Abstract Orthostatic hypotension (OH), defined as a sustained reduction of ≥ 20 mmHg in systolic or ≥ 10 mmHg in diastolic blood pressure within 3 minutes of standing, represents one of the most clinically significant manifestations of autonomic failure. Beyond its hemodynamic definition, OH is associated with disabling symptoms, falls, syncope, reduced quality of life, increased healthcare utilization, and excess mortality. In clinical practice, management often requires balancing objective blood pressure measurements with the patient’s lived experience of orthostatic intolerance. This viewpoint argues that symptoms represent an appropriate and clinically meaningful target for screening and management of OH. Three central assumptions support this perspective. First, patients are reliable reporters of orthostatic symptoms and clinicians are capable interpreters of these reports. Validated patient-reported outcome measures, such as the Orthostatic Hypotension Questionnaire (OHQ), demonstrate that symptom burden and functional impairment can be reproducibly quantified and that clinically meaningful changes can be detected. Second, although the relationship between orthostatic blood pressure changes and symptoms is not absolute, evidence supports a clinically relevant association, with symptomatic individuals often experiencing greater cerebral hypoperfusion when upright. Third, symptoms serve as a practical proxy for meaningful OH-related outcomes, including functional independence, fall risk, and quality of life, and have been accepted as primary endpoints in pivotal clinical trials. A symptom-centered framework complements objective hemodynamic assessment by contextualizing physiological findings within patients’ functional experience. Integrating symptom reporting with orthostatic measurements provides a pragmatic, patient-centered approach to screening, treatment decisions, and evaluation of therapeutic response in OH.

PurposeThe aim of this study was to investigate the relationship between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis (ALS).MethodsThe heart activity of 65 patients with ALS (28 with normal cognition [ALS-CN]; 37 with impaired cognition [ALS-CI]) and 38 healthy controls (HCs) was measured by 24-h Holter monitoring. Heart rate (HR) measures and heart rate variability (HRV) parameters were compared between the three study groups and, additionally, correlated with five Edinburgh Cognitive and Behavioral ALS Screen (ECAS) domains in the ALS subgroups. Age, gender, and educational level were adjusted. Factors associated with cognitive status were assessed using logistic regression. Survival predictors in patients with ALS were analyzed using the Kaplan–Meier estimator and Cox regression.ResultsCompared to the HCs, patients with ALS-CI exhibited lower RRI (R-R-interval; P = 0.017), SDNN (standard deviation of all normal RR intervals; P = 0.013), SDNN Index (P = 0.044), and VLF power (very low-frequency power; P = 0.012). Total power was reduced in the ALS-CI group compared to the HCs (P = 0.036) and ALS-CN group (P = 0.048). In patients with ALS-CN, language negatively correlated with mean HR (P = 0.001) and positively with the RRI (P = 0.003), SDNN (P = 0.001), SDANN (standard deviation of the average NN intervals; P = 0.005), total power (P = 0.006), VLF power (P = 0.011), and low-frequency power (P = 0.026). Visuospatial function correlated positively with the SDNN Index (P = 0.041). In patients with ALS-CI, executive function (P = 0.015) and ECAS total score (P = 0.009) negatively correlated with the RMSSD (square root of mean sum-of-squares of differences between adjacent NN intervals), while visuospatial function correlated positively with normalized LF value (LFnu; P = 0.049). No associations were observed between the other cognitive domains and any of the 14 HRV/HR measures in patients with either ALS-CI or ALS-CN. SDNN ≤ 100 ms was linked to cognitive impairment (P = 0.039) and also showed a borderline association (P = 0.066) with poorer survival, while cognitive impairment (P = 0.010) was significantly linked to worse outcomes.ConclusionsPatients with ALS with cognitive impairment demonstrated reduced cardiac autonomic modulations and altered cognitive autonomic associations. Cognitive impairment was linked to reduced survival, with baseline SDNN ≤ 100 ms identified as a potential marker.

BackgroundPostural orthostatic tachycardia syndrome (POTS) is a complex disorder with serious health consequences, while its etiology remains largely elusive.ObjectiveThe purpose of this study was to investigate the genetic landscape of POTS using genomic approaches in a unique pediatric cohort.MethodsWe conducted a combined genome wide genotyping and whole exome sequencing (WES) study to systemically examine the molecular mechanisms of POTS pathogenesis. The patients were genotyped as two independent cohorts: a family cohort of 100 complete families and a case–control cohort of 207 unrelated European cases and 4063 ethnicity-matched control subjects. The WES component consisted of a subset of the genotyped subjects, including 87 unrelated European cases and 2719 unrelated European control subjects.ResultsThe heterogeneous phenotype of POTS made achieving genome-wide significance improbable. Instead, 5670 SNPs with nominal significance (P < 0.05) were identified in both the family and case–control cohorts, with effects in the same direction. We conducted an over-representation analysis (ORA) by considering all genes that showed nominal significance. The ORA identified gene sets linked to cell–cell junction, early estrogen response, and substance-related disorders with statistical significance. Moreover, WES revealed 55 genes with genome-wide significance through rare variant burden analysis, harboring 92 variants classified as pathogenic or likely pathogenic by ClinVar.ConclusionsThis study showcases the complex interplay between common and rare genetic variants in POTS development, marking a pioneering step forward in deciphering its complex etiologies. The insights from this research enrich our understanding of POTS, offering new avenues for precise treatment strategies and highlighting areas for further research.

PurposeThe aim of the study is to analyze and compare the cognitive profile between 59 patients with long-COVID [LC; 30 of them with and 29 without a positive coronavirus disease 2019 (COVID-19) confirmatory test] and 31 patients with postural orthostatic tachycardia syndrome (POTS) and a matched group of 39 healthy control participants.MethodsParticipants were examined on a battery of neuropsychological tests, including verbal memory, visuospatial abilities, attention, processing speed, verbal fluency, working memory, and visual memory. Anxious–depressive symptomatology was also analyzed and then controlled for possible influence on cognitive performance.ResultsPatients with LC and POTS showed significantly lower performance compared with healthy peers. Differences on anxious and depressive symptoms were also found between the clinical and control groups, resulting in LC without a positive confirmatory test group exhibiting the highest rates of anxious symptoms. After controlling the effects of anxious–depressive symptomatology, the differences were eliminated for some of the cognitive variables, but additional differences were found between patients with LC and POTS after post hoc analysis.ConclusionsFindings from the present study contribute toward the reinforcement of the evidence on cognitive alterations associated with LC and POTS. Anxious–depressive symptomatology has to be considered in both clinical groups since it could be affecting cognitive performance.

The article "Influence of a 2-week transcutaneous auricular vagus nerve stimulation on memory: findings from a randomized placebo controlled trial in non-clinical adults", written by Veronika Cibulcova, Julian Koenig, Marta Jackowska, and Vera Kr Jandackova.,

PurposeHypertension is characterised by both enlarged perivascular spaces (ePVS) and chronically elevated resting sympathetic outflow. ePVS is associated with heart rate variability, suggesting links to autonomic outflow; however, heart rate variability offers limited information on sympathetic nerve activity. Here, we assessed whether ePVS are associated with muscle sympathetic nerve activity (MSNA) in 25 hypertensive patients and 50 healthy normotensive adults.MethodsT1-weighted MRI anatomical brain images were analysed for ePVS using a deep learning-based segmentation algorithm (nnU-Net). Spontaneous bursts of MSNA were recorded from the right common peroneal nerve via a tungsten microelectrode immediately before the MRI scan in a supine position. A backward regression analysis was conducted to test the relationship between ePVS and MSNA.ResultsSignificant associations were found between MSNA and ePVS in the white matter (β = 1.02, p = 0.007), basal ganglia (β = 0.43, p = 0.001), and hippocampus (β = 0.24, p = 0.010) in healthy normotensive adults. Similar associations were observed in individuals with hypertension. Notably, the association between MSNA and midbrain ePVS cluster was only observed in the hypertensive group (β = 0.41, p = 0.005).ConclusionePVS were associated with MSNA in both normotensive and hypertensive patients. These findings warrant further research into the causal relationship between MSNA and ePVS and highlight the potential for ePVS as a neuroimaging biomarker for sympathetic nerve activity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10286-025-01160-6.

BackgroundThe 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.MethodsWe 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 included healthy volunteers or patients with orthostatic intolerance.ResultsCSF DHPG was decreased in MSA (N = 67, p < 0.0001) compared to the controls but also tended to be decreased in PD+OH (N = 31, p = 0.0776). Antecubital venous plasma DHPG was decreased in PD+OH (N = 47, p = 0.0064) but not in MSA. CSF/plasma concentration ratios of DHPG were lower in MSA than in PD+OH (p = 0.0005). 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.ConclusionsCSF/plasma ratios of DHPG, cardiac arteriovenous increments in plasma DHPG, and cardiac norepinephrine spillovers separate MSA from PD+OH. On the basis of our results we propose that biomarker combinations involving DHPG in biofluids may enable a clinical laboratory distinction of MSA from PD+OH.

PurposePostprandial hypotension (PPH) defined as a decrease in systolic blood pressure of more than 20 mmHg within 2 h post meal is prevalent in patients with autonomic failure and is associated with negative cardiovascular outcomes. Previous studies reported peripheral autonomic failure with less residual sympathetic tone in Parkinson disease (PD). Therefore, we hypothesized that PPH is more severe in PD than in multiple system atrophy (MSA) with central autonomic failure.MethodsThirteen patients with PD and 13 patients with MSA were enrolled. Autonomic function testing and neurohormonal measurements were performed to assess autonomic failure and residual sympathetic activity. Subjects were fed a standard breakfast. Systolic and diastolic blood pressure and heart rate were monitored every 5 min from 30 min before to 120 min post meal. Postprandial hemodynamic changes were summarized using area under the curve (AUC). Differences between the groups were assessed with two-sample independent t test and linear regression.ResultsPatients with PD (69% male, 72 ± 9 years) had a significantly lower post-meal diastolic blood pressure (P = 0.003) and heart rate AUC (P = 0.007) than patients with MSA (62% male, 62 ± 8 years). After adjusting for age and supine systolic blood pressure, PD as diagnosis still had significant estimate effect for diastolic blood pressure AUC (P = 0.019). No significant difference was found in the mean systolic blood pressure AUC, but at 30 min post meal, systolic blood pressure decrease was significantly lower in PD (P = 0.016).ConclusionThe PD group with peripheral autonomic failure exhibits more severe PPH than the MSA group. This highlights the need for tailored management for PPH in PD.