Intra-neuronal alpha-synuclein deposition is related to cardiac noradrenergic deficiency and olfactory dysfunction in neurogenic orthostatic hypotension.

Purpose: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH entail low 18F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (ɑ-syn) in dermal sympathetic noradrenergic nerves by the ɑ-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH. Methods: Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18F-dopamine-derived radioactivity was 6,000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased ɑ-syn-TH colocalization index ≥ 1.57. Results: A total of 44 patients (31 LB, 13 non-LB nOH) had data for all 3 biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18F-dopamine-derived radioactivity, low UPSIT scores, and high ɑ-syn-TH colocalization indexes (p<0.0001 each). Combining the 3 biomarkers completely separated the groups. Cluster analysis identified 2 distinct groups (p<0.0001) independently of the clinical diagnosis, 1 cluster corresponding exactly to LB nOH. Conclusion: LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased ɑ-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients.

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases.

BACKGROUND: In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. METHODS: Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. RESULTS: Nine participants had low initial myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher's exact test). Conversely, all 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 by Fisher's exact test). CONCLUSION: Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. CLINICALTRIALS: gov NCT00775853. FUNDING: Division of Intramural Research, NIH, NINDS.

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.

Development of the Edinburgh Postnatal Depression Scale-United States: An Updated Perinatal Mental Health Screening Tool Using a Respectful Care and Trauma-Informed Approach.

Purpose: To present the development protocol of the Edinburgh Postnatal Depression Scale-United States (EPDS-US), an adapted version of the EPDS, that is inclusive and easy to understand for U.S. populations and incorporates a trauma-informed approach to perinatal mental health (PMH). Methods: Our team adapted the wording of the original EPDS to be more linguistically appropriate for current use with U.S. populations by incorporating principles from Trauma-Informed Care and the Cycle to Respectful Care. Results: Through small but impactful linguistic updates, the EPDS-US offers inclusive person-first language and eliminates confusing phrases or wording that may be perceived as judgmental. The goal of the adapted EPDS-US is to foster symptom disclosure in an environment of safety and trust. The EPDS-US removes preidentified barriers patients experience related to PMH screenings. Conclusions: The EPDS-US, a trauma-informed and respectful care screening tool, may lead to earlier recognition of symptoms, may allow for more person-focused treatment plans, and may serve as a platform for a culture change in addressing PMH, particularly when the screening tool is accompanied by open conversation, education, and resources. Validation studies are required at this time and this team welcomes direct communication with research and clinical sites interested in doing so.

Cardiac 18F-Dopamine Positron Emission Tomography Predicts the Type of Phenoconversion of Pure Autonomic Failure.

Background: Pure autonomic failure (PAF) is a rare disease characterized clinically by neurogenic orthostatic hypotension (nOH) and biochemically by peripheral noradrenergic deficiency. 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). We examined whether cardiac 18F-dopamine positron emission tomography (PET) predicts the trajectory of phenoconversion in PAF. Since cardiac 18F-dopamine-derived radioactivity always is decreased in LBDs with nOH and usually is normal in MSA, we hypothesized that PAF patients with low cardiac 18F-dopamine-derived radioactivity may phenoconvert to a central LBD but do not phenoconvert 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 serial 18F-dopamine PET. Results: Twenty patients met the above criteria. Of 15 with low cardiac 18F-dopamine-derived radioactivity, 6 (40%) phenoconverted to PD or DLB and none to MSA. Of 5 patients with consistently normal 18F-dopamine PET, 4 phenoconverted to MSA, and the other at autopsy had neither a central LBD nor MSA. Conclusion: In this case series, 40% of patients with nOH and low cardiac 18F-dopamine-derived radioactivity phenoconverted to PD or DLB during follow-up; none phenoconverted to MSA. Cardiac 18F-DA PET therefore can predict the type of phenoconversion in PAF. This capability could refine eligibility criteria for entry into disease-modification trials aiming to prevent evolution of PAF to symptomatic central LBDs.

Is 18F-DOPA a valid cardiac sympathetic neuroimaging agent?

PURPOSE: 18F-Dopamine positron emission tomography is a validated method for identifying cardiac noradrenergic deficiency, a characteristic feature of Lewy body forms of neurogenic orthostatic hypotension; however, 18F-dopamine is a research drug. Brain 18F-DOPA positron emission tomography is FDA-approved. Since 18F-DOPA is converted to 18F-dopamine in the heart, 18F-DOPA might be useful for cardiac sympathetic neuroimaging. We compared 18F-DOPA with 18F-dopamine in patients who either had or did not have low 18F-dopamine-derived radioactivity. METHODS: Brain and cardiac 18F-DOPA scanning and cardiac 18F-dopamine scanning were done on separate days in patient groups with neurogenic orthostatic hypotension or Parkinsonism or control subjects across a range of values for 18F-dopamine-derived radioactivity. The lower limit of normal for myocardial 18F-dopamine-derived radioactivity was 6000 Bq-kg/cc-MBq. We also examined inter-relationships among cardiac 18F-DOPA-derived radioactivity, cardiac 18F-dopamine-derived radioactivity, putamen/occipital cortex ratios of 18F-DOPA-derived radioactivity, and Unified Parkinson Disease Rating Scale scores in patients with or without Parkinsonism. For putamen/occipital cortex ratios, the cutoff value was 2.70. RESULTS: Twelve subjects had severely decreased and eight normal cardiac 18F-dopamine-derived radioactivity. Cardiac 18F-DOPA-derived radioactivity did not distinguish the two groups and was unrelated to 18F-dopamine-derived radioactivity. Left ventricular myocardial 18F-DOPA-derived radioactivity was poorly resolved from that in the chamber. Putamen/occipital cortex ratios of 18F-DOPA-derived radioactivity were negatively correlated with Unified Parkinson Disease Rating Scale scores (- 0.67, p = 0.0015). CONCLUSIONS: 18F-DOPA does not seem to be a valid cardiac sympathetic neuroimaging agent, although brain 18F-DOPA scanning provides a biomarker of Parkinsonism.

Multiple catechols in human plasma after drinking caffeinated or decaffeinated coffee.

BACKGROUND: Coffee is one of the most frequently consumed beverages worldwide. Research on effects of coffee drinking has focused on caffeine; however, coffee contains myriad biochemicals that are chemically unrelated to caffeine, including 3,4-dihydroxyphenyl compounds (catechols) such as caffeic acid and dihydrocaffeic acid (DHCA). OBJECTIVE: This prospective within-subjects study examined effects of drinking caffeinated or decaffeinated coffee on plasma free (unconjugated) catechols measured by liquid chromatography with series electrochemical detection (LCED) after batch alumina extraction. To confirm coffee-related chromatographic peaks represented catechols, plasma was incubated with catechol-O-methyltransferase and S-adenosylmethionine before the alumina extraction; reductions in peak heights would identify catechols. METHODS: Ten healthy volunteers drank 2 cups each of caffeinated and decaffeinated coffee on separate days after fasting overnight. With subjects supine, blood was drawn through an intravenous catheter up to 240 min after coffee ingestion and the plasma assayed by alumina extraction followed by LCED. RESULTS: Within 15 min of drinking coffee of either type, >20 additional peaks were noted in chromatographs from the alumina eluates. Most of the coffee-related peaks corresponded to free catechols. Plasma levels of the catecholamines epinephrine and dopamine increased with both caffeinated and decaffeinated coffee. Levels of other endogenous catechols were unaffected. Plasma DHCA increased bi-phasically, in contrast with other coffee-related free catechols. INTERPRETATION: Drinking coffee-whether caffeinated or decaffeinated-results in the rapid appearance of numerous free catechols in the plasma. These might affect the disposition of circulating catecholamines. The bi-phasic increase in plasma DHCA is consistent with production by gut bacteria.

Differential abnormalities of cerebrospinal fluid dopaminergic versus noradrenergic indices in synucleinopathies.

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), DHPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen 18 F-DOPA and cardiac 18 F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.

Do indices of baroreflex failure and peripheral noradrenergic deficiency predict the magnitude of orthostatic hypotension in Lewy body diseases?

INTRODUCTION: Patients with neurogenic orthostatic hypotension in the setting of Lewy body diseases (LBnOH) typically have baroreflex failure and peripheral noradrenergic deficiency. Either or both of these abnormalities might determine the magnitude of OH in individual patients. We retrospectively correlated the orthostatic fall in systolic blood pressure (∆BPs) during active standing or 5 min of head-up tilt at 90° from horizontal as a function of several baroreflex and sympathetic noradrenergic indices. METHODS: Physiological, neurochemical, and sympathetic neuroimaging data from the Valsalva maneuver, head-up tilt table testing, and thoracic 18F-dopamine positron emission tomographic scanning (18F-DA PET) were analyzed from 72 patients with LBnOH [44 with Parkinson disease (PD) and nOH, 28 with pure autonomic failure]. Comparison subjects had PD without OH (N = 44) or PD risk factors without parkinsonism or OH (N = 28) or were healthy volunteers (N = 8). Indices of baroreflex function included the Valsalva maneuver-associated baroreflex areas in Phase II (BRA-II) and IV (BRA-IV), the pressure recovery time (PRT), and baroreflex-cardiovagal and adrenergic sensitivities (BRS-V and BRS-A). The fractional orthostatic increment in plasma norepinephrine (Fx∆NE) provided a neurochemical index of baroreflex-sympathoneural function. RESULTS: As expected, the LBnOH group had baroreflex-sympathoneural and baroreflex-cardiovagal impairment and low cardiac 18F-DA-derived radioactivity. Among patients, values for ∆BPs correlated with BRA-II, BRA-IV, BRS-V, and Fx∆NE but not with values for PRT, BRS-A, supine plasma NE, or 18F-DA-derived radioactivity. CONCLUSION: Across individual patients with LBnOH, quantitative indices of baroreflex dysfunctions and peripheral noradrenergic deficiency are inconsistently associated with the magnitude of OH, even under controlled laboratory conditions.

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.

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.

Mechanisms of Chronotropic Incompetence in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Chronotropic incompetence is common in heart failure with preserved ejection fraction (HFpEF) and is associated with impaired aerobic capacity. We investigated the integrity of cardiac ß-receptor responsiveness, an important mechanism involved in exertional increases in HR, in HFpEF and control subjects. METHODS: Thirteen carefully screened patients with HFpEF and 13 senior controls underwent exercise testing and graded isoproterenol infusion to quantify cardiac ß-receptor-mediated HR responses. To limit autonomic neural influences on heart rate (HR) during isoproterenol, dexmedetomidine and glycopyrrolate were given. Isoproterenol doses were increased incrementally until HR increased by 30 beats per minute. Plasma levels of isoproterenol at each increment were measured by liquid chromatography with electrochemical detection and plotted against HR. RESULTS: Peak VO2 and HR (117±15 versus 156±15 beats per minute; P<0.001) were lower in HFpEF than senior controls. Cardiac ß-receptor sensitivity was lower in HFpEF compared to controls (0.156±0.133 versus 0.254±0.166 beats per minute/[isoproterenol ng/mL]; P<0.001). Seven of 13 HFpEF subjects had ß-receptor sensitivity similar to senior controls but still had lower peak HRs (122±14 versus 156±15 beats per minute; P<0.001). CONCLUSIONS: Contrary to our hypothesis, patients with HFpEF displayed impaired cardiac ß-receptor sensitivity compared with senior controls. In the 7 out of 13 patients with HFpEF with age-appropriate ß-receptor sensitivity, peak HR remained low, suggesting impaired sinus node ß-receptor function may not fully account for low exercise HR response. Rather in some patients with HFpEF, chronotropic incompetence might reflect premature cessation of exercise before maximal sinus node activation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02524145.

A changing world, again. How Appreciative Inquiry can guide our growth.

COVID-19 is an interconnecting, cascading tsunami of up-rootedness and change on many levels. The global challenge we face is twofold: 1) how do we sustain our psychological, physical, social and economic capital and wellbeing in a time of great uncertainty; and 2) how do we adapt and create a new existence in an altered reality? Appreciative Inquiry (AI) is a well-documented approach to helping individuals and systems move from a deficit-based paradigm to a strengths-based perspective. AI holds myriad potential benefits for individuals, communities, and macro systems to build resilience and promote growth during and after COVID-19. This article will provide an overview of AI and its relevance to the current situation, as well as provide specific strategies for how people and systems can use AI as they transition through the pandemic and afterward.

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.

Alpha-Synuclein Deposition Within Sympathetic Noradrenergic Neurons Is Associated With Myocardial Noradrenergic Deficiency in Neurogenic Orthostatic Hypotension.

Lewy body diseases involve neurogenic orthostatic hypotension (nOH), cardiac noradrenergic deficiency, and deposition of the protein AS (alpha-synuclein) in sympathetic ganglion tissue. Mechanisms linking these abnormalities are poorly understood. One link may be AS deposition within sympathetic neurons. We validated methodology to quantify AS colocalization with TH (tyrosine hydroxylase), a marker of sympathetic noradrenergic innervation, and assessed associations of AS/TH colocalization with myocardial norepinephrine content and cardiac sympathetic neuroimaging data in nOH. Postmortem sympathetic ganglionic AS/TH colocalization indices and myocardial norepinephrine contents were measured in 4 Lewy body and 3 rare non-Lewy body nOH patients. Sixteen Lewy body and 11 non-Lewy body nOH patients underwent in vivo skin biopsies and thoracic 18F-dopamine positron emission tomographic scanning, with cutaneous colocalization indices expressed versus cardiac 18F-dopamine-derived radioactivity. Ganglionic AS/TH colocalization indices were higher and myocardial norepinephrine lower in Lewy body than non-Lewy body nOH ( P=0.0020, P=0.014). The Lewy body nOH group had higher AS/TH colocalization indices in skin biopsies and lower myocardial 18F-dopamine-derived radioactivity than did the non-Lewy body nOH group ( P<0.0001 each). All Lewy body nOH patients had colocalization indices >1.5 in skin biopsies and 18F-dopamine-derived radioactivity <6000 nCi-kg/cc-mCi, a combination not seen in non-Lewy body nOH patients ( P<0.0001). In Lewy body nOH, AS deposition in sympathetic noradrenergic nerves is related to postmortem neurochemical and in vivo neuroimaging evidence of myocardial noradrenergic deficiency. These associations raise the possibility that intraneuronal AS deposition plays a pathophysiological role in the myocardial sympathetic neurodegeneration attending Lewy body nOH.

Substantial renal conversion of L-threo-3,4-dihydroxyphenylserine (droxidopa) to norepinephrine in patients with neurogenic orthostatic hypotension.

BACKGROUND: The pressor effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxidopa, Northera™) results from conversion of L-DOPS to norepinephrine (NE) in cells expressing L-aromatic-amino-acid decarboxylase (LAAAD). After L-DOPS administration the increase in systemic plasma NE is too small to explain the increase in blood pressure. Renal proximal tubular cells abundantly express LAAAD. Since NE generated locally in the kidneys could contribute to the pressor effect of L-DOPS, in this study we assessed renal conversion of L-DOPS to NE. METHODS: Ten patients who were taking L-DOPS for symptomatic orthostatic hypotension had blood and urine sampled about 2 h after the last L-DOPS dose. L-DOPS and NE were assayed by alumina extraction followed by liquid chromatography with electrochemical detection. Data were compared in patients off vs. on levodopa/carbidopa. RESULTS: In patients off levodopa/carbidopa the ratio of NE/L-DOPS in urine averaged 63 times that in plasma (p = 0.0009 by t test applied to log-transformed data). In marked contrast, in the three patients on levodopa/carbidopa the ratio of NE/L-DOPS in urine did not differ from that in plasma. CONCLUSION: There is extensive renal production of NE from L-DOPS. Carbidopa seems to attenuate the conversion of L-DOPS to NE in the kidneys. Further research is needed to assess whether the proposed paracrine effect of L-DOPS in the kidneys contributes to the systemic pressor response.

Clinical Outcomes of Oral Suspension versus Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections.

Posaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared the incidence of breakthrough IFIs and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole. This was a retrospective cohort study of patients receiving posaconazole between 1 January 2010 and 30 June 2016. We defined probable or proven breakthrough IFIs using the European Organization for Research and Treatment of Cancer (EORTC) criteria. Overall, 547 patients received 860 courses of posaconazole (53% received the oral suspension and 48% received the tablet); primary indications for prophylaxis were acute myeloid leukemia (69%), graft-versus-host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indications between patients receiving the different formulations. The incidence and incidence rate of probable or proven IFIs were 1.6% and 3.2 per 10,000 posaconazole days, respectively. There was no significant difference in the rate of IFIs between suspension courses (2.8 per 10,000 posaconazole days) and tablet courses (3.7 per 10,000 posaconazole days) (rate ratio = 0.8, 95% confidence interval [CI] = 0.3 to 2.3). Of the 14 proven or probable cases of IFI, 8/14 had posaconazole serum concentrations measured, and the concentrations in 7/8 were above 0.7 µg/ml. Posaconazole was discontinued early in 15.5% of courses; however, the frequency of discontinuation was also not significantly different between the tablet (16.5%) and oral suspension (14.6%) formulations (95% CI for difference = -0.13 to 0.06). In conclusion, the incidence of breakthrough IFIs was low among patients receiving posaconazole prophylaxis and not significantly different between patients receiving the tablet formulation and those receiving the oral suspension formulation.

Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson's disease.

BACKGROUND: Consistent with nigrostriatal dopamine depletion, low cerebrospinal fluid (CSF) concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, characterize Parkinson's disease (PD) even in recently diagnosed patients. Whether low CSF levels of DOPAC or DOPA, the precursor of dopamine, identify pre-clinical PD in at-risk healthy individuals has been unknown. METHODS: Participants in the intramural NINDS PDRisk study entered information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. After at least 3 risk factors were confirmed by on-site screening, 26 subjects had CSF sampled for levels of catechols and were followed for at least 3 years. RESULTS: Of 26 PDRisk subjects, 4 were diagnosed with PD (Pre-Clinical PD group); 22 risk-matched (mean 3.2 risk factors) subjects remained disease-free after a median of 3.7 years (No-PD group). The Pre-Clinical PD group had lower initial DOPA and DOPAC levels than did the No-PD group (p = 0.0302, p = 0.0190). All 3 subjects with both low DOPA (<2.63 pmol/mL) and low DOPAC (<1.22 pmol/mL) levels, based on optimum cut-off points using the minimum distance method, developed PD, whereas none of 14 subjects with both normal DOPA and DOPAC levels did so (75% sensitivity at 100% specificity, p = 0.0015 by 2-tailed Fisher's exact test). CONCLUSIONS: In people with multiple PD risk factors, those with low CSF DOPA and low CSF DOPAC levels develop clinical disease during follow-up. We suggest that neurochemical biomarkers of central dopamine deficiency identify the disease in a pre-clinical phase.

Plasma Catechols After Eating Olives.

Olives contain 3,4-dihydroxyphenyl compounds (catechols)-especially 3,4-dihydroxyphenylethanol (DOPET)-that have therapeutic potential as nutraceuticals. Whether olive ingestion affects plasma levels of free (unconjugated) catechols has been unknown. Arm venous blood was sampled before and 15, 30, 45, 60, 120, 180, and 240 min after six healthy volunteers ate 10 Kalamata olives. Catechols were assayed by alumina extraction followed by liquid chromatography with series electrochemical detection. Plasma DOPET increased to 18.5 times baseline at 30 min (area under the curve (AUC) 39.2 ± 9.2 pmol-min/mL, P = 0.008). 3,4-Dihydroxyphenylacetic acid (DOPAC) increased markedly (peak 37.4 times baseline, AUC 23,490 ± 4,151 pmol-min/mL, P = 0.002). The sum of 10 catechols increased 12-fold (P < 0.0001). Eating olives produces large-magnitude increases in plasma levels of catechols, mainly DOPAC. DOPET seems to go undergo extensive hepatic metabolism to DOPAC.

Cardiac sympathetic denervation predicts PD in at-risk individuals.

INTRODUCTION: By the time a person develops the motor manifestations of Parkinson's disease (PD), substantial loss of nigrostriatal dopamine neurons has already occurred. There is great interest in identifying biomarkers that can detect pre-clinical PD. Braak's neuropathological staging concept imputes early autonomic involvement. Here we report results from a small prospective cohort study about the utility of neuroimaging evidence of cardiac sympathetic denervation in predicting PD among individuals with multiple PD risk factors. METHODS: Subjects provided information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. From this pool, 27 people with at least 3 risk factors confirmed underwent cardiac 18F-dopamine positron emission tomographic scanning and were followed for at least 3 years. Interventricular septal and left ventricular free wall concentrations of 18F-dopamine-derived radioactivity were measured. RESULTS: Of the 27 subjects, 4 were diagnosed with PD within the 3-year follow-up period (Pre-Clinical PD group); 23 risk-matched (mean 3.2 risk factors) subjects remained disease-free (No-PD group). Compared to the No-PD group, the Pre-Clinical PD group had lower initial values for septal and free wall concentrations of 18F-dopamine-derived radioactivity (p = 0.0248, 0.0129). All 4 Pre-Clinical PD subjects had evidence of decreased cardiac sympathetic innervation in the interventricular septum or left ventricular free wall, in contrast with 3 of 23 (13%) No-PD subjects (p = 0.0020 by Fisher's exact test). CONCLUSION: People with multiple PD risk factors and diagnosed with PD within 3 years have evidence of antecedent cardiac sympathetic denervation. The findings fit with Braak's staging concept.