG将PD+OH与MSA-P（Goldstein DS，Kopin IJ，Sharabi Y，Holmes C.囊泡储存降低的血浆生物标记物降低的帕克森氏症症状较低的血浆生物标志物区分开了parkinsonian Systone a parkinsonian systorme atrophy的parkinsonian Syston-inter autophy 7 reson。 大约1/3的PD患者，大多数MSA患者和所有PAF患者均具有神经源性体性低血压（OH）。在一项前瞻性队列研究中，我们比较了这些突触核苷病中的长期生存。我们发现，生存取决于特定疾病，MSA的死亡风险大于PD+OH和PD+OH中的死亡风险，而不是没有OH或PAF中的PD。该分析还证明了基于18F-DOPA鬼po和18F-DA心脏神经影像学数据的差异存活，无论临床诊断如何（Goldstein DS，Holmes C，Sharabi Y，Wu T.突触核蛋白酶病中的长期生存：突触症：Prosentive cohort conterive of Propertive cohort cohort conterive of Parkinson Pressive of Parkinson Pressitive of Parkinson system and propure System Altopary and Pure pure pure ne自动疗法）（纯自动化）。 我们最近在PD和MSA中发表了尸检后神经化学证据，以减少毒壳醛脱氢酶（ALDH）活性（Cook GA，Sullivan P，Holmes C，Holmes C，Goldstein DS。心脏交感神经去处，无液体，在多个系统的情况下没有Ley。 Holmes C，Kopin IJ，Sharabi Y，Mash DC。我们寻求中央ALDH活性的体内生物标志物。 降低的ALDH活性应相对于DA酶促氧化指数增加DA自动氧化指数的CSF水平。 我们先前发表的PD和MSA涉及DOPAC的CSF水平降低，DOPAC是DA的主要脱氨酸代谢产物。为了评估DA自动氧化，我们开发并应用了一种测定方法，用于与DOPAC同时测量Cysteinyl-Da（Cys-Da）。 初步的CSF CYS-DA：DOPAC的PD和MSA大约是对照组的两倍。 CSF CYS-DA升高：DOPAC可能会提供帕金森氏症中心疾病中心活性降低的体内生物标志物。 在与Alessandro Stefani博士（意大利罗马托尔加塔大学）的合作研究中，我们从PD患者，进行性上核次核麻痹（PSP），阿尔茨海默氏病（AD）和对照组中分析了CSF的Catechols。从初步的角度来看，我们发现PD和PSP中的CSF DOPAC降低，而不是在AD中，基于提到NIH的患者，对我们先前的报告进行了复制和扩展。在帕金森氏症中，低CSF DOPAC似乎可以提供中央多巴胺能缺乏症的生物标志物，无论特定的致病机制如何。 我们正在使用11C-甲基二羧酸酯（11C-MRB），这是一种用于细胞膜去甲肾上腺素转运蛋白（NET）的正电子发射配体，作为一种生物标志物，可通过PET扫描可视化甲肾上腺素能神经支配部位。 11C-MRB PET扫描的潜在局限性是示踪剂的非特异性结合。为了评估非特异性结合，我们正在检查脱哌丁胺对心脏11C-MRB衍生的放射性的净封锁作用，并正在研究心脏后移植后状态的患者，因此具有剥夺的心脏。 在NINDS PDRISK研究（NIH临床方案09-N-0010）中，我们正在关注具有多个PD危险因素（家族病史，嗅觉丧失，梦境的颁布行为，体位低血压）的人，以确定儿茶酚胺缺乏症的生物标志物是否能预测PD的后期发展。我们关注的生物标志物是CSF DOPAC，壳壳：枕皮层（PUT：OCC）通过脑PET扫描评估的18F-DOPA衍生放射性的比率，以及通过Torracic Pet扫描评估的18F-DA衍生放射性的介入的室内室心肌浓度。在本报告时，有131,084人访问了特定的PDRISK网站，有3,030人输入了他们的风险因素数据，371人已被标记为符合该网站的资格，而78个已进入NIH临床中心并已被累积。在78名应计风险参与者中，有35名已经确认了所有风险因素。在筛查时，35个已经进行了PD，并且没有进一步研究，并且已邀请32名受筛选的参与者进行住院生物标志物测试。在32个生物标志物的32个中，有29个数据获得了数据。在29个（55％）中，有16个（55％）至少具有阳性生物标志物，而到目前为止的4（25％）中，有PD（1名患者的Lewy身体痴呆症）。 13名具有确认危险因素的应计受试者都没有发展为PD。 根据NIH临床方案03-N-0004，我们正在从具有不同形式的α-突触核疾病的患者中获得皮肤活检标本。与校外副研究者合作，我们正在测试α-突触核蛋白，酪氨酸羟化酶或Da-beta-羟化酶免疫抑制剂是否提供与病理生理相关的生物标志物。