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Following on from the COVID-19 pandemic is another worldwide public health challenge that is referred to variously as long COVID, post-COVID syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC). PASC comes in many forms and affects all body organs. This heterogeneous presentation suggests involvement of the autonomic nervous system (ANS), which has numerous roles in the maintenance of homeostasis and coordination of responses to various stressors. Thus far, studies of ANS dysregulation in people with PASC have been largely observational and descriptive, based on symptom inventories or objective but indirect measures of cardiovascular function, and have paid little attention to the adrenomedullary, hormonal and enteric nervous components of the ANS. Such investigations do not consider the syndromic nature of autonomic dysfunction. This Review provides an update on the literature relating to ANS abnormalities in people with post-COVID syndrome and presents a theoretical perspective on how the ANS might participate in common features of PASC. Autonomic nervous system dysregulation contributes to the chronic, debilitating disorders referred to as 'long COVID' or post-acute sequelae of SARS-CoV-2 infection (PASC). Here, Goldstein describes a multisystem, multidisciplinary approach to understanding PASC-induced alterations in feedback-regulated, plastic networks that determine homeostasis and allostasis. Key points: The diverse nature of post-COVID syndrome suggests involvement of the autonomic nervous system (ANS), which plays numerous roles in homeostasis and coordinates responses to essentially all stressors. The ANS concept was promulgated before the discoveries of neuroendocrine systems, immune and inflammatory systems, and the central autonomic network; the extended autonomic system theory is a necessary update. Publications on post-COVID dysautonomias have not considered the syndromic nature of autonomic dysfunctions. Such studies have been largely observational and descriptive, based on symptom inventories or objective but indirect cardiovascular measures; the hormonal and enteric components of the ANS have generally been ignored. Understanding of multisystem disorders of regulation, such as post-COVID syndrome, requires a shift towards consideration of the feedback-regulated, plastic networks that, via the extended autonomic system, determine homeostasis and allostasis. [ABSTRACT FROM AUTHOR]

The pandemic viral illness COVID-19 is especially life-threatening in the elderly and in those with any of a variety of chronic medical conditions. This essay explores the possibility that the heightened risk may involve activation of the "extended autonomic system" (EAS). Traditionally, the autonomic nervous system has been viewed as consisting of the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. Over the past century, however, neuroendocrine and neuroimmune systems have come to the fore, justifying expansion of the meaning of "autonomic." Additional facets include the sympathetic adrenergic system, for which adrenaline is the key effector; the hypothalamic-pituitary-adrenocortical axis; arginine vasopressin (synonymous with anti-diuretic hormone); the renin-angiotensin-aldosterone system, with angiotensin II and aldosterone the main effectors; and cholinergic anti-inflammatory and sympathetic inflammasomal pathways. A hierarchical brain network—the "central autonomic network"—regulates these systems; embedded within it are components of the Chrousos/Gold "stress system." Acute, coordinated alterations in homeostatic settings (allostasis) can be crucial for surviving stressors such as traumatic hemorrhage, asphyxiation, and sepsis, which throughout human evolution have threatened homeostasis; however, intense or long-term EAS activation may cause harm. While required for appropriate responses in emergencies, EAS activation in the setting of chronically decreased homeostatic efficiencies (dyshomeostasis) may reduce thresholds for induction of destabilizing, lethal vicious cycles. Testable hypotheses derived from these concepts are that biomarkers of EAS activation correlate with clinical and pathophysiologic data and predict outcome in COVID-19 and that treatments targeting specific abnormalities identified in individual patients may be beneficial. [ABSTRACT FROM AUTHOR]

The most important autonomic function test-the autonomic medical history-is the patient's account, interpreted by a clinician skilled in asking the right questions, of symptoms during daily activities that relate to the autonomic nervous system. The chronology and pattern of these symptoms combine to create a portrait of autonomic function or dysfunction. We summarize the steps in obtaining a comprehensive autonomic medical history. [ABSTRACT FROM AUTHOR]

This review of clinical catecholamine neurochemistry is based on the Streeten Memorial Lecture at the 19th annual meeting of the American Autonomic Society and lectures at a satellite of the 6th Congress of the International Society of Autonomic Neuroscience. Here I provide historical perspective, describe sources and meanings of plasma levels of catecholamines and their metabolites, present a model of a sympathetic noradrenergic neuron that conveys how particular aspects of sympathetic nervous function affect plasma levels of catecholamines and their metabolites, and apply the model to understand plasma neurochemical patterns associated with some drugs and disease states. [ABSTRACT FROM AUTHOR]

Pure autonomic failure (PAF) and Parkinson’s disease (PD) share several clinical laboratory abnormalities; however, PAF is not associated with parkinsonism. In this study, we tested the hypothesis that preservation of nigrostriatal dopaminergic innervation explains the absence of motor dysfunction in PAF. Patients with PAF ( N = 5) or PD ( N = 21) and control subjects ( N = 14) had brain 6-[18F]fluorodopa positron emission tomographic scanning and cerebrospinal fluid catechol measurements. A patient with PAF and another with PD had rapid postmortem striatal, nigral, and sympathetic ganglion sampling, with assays of catechols and tyrosine hydroxylase activity. The PAF and PD groups had similarly low mean substantia nigra (SN):occipital (OCC) ratios of 6-[18F]fluorodopa-derived radioactivity and similarly low cerebrospinal fluid dihydroxyphenylacetic acid and DOPA levels. Only the PD group, however, had low PUT:OCC, caudate:OCC, or PUT:SN ratios. The PAF and PD cases had similarly low SN tissue concentrations of dopamine and tyrosine hydroxylase activity, but the PD patient had tenfold lower PUT dopamine and the PAF patient 15-fold lower myocardial norepinephrine concentrations. Surprisingly, PAF and PD entail similarly severe nigral and overall central dopaminergic denervation. There is more severe loss of striatal dopaminergic terminals in PD than in PAF and more severe loss of sympathetic noradrenergic terminals in PAF than in PD. These differences explain the distinctive clinical manifestations of the two Lewy body diseases. Parkinsonism appears to reflect striatal dopamine deficiency rather than loss of nigral dopaminergic neurons per se. [ABSTRACT FROM AUTHOR]

There is substantial interest in identifying biomarkers to detect early Parkinson disease (PD). Cardiac noradrenergic denervation and attenuated baroreflex-cardiovagal function occur in de novo PD, but whether these abnormalities can precede PD has been unknown. Here we report the case of a patient who had profoundly decreased left ventricular myocardial 6-[18F]fluorodopamine-derived radioactivity and low baroreflex-cardiovagal gain, 4 years before the onset of symptoms and signs of PD. The results lead us to hypothesize that cardiac noradrenergic denervation and decreased baroreflex-cardiovagal function may occur early in the pathogenesis of PD. [ABSTRACT FROM AUTHOR]

In this study we evaluated by indirect immunohistochemistry the prevalence of cerebrospinal fluid (CSF) antibodies reacting with structures of rat pons/medulla in patients with multiple system atrophy (MSA) ( n = 29), Parkinson disease with neurogenic orthostatic hypotension ( n = 13), or pure autonomic failure ( n = 11) and in control subjects without autonomic failure ( n = 33). About 10–20% of CSF samples had positive immunoreactivity to rat locus coeruleus (LC), regardless of clinical diagnosis. The results failed to confirm the previously reported high prevalence of immune binding to rat LC in CSF from patients with MSA. [ABSTRACT FROM AUTHOR]

Patients with Parkinson’s disease (PD) commonly have clinically significant orthostatic hypotension (OH). In such patients PD+OH might be confused with multiple system atrophy (MSA), in which OH is a frequent finding, or with pure autonomic failure (PAF), if OH preceded clinical manifestations of the movement disorder. This study addressed whether OH can occur as an early finding in PD+OH.Historical data were analyzed from 35 patients with PD+OH evaluated at the NIH. OH was considered early if the patient had OH before, concurrent with, or starting within 1 year after onset of a symptomatic movement disorder. MSA was excluded by myocardial 6-[18F]fluorodopamine-derived radioactivity more than 2 standard deviations below the normal mean. Among the 35 PD+OH patients, 21 (60 %) had documentation of OH as an early finding. In 4 such patients, OH had preceded parkinsonism, and in 4 others, OH had dominated the early clinical picture, even after cessation of levodopa treatment for the movement disorder. In PD, OH can occur early in the disease, occasionally preceding or overshadowing the movement disorder. [ABSTRACT FROM AUTHOR]

Patient groups with chronic autonomic failure and neuroimaging evidence of intact or absent cardiac sympathetic innervation had similar mean values for myocardial perfusion. Cardiac sympathetic outflow does not seem to contribute to coronary vascular resistance. [ABSTRACT FROM AUTHOR]