Peripheral Autonomic Dysfunction Research Articles

Altered connectivity of central autonomic network: effects of dysautonomia in hereditary transthyretin amyloidosis with polyneuropathy

Background Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive fatal disorder caused by deposition of mutant transthyretin (TTR) amyloids mainly in the nerves and heart. Autonomic dysfunction is a major disabling manifestation, affecting 90% of patients with late-onset ATTRv-PN. The current study aimed to investigate brain functional alterations associated with dysautonomia due to peripheral autonomic nerve degeneration in ATTRv-PN. Methods Resting-state functional MRI data were acquired from 43 ATTRv-PN patients predominantly of A97S (p.A117S) genotype, and the functional connectivity of central autonomic regions was assessed. Results Compared with age-matched healthy controls, the ATTRv-PN patients exhibited (1) reduced functional connectivity of the central autonomic regions such as hypothalamus, amygdala, anterior insula, and middle cingulate cortex with brain areas of the limbic, frontal, and somatosensory systems, and (2) correlations of reduced functional autonomic connectivity with the severity of autonomic dysfunction especially orthostatic intolerance, decreased heart rate variability, and greater clinical disability. Conclusions Our findings provide evidence linking peripheral autonomic dysfunction with altered connectivity in the central autonomic network in ATTRv-PN.

Insular and limbic abnormal functional connectivity in early-stage Parkinson's disease patients with autonomic dysfunction.

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-β-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease.

Lower vascular conductance responses to handgrip exercise are improved following acute antioxidant supplementation in young individuals with post-traumatic stress disorder.

Young individuals with post-traumatic stress disorder (PTSD) display peripheral vascular and autonomic nervous system dysfunction, two factors potentially stemming from a redox imbalance. It is currently unclear if these aforementioned factors, observed at rest, alter peripheral haemodynamic responses to exercise in this population. This study examined haemodynamic responses to handgrip exercise in young individuals with PTSD following acute antioxidant (AO) supplementation. Thirteen young individuals with PTSD (age 23±3years), and 13 age- and sex-matched controls (CTRL) participated in the study. Exercise-induced changes to arm blood flow (BF), mean arterial pressure (MAP) and vascular conductance (VC) were evaluated across two workloads of rhythmic handgrip exercise (3 and 6kg). The PTSD group participated in two visits, consuming either a placebo (PL) or AO prior to their visits. The PTSD group demonstrated significantly lower VC (P=0.04) across all exercise workloads (vs. CTRL), which was significantly improved following AO supplementation. In the PTSD group, AO supplementation improved VC in participants possessing the lowest VC responses to handgrip exercise, with AO supplementation significantly improving VC responses (3 and 6kg: P<0.01) by blunting elevated exercise-induced MAP responses (3kg: P=0.01; 6kg: P<0.01). Lower VC responses during handgrip exercise were improved following AO supplementation in young individuals with PTSD. AO supplementation was associated with a blunting of exercise-induced MAP responses in individuals with PTSD displaying elevated MAP responses. This study revealed that young individuals with PTSD exhibit abnormal, peripherally mediated exercise responses that may be linked to a redox imbalance.

Cardiac sympathetic denervation and anxiety in Parkinson disease

BackgroundAnxiety in Parkinson disease (PD) negatively impacts quality of life. While research predominantly focuses on central nervous system changes, some evidence suggests a connection between peripheral autonomic dysfunctions and PD-related anxiety. The role of the peripheral autonomic nervous system in this context may be overlooked. ObjectivesThis study explores the link between anxiety symptoms and cardiac sympathetic denervation in PD using 11C-meta-hydroxyephedrine ([11C]HED) PET cardiac imaging. MethodsWe studied 34 non-demented PD subjects, assessing anxiety levels through the Spielberg Anxiety State-Trait test trait section (STAI-T). Patients underwent comprehensive assessments along with [11C]HED cardiac and [11C]DTBZ brain PET. To identify subdimensions of STAI-T, we employed principal components analysis (PCA). We examined associations between the anxiety subdimensions and two measures of cardiac sympathetic denervation from [11C]HED PET. We utilized correlation and linear regression models for these analyses. ResultsPCA revealed two STAI-T results components: anxiety-depressive and pure anxiety subcomponents. Only pure anxiety significantly correlated with measures of cardiac sympathetic denervation (rhos −0.40, p = 0.018; 0.35, p = 0.043). Regression models confirmed a significant association, with cardiac sympathetic denervation explaining ∼20 % of pure anxiety variance, independent of sex, dopaminergic impairment, and anxiolytic treatments. DiscussionThis study provides preliminary evidence of peripheral autonomic nervous system abnormalities contributing to PD-related anxiety, suggesting dysregulation in peripheral autonomic functions influencing anxiety perception.

Evaluation of peripheral and autonomic nervous systems dysfunctions in patients with Parkinson’s disease

BackgroundPeripheral neuropathy (PN) is increasingly recognized in Parkinson’s disease (PD). This study aimed to evaluate peripheral nerve and autonomic nervous system dysfunction in PD. Forty patients with PD (20 drug-naïve, 20 on treatment) and 20 controls underwent neurological examination, Toronto Clinical Neuropathy Score (TCNS), nerve conduction studies, autonomic function tests including (heart rate variability, Blood pressure changes with standing and sustained handgrip, and sudomotor pathways. The Ewing classification system scored each test to quantify autonomic failure severity). Laboratory tests (B12, homocysteine, methylmalonic acid).ResultsTreated patients with PD had higher MDS-UPDRS scores than drug-naïve (p = 0.001). TCNS indicated mild PN in some drug-naïve patients, and mild–moderate PN in treated patients. Nerve conduction studies showed significant sensory and motor neuropathy in treated versus drug-naïve PD and controls. Treated patients had lower B12, higher homocysteine/methylmalonic acid than other groups. Across autonomic tests, controls had the most normal results, followed by drug-naïve patients, with treated patients being most abnormal. Autonomic dysfunction correlated with disease duration, severity, L-dopa dose. Lower B12, higher homocysteine/methylmalonic acid levels were associated with greater neuropathy and disease severity.ConclusionPatients with PD show evidence of PN and autonomic dysfunction, which is milder in drug-naïve patients but worsens with disease progression and treatment. Peripheral nervous system assessments may help diagnose and monitor PD neuropathy and effects of interventions.

Clinical physiology: the crucial role of MRI in evaluation of peripheral artery disease.

Peripheral artery disease (PAD) is a common vascular disease that primarily affects the lower limbs and is defined by the constriction or blockage of peripheral arteries and may involve microvascular dysfunction and tissue injury. Patients with diabetes have more prominent disease of microcirculation and develop peripheral neuropathy, autonomic dysfunction, and medial vascular calcification. Early and accurate diagnosis of PAD and disease characterization are essential for personalized management and therapy planning. Magnetic resonance imaging (MRI) provides excellent soft tissue contrast and multiplanar imaging capabilities and is useful as a noninvasive imaging tool in the comprehensive physiological assessment of PAD. This review provides an overview of the current state of the art of MRI in the evaluation and characterization of PAD, including an analysis of the many applicable MR imaging techniques, describing the advantages and disadvantages of each approach. We also present recent developments, future clinical applications, and future MRI directions in assessing PAD. The development of new MR imaging technologies and applications in preclinical models with translation to clinical research holds considerable potential for improving the understanding of the pathophysiology of PAD and clinical applications for improving diagnostic precision, risk stratification, and treatment outcomes in patients with PAD.

A Review on Relationship Between Charcot Neuroarthropathy and Diabetic Patients.

Charcot Neuroarthropathy (CN) is a complex and incapacitating disorder characterized by neuropathy, progressive deformity, and joint destruction. It is of substantial interest within the diabetic population as this ailment chiefly affects individuals with diabetes. The pathophysiology of CN is multidimensional, connecting peripheral neuropathy, repetitive trauma, and autonomic dysfunction. The review analyses the mechanisms directing the development of CN, emphasizing the influence of diabetes in individuals who lean toward this condition. Clinical presentation and diagnosis of CN in diabetic patients present unique challenges. Complex clinical features have also been discussed, including joint deformities, insidious onset, and painless swelling, which mimic other musculoskeletal conditions. The diagnostic approaches, involving clinical examination and radiological imaging, are analyzed for early and accurate diagnosis. Risk factors and epidemiology emphasize the prevalence of CN within the diabetic population and draw attention to common risk factors contributing to its development. Significant factors such as glycemic control, duration of the disease, and type of diabetes are important in estimating an individual's risk for CN. Complications, such as foot ulcers and amputations, provide an understanding of the severe outcome of this condition on patients' quality of life. Management approaches and treatment involving conservative and surgical approaches are reviewed in depth. A multidisciplinary approach to patient care is emphasized, given the complex nature of CN and the comorbidities existing in diabetic individuals. Prognosis and prevention comprise approaches for mitigating the risk of CN in diabetic patients, such as glycemic control, regular foot examinations, and patient education. This thorough review aims to outline the intricate relationship between CN and diabetes, offering an understanding of pathophysiology, clinical complexities, diagnostic nuances, treatment modalities, and prevention strategies.

Cyclic vomiting syndrome plus accompanying Ross syndrome: More than a peripheral autonomic dysfunction

Ross syndrome is a rare syndrome consisting of areflexia, tonic pupil and segmental anhidrosis. It has been shown to accompany neuropsychiatric diseases such as psychiatric disorders, headache, and epilepsy. We report here a 19-year-old female who was the first case in which cyclic vomiting syndrome plus was shown to accompany Ross syndrome.

Evaluation of skin temperature in the hands of leprosy patients to detect peripheral autonomic dysfunction, by infrared thermography

Evaluation of skin temperature in the hands of leprosy patients to detect peripheral autonomic dysfunction, by infrared thermography

Peripheral temperature dysregulation associated with functionally altered NaV1.8 channels.

The voltage-gated sodium channel NaV1.8 is prominently expressed in the soma and axons of small-caliber sensory neurons, and pathogenic variants of the corresponding gene SCN10A are associated with peripheral pain and autonomic dysfunction. While most disease-associated SCN10A variants confer gain-of-function properties to NaV1.8, resulting in hyperexcitability of sensory neurons, a few affect afferent excitability through a loss-of-function mechanism. Using whole-exome sequencing, we here identify a rare heterozygous SCN10A missense variant resulting in alteration p.V1287I in NaV1.8 in a patient with a 15-year history of progressively worsening temperature dysregulation in the distal extremities, particularly in the feet. Further symptoms include increasingly intensifying tingling and numbness in the fingers and increased sweating. To assess the impact of p.V1287I on channel function, we performed voltage-clamp recordings demonstrating that the alteration confers loss- and gain-of-function characteristics to NaV1.8 characterized by a right-shifted voltage dependence of channel activation and inactivation. Current-clamp recordings from transfected mouse dorsal root ganglion neurons further revealed that NaV1.8-V1287I channels broaden the action potentials of sensory neurons and increase their firing rates in response to depolarizing current stimulations, indicating a gain-of-function mechanism of the variant at the cellular level in a heterozygous setting. The data support the hypothesis that the properties of NaV1.8 p.V1287I are causative for the patient's symptoms and that nonpainful peripheral paresthesias should be considered part of the clinical spectrum of NaV1.8-associated disorders.

Effect of neoadjuvant chemotherapy on intraoperative core temperature in patients with breast cancer: a retrospective cohort study.

Clinical evidence suggests that chemotherapeutic agents are associated with neuropathy and peripheral autonomic dysfunction. However, the possible effects of neoadjuvant chemotherapy on intraoperative temperature remain poorly characterised. We evaluated patients who underwent a mastectomy for breast cancer between April 2016 and July 2020. Propensity scores were used to match patients who received neoadjuvant chemotherapy with those who did not, and intraoperative core temperature patterns were analysed in the matched cohort. The independent associations between vasopressor use and heart rate during general anaesthesia in the matched cohort were also analysed. Data from 1764 patients were analysed (882 patients in each group). Both groups presented a similar pattern of heat redistribution and subsequent rewarming; however, the neoadjuvant chemotherapy group did not reach the same intraoperative plateau temperature as the group that did not receive prior chemotherapy, with differences of up to 0.4°C (95% confidence interval: 0.11-0.63°C; P=0.005). In a subgroup analysis, neuropathy in patients who received neoadjuvant chemotherapy was associated with increased use of vasopressors and higher heart rate. In patients with breast cancer, neoadjuvant chemotherapy is associated with lower plateau core temperatures, increased vasopressor use, and higher heart rates during general anaesthesia, which is more severe in the presence of neuropathy.

α-Synuclein induces prodromal symptoms of Parkinson’s disease via activating TLR2/MyD88/NF-κB pathway in Schwann cells of vagus nerve in a rat model

BackgroundIncreasing evidence suggests that patients with Parkinson's disease (PD) present with peripheral autonomic dysfunction (AutD) that even precedes motor deficits, through which α-synuclein can spread to the central nervous system. However, the pathological mechanisms underlying AutD in prodromal PD remain unclear. Here, we investigated the role of α-synuclein and its interplay with the activation of Schwann cells (SCs) of the vagus nerve in AutD.MethodsRats were subjected to injection with adeno-associated viruses containing the human mutated A53T gene (AAV-A53T) or an empty vector into the left cervical vagus nerve and evaluated for gastrointestinal symptoms, locomotor functions, intestinal blood flow, and nerve electrophysiology. Further, we examined the impact of α-synucleinopathy on vagus nerves, SCs, and central nervous system neurons using electron microscopy, immunofluorescence, immunohistochemistry, and western blot. Finally, the role of Toll-like receptor 2 (TLR2) in regulating the neuroinflammation in the vagus nerve via MyD88 and NF-κB pathway was determined using genetic knockdown.ResultsWe found that rats injected with AAV-A53T in the vagus nerve exhibited prominent signs of AutD, preceding the onset of motor deficits and central dopaminergic abnormalities by at least 3 months, which could serve as a model for prodromal PD. In addition, reduced intestinal blood flow and decreased nerve conduction velocity were identified in AAV-A53T-injected rats, accompanied by disrupted myelin sheaths and swollen SCs in the vagus nerve. Furthermore, our data demonstrated that p-α-synuclein was deposited in SCs but not in axons, activating the TLR2/MyD88/NF-κB signaling pathway and leading to neuroinflammatory responses. In contrast, silencing the TLR2 gene not only reduced inflammatory cytokine expression but also ameliorated vagal demyelination and secondary axonal loss, consequently improving autonomic function in rats.ConclusionsThese observations suggest that overexpression of α-synuclein in the vagus nerve can induce symptoms of AutD in prodromal PD, and provide support for a deeper understanding of the pathological mechanisms underlying AutD and the emergence of effective therapeutic strategies for PD.

Long COVID: mechanisms, risk factors and recovery.

What is the topic of this review? The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic. What advances does it highlight? Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies. Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance - namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology - including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

Quantitative sensory testing and norepinephrine levels in REM sleep behaviour disorder – a clue to early peripheral autonomic and sensory dysfunction?

IntroductionStudies have reported autonomic impairment in patients with idiopathic REM sleep behaviour disorder (iRBD), which is considered a prodromal stage of alpha-synucleinopathies. It is still debated whether central or peripheral pathologies are first manifestations of alpha-synucleinopathies. This study aimed to characterize autonomic and somatosensory function in iRBD patients.MethodsThis cross-sectional prospective case–control study included 17 iRBD patients (mean age 66.3 ± 9.2 years) and 16 healthy controls (HCs, 66.6 ± 11.3 years). Quantitative sensory testing, neurological and neuropsychological assessments, norepinephrine blood plasma levels, tilt table examination with orthostatic blood pressure, and heart rate variability were carried out. Longitudinal data of 10 iRBD patients, including neurological, neuropsychological, and tilt table examination, were assessed.ResultsiRBD patients more frequently presented with orthostatic dysfunction than HCs (70.6% vs. 6.3%, p < 0.0001). Supine norepinephrine plasma levels were normal, but lower in iRBD (249.59 ± 99.78 pg/ml iRBD, 354.13 ± 116.38 pg/ml HCs, p < 0.05). Quantitative sensory testing revealed impaired cold (CDT) and vibration detection thresholds (VDT) on the foot in iRBD (CDT foot iRBD − 1.24 ± 0.31, HCs − 9.89E-17 ± 0.25, VDT iRBD − 1.11 ± 0.47, HCs − 1.46E-16 ± 0.25, p < 0.05). Cold detection thresholds differed between the foot and hand among iRBD patients (foot − 1.24 ± 0.31, hand − 0.56 ± 0.25, p < 0.05). Longitudinal data revealed an increase in maximum systolic and diastolic orthostatic blood pressure changes and a decrease in the Valsalva ratio in the follow-up group (p < 0.05).ConclusionThis study revealed autonomic dysfunction with somatosensory impairment, and decreased norepinephrine levels in iRBD, which may serve as a possible prodromal marker for developing alpha-synucleinopathy.

CLINICAL SPECTRUM OF MORVAN SYNDROME: A SINGLE CENTRE STUDY

INTRODUCTION: Morvan syndrome (MoS) is a rare autoimmune disorder characterised by peripheral nerve hyperexcitability, autonomic dysfunction and central nervous system symptoms. It has strong association with autoantibodies to voltage gated potassium channel complex. This was a prospective observationa METHODS: l study. We reported 6 cases of Morvan syndrome. Clinical features, investigations, treatment and outcome were described and review of literature was done. All RESULT: subjects were male. Myokymia and insomnia were present in all patients and no patient had seizure. Voltage gated potassium channel (VGKC) antibody was positive in 66% (n=4) of subjects, all four were positive for CASPER2 and 2 were also weakly positive for LGI1. All patients were treated with immunomodulation and we found good response to therapy. Pain was treated with carbamazepine and phenytoin. CONCLUSION: Morvan syndrome, a VGKC antibody spectrum disorder, is a clinical diagnosis. We found myokymia and insomnia in all patients and no patient had seizure. In our study, response to immunotherapy was good. Awareness about MoS is necessary, as it can be treated successfully.

Characterization of Autonomic Dysfunction Among Migraineurs With and Without Complaints of Orthostatic Intolerance

Purpose and Hypothesis: To identify and distinguish central autonomic dysfunction from peripheral autonomic dysfunction (or both) in migraineurs suffering from orthostatic intolerance (OI) compared to migraineurs not suffering from OI. We hypothesize that OI manifests from a predominantly central autonomic component. Methods: We studied two populations of migraineurs, one group complaining of symptoms of OI for 6 months or longer and a group without OI symptoms, using a 70-degree, 45-minute passive head-up tilt-table test (HUT), R-R interval measurements during deep breathing, blood pressure and heart rate monitoring during Valsalva maneuver and release, Quantitative Sudomotor Axon Reflex Test (QSART), and skin biopsy for intraepidermal nerve fiber density. Categorical differences between the two populations were compared using exact likelihood ratio chi-square tests, and 95% confidence intervals for sensitivity, specificity, positive and negative predictive values were calculated. Results: Thirty-seven migraineurs with OI (Group 1) and 22 migraineurs without (Group 2) were studied and were demographically similar except for a greater representation of migraines with brainstem auras in Group 1 (27% v 5%; p= 0.032). Ninety-seven percent of Group 1 patients, versus 68% Group 2, manifested abnormal 45-minutes HUT, a significant difference (p=0.020, Fisher’s exact test). The first 5-minute evaluation of the HUT exhibited high specificity (1.00; 95% CI: 0.85-1.00) for the diagnosis of postural tachycardia syndrome (POTS) with a positive predictive value of 1.00 (0.59, 1.00; p=0.037). The HUT extended to 45-minutes however showed greater sensitivity compared with the 10-minute HUT (0.95; 95% CI:0.82-0.99; p=0.020). We found no differences between groups in autonomic laboratory or skin biopsy findings. Fifty-seven percent of Group 1 and 50% of Group 2 exhibited biopsy-proven small fiber neuropathy (SFN), a difference that did not reach statistical significance. Conclusions: We failed to confirm our hypothesis that OI is a manifestation of a central autonomic dysfunction in migraineurs. The finding of SFN in a majority of subjects points to peripheral autonomic contributions and raises the possibility of an underlying systemic disorder. Extending HUT table testing to 45-minutes increases diagnostic sensitivity and better reflects life events. Funding Statement: This study was supported by a grant from the Bakken Heart-Brain Institute, Cleveland Clinic, Cleveland, Ohio, USA. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study was approved by the Cleveland Clinic’s Institutional Review Board. Informed consent was obtained from all participants in the study.

Skin Temperature in Parkinson’s Disease Measured by Infrared Thermography

Background Patients with Parkinson's disease (PD) often show peripheral autonomic dysfunction and depositions of pathological alpha-synuclein aggregates in the skin. However, functional consequences of this skin involvement have received little attention. Objective To determine thermographic differences in the skin between healthy controls (HCs) and PD patients on hands, feet, and trunk and to correlate findings with symptoms and signs of dysautonomia. Between-group differences in autonomic parameters and questionnaires were explored. Methods Twenty-one PD patients and 19 HCs were examined by thermographic infrared imaging of standardized anatomical locations on the trunk and upper and lower extremities at baseline and after exposure to cold stress test (CST). Thermal recovery rates (RRs) were determined on the basis of thermograms. Correlation analyses between alterations in skin temperature and autonomic dysfunction were performed. Results The most significant RR difference between PD patients and HCs was seen on the fifth distal phalanx 10 minutes post-CST (mean RR ± SD: 51 ± 18% vs. 70 ± 23%, p = 0.003). No between-group differences were seen in baseline or post-CST values of the feet. No correlations were seen between thermal parameters and clinical and autonomic data. In the HC group, a positive, moderate correlation was seen between post-CST recovery values on the 3rd and 5th phalanx and body mass index (BMI) (r = 0.661, p = 0.002). Conclusions The PD patients exhibited significant reduction in RR compared to HC and patients also displayed altered thermal responses in multiple anatomical locations. Thus, infrared thermography could become an important future tool in investigation of autonomic deficiency in PD.

0556 Sex-Specific Relationship Between Anxiety and Autonomic Nervous System Dysfunction in Obstructive Sleep Apnea

Abstract Introduction Cardiovascular co-morbidities in obstructive sleep apnea (OSA) are hard to treat, perhaps due to autonomic nervous system (ANS) dysfunction. In OSA, intermittent hypoxia and poor tissue oxygen perfusion damage endothelial and nervous tissue, potentially underlying the dysfunction. Moreover, OSA is strongly associated with anxiety, which is independently associated with ANS dysfunction. We assessed sex-specific relationships between anxiety and cardiovascular markers of ANS dysfunction in OSA. Methods We studied people diagnosed with OSA and healthy controls. We collected 5 minutes of wakeful resting ECG, continuous non-invasive blood pressure, and respiration data. We calculated heart rate (HR), heart rate variability (HRV; sympathetic-vagal balance related to brainstem ANS output), mean arterial blood pressure (MAP), beat-to-beat MAP variability (BPV; related to peripheral autonomic function) and breathing rate (BR). We analyzed these measures with a multivariate regression model of anxiety symptoms (generalized anxiety disorder; GAD-7 scores), sex, and group (OSA vs. control), age/BMI/AHI covariates, and Bonferroni-corrected post-hoc comparisons (p≤0.05). Results We analyzed 64 subjects (32 OSA: AHI [mean±SEM] 24±4events/hour, 12 female, age 52±21years, BMI 33±2kg/m2; 32 control: 19 female, age 46±2; BMI 26±1). We observed significant main effects of anxiety, BMI, AHI, sex on HRV, but only group on BPV; post-hoc comparisons revealed high BPV only in OSA females. Secondary analyses included classifying by anxiety symptoms (GAD-7≥5), showing only OSA females with anxiety had higher BPV. Males showed higher HRV. AHI and anxiety were positively correlated with HRV in OSA males. AHI was negatively correlated with BR in OSA females. Conclusion We observed higher anxiety associated with higher BPV in OSA, especially in females. Unexpectedly, BR was lower in OSA females; longer breaths may have led to the greater BPV. Higher HRV in males complicated by OSA severity and anxiety could be related to higher sympathetic tone. The slightly older control group may have influenced the findings. Overall, our findings suggest anxiety in OSA is associated with peripheral and centrally-mediated autonomic dysfunction, but in a sex-specific manner. Support National Institutes of Health R56-NR-017435 and RO1-HL-135562.

Demyelinating Neuropathy in a Patient Treated With Revusiran for Transthyretin (Thr60Ala) Amyloidosis

Transthyretin amyloidosis patients develop length-dependent peripheral neuropathy, autonomic dysfunction, and restrictive cardiomyopathy associated with deposition of amyloid fibrils in these tissues. Despite advances in management over the past decade, this disorder causes profound debilitation and ultimately proves fatal. In this report, we describe a man with late-onset cardiac amyloidosis due to a transthyretin Thr60Ala mutation who was treated with an investigational RNAi therapeutic, revusiran, which targets hepatic transthyretin production. Sixteen months into treatment, he developed bilateral lower-extremity weakness and numbness, worsening balance, difficulty manipulating objects with his hands, and finger numbness. Nerve conduction studies were consistent with multifocal demyelinating neuropathy. Intravenous immunoglobulin therapy improved sensation in his hands and feet, and improved hand dexterity. A sural nerve biopsy demonstrated demyelination with substantial axonal loss in the absence of histologically detectable endoneurial amyloid deposition. This case expands the clinicopathologic spectrum of transthyretin amyloidosis and may represent complex disease and treatment effects.

Reduced brainstem functional connectivity in patients with peripheral autonomic failure

Autonomic homeostasis is dependent upon several brainstem nuclei, as well as several cortical and subcortical structures. Together, these sites make up, in part, the central autonomic network. Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic failure that occurs due to a failure to increase sympathetic efferent activity in response to postural changes. Therefore, the purpose of the current study was to investigate brainstem functional connectivity in NOH patients with peripheral autonomic lesions resulting in autonomic failure.Fifteen controls (63 ± 13 years) and fifteen Neurogenic Orthostatic Hypotension patients (67 ± 6 years; p = .2) with peripheral autonomic dysfunction completed 5-min of rest and three Valsalva maneuvers during a functional brain scan. Functional connectivity from the brainstem to cortical and subcortical structures were contrasted between patients and controls.At rest controls had significantly greater brainstem connectivity to the anterior cingulate cortex (T-value: 4.29), left anterior insula (T-value:3.31), left putamen (T-value:3.31) and bilateral thalamus (TRIGHT-value: 3.83; TLEFT-value:4.25) (p-FDR < 0.005). During Valsalva, controls showed significantly more connectivity between the brainstem and both the left anterior (cerebellum 4/5) and bilateral posterior cerebellum (cerebellar 9 and left cerebellar 6). Other cerebellar regions included brainstem-to-vermis. Other brainstem-to-cortical and subcortical regions included: bilateral putamen, posterior cingulate cortex (PCC), amygdala and medial prefrontal cortex. There was a significant negative correlation between the brainstem-cerebellar connectivity and severity of autonomic dysfunction (p < .01). During recovery phase of the Valsalva, controls had greater brainstem connectivity to the left thalamus (T-value:4.17); PCC (T-value:3.32); right putamen (T-value:3.28); right paracingulate gyrus (T-value:3.25) and left posterior cerebellum (C9) (T-value:3.21) (p-FDR < 0.05). The effect sizes for each brainstem connectivity during Valsalva and recovery ranged from moderate to strong.Patients with autonomic failure show reduced coupling between the brainstem and regions of the central autonomic network, including the cerebellum, insula, thalamus and cingulate cortices. Connectivity was associated with autonomic impairment. These findings may suggest impaired brainstem connectivity in patients with autonomic failure.