David S. Goldstein

Putamen dopamine depletion characterizes Parkinson disease (PD). Intraneuronal processes determining dopamine stores have not been systematically examined. This study explored relative contributions of dopamine synthesis, storage, and metabolism to control-PD differences. We updated an intramural tabulation from 2002 to 2024 of postmortem putamen tissue contents of reactants, including the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), from patients with PD and controls. Based on computational models applying first-order kinetics and equilibrium equations, we then compared estimated rates of dopamine synthesis through tyrosine hydroxylase (TH), L-aromatic-amino-acid decarboxylase, vesicular active uptake and passive leakage, exocytotic release and reuptake, and other intraneuronal processes. Results from the modeling were compared with those from in vivo ¹⁸F-DOPA PET. Postmortem data were analyzed from 13 patients with PD (median age 77 years, range 73-85 years) and 20 controls (median age 77 years, range 35-91 years). There was approximately a 98% decrease in putamen tissue dopamine in PD, and the concentration ratio of DOPAL/dopamine (DA) was approximately 9 times that of control. Applying the simplest kinetic model, vesicular sequestration was estimated to be decreased by 98.5% (0.073 vs 4.91 nmol/minute). Approximately 3-fold greater in vivo "washout" of putamen ¹⁸F-DOPA-derived radioactivity compared with controls also indicated attenuated vesicular storage in PD. According to the complete model, control-PD differences in intraneuronal reaction rates were in descending order of vesicular uptake ≈ vesicular leakage > exocytotic release ≈ neuronal reuptake > L-aromatic-amino-acid decarboxylase activity ≈ TH activity > other reactions. Convergent quantitative evidence points to a substantial vesicular storage defect in residual dopaminergic terminals in PD. This finding challenges the sufficiency of nigrostriatal dopaminergic denervation alone to account for the biochemical phenotype of PD and highlights vesicular dopamine handling as a critical determinant of putamen dopamine deficiency. The reaction rate estimates were drawn from published point values rather than fitted to an experimental data set, and so conventional goodness-of-fit regression statistics were not conducted. Because of the assumption of steady-state conditions for calculating reaction rates based on equilibrium equations, the model does not address the dynamics of disease pathogenesis over years but does provide a platform for further extension to disease progression. We estimated rates of reactions involved with the synthesis, storage, release, reuptake, and metabolism of dopamine in the putamen in PD and found that the main intraneuronal functional abnormality separating PD from controls was attenuated vesicular sequestration, implicating decreased vesicular uptake through the vesicular monoamine transporter and increased vesicular leakiness as key determinants of putamen dopamine deficiency in PD.

Background: The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP‐MSA) have not been prospectively validated. Objective: To evaluate the diagnostic performance of the PP‐MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. Methods: Seventy‐six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP‐MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. Results: Thirty‐eight participants met PP‐MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%–97%) and PPV (53%–83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. Conclusions: The PP‐MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

In the diagnostic evaluation of Parkinson's disease (PD), cardiac sympathetic neuroimaging has been viewed as a supportive test. This review argues that the clinical and scientific value of cardiac sympathetic neuroimaging is broader than being merely confirmatory. ¹²³ I‐metaiodobenzylguanidine ( ¹²³ I‐MIBG) single photon emission computed tomography (SPECT) is the practical clinical modality for detecting cardiac sympathetic denervation, whereas ¹⁸ F‐dopamine positron emission tomography (PET) also provides a pathophysiologic probe of sympathetic neuronal uptake, vesicular sequestration, and intra‐neuronal catecholamine metabolism. In autonomic synucleinopathies, this distinction is especially relevant for separating PD with orthostatic hypotension (PD + OH) from the parkinsonian form of multiple system atrophy (MSA‐P), for predicting phenoconversion in isolated neurogenic OH, for delineating specific intra‐neuronal functional abnormalities, and for stratifying patients for mechanism‐based treatment trials. Evidence from prospective longitudinal studies and computational modeling supports a body‐first pathway in some central Lewy body diseases, with cardiac noradrenergic deficiency preceding overt motor or cognitive manifestations. Cardiac sympathetic neuroimaging therefore may help move the field from clinical confirmation toward biomarker‐based diagnosis, prognostication, and preclinical intervention.

After a previous overview published more than 20 years ago, key aspects of catecholamine metabolism remain incompletely understood by physiologists. Meanwhile, the repertoire of assayable catecholamine-related compounds has expanded. Moreover, alterations in catecholamine metabolic patterns associated with physiological changes, drug effects, and pathophysiological states were not covered; and biochemical phenotyping via kinetic models now makes it possible to elucidate physiology and pathophysiology in individuals. Accordingly, this review starts with the inventory of catecholamine-related compounds and the three main peripheral catecholamine systems (sympathoneuronal, adrenomedullary, and autocrine/paracrine). Catecholamine systems contribute to virtually every organ function, behavior, and emotional state, and we describe situations where alterations in those systems exert syndromic pathophysiological effects. We then describe the relationships of catecholamine metabolic patterns to synthesis, storage, release, reuptake, and intra-neuronal and extra-neuronal metabolism of catecholamines; effects of physiological processes and drugs on those patterns; and catecholamine biochemical patterns associated with pathophysiologic states. We provide examples of how detailed, comprehensive knowledge acquired over the past half century has led to computational models for estimating the rates of processes that characterize specific physiological changes and some clinical disorders. The integrative physiological approach presented here has the potential to pinpoint specific functional abnormalities within catecholaminergic cells and thereby rationalize novel, testable treatment and prevention strategies.

Background and Objectives The arterial baroreflex has sympathoneural and cardiovagal efferent limbs. Whether quantitative measures represent interchangeable indicators of a single physiological construct has been unclear. Moreover, the extent to which results agree in the synucleinopathies pure autonomic failure (PAF), Parkinson disease with or without orthostatic hypotension (PD + OH, PD No OH), and multiple system atrophy (MSA) remains incompletely understood. In a retrospective observational study we comprehensively assessed physiological and neurochemical biomarkers of arterial baroreflex function in these disorders. Methods Data for 10 baroreflex-sympathoneural and 6 baroreflex-cardiovagal indices were compared among 38 patients with PAF, 63 with PD + OH, 63 with PD No OH, and 72 with MSA, along with 44 controls with complete datasets. Results Indices of baroreflex-sympathoneural and baroreflex-cardiovagal function were only weakly correlated. Within the two domains, correlations across subjects were much stronger. Among sympathoneural measures, pressure recovery time after the Valsalva maneuver, the logarithm of the total baroreflex area, and the fractional orthostatic increment in plasma norepinephrine best distinguished patients with autonomic synucleinopathies from controls. Among cardiovagal measures, the Baroslope derived from Phase II of the Valsalva maneuver and the logarithms of low- and high-frequency heart rate variability during supine rest were the most informative. No baroreflex measure separated PAF from PD + OH or MSA. Conclusions Indices derived from blood pressure and interbeat interval responses during the Valsalva maneuver capture much of the physiologically meaningful variation in arterial baroreflex function and provide efficient assessment of the sympathoneural and cardiovagal limbs in autonomic synucleinopathies.

Fatigue, brain fog and post-exertional malaise are major features of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2. To date, no specific neurotransmitter abnormalities have been found in either condition. We examined the possibility of central catecholaminergic involvement and clinical correlates in post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 groups compared to healthy volunteers and, as positive controls, Parkinson’s disease patients. In an observational, cross-sectional cohort study conducted at the National Institutes of Health Clinical Center we measured CSF levels of catecholamines and metabolites in the four groups and assessed correlations with neurobehavioral measures. CSF indices of the central Norepinephrine Pathway (norepinephrine + 3,4-dihydroxyphenylglycol + 3-methoxy-4-hydroxyphenylglycol) and Dopamine Pathway (dopamine + 3,4-dihydroxyphenylacetic acid + homovanillic acid) were measured and related to patient-recorded outcomes and physiological assessments. Mean values for Norepinephrine Pathway activity (in pmol/mL) were lower in the post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, post-acute sequelae of severe acute respiratory syndrome coronavirus 2, and Parkinson’s disease groups compared to the healthy volunteer cohort (post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (−15.9, 95% confidence interval [−26.1, −5.7], P = 0.0006); post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (−9.62, [−17.9, −1.4], P = 0.015); Parkinson’s disease (−19.4, [−27.5, −11.3], P < 0.0001)). Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 participants with post-exertional malaise had evidence of central noradrenergic deficiency compared to healthy volunteers (−18.3 [−31.3, −5.3], P = 0.0018). The post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 groups did not differ from the healthy group in values for the Dopamine Pathway index. Across all participants, Norepinephrine Pathway activity correlated positively with handgrip duration and general health and negatively with fatigue. We conclude that post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 feature a specific central neurotransmitter pattern involving noradrenergic but not dopaminergic deficiency. The noradrenergic abnormality is associated with major symptoms such as post-exertional malaise.

Background: Depletion of putamen dopamine (DA) characterizes Parkinson disease (PD) and precedes the onset of motor symptoms by years. Increasing evidence implicates impaired vesicular sequestration and attenuated detoxification of the toxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL) in disease pathogenesis. We applied a mechanistic kinetic model to examine how perturbations in dopamine handling from DOPAL-induced autotoxicity affect the timing and trajectory of symptomatic PD. Methods: Using an icon-based application we constructed a model of intraneuronal dopamine synthesis, vesicular storage, leakage, metabolism, aldehyde detoxification, delayed toxicity, and a-synuclein modification. Model behavior was evaluated by internal consistency and concordance with empirical cellular, animal, imaging, and post-mortem neurochemical data. We examined predicted effects of genetic variants, acquired factors (e.g., stress, environmental exposures), and treatments on vesicular dopamine content across the lifespan. Results: Without imposing a pre-defined disease curve, the model generated a tri-phasic trajectory of vesicular dopamine loss—homeostasis, dyshomeostasis, and symptomatic decline—from delayed DOPAL-mediated toxicity, with progressive impairment of vesicular sequestration and other intra-neuronal processes. The model predicted that genetic decreases in vesicular uptake or aldehyde detoxification and increases in dopamine biosynthesis would shorten the time to the onset of symptomatic disease, whereas monoamine oxidase inhibition, levodopa, and anti-oxidant treatment applied early and in combination would be protective. Preclinical, multi-target interventions would delay or prevent crossing a symptomatic threshold within the modeled lifespan. Conclusion: Systems modeling across the lifespan predicts a tri-phasic decline in putamen dopamine stores in PD. The timing and combination of interventions may be decisive for delaying or preventing symptomatic disease.

Background: Severe putamen dopamine depletion in Parkinson disease (PD) has been attributed to nigrostriatal denervation; however, there are also functional abnormalities in extant terminals (the “sick-but-not-dead” phenomenon). Rates of intra-neuronal processes of synthesis, storage, and metabolism of dopamine complexly influence releasable dopamine stores but have not yet been systematically estimated. Methods: Post-mortem empirical data were available about putamen tissue contents of 7 reactants, including the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). We constructed kinetic models depicting reactions related to putamen dopamine content, the simplest model consisting of 7 reactions and the most complete model 18 reactions among 10 intra-neuronal reactants. We used the post-mortem data, in vivo results of ¹⁸ F-DOPA positron emission tomography (PET), and the models to estimate rates of the intra-neuronal processes and rank their contributions to control-PD differences. Results: There was about a 98% decrease in putamen tissue dopamine in PD. The concentration ratio of DOPAL/DA was about 9 times control. Applying the simplest kinetic model, vesicular sequestration was estimated to be decreased by 98.5% (0.073 vs. 4.91 nmol/min). About 3-fold greater in vivo “washout” of putamen ¹⁸ F-DOPA-derived radioactivity compared to controls also indicated attenuated vesicular storage in PD. According to the complete model, control-PD differences in intra-neuronal reaction rates were, in descending order, vesicular uptake ≈ vesicular leakage > exocytotic release ≈ neuronal reuptake > L-aromatic-amino-acid decarboxylase activity ≈ tyrosine hydroxylase activity > other reactions. Discussion: Empirical post-mortem and in vivo data and application of kinetic models provide convergent quantitative evidence for a substantial vesicular storage defect in residual dopaminergic terminals in PD, a potential target for disease-modifying treatment or prevention strategies. Trial Registration: None BRIEF SUMMARY: We estimated rates of reactions involved with synthesis, storage, release, reuptake, and metabolism of dopamine in the putamen in Parkinson disease and found that the main intra-neuronal functional abnormality separating Parkinson disease from controls was attenuated vesicular sequestration, implicating decreased vesicular uptake via the vesicular monoamine transporter and increased vesicular leakiness as key determinants of putamen dopamine deficiency in PD.