Draft:David S. Goldstein

David S. Goldstein is an American internist who has researched biomarkers and pathophysiologic mechanisms of autonomic and catecholamine-related disorders including pure autonomic failure, Parkinson's disease, and multiple system atrophy at the NIH. He currently serves as Chief of the Autonomic Medicine Section (AMS), in the Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke (NINDS). Goldstein has worked at the NIH for 45 years, including more than 30 years at the NINDS, acting sequentially as Chief of the Clinical Neurochemistry Section, Clinical Neurocardiology Section, and AMS.

Research

Goldstein has contributed work in 5 areas related to autonomic and catecholaminergic systems of the body: (a) clinical catecholamine neurochemistry, (b) clinical sympathetic neuroimaging, (c) cardiac autonomic physiology and pathophysiology, (d) mechanisms of catecholaminergic neurodegeneration, and (e) stress and homeostasis. He is noted for his prolific research output throughout his career, with an h-index of 125 according to Google Scholar. His work is considered to be pioneering in the field of autonomic medicine.

Clinical catecholamine neurochemistry

Goldstein and colleagues were the first to validate liquid chromatography with electrochemical detection for measuring plasma levels of the catecholamines norepinephrine and epinephrine in humans. The methodology was expanded to plasma levels of 3,4-dihydroxy compounds (catechols), which includes the catecholamines, 3,4-dihydroxyphenylglycol (DHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), and 3,4-dihydroxyphenylalanine (DOPA). Applying this methodology, Goldstein showed that plasma levels of DHPG provide information on the fate of the sympathetic neurotransmitter norepinephrine in sympathetic nerves. With Irwin J. Kopin he elucidated the sources and meanings of plasma levels of catechols and showed that particular abnormal plasma catechol patterns characterize Menkes disease, L-aromatic-amino-acid decarboxylase deficiency, dopamine-beta-hydroxylase deficiency, and familial dysautonomia. With Graeme Eisenhofer, he estimated the rates of all the intra-neuronal processes in the synthesis, storage, release, reuptake, and metabolism in the human heart and discovered the bases for norepinephrine depletion despite increased norepinephrine release in congestive heart failure. Expanding the assay methodology to post-mortem brain tissue, Goldstein reported evidence for a vesicular storage defect in residual putamen catecholaminergic neurons. Post-mortem assays of myocardial tissue revealed a similar abnormality in cardiac sympathetic nerves in Lewy body diseases. The autotoxic catecholaldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in neuronal dopamine metabolism, is a catechol, and Goldstein discovered DOPAL buildup with respect to dopamine in post-mortem putamen from patients with Parkinson's disease. He also reported the mechanisms of DOPAL buildup, including a shift from vesicular uptake to oxidative deamination of cytoplasmic dopamine. Application of the catechols assay to cerebrospinal fluid (CSF) revealed that low DOPAC levels predict the later development of PD in individuals at risk for the disease.

Clinical sympathetic neuroimaging

Goldstein and colleagues pioneered clinical sympathetic neuroimaging by 18F-dopamine positron emission tomography (PET) beginning in the late 1980s. Applying this technology the group described cardiac sympathetic denervation in Parkinson's disease (PD) and pure autonomic failure (PAF), in contrast with intact innervation in most patients with multiple system atrophy (MSA). These findings subsequently were confirmed by post-mortem immunohistochemistry and neurochemistry. This was early evidence that PD is not only a brain disease and movement disorder but a generalized disease that involves a lesion of the autonomic nervous system in the heart. Goldstein and colleagues went on to validate cardiac 18F-dopamine PET as an in vivo biomarker of myocardial norepinephrine stores. Computational modeling based on 18F-dopamine PET and catecholamine neurochemistry identified multiple functional abnormalities in cardiac sympathetic nerves in Lewy body diseases (LBDs). In the intramural NINDS PDRisk study, Goldstein et al. reported in 2024 that low cardiac 18F-dopamine-derived radioactivity predicts the later development of central LBDs in at-risk individuals. These and many other studies have demonstrated the remarkable power of 18F-dopamine PET for elucidating pathophysiological mechanisms and enhancing the diagnosis and informing the prognosis of diseases involving catecholaminergic neurodegeneration.

Autonomic circulatory physiology and pathophysiology

Goldstein has developed, validated, and applied several clinical laboratory physiological tests to assess different aspects of autonomic circulatory physiology and pathophysiology. A relatively early study compared techniques for assessing baroreflex function in humans. With a co-worker he validated non-invasive methods for evaluating blood pressure continuously using finger cuff or radial tonometric devices. Applying this methodology he reported a non-invasive means to detect sympathetic neurocirculatory failure. He noted that tracking the blood pressure continuously after premature heartbeats provided a "one-beat Valsalva maneuver" for identifying baroreflex-sympathoneural dysfunction. His team developed, validated, and applied the baroreflex areas method for quantifying baroreflex-sympathoneural function. Subsequently Goldstein and Sharabi found that baroreflex-sympathoneural dysfunction predicts central Lewy body diseases in at-risk individuals.

Mechanisms of catecholaminergic neurodegeneration

Goldstein has advanced the "catecholaldehyde hypothesis," according to which the obligate intra-neuronal dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) causes or contributes to catecholaminergic neurodegeneration. His group discovered that putamen catecholamine depletion in Parkinson's disease and multiple system atrophy (MSA) is related to DOPAL buildup, and they identified a "double hit" determining intra-neuronal DOPAL accumulation—decreased vesicular sequestration of cytoplasmic dopamine and decreased DOPAL detoxification by aldehyde dehydrogenase. Consistent with pathogenic toxic interactions between DOPAL and the protein alpha-synuclein, they discovered that DOPAL potently oligomerizes, aggregates, and forms quinoprotein adducts with alpha-synuclein. Reducing DOPAL production and inhibiting harmful DOPAL-alpha-synuclein interactions could be the basis for a disease-modification strategy to delay the onset or slow the progression of catecholaminergic neurodegeneration. Using a novel computational approach his group identified multiple functional abnormalities in cardiac sympathetic nerves in LBDs and modeled the progression of LBDs and effects of genetic predispositions and treatments on that progression. The modeling identified tri-phasic progression of catecholamine depletion in LBDs, confirmed by analysis of prospective longitudinal data from the intramural NINDS PDRisk study. Treatment begun at the transition from the first homeostatic phase to the second dyshomeostatic phase could be far more effective than the same treatment begun in the third symptomatic phase.

Stress and homeostasis

In several essays and books Goldstein has conveyed the "homeostat theory," a cohesive concept that refines stress and distress as medical scientific ideas. Walter B. Cannon's views about homeostasis and a unitary sympathoadrenal system maintaining homeostasis during emergencies and Hans Selye's notion of non-specificity of the stress response have required revision. Goldstein's team provided early evidence for increased sympathetic noradrenergic outflow even during non-emergency activities such as mental challenge and for differential adrenomedullary and sympathoneural responses in neurocardiogenic syncope. Based on simultaneous measurements of norepinephrine, epinephrine, and corticotropin responses to various stressors, Goldstein's team tested Selye's doctrine of non-specificity for the first time, and the results refuted the notion of a unitary stress response regardless of the stressor. Our meta-analysis of the literature showed that across a variety of stressors plasma epinephrine responses are more closely tied to corticotropin than to norepinephrine responses, disconfirming Cannon's notion of a unitary sympathoadrenal response to stress. He has contrasted integrative physiology with systems biology and predicted rapprochement between these two epistemologies in a way that avoids teleological purposiveness, transcends pure mechanism, and incorporates adaptiveness in evolution. Recently Goldstein introduced the concept of the extended autonomic system (EAS), which contains John Newport Langley's autonomic nervous system, neuroendocrine systems (including the sympathetic adrenergic system), the inflammatory/immune system, and the central autonomic network (within which is embedded the central stress system). The EAS concept provides a systems-based framework for understanding multi-system disorders of regulation such as myalgic encephalomyelitis/chronic fatigue syndrome, postural tachycardia syndrome, Gulf War Illness, and acute and post-acute SARS-CoV2 (PASC).