Biomarkers of Catecholaminergic Neurodegeneration

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(A) Predicting the phenoconversion trajectory of pure autonomic failure (PAF): Clinically diagnosed PAF can evolve (phenoconvert) to a central Lewy body disease (LBD) (i.e., to Parkinsons disease (PD) or dementia with Lewy bodies (DLB)) or to the non-LBD synucleinopathy multiple system atrophy (MSA). Since cardiac 18F-dopamine-derived radioactivity usually is low in LBDs and usually is normal in MSA, we hypothesized that PAF patients with low cardiac 18F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA. To test this hypothesis we reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 who had a clinical diagnosis of PAF and had data about 18F-dopamine PET. Nineteen patients (15 with low 18F-dopamine-derived radioactivity, 4 with normal radioactivity) had follow-up data. Nine (47%) phenoconverted to a central synucleinopathy over a mean of 6.6 years (range 1.5-18.8 years). Of 6 patients with low cardiac 18F-dopamine-derived radioactivity who phenoconverted during follow-up, all 6 developed a central LBD, whereas of 4 with consistently normal 18F-dopamine PET, none phenoconverted to a central LBD (p=0.0048), 3 evolving to probable MSA and 1 upon autopsy having neither a LBD nor MSA. From these results we have concluded that cardiac 18F-dopamine PET can predict the type of phenoconversion of PAF. This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs. (B) Identifying preclinical central Lewy body diseases (the NINDS PDRisk study): The recently completed prospective, longitudinal, long-term follow-up PDRIsk study was based on intramural NINDS Clinical Protocol 09N0010. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-yearly intervals for up to 7.5 years or until PD was diagnosed. Upon initial evaluation, 9 participants had low myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 normal radioactivity. During follow-up, 8 of the 9 with low initial radioactivity were diagnosed with a central LBD (LBD+), in contrast with 1 of 25 with normal radioactivity (p<0.0001). Conversely, all of 9 LBD+ participants had low 18F-dopamine-derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (p<0.0001). From these results we have concluded that cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. In the PDRisk study we also asked whether relatively inexpensive, non-invasive cardiovascular physiological biomarkers that do not involve radioactivity exposure might detect preclinical central LBDs in at-risk individuals. Variables of interest were blood pressure and heart rate responses to head-up tilt table testing and indices of baroreflex-sympathoneural and baroreflex-cardiovagal function. Baroreflex-sympathoneural measures included the blood pressure recovery time (PRT) after release of the Valsalva maneuver and calculation of baroreflex areas (PMID 24706176); and baroreflex-cardiovagal measures included heart rate variability in the time and frequency domains and Valsalva baroslopes (PMID 7094250). Data were compared from groups with or without a subsequent diagnosis of a central LBD (LBD+, N=9; LBD-, N=25) and PDRisk participants with <3 confirmed risk factors (PDRisk-, N=25). The LBD+ group had larger orthostatic falls in systolic blood pressure than did the LBD- and PDRisk- groups (p<0.0001 each). The LBD+ group had increased PRTs (p=0.0114 vs. LBD-, p=0.0094 vs. PDRisk-) and baroreflex areas (p=0.0225 vs. LBD-, p=0.0028 vs. PDRisk), whereas the groups did not differ in indices of baroreflex-cardiovagal function. Therefore, orthostatic hypotension and baroreflex-sympathoneural dysfunction characterize at-risk individuals who go on to be diagnosed with a central LBD during long-term follow-up (PMID 36507976). (C) Persistent abnormalities in domains of the extended autonomic system (EAS) in post-acute SARS-CoV2 with neuropsychological symptoms (Neuro-PASC): After recovery from acute coronavirus disease-2019 (COVID-19), people often experience fatigue, brain fog, and other central neurological symptoms (neuro-post-acute SARS-CoV2, or Neuro-PASC) that can produce substantial disability. Deep phenotyping of Neuro-PASC patients has revealed several autonomic and immune/inflammatory abnormalities that correspond to domains of the extended autonomic system (EAS, PMID 37257231). We asked whether abnormalities noted by deep phenotyping at the time of the initial evaluation persist. Patients who had undergone comprehensive inpatient testing at the NIH Clinical Center for Neuro-PASC were invited back for follow-up assessments after at least another year. The battery of tests included Karnofsky functional scores, the University of Pennsylvania Smell Identification Test (UPSIT), the Montreal Cognitive Assessment (MoCA), magnetic resonance imaging, lumbar puncture for biochemical and cellular assays of the cerebrospinal fluid (CSF), multi-modal physiological recordings during the Valsalva maneuver and head-up tilting, serial measurements of plasma levels of catechols and cardiac Doppler-ultrasound during tilting, and blood sampling for a variety of neuroendocrine and immunologic measures. Seven Neuro-PASC patients underwent deep phenotyping after more than 1 year from the initial visit. Preliminarily, across more than 300 tests in the 4 domains of the EAS, most of the abnormal test results were still abnormal at follow-up. In all 7 patients the majority of initially abnormal results remained abnormal, including overall well-being, olfactory and cognitive scores, CSF indices of central catecholamine deficiency, baroreflex-cardiovagal dysfunction, the occurrence of tilt-evoked sudden hypotension, and the pattern of abnormal CSF and serum oligoclonal bands. Therefore, preliminarily, in Neuro-PASC most of the autonomic and immune/inflammatory abnormalities found upon initial evaluation persist for at least another year.