Faculty Bibliography

PURPOSE/OBJECTIVE:The primary objective of this study was to examine the relationship of longitudinal changes in autonomic symptom burden and longitudinal changes in activities of daily living (ADLs); a secondary analysis examined the impact of depressive symptoms in this relationship. METHODS:Data were retrieved from the Parkinson's Progression Markers Initiative (PPMI), a dataset documenting the natural history of newly diagnosed Parkinson's disease (PD). The analysis focused on data from baseline, visit 6 (24 months after enrollment), and visit 12 (60 months after enrollment). The impact of longitudinal changes in autonomic symptom burden on longitudinal changes in ADLs function was examined. A secondary mediation analysis was performed to investigate whether longitudinal changes in depressive symptoms mediate the relationship between longitudinal changes in autonomic symptom burden and ADLs function. RESULTS:Changes in autonomic symptom burden, cognitive function, depressive symptoms, and motor function all correlated with ADLs. Only changes in ADLs and depression were found to be associated with changes in autonomic symptom burden. We found that longitudinal change in autonomic symptoms was a significant predictor of change in ADLs at 24 and 60 months after enrollment, with the cardiovascular subscore being a major driver of this association. Mediation analysis revealed that the association between autonomic symptoms and ADLs is partially mediated by depressive symptoms. CONCLUSIONS:Longitudinal changes in autonomic symptoms impact ADLs function in patients with early signs of PD, both directly and indirectly through their impact on depressive symptoms. Future investigation into the influence of treatment of these symptoms on outcomes in PD is warranted.

INTRODUCTION/BACKGROUND:In addition to neurogenic orthostatic hypotension (nOH), patients with synucleinopathies frequently have hypertension when supine. The long-term consequences of both abnormalities are difficult to disentangle. We aimed to determine if supine hypertension is associated with target organ damage and worse survival in patients with nOH. METHODS:Patients with nOH due to multiple system atrophy (MSA), Parkinson disease (PD), or pure autonomic failure (PAF) were classified into those with or without supine hypertension (systolic BP of at least 140 mmHg or diastolic BP of at least 90 mmHg). Organ damage was assessed by measuring cerebral white matter hyperintensities (WMH), left ventricular hypertrophy (LVH), and renal function. We prospectively followed patients for 30 months (range: 12-66 months) and recorded incident cardiovascular events and all-cause mortality. RESULTS:Fifty-seven patients (35 with probable MSA, 14 with PD and 8 with PAF) completed all evaluations. In addition to nOH (average fall 35 ± 21/17 ± 14 mmHg, systolic/diastolic, mean ± SD), 38 patients (67%) had supine hypertension (systolic BP > 140 mmHg). Compared to those without hypertension, patients with hypertension had higher blood urea nitrogen levels (P = 0.005), lower estimated glomerular filtration rate (P = 0.008), higher prevalence of LVH (P = 0.040), and higher WMH volume (P = 0.019). Longitudinal follow-up of patients for over 2 years (27.1 ± 14.5 months) showed that supine hypertension was independently associated with earlier incidence of cardiovascular events and death (HR = 0.25; P = 0.039). CONCLUSIONS:Supine hypertension in patients with nOH was associated with an increased risk for target organ damage, cardiovascular events, and premature death. Defining management strategies and safe blood pressure ranges in patients with nOH remains an important research question.

Background and aims: Inadequate norepinephrine (NE) release in neurogenic orthostatic hypotension (nOH) causes fall in standing blood pressure. Ampreloxetine, a novel, long-acting NE reuptake inhibitor may improve symptoms of nOH. The objective of this study was to explore durability of effect and safety of once-daily oral ampreloxetine for symptomatic treatment of nOH.
Method(s): In an open-label, phase 2, exploratory study, subjects received ampreloxetine (3-20mg) once-daily for up to 20 weeks, with 4-week follow-up after ampreloxetine withdrawal and restarting alternative pressor agents. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 (OHSA#1; dizziness, lightheadedness, feeling faint), OHSA/Orthostatic Hypotension Daily Activities Scale (OHDAS) composite scores, and change in Patient Global Impression of Severity (PGI-S).
Result(s): Seventeen symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). At Weeks 4 and 20, mean (SD) improvement on OHSA#1 was -3.8 (3.1) and -3.1 (3.0) point, and ~77% and ~86% of subjects reported >=1-point improvement, respectively. Improvement, seen as early as Week 1, was sustained throughout the study. Deterioration to baseline severity was observed after ampreloxetine withdrawal. Similar trends were seen in OHSA/OHDAS composite scores, and change in PGI-S. Most common adverse events (AEs) were urinary tract infection (24%), hypertension (19%) and headache (14%), with no study-drug-related serious AEs. Ampreloxetine showed durable symptom improvement over 20 weeks, with return to baseline severity after ampreloxetine withdrawal. Ampreloxetine was well tolerated.
Conclusion(s): These encouraging findings of durable symptom improvement with open-label ampreloxetine treatment are being evaluated in ongoing Phase 3, doubleblind, confirmatory studies in subjects with nOH

Background and aims: Distinguishing neurogenic orthostatic hypotension (nOH) from other causes of blood pressure (BP) instability is of pivotal importance in clinical practice. Norcliffe-Kaufmann et al. recently showed that when the ratio between the heart rate increase and the systolic BP fall after 3 minutes of passive head-up tilt (HUT) is <0.492, this indicates nOH. Here we aimed at validating this nOH ratio with standard arm-cuff BP measurements upon active standing (AS).
Method(s): We screened all patients who had undergone cardiovascular autonomic function testing at the Innsbruck Medical University between January 2008 and September 2019.
Result(s): We included 51 patients (27 with Parkinson's disease, 22 with multiple system atrophy) diagnosed with orthostatic hypotension either upon AS or HUT. 49 patients showed no BP overshoot after the Valsalva maneuver and were thus classified as having nOH. Out of these, 27 patients showed a systolic BP fall >=20mmHg in both the HUT and the AS and were considered for further analysis. The nOH ratio was <0.492 for 20 patients during HUT and for 19 patients during the AS. The sensitivity of the nOH ratio for neurogenic OH was therefore 74% upon HUT and 70% upon AS. The correlation between the nOH-ratio upon HUT and AS was strong (rho=0.86, p<0.001).
Conclusion(s): A nOH ratio <0.492 evaluated with standard arm-cuff heart rate and BP measurements has a good sensitivity for nOH both upon HUT and AS. This ratio can be therefore used as bedside nOH screening measure, if no tilt-test facilities are available

Background and aims: In neurogenic orthostatic hypotension (nOH), standing blood pressure (BP) falls due to inadequate norepinephrine (NE) release. Ampreloxetine, a novel, long-acting, NE reuptake inhibitor, has shown durable symptom improvement in subjects with nOH associated with synucleinopathies. The objective of this study was to evaluate BP regulation in subjects with symptomatic nOH treated with open-label ampreloxetine.
Method(s): In a phase 2 study, subjects received ampreloxetine once-daily (3-20mg) for up to 20 weeks, with 4-week follow-up after ampreloxetine withdrawal. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 score (OHSA#1; dizziness, lightheadedness, feeling faint); standing/sitting/supine systolic BP (SBP); standing duration; and plasma NE.
Result(s): 17 symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). Mean increase in 3-minute standing SBP from baseline at Weeks 4 and 20 was 9.0mmHg and 10.8mmHg, respectively; >50% of subjects maintained SBP >80mmHg. Sitting SBP changes were less, with little change in supine SBP. At Week 4, 67% of subjects could stand for >5 mins, 31% improvement from baseline. NE plasma levels rose from pre-dose to Week 4 (1664.93-2231.67pmol/l). Baseline NE plasma levels correlated with standing BP increase. Ampreloxetine was well tolerated. Durable symptom improvement in nOH was accompanied by increase in standing and sitting SBP, standing duration, and NE plasma levels, with little effect on supine SBP.
Conclusion(s): These encouraging findings on BP regulation in nOH with ampreloxetine treatment for up to 5 months are being evaluated in ongoing Phase 3, double-blind, confirmatory studies in subjects with nOH

Background and aims: Dementia is considered a nonsupportive diagnostic feature for multiple system atrophy (MSA). Nevertheless, post-mortem verified dementia with Lewy bodies and Parkinson's disease masquerade as MSA. Cognitive impairment (CI), especially executive dysfunction, may occur in MSA patients. It is, however, unclear whether CI manifests in early disease stages.
Objective(s): To compare the prevalence of CI in MSA versus other Lewy Body disorders (LBD), including dementia with Lewy bodies and Parkinson's disease, in early (<3 years from symptom onset) versus more advanced disease stages (>=3 years from symptom onset).
Method(s): A total of 364 patients (LBD: n=83; MSA: n=281) of the natural history study of synucleinopathies register have been analysed. Consensus diagnostic criteria for dementia with Lewy bodies, Parkinson's disease and MSA were applied. To assess CI, the Montreal Cognitive Assessment (MoCA) has been used.
Result(s): In early disease stages, median MoCA scores did not differ significantly between MSA and LBD. In advanced disease stages, MSA patients had a significantly higher median MoCA score compared to LBD patients (27 versus 25, p=0.006). Comparison of the median MoCA Scores of LBD versus MSA patients at early and advanced disease stages
Conclusion(s): In patients with longer disease duration severity of CI helps to differentiate LBD from MSA

Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing that can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions. OH can be caused by volume depletion, blood loss, cardiac pump failure, large varicose veins, medications, or defective activation of sympathetic nerves and reduced norepinephrine release upon standing. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and it is commonly associated with supine hypertension. Several therapeutic options are available.

PURPOSE OF REVIEW/OBJECTIVE:This article reviews the management of orthostatic hypotension with emphasis on neurogenic orthostatic hypotension. RECENT FINDINGS/RESULTS:Establishing whether the cause of orthostatic hypotension is a pathologic lesion in sympathetic neurons (ie, neurogenic orthostatic hypotension) or secondary to other medical causes (ie, non-neurogenic orthostatic hypotension) can be achieved by measuring blood pressure and heart rate at the bedside. Whereas fludrocortisone has been extensively used as first-line treatment in the past, it is associated with adverse events including renal and cardiac failure and increased risk of all-cause hospitalization. Distinguishing whether neurogenic orthostatic hypotension is caused by central or peripheral dysfunction has therapeutic implications. Patients with peripheral sympathetic denervation respond better to norepinephrine agonists/precursors such as droxidopa, whereas patients with central autonomic dysfunction respond better to norepinephrine reuptake inhibitors. SUMMARY/CONCLUSIONS:Management of orthostatic hypotension is aimed at improving quality of life and reducing symptoms rather than at normalizing blood pressure. Nonpharmacologic measures are the key to success. Pharmacologic options include volume expansion with fludrocortisone and sympathetic enhancement with midodrine, droxidopa, and norepinephrine reuptake inhibitors. Neurogenic supine hypertension complicates management of orthostatic hypotension and is primarily ameliorated by avoiding the supine position and sleeping with the head of the bed elevated.