Draft:David S. Goldstein

David S. Goldstein

David S. Goldstein is a founder and thought leader in the nascent field of autonomic medicine, with substantial experience and expertise in clinical catecholamine neurochemistry, sympathetic neuroimaging, autonomic pathophysiology, mechanisms of catecholaminergic neurodegeneration, and stress and homeostasis as medical scientific ideas. Goldstein's interest in brain regulation of the circulation began when he was a psychology major at Yale College <1> and grew when he was an MD-PhD student in Behavioral Science at Johns Hopkins and a resident in internal medicine at the University of Washington <2>. After coming to the National Heart, Lung, and Blood Institute as a Clinical Associate in 1978, he was the first to validate liquid chromatography with electrochemical detection for measuring plasma levels of catecholamines in humans <3>. Clinical catecholamine neurochemistry remains a fixture of the lab. After transferring to the National Institute of Neurological Disorders and Stroke (NINDS) in 1990 to head the Clinical Neurochemistry Section in the Clinical Neuroscience Branch, Goldstein's group pioneered cardiac sympathetic neuroimaging by 18F-dopamine positron emission tomographic (PET) scanning. Applying this technology they discovered cardiac sympathetic denervation in Parkinson disease (PD) <4>. This seminal finding provided key early evidence that PD is not only a brain disease and a movement disorder but also a form of dysautonomia characterized by cardiac noradrenergic deficiency. Comprehensive clinical physiological, neurochemical, and neuroimaging evaluations have led to many other discoveries, including sympathoadrenal imbalance before neurocardiogenic syncope, multiple functional abnormalities in intact catecholaminergic neurons (“sick-but-not-dead” phenomenon) in Lewy body diseases (LBDs), and catecholaminergic biomarkers predicting PD in at-risk individuals. He has advanced the catecholaldehyde hypothesis for the pathogenesis of LBDs, a homeostatic theory of stress, and the concept of the “extended autonomic system.” Goldstein has 147 first-authored original research articles and 663 cited publications, of which 143 have been cited >100 times each. Single-authored books he has written include Stress, Catecholamines, and Cardiovascular Disease (1995), The Autonomic Nervous System in Health and Disease (2000), Adrenaline and the Inner World: An Introduction to Scientific Integrative Medicine (2006), and the e-textbooks, Principles of Autonomic Medicine and Autonomic Medicine for Students.

His awards and honors include the Distinguished Investigator Award of the Society for Clinical and Translational Science, the Schatz Award in Autonomic Disorders of the American Academy of Neurology, the NIH Distinguished Clinical Teacher Award, 2 NINDS Director’s Awards for Mentorship, membership in the Association of American Physicians, and the 2023 Johns Hopkins School of Medicine Distinguished Medical Alumnus Award.

Dr. Goldstein's strategic goals are to establish autonomic medicine as a clinical and scientific discipline, promote patient-oriented research on autonomic and catecholamine-related disorders, and mentor rising investigators in the field.

Contribution to Science

1. Clinical Catecholamine Neurochemistry: Catecholamines differ from other neurotransmitters in that levels of the chemical messengers and their metabolites can be measured simultaneously in biofluids. This characteristic enabled Goldstein to found the field of clinical catecholamine neurochemistry. He discovered that a particular catechol neurochemical pattern provides a perfectly sensitive and specific test with which to diagnose Menkes disease in at-risk newborns <5>. He also reported characteristic catecholaminergic abnormalities in familial dysautonomia, dopamine-beta-hydroxylase deficiency, dihydropteridine reductase deficiency, and L-aromatic-amino-acid decarboxylase deficiency. He found that there are differential cerebrospinal fluid (CSF) abnormalities in dopaminergic vs. noradrenergic indices across synucleinopathies <6>; obtained evidence that the profound myocardial norepinephrine depletion found in Parkinson’s disease (PD) results partly from a shift from vesicular sequestration to oxidative deamination of cytoplasmic catecholamines in residual sympathetic nerves <7>; and provided the first evidence that CSF biomarkers of central catecholamine deficiency predict PD in at-risk individuals <8>.

2. Catecholaminergic Neuroimaging: Goldstein pioneered sympathetic neuroimaging by positron emission tomographic (PET) scanning. Cardiac 18F-dopamine PET scanning provides a valuable diagnostic and progression marker in LBDs <9>. Using this methodology he reported the first evidence for decreased intra-neuronal vesicular uptake of catecholamines in LBDs <10>, a finding that has been confirmed by both in vivo multi-tracer neuroimaging and post-mortem neurochemistry. More recently he introduced quantitative immunofluorescence microscopy to assess intra-neuronal alpha-synuclein deposition in skin biopsies. Applying this approach he discovered that in patients with the Lewy body form of neurogenic orthostatic hypotension increased alpha-synuclein-tyrosine hydroxylation colocalization indexes provide a sensitive biomarker of myocardial noradrenergic deficiency <11>. In the intramural NINDS PDRisk study he reported the first evidence that neuroimaging indices of cardiac noradrenergic deficiency predict central LBDs in at-risk individuals <12>.

3. Cardiovascular Autonomic Physiology and Pathophysiology: Goldstein introduced several clinical physiological tests that enhance the ability to assess autonomic functions in a wide variety of disorders. These tools include continuous non-invasive blood pressure recording to identify baroreflex-sympathoneural failure <13>. His group was the first to describe afferent baroreflex failure as a late sequela of neck irradiation <14>; found that low frequency power of heart rate variability is not a measure of cardiac autonomic tone but may indicate the ability to modulate that tone via baroreflexes <15>; and developed the baroreflex areas method to quantify baroreflex-sympathoneural function <16>.

4. Mechanisms of Catecholaminergic Neurodegeneration: Dr. 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 in a variety of common and rare diseases. His group discovered that putamen catecholamine depletion in PD and multiple system atrophy (MSA) is related to DOPAL buildup <17>, and they identified a “double hit” determining intra-neuronal DOPAL accumulation—decreased vesicular sequestration of cytoplasmic dopamine and decreased DOPAL detoxification by aldehyde dehydrogenase <18>. Consistent with pathogenic toxic interactions between DOPAL and alpha-synuclein, Dr. Goldstein's group discovered that DOPAL potently oligomerizes, aggregates, and forms quinoprotein adducts with alpha-synuclein <19>. 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 he 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 <20>. The modeling identified tri-phasic progression of catecholamine depletion in LBDs. 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.

5. Stress and Homeostasis: In several essays and books Dr. Goldstein has conveyed the homeostat theory, a cohesive concept that refines stress and distress as medical scientific ideas <21, 22>. Cannon’s views about homeostasis and a unitary sympathoadrenal system maintaining homeostasis during emergencies and Selye’s notion of non-specificity of the stress response have required revision. Goldstein 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, his group 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. A 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. Goldstein has contrasted integrative physiology with systems biology and have predicted rapprochement between these two epistemologies in a way that avoids teleological purposiveness, transcends pure mechanism, and incorporates adaptiveness in evolution <22). Recently Goldstein introduced the concept of the extended autonomic system (EAS) <23, 24>, which contains 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).

REFERENCES <1> Goldstein DS, Fink DJ, Mettee DR. Cognition of arousal and actual arousal as determinants of emotion. J Pers Soc Psychol 1972;21:41-51. (PMID 5058255) <2> Goldstein DS. The electrocardiogram in stroke: Relationship to pathophysiologic type and comparison with prior tracings. Stroke 1979;3:253-259. (PMID 462510) <3> Goldstein DS, Feuerstein GZ, Izzo JL Jr, Kopin IJ, Keiser HR. Validity and reliability of liquid chromatography with electrochemical detection for measuring plasma levels of norepinephrine and epinephrine in man. Life Sci 1981;28:467-475. (PMID 7207028) <4> Goldstein DS, Holmes C, Cannon RO III, Eisenhofer G, Kopin IJ. Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 1997;336:696-702. (PMID 9327977) <5> Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, Liew, CJ, Sato S, Patronas N. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 2008;358:605-614. (PMCID 3477514) <6> Goldstein DS, Sullivan P, Holmes C, Lamotte G, Lenka A, Sharabi Y. Differential abnormalities of cerebrospinal fluid dopaminergic vs. noradrenergic indices in synucleinopathies. J Neurochem 2021 Apr 24. doi: 10.1111/jnc.15371. (PMID 33894018) <7> Goldstein DS, Sullivan P, Holmes C, Miller GW, Sharabi Y, Kopin IJ. A vesicular sequestration to oxidative deamination shift in myocardial sympathetic nerves in Parkinson disease. J Neurochem 2014:131:219-228. (PMID 24848581) <8> Goldstein DS, Holmes C, Lopez, GJ, Wu T, Sharabi Y. Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson’s disease. Park Rel Dis 2018;50:108-112. (PMID 29475591) <9> Lamotte G, Holmes C, Wu T, Goldstein DS. Long-term trends in myocardial sympathetic innervation and function in synucleinopathies. Park Rel Dis 2019;67:27-33. (PMID 31621602) <10> Goldstein DS, Holmes C, Kopin IJ, Sharabi Y. Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases. J Clin Invest 2011;121:3320-3330. (PMC 3148734) <11> Isonaka R, Rosenberg AZ, Sullivan P, Corrales A, Holmes C, Sharabi Y, Goldstein DS. Alpha-synuclein deposition within sympathetic noradrenergic neurons is associated with myocardial noradrenergic deficiency in neurogenic orthostatic hypotension. Hypertension 2019;73:910-918. (PMID 30798661) <12> Goldstein DS, Holmes C, Sullivan P, Lopez G, Gelsomino J, Moore S, Isonaka R, Wu T, Sharabi Y. Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases. J Clin Invest 2023;Oct 26:e172460. doi: 10.1172/JCI172460. (PMID 37883190) <13> Goldstein DS, Tack C. Noninvasive detection of sympathetic neurocirculatory failure. Clin Auton Res 2000;10:285-291. (PMID 11198484) <14> Sharabi Y, Dendi R, Holmes C, Goldstein DS. Baroreflex failure as a late sequela of neck irradiation. Hypertension 2003;42:110-116. (PMID 12782644) <15> Goldstein DS, Bentho O, Park M-Y, Sharabi Y. Low-frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes. Exp Physiol 2011;96:1255-1261. (PMID 21890520) <16> Rahman F, Goldstein DS. Quantitative indices of baroreflex-sympathoneural function. Clin Auton Res 2014;24:103-110. (PMID 24706176) <17> Goldstein DS, Sullivan P, Holmes C, Kopin IJ, Basile MJ, Mash DC. Catechols in post-mortem brain of patients with Parkinson disease. Eur J Neurol 2011;18:703-710. (PMID 21073636) <18> Goldstein DS, Sullivan P, Holmes C, Miller GW, Alter S, Strong G, Mash DC, Kopin IJ, Sharabi Y. Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson disease. J Neurochem 2013;126:591-603. (PMID 23786406) <19> Jinsmaa Y, Sharabi Y, Sullivan P, Isonaka R, Goldstein DS. 3,4-Dihydroxyphenylacetaldehyde-induced protein modifications and their mitigation by N-acetylcysteine. J Pharmacol Exp Ther 2018;366:113-124. (PMID 29700232) <20> Goldstein DS, Pekker M, Sullivan P, Isonaka R, Sharabi Y. Modeling the progression of cardiac catecholamine deficiency in Lewy body diseases. J Am Heart Assoc 2022;e024411. doi: 10.1161/JAHA.121.024411. (PMID 35621196) <21> Goldstein DS. Stress, Catecholamines, and Cardiovascular Disease. New York: Oxford Univ. Press, 1995. <22> Goldstein DS. How does homeostasis happen? Integrative physiologic, systems biologic, and evolutionary perspectives. Am J Physiol (Regul Integr Comp Physiol) 2019 316:R301-R317. (PMID 30649893) <23> Goldstein DS. Stress and the “extended autonomic system.” Auton Neurosci 2021 Oct 2;236:102889. doi: 10.1016/j.autneu.2021.102889. (PMID 34656967). <24> Goldstein DS. The extended autonomic system, dyshomeostasis, and COVID-19. Clin Auton Res 2020;22:1-17. (PMID 32700055)