Abnormal dopamine transporter imaging in pure autonomic failure: a potential biomarker of central nervous system involvement.

BACKGROUND AND PURPOSE: Pure autonomic failure (PAF) is a rare progressive neurodegenerative disease characterized by neurogenic orthostatic hypotension at presentation, without other neurological abnormalities. Some patients may develop other central neurological features indicative of multiple system atrophy or a Lewy body disorder. There are currently no biomarkers to assess possible central nervous system involvement in probable PAF at an early stage. A possibility is to evaluate the nigrostriatal dopaminergic degeneration by imaging of dopamine transporter with DaTscan brain imaging. The objective was to evaluate subclinical central nervous system involvement using DaTscan in PAF. METHODS: We retreospectively reviewed pure autonomic failure patients who were evaluated at the Autonomic Unit between January 2015 and August 2021 and underwent comprehensive autonomic assessment, neurological examination, brain magnetic resonance imaging and DaTscan imaging. DaTscan imaging was performed if patients presented with atypical features which did not meet the criteria for Parkinson's disease or multiple system atrophy or other atypical parkinsonism. RESULTS: In this cohort, the median age was 49.5 years at disease onset, 57.5 years at presentation, and the median disease duration was 7.5 years. Five of 10 patients had an abnormal DaTscan without neurological features meeting the criteria of an alternative diagnosis. Patients with abnormal DaTscan were predominantly males, had shorter disease duration and had more severe genitourinary symptoms. DISCUSSION: Degeneration of nigrostriatal dopaminergic neurons measured using DaTscan imaging can present in patients with PAF without concurrent signs indicating progression to widespread α-synucleinopathy. It is advocated that DaTscan imaging should be considered as part of the workup of patients with emerging autonomic failure who are considered to have PAF.

Cardiac 18F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure.

PURPOSE: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), no known secondary cause, and lack of a neurodegenerative movement or cognitive disorder. Clinically diagnosed PAF can evolve ("phenoconvert") to a central Lewy body disease [LBD, e.g., Parkinson's 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 patients with PAF with low cardiac 18F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA. METHODS: We reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 with a clinical diagnosis of PAF and data about 18F-dopamine positron emission tomography (PET). RESULTS: Nineteen patients (15 with low 18F-dopamine-derived radioactivity, 4 with normal radioactivity) met the above criteria and had follow-up data. Nine (47%) phenoconverted to a central synucleinopathy over a mean of 6.6 years (range 1.5-18.8 years). All 6 patients with low cardiac 18F-dopamine-derived radioactivity who phenoconverted during follow-up developed a central LBD, whereas none of 4 patients with consistently normal 18F-dopamine PET phenoconverted to a central LBD (p = 0.0048), 3 evolving to probable MSA and 1 upon autopsy having neither a LBD nor MSA. CONCLUSION: 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.

Elevated cerebral blood flow in patients with pure autonomic failure.

PURPOSE: Pure autonomic failure (PAF) results from an impaired peripheral autonomic nervous system, and clinical symptoms present with orthostatic hypotension. While the impact on cardiovascular indices of orthostatic intolerance are well-characterized, more limited information is available regarding cerebral hemodynamic dysfunction in PAF. The objective of this study was to test the hypothesis that cerebral blood flow (CBF) is reduced in PAF, and to quantify the relationship between CBF and clinical indicators of disease severity, including peripheral supine arterial blood pressure. METHODS: Participants with PAF (n = 17) and age- and sex-matched normotensive healthy controls (n = 17) were examined using established clinical rating scales, cardiovascular autonomic function tests, and 3T MRI measurements of CBF. CBF-weighted images were also used to determine the prevalence of venous hyperintensities from the major dural sinuses as evidence of abnormal capillary flow. Nonparametric tests and general linear models were used to evaluate differences and correlations between study variables. RESULTS: Gray matter CBF was higher in PAF (51.1 ± 13.4 mL/100 g/min) compared to controls (42.9 ± 6.5 mL/100 g/min, p = 0.007). Venous hyperintensities were more prevalent in PAF relative to controls, and the presence and degree of venous hyperintensities was associated with higher mean CBF (p = 0.027). In PAF participants, CBF and supine systolic blood pressure were inversely related (Spearman's rho = -0.545, p = 0.024). CONCLUSIONS: Findings suggest that PAF patients may exhibit elevated CBF and provide evidence that this condition exerts a hemodynamic impact in the central nervous system.

Autoimmunity-associated autonomic failure with sympathetic denervation.

We report a case of autoimmunity-associated autonomic failure in a young adult woman who developed arthritis followed 3 years later by pandysautonomia. There was early recovery of parasympathetic functions but persistent neurogenic orthostatic hypotension from post-ganglionic sympathetic denervation. Clinical laboratory testing indicated variable amounts of sympathetic neuronal re-sprouting in the heart, kidneys, eyes, and body as a whole upon follow-up evaluation after 1.5 years.

Pure autonomic failure without synucleinopathy.

Pure autonomic failure is a rare form of chronic autonomic failure manifesting with neurogenic orthostatic hypotension and evidence of sympathetic noradrenergic denervation unaccompanied by signs of central neurodegeneration. It has been proposed that pure autonomic failure is a Lewy body disease characterized by intra-neuronal deposition of the protein alpha-synuclein in Lewy bodies and neurites. A middle-aged man with previously diagnosed pure autonomic failure experienced a sudden, fatal cardiac arrest. He was autopsied, and tissues were harvested for neurochemical and immunofluorescence studies. Post-mortem microscopic neuropathology showed no Lewy bodies, Lewy neurites, or alpha-synuclein deposition by immunohistochemistry anywhere in the brain. The patient had markedly decreased immunofluorescent tyrosine hydroxylase in sympathetic ganglion tissue without detectable alpha-synuclein even in rare residual nests of tyrosine hydroxylase-containing ganglionic fibers. In pure autonomic failure, sympathetic noradrenergic denervation can occur without concurrent Lewy bodies or alpha-synuclein deposition in the brain or sympathetic ganglion tissue.

Superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus: a case report.

We describe the case of a man whose initial clinical presentation included sensorineural hearing loss and orthostatic hypotension. The patient was diagnosed with superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus.

Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson's disease and other synucleinopathies.

Central catecholamine deficiency characterizes α-synucleinopathies such as Parkinson's disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson's disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects-108 synucleinopathy patients (34 Parkinson's disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson's disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86 ± 0.09 (SEM), 1.00 ± 0.09, 1.32 ± 0.12 nmol/l] than controls (2.15 ± 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 ± 0.44, 7.75 ± 0.42, 5.82 ± 0.65 nmol/l) than controls (11.0 ± 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson's disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson's disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson's disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid dihydroxyphenylacetic acid seems to provide a sensitive means to identify even early Parkinson's disease.

Neurogenic orthostatic hypotension as the initial feature of Parkinson disease.

Autonomic failure is a common finding in patients with Parkinson disease (PD). Here we describe a patient with PD in whom autonomic symptoms began 3 years before motor deficits.

Cardiac sympathetic innervation and vesicular storage in pure autonomic failure.

OBJECTIVE: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using 11 C-methylreboxetine (11 C-MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using 18 F-dopamine (18 F-DA) to assess intraneuronal vesicular storage in the same subjects. METHODS: Seven comprehensively tested PAF patients and 11 controls underwent 11 C-MRB PET scanning for 45 minutes (dynamic 5X1', 3X5', 1X10', static 15 minutes) and 18 F-DA scanning for 30 minutes (same dynamic imaging sequence) after 3-minute infusions of the tracers on separate days. RESULTS: In the PAF group septal 11 C-MRB-derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of 11 C-MRB, the PAF group had a 41.1% mean decrease in myocardial 11 C-MRB-derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of 18 F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001). At all time points after infusion of 18 F-DA and 11 C-MRB mean 18 F/11 C ratios in septal myocardium were lower in the PAF than control group. INTERPRETATION: PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves.

Cardioselective peripheral noradrenergic deficiency in Lewy body synucleinopathies.

OBJECTIVE: Lewy body (LB) synucleinopathies such as Parkinson's disease (PD) entail profound cardiac norepinephrine deficiency. The status of sympathetic noradrenergic innervation at other extracranial sites has been unclear. Although in vivo neuroimaging studies have indicated a cardioselective noradrenergic lesion, no previous study has surveyed peripheral organs for norepinephrine contents in LB diseases. We reviewed 18 F-dopamine (18 F-DA) positron emission tomographic images and postmortem neurochemical data across several body organs of controls and patients with the LB synucleinopathies PD and pure autonomic failure (PAF) and the non-LB synucleinopathy multiple system atrophy (MSA). METHODS: 18 F-DA-derived radioactivity in the heart, liver, spleen, pancreas, stomach, kidneys, thyroid, and submandibular glands were analyzed from 145 patients with LB synucleinopathies (112 PD, 33 PAF), 74 controls, and 85 MSA patients. In largely separate cohorts, postmortem tissue norepinephrine data were reviewed for heart, liver, spleen, pancreas, kidney, thyroid, submandibular gland, and sympathetic ganglion tissue from 38 PD, 2 PAF, and 5 MSA patients and 35 controls. RESULTS: Interventricular septal 18 F-DA-derived radioactivity was decreased in the LB synucleinopathy group compared to the control and MSA groups (P < 0.0001 each). The LB and non-LB groups did not differ in liver, spleen, pancreas, stomach, or kidney 18 F-DA-derived radioactivity. The LB synucleinopathy group had markedly decreased apical myocardial norepinephrine, but normal tissue norepinephrine in other organs. The MSA group had normal tissue norepinephrine in all examined organs. INTERPRETATION: By in vivo sympathetic neuroimaging and postmortem neurochemistry peripheral noradrenergic deficiency in LB synucleinopathies is cardioselective. MSA does not involve peripheral noradrenergic deficiency.

Comparison of 123I-MIBG scintigraphy and phosphorylated α-synuclein skin deposits in synucleinopathies.

INTRODUCTION: Cardiac [123I]metaiodobenzylguanidine scintigraphy (123I-MIBG) is considered a useful test in differentiating multiple system atrophy (MSA) and Lewy body disorders (LBD), including idiopathic Parkinson's disease (IPD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). The detection of skin nerve phosphorylated α-synuclein (p-α-syn) deposits could be an alternative marker in vivo. We sought to compare 123I-MIBG scintigraphy and skin biopsy findings in α-synucleinopathies. METHODS: We studied 54 patients (7 DLB, 21 IPD, 13 PAF, 13 MSA) who underwent 123I-MIBG scintigraphy and skin biopsy to evaluate cardiac innervation and skin p-α-syn deposition, respectively. RESULTS: Cardiac denervation was observed in 90.5% IPD, 100% DLB and PAF and in none of the MSA patients (P < 0.0001) whereas p-α-syn deposits were detected in all DLB and PAF, in 95.2% of IPD and 69.2% of MSA patients (P = 0.02). However, the analysis of skin structures disclosed a different distribution of the deposits in somatic subepidermal plexus and autonomic fibers among groups, showing that p-α-syn deposits rarely affected the autonomic fibers in MSA as opposed to LBD. Studying the p-α-syn deposition in autonomic nerves, concordance among I123-MIBG scintigraphy and skin biopsy results was observed in 100% of DLB and PAF, 95.2% IPD and 92.3% MSA patients. I123-MIBG scintigraphy and autonomic p-α-syn deposits analysis both showed a sensitivity of 97.5% and a specificity of 100% and 92.3%, respectively, in distinguishing LBD and MSA. CONCLUSION: Skin biopsy and 123-MIBG scintigraphy can be considered alternative tests for the differential diagnosis of IPD, PAF and DLB versus MSA.

Long-term trends in myocardial sympathetic innervation and function in synucleinopathies.

INTRODUCTION: Parkinson disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA) are characterized by intra-cerebral deposition of the protein alpha-synuclein and are termed synucleinopathies. Lewy body synucleinopathies involve decreased cardiac sympathetic innervation and functional abnormalities in residual noradrenergic terminals. This observational, retrospective, cohort study describes long-term trends in indices of cardiac sympathetic innervation and function in synucleinopathies. METHODS: Patients with PD (N = 31), PAF (N = 9), or MSA (N = 9) underwent repeated 18F-dopamine positron emission tomography (median follow-up 3.5 years). Interventricular septal 18F-dopamine-derived radioactivity 8 min after tracer injection (8' Radioactivity) was used as an index of sympathetic innervation and the slope of mono-exponential decline of radioactivity between 8 and 25 min (k8'-25') as an index of intraneuronal vesicular storage. Healthy volunteers (HVs) (N = 33) and individuals at high risk of PD (N = 15) were controls. RESULTS: Upon initial evaluation the groups with PD and orthostatic hypotension (OH), PAF, or PD and no OH had low mean 8' Radioactivity compared to HVs (p < 0.0001, p = 0.0002, p = 0.006) and had elevated k8'-25' (p = 0.0007, p = 0.007, p = 0.06). There was no significant difference between MSA and HVs. In PD 8' Radioactivity decreased by a median of 4% per year and did not decrease in MSA. k8'-25' values did not change during follow-up in any group. CONCLUSIONS: Neuroimaging evidence of decreased vesicular uptake in cardiac sympathetic nerves is present upon initial evaluation of patients with Lewy body synucleinopathies and may provide a biomarker of catecholaminergic dysfunction early in the disease process.

Survival in synucleinopathies: A prospective cohort study.

OBJECTIVES: Parkinson disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) involve cytoplasmic deposition of α-synuclein and are considered to be synucleinopathies. Approximately 40% of patients with PD, most patients with MSA, and all patients with PAF have neurogenic orthostatic hypotension (OH). This study compared long-term survival in these synucleinopathies. METHODS: In this prospective cohort study, survival data were obtained for 97.6% of 206 referred patients evaluated between 1994 and 2014 (47 PD + OH, 54 PD no OH, 15 cerebellar MSA [MSA-C], 57 parkinsonian MSA [MSA-P], 28 PAF). Individual diagnoses were confirmed by clinical criteria and results of pharmacologic, neurochemical, and neuroimaging tests of sympathetic noradrenergic innervation. The Cox proportional hazard model was used to calculate hazard ratios (HRs) from symptom onset and from time of evaluation to death. RESULTS: Patients with MSA-C or MSA-P had shorter survival from symptom onset than did patients with PD + OH (age- and sex-adjusted HR = 6.1, 5.6; p < 0.0001 each), PAF (HR = 10.8, 9.9; p < 0.0001 each) or PD no OH (HR = 14.9, 13.6; p < 0.0001 each). Among parkinsonian patients who died, median times from motor onset to death were 7.5 years in MSA-P, 11.6 years in PD + OH, and 15.8 years in PD no OH. Probabilities of survival for 10 years from onset of relevant symptoms were 0.39 in MSA-C, 0.33 in MSA-P, 0.74 in PD + OH, 0.87 in PAF, and 0.93 in PD no OH. CONCLUSIONS: In synucleinopathies, survival depends on the particular disease, with the risk of death greater in MSA-P than in PD + OH and in PD + OH than in PD no OH.

Pure autonomic failure.

A 1925 report by Bradbury and Eggleston first described patients with extreme orthostatic hypotension and a low, steady heart rate. Evidence accumulated over the next two decades that patients with orthostatic hypotension include those with pure autonomic failure (PAF), characterized by isolated peripheral autonomic dysfunction and decreased norepinephrine synthesis; multiple system atrophy (MSA) with symptoms of a central Parkinson-like syndrome and normal resting plasma norepinephrine; and Parkinson's disease (PD), with lesions in postganglionic noradrenergic neurons and signs of autonomic dysfunction. All three disorders are classified as α-synucleinopathies. Insoluble deposits of α-synuclein are found in glia in MSA, whereas they take the form of neuronal cytoplasmic inclusions called Lewy bodies in PAF and PD. The exact relationship between α-synuclein deposits and the pathology remains undetermined. PAF occurs sporadically, and progresses slowly with a relatively good prognosis. However, it has been proposed that some cases of PAF may develop a central neurodegenerative disorder. Differentiation between PAF, MSA, and PD with autonomic failure can be facilitated by a number of biochemical and functional tests and by imaging studies. Cardiac sympathetic innervation is generally intact in MSA but decreased or absent in Parkinson's disease with autonomic failure and PAF. Treatment of PAF is directed at relieving symptoms with nonpharmacological interventions and with medications producing volume expansion and vasoconstriction. Future studies should focus on determining the factors that lead to central rather than solely peripheral neurodegeneration.

Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases.

BACKGROUND: Pure autonomic failure (PAF) and Parkinson disease (PD) both are Lewy body diseases, and both entail substantia nigra dopaminergic, locus ceruleus noradrenergic, and cardiac sympathetic denervation. Multiple system atrophy (MSA) is a non-Lewy body disease in which alpha-synuclein accumulates in glial cells, with central catecholamine deficiency but preserved cardiac sympathetic innervation in most patients. PD is associated with more severe and consistent olfactory dysfunction than in MSA; whether PAF entails olfactory dysfunction has been unknown. In this study we assessed olfactory function in PAF in comparison with the two other synucleinopathies and whether olfactory dysfunction correlates with neuroimaging evidence of cardiac noradrenergic or nigrostriatal dopaminergic denervation. METHOD: The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 8 patients with PAF, 23 with PD, and 20 with MSA. 6-[(18)F]Fluorodopamine positron emission tomographic (PET) scanning was used to indicate cardiac noradrenergic innervation and the putamen:occipital cortex (PUT:OCC) and substantia nigra (SN):OCC ratios of 6-[(18)F]fluorodopa-derived radioactivity to indicate nigrostriatal dopaminergic innervation. RESULTS: The PAF group had a low mean UPSIT score (22+/-3), similar to that in PD (20+/-2) and lower than in MSA (31+/-2, p=0.004). Individual UPSIT scores correlated positively with cardiac 6-[(18)F]fluorodopamine-derived radioactivity (r=0.63 in the septum, p<0.0001; r=0.64 in the free wall, p<0.0001) but not with PUT:OCC or SN:OCC ratios of 6-[(18)F]fluorodopa-derived radioactivity. DISCUSSION: In synucleinopathies, olfactory dysfunction is related to Lewy body pathology and cardiac sympathetic denervation, independently of parkinsonism or striatal dopamine deficiency.

Clinical laboratory evaluation of autoimmune autonomic ganglionopathy: Preliminary observations.

Several forms of chronic autonomic failure manifest as neurogenic orthostatic hypotension, including autoimmune autonomic ganglionopathy (AAG) and pure autonomic failure (PAF). AAG and PAF are thought to differ in pathogenesis, AAG reflecting decreased ganglionic neurotransmission due to circulating antibodies to the neuronal nicotinic receptor and PAF being a Lewy body disease with prominent loss of sympathetic noradrenergic nerves. AAG therefore would be expected to differ from PAF in terms of clinical laboratory findings indicating post-ganglionic noradrenergic denervation. Both diseases are rare. Here we report preliminary observations about clinical physiologic, neuropharmacologic, neurochemical, and neuroimaging data that seem to fit with the hypothesized pathogenetic difference between AAG and PAF. Patients with either condition have evidence of baroreflex-sympathoneural and baroreflex-cardiovagal failure. Both disorders feature low plasma levels of catecholamines during supine rest, but plasma levels of the other endogenous catechols, dihydroxyphenylalanine (DOPA), dihydroxyphenylacetic acid (DOPAC), and dihydroxyphenylglycol (DHPG), seem to be lower in PAF than in AAG, probably reflecting decreased norepinephrine synthesis and turnover in PAF, due to diffuse sympathetic noradrenergic denervation. PAF entails cardiac sympathetic denervation, whereas cardiac sympathetic neuroimaging by thoracic 6-[(18)F]fluorodopamine scanning indicates intact myocardial sympathetic innervation in AAG.