Biomarkers of Catecholaminergic Neurodegeneration

National Institute Of Neurological Disorders And Stroke

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Abstract

(A) “Body-First” dementia with Lewy bodies (DLB): The recently completed prospective, longitudinal, long-term follow-up PDRIsk study was based on intramural NINDS Clinical Protocol 09N0010. We reported the case of a participant in the PDRisk study who subsequently was diagnosed with DLB and had postmortem neuropathological and neurochemical assessments. The patient had long-standing cardiac noradrenergic deficiency revealed by 18F-dopamine PET. During longitudinal follow-up over about 8 years in the PDRisk study he did not manifest cognitive dysfunction, and serial 18F-DOPA PET indicated intact nigrostriatal innervation. Postmortem, the patient had profound myocardial norepinephrine deficiency and striking α-synucleinopathy in the thoracic sympathetic chain. These data fit with body-first progression of catecholamine deficiency and synucleinopathy [1]. (B) Elevated cerebrospinal fluid alpha-synuclein seeding activity predicts central Lewy body diseases in at-risk individuals: Cerebrospinal fluid (CSF) α-synuclein seeding activity (SSA) via a seed amplification assay might predict central Lewy body diseases (LBD) in at-risk individuals. The aim of this study was to assess CSF SSA in a prospective, longitudinal study. Participants self-reported risk factors were genetics, olfactory dysfunction, dream enactment behavior, orthostatic intolerance, or hypotension; individuals who had ≥3 confirmed risk factors underwent CSF sampling and were followed for up to 7.5 years. Participants who developed a central LBD (LBD+) were compared to those who did not. Quadruplicate SSA areas under the curve (AUC) were averaged. Of 11 subjects with average AUCs above 500,000 units, 7 (64%) developed a central LBD compared to 1 of 20 (5%), with AUCs below the cutoff value (P = 0.0011 by log-rank test). Conversely, 7 of 8 (88%) LBD+ participants had elevated initial AUCs. Increased CSF SSA predicts central LBDs. Individuals who develop a central LBD have elevated initial SSA AUCs [2]. (C) Multi-tracer positron emission tomography to assess cardiac sympathetic innervation and vesicular storage in Lewy body diseases: Lewy body diseases (LBDs) feature profound myocardial depletion of the sympathetic neurotransmitter norepinephrine. In addition to sympathetic neuronal loss, the norepinephrine deficiency may reflect decreased vesicular sequestration of cytoplasmic catecholamines in dysfunctional but living nerve terminals. To evaluate intraneuronal vesicular storage in patients with LBDs, we retrospectively analyzed multitracer PET using 18F-6-fluorodopamine (18F-DA, a sympathetic neuroimaging agent) and 11C-methylreboxetine (11C-MRB, a ligand for the cell membrane norepinephrine transporter). If there were a vesicular storage defect, then the decrease in 18F-DA–derived radioactivity would be greater than the decrease in 11C-MRB–derived radioactivity. Twenty-three patients with Parkinson disease or the Lewy body form of pure autonomic failure and 15 controls underwent 18F-DA dynamic scanning (9 frames; last frame, 10-min duration with midpoint at 25 min) and on a separate day underwent 11C-MRB PET for 45 min (dynamic for 30 min, then a static 15-min frame with midpoint at 38 min). All patients in the LBD group had interventricular septal 18F-DA–derived radioactivity below the range of values in the control group (mean decrease, 75%; P , 0.0001). The LBD group also had a mean decrease of 37% in 11C-MRB–derived radioactivity from the control group in the static frame with midpoint at 38 min (P< 0.0001). At all time points after tracer administration, septal myocardial 18F-DA/11C-MRB ratios were lower in the LBD group (by 68% at 25 min; P< 0.0001). Therefore, LBDs entail substantially decreased vesicular storage in cardiac sympathetic nerves. This abnormality has direct implications for disease-modifying treatment and prevention strategies, since extant but dysfunctional (“sick-but-not-dead”) neurons may be salvageable [3]. (D) 3,4-Dihydroxyphenylglycol levels separate multiple system atrophy from Parkinson disease with orthostatic hypotension: The autonomic synucleinopathy multiple system atrophy (MSA) can be difficult to distinguish clinically from Parkinson disease with orthostatic hypotension (PD+OH). 18F-Dopamine positron emission tomography separates these conditions based on cardiac noradrenergic deficiency in PD+OH and not in MSA but is available only at the NIH Clinical Center. 3,4-Dihydroxyphenylglycol (DHPG) is the main neuronal metabolite of norepinephrine. This retrospective observational study examined whether DHPG levels in cerebrospinal fluid (CSF) or plasma differentiate MSA from PD+OH. We reviewed CSF and plasma neurochemical data from all patients referred for evaluation at the NIH Clinical Center between 1995 and 2024 for chronic autonomic failure or parkinsonism. A concurrently studied comparison group were healthy volunteers or patients with orthostatic intolerance. CSF DHPG was decreased in MSA (N=46, p<0.0001) compared to the controls but also tended to be decreased in PD+OH (N=16, p=0.0598). Antecubital venous plasma DHPG was decreased in PD+OH (N=40, p<0.0001) but also in MSA (N=59, p=0.0458). CSF/plasma concentration ratios of DHPG were lower in MSA than in PD+OH (p<0.0001). Cardiac arteriovenous increments in plasma DHPG and cardiac norepinephrine spillovers were strikingly decreased in PD+OH (N=6) and were lower than in MSA (N=20, p<0.0001 each). Combining cardiac arteriovenous increments in plasma DHPG with norepinephrine spillovers completely separated PD+OH from MSA. Therefore, CSF/plasma ratios of DHPG, cardiac venous-arterial differences in plasma DHPG, and cardiac norepinephrine spillovers separate MSA from PD+OH. From our results we propose that biomarker combinations involving DHPG in biofluids may enable a pathophysiological differential diagnosis of MSA vs. PD+OH [4]. (E) Pathophysiological significance of α-synuclein in sympathetic nerves: In vivo observations: Lewy body diseases (LBDs) such as Parkinson disease (PD) feature increased deposition of α-synuclein (α-syn) in cutaneous sympathetic noradrenergic nerves. The pathophysiologic significance of sympathetic intraneuronal α-syn is unclear. We reviewed data about immunoreactive α-syn, tyrosine hydroxylase (TH, a marker of catecholaminergic fibers), and the sympathetic neurotransmitter norepinephrine (NE) in skin biopsies from control participants and patients with PD, the related LBD pure autonomic failure (PAF), the non-LBD synucleinopathy multiple system atrophy (MSA), or neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (neuro-PASC). Data were analyzed about α-syn-TH colocalization indexes and immunoreactive α-syn and TH signal intensities in arrector pili muscles, blood vessels, and sweat glands from neck skin biopsies and NE concentrations in simultaneously obtained thigh skin biopsies from participants studied at the NIH Clinical Center. LBD, MSA, and control group data were assessed by analyses of variance with the Tukey post hoc test for multiple comparisons. Similar analyses were performed for patients with PD or neuro-PASC vs control. Dermal α-syn-TH colocalization indexes and α-syn signal intensities from neck skin biopsies were examined in 18 controls (mean age 58 years, 50% female) and 53 LBD (66, 34%), 15 MSA (61, 33%), and 11 neuro-PASC (52, 82%) patients. The LBD group had higher α-syn-TH colocalization indexes than the controls (mean difference = 1.495, 95% CI 1.081-1.909, p < 0.0001) and increased α-syn signal intensities in all 3 skin constituents (arrector pili: mean difference = 2.743, 95% CI 1.608-3.879, p < 0.0001; blood vessels: mean difference = 2.157, 95% CI 1.095-3.219, p < 0.0001; sweat glands: mean difference = 4.136, 95% CI 1.704-6.567, p < 0.0001). The groups did not differ in either immunoreactive TH or NE. The neuro-PASC and PD groups had elevated α-syn-TH colocalization indexes compared with the controls, also with no group differences in immunoreactive TH or NE contents. Therefore, LBDs and neuro-PASC entail increased α-syn-TH colocalization indexes in skin biopsies, without evidence of local denervation or noradrenergic deficiency. The results fail to support toxicity of intraneuronal α-syn in cutaneous sympathetic noradrenergic nerves in either LBDs or neuro-PASC. The neuro-PASC data raise the possibility of sympathetic intraneuronal α-syn deposition as part of postinfectious immune or inflammatory processes [5,6]. REFERENCES 1. Goldstein DS, Holmes C, Sullivan P, et al. "Body-first" dementia with Lewy bodies. Clin Auton Res 2025;35:623–627. 2. Goldstein DS, Alam P, Sullivan P, et al. Elevated Cerebrospinal Fluid alpha-Synuclein Seeding Activity Predicts Central Lewy Body Diseases. Mov Disord Clin Pract 2025;(in press), doi 10.1002/mdc3.14333. 3. Goldstein DS, Holmes C, Ding Y-S. Multi-tracer positron emission tomography to assess cardiac sympathetic innervation and vesicular storage in Lewy body diseases. J Nucl Med (in press). 4. Goldstein DS, Sullivan P, Holmes C. 3,4-Dihydroxyphenylglycol levels separate multiple system atrophy from Parkinson disease with orthostatic hypotension. Clin Auton Res (in press). 5. Isonaka R, Sullivan P, Goldstein DS. Pathophysiological significance of a-synuclein in sympathetic nerves: In vivo observations. Neurology 2025;104(3):e210215. (PMID 39817492) 6. Isonaka R, Goldstein DS. Author Response: Pathophysiologic Significance of α-Synuclein in Sympathetic Nerves. Neurology (in press)