Peripheral Autonomic Function Research Articles

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.

Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear. Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Bidirectional brain-body interactions during natural story listening

Narratives can synchronize neural and physiological signals between individuals, but the relationship between these signals, and the underlying mechanism, is unclear. We hypothesized a top-down effect of cognition on arousal and predicted that auditory narratives will drive not only brain signals but also peripheral physiological signals. We find that auditory narratives entrained gaze variation, saccade initiation, pupil size, and heart rate. This is consistent with a top-down effect of cognition on autonomic function. We also hypothesized a bottom-up effect, whereby autonomic physiology affects arousal. Controlled breathing affected pupil size, and heart rate was entrained by controlled saccades. Additionally, fluctuations in heart rate preceded fluctuations of pupil size and brain signals. Gaze variation, pupil size, and heart rate were all associated with anterior-central brain signals. Together, these results suggest bidirectional causal effects between peripheral autonomic function and central brain circuits involved in the control of arousal.

Bromocriptine quick-release as adjunct therapy in youth and adults with type 1 diabetes: A randomized, placebo-controlled crossover study.

To evaluate the potential for glycaemic, renal and vascular benefits of bromocriptine quick release (BCQR) in adolescents and adults with type 1 diabetes. Forty adolescents and 40 adults with type 1 diabetes aged 12-60 years old were enrolled in a double-blind, placebo-controlled, random order crossover study of 4 weeks of treatment in the morning with BCQR (titrated weekly from 0.8mg to 1.6mg to 3.2mg, minimum dose 1.6mg). Study assessments after each phase included blood pressure (BP), lipids, peripheral arterial stiffness and autonomic function, mixed meal tolerance test, continuous glucose monitoring (CGM), creatinine, estimated glomerular filtration rate, estimated insulin sensitivity, insulin dose and indirect calorimetry. Adolescents displayed baseline hyperglycaemia, insulin resistance, metabolic dysfunction and increased renal filtration compared with adults. In both age groups, continuous glucose monitoring measures, estimated insulin sensitivity and insulin dose did not differ with BCQR treatment. In adolescents, BCQR decreased systolic BP, diastolic BP and triangular index and increased serum creatinine. In adults, systolic BP, mean arterial pressure, systemic vascular resistance, and mixed meal tolerance test glucose and glucagon-like peptide 1 areasunder the curve were lower, and the orthostatic drop in systolic BP was greater with BCQR. Greater hyperglycaemia, insulin resistance, metabolic dysfunction and renal hyperfiltration in adolescents argues for increased attention during this high-risk age period. Although BCQR had little impact on glycaemia or insulin sensitivity, initial vascular and renal responses suggest potential benefits of BCQR in adolescents and adults with type 1 diabetes requiring further study.

Longitudinal effects of one-leg standing time on neuropathy outcomes in association with glycemic control in non-elderly patients with type 2 diabetes.

Aims/IntroductionDiabetic neuropathy leads to postural instability. This study compared longitudinal changes in neuropathy outcomes relative to long‐term glycemic control in patients aged <60 years with uncontrolled type 2 diabetes with and without a short one‐leg standing time (OLST <60 s).Materials and MethodsIn this retrospective study, 58 hospitalized patients with type 2 diabetes (glycated hemoglobin [HbA1c] >7.0%; aged 17–59 years), who underwent re‐evaluation of neuropathic sensory symptoms, ankle reflexes and nerve conduction attributes, and cardiac autonomic function (R‐R interval), >1 year after discharge were divided into OLST <60 and ≥60 s groups. Patients were followed up every 2–3 months for HbA1c levels for up to 8 years. Neuropathy outcomes relative to OLST and HbA1c levels at baseline and over follow up were compared.ResultsAdditional development of sensory symptoms (one patient) and abnormal ankle reflexes (five patients) were identified during follow up, and decreased peripheral and cardiac autonomic function at both baseline and follow up, only in patients with OLST <60 s. Mean HbA1c levels were significantly higher in patients with OLST <60 s versus ≥60 s (7.8 ± 0.9% vs 7.2 ± 1.2%; P = 0.022). Better glycemic control during follow up was associated with better neuropathy outcomes only in patients with OLST ≥60 s.ConclusionNon‐elderly type 2 diabetes patients with OLST <60 s and decreased peripheral nerve function at baseline are at increased risk for intractable diabetic neuropathy. Better glycemic control alone might not improve neuropathy outcomes in these patients.

Assessment of neuropathic pain in leprosy patients with relapse or treatment failure by infrared thermography: A cross-sectional study.

BackgroundNeuropathic pain (NP) is one of the main complications of leprosy, and its management is challenging. Infrared thermography (IRT) has been shown to be effective in the evaluation of peripheral autonomic function resulting from microcirculation flow changes in painful syndromes. This study used IRT to map the skin temperature on the hands and feet of leprosy patients with NP.Methodology/Principal findingsThis cross-sectional study included 20 controls and 55 leprosy patients, distributed into 29 with NP (PWP) and 26 without NP (PNP). Thermal images of the hands and feet were captured with infrared camera and clinical evaluations were performed. Electroneuromyography (ENMG) was used as a complementary neurological exam. Instruments used for the NP diagnosis were visual analog pain scale (VAS), Douleur Neuropathic en 4 questions (DN4), and simplified neurological assessment protocol. The prevalence of NP was 52.7%. Pain intensity showed that 93.1% of patients with NP had moderate/severe pain. The most frequent DN4 items in individuals with NP were numbness (86.2%), tingling (86.2%) and electric shocks (82.7%). Reactional episodes type 1 were statistically significant in the PWP group. Approximately 81.3% of patients showed a predominance of multiple mononeuropathy in ENMG, 79.6% had sensory loss, and 81.4% showed some degree of disability. The average temperature in the patients’ hands and feet was slightly lower than in the controls, but without a significant difference. Compared to controls, all patients showed significant temperature asymmetry in almost all points assessed on the hands, except for two palmar points and one dorsal point. In the feet, there was significant asymmetry in all points, indicating a greater involvement of the lower limbs.ConclusionIRT confirmed the asymmetric pattern of leprosy neuropathy, indicating a change in the function of the autonomic nervous system, and proving to be a useful method in the approach of pain.

Electrochemical Skin Conductance Alterations during Spinal Cord Stimulation: An Experimental Study.

Despite the well-known clinical effects of spinal cord stimulation (SCS), the mechanisms of action have not yet been fully unraveled. The primary aim of this study was to measure whether electrochemical skin conductance, as a measure of peripheral sympathetic autonomic function, is altered by SCS. A second aim was to compare skin conductance levels of patients with failed back surgery syndrome (FBSS) with age- and sex-matched healthy controls. Twenty-three patients with FBSS treated with SCS participated in this study. Sudomotor function was measured with the SudoscanTM instrument on the hands and feet during SCS on and off states. Difference scores in skin conductance between patients and age- and sex-matched healthy controls were calculated. Normal sudomotor function at the painful lower limb was revealed for 61% of the patients when SCS was activated. Skin conductance levels were not altered between on and off states of SCS. Differences in scores between patients and healthy controls were significantly different from zero. This study showed that SCS does not influencing the sympathetic nervous system in patients with FBSS, as measured by skin conductance levels. Moreover, it suggested that there is no normalization of the functioning of the sympathetic nervous system, despite the effectiveness of SCS to reduce pain intensity.

Neurodegenerative disorders affecting the autonomic nervous system: Pure autonomic failure and multiple system atrophy

AbstractPure autonomic failure (PAF) and multiple system atrophy (MSA) are representative neurodegerative diseases present with a severe autonomic dysfunction in the urinary, cardiovascular, and pupillary systems, as well as the gastrointestinal tract and skin/sweat glands. Clinically PAF is characterized by chronic progressive pure autonomic dysfunction occasionally associated with parkinsonism or cognitive dysfunction (Lewy body disease), whereas MSA is associated with cerebellar manifestation and/or parkinsonism. Pathology of both PAF and MSA is characterized by α‐synuclein deposition, but in PAF major involvement exists in the sympathetic ganglion and postganglionic autonomic nerve fibers, whereas MSA mainly affects the central autonomic system, such as the vagal nerve lateral nucleus, locus coeruleus, spinal cord medial lateral nucleus, and sacral Onuf's nucleus. Therefore, it is necessary to evaluate whether peripheral or central autonomic function is predominantly affected by the differential diagnosis of PAF and MSA. Autonomic dysfunction is also frequently present in patients with Parkinson's disease, but usually not so severe as in PAF or MSA. This review summarizes features of autonomic dysfunction in PAF and MSA.

Nerve growth factor in muscle afferent neurons of peripheral artery disease and autonomic function.

In peripheral artery disease patients, the blood supply directed to the lower limbs is reduced. This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs. The painful perception is induced and exaggerate during walking, and is relieved by rest. This symptom is termed by intermittent claudication. The limb ischemia also amplifies autonomic responses during exercise. In the process of pain and autonomic responses originating exercising muscle, a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses. This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle. For the sensory nerve receptors, we emphasize the role played by transient receptor potential vanilloid type 1, purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.

Effect of exercise training on cardiovascular autonomic and muscular function in subclinical Chagas cardiomyopathy: a randomized controlled trial.

Patients with chronic chagasic cardiomyopathy with preserved ventricular function present with autonomic imbalance. This study evaluated the effects of exercise training (ET) in restoring peripheral and cardiac autonomic control and skeletal muscle phenotype in patients with subclinical chronic chagasic cardiomyopathy. This controlled trial (NCT02295215) included 24 chronic chagasic cardiomyopathy patients who were randomized www.random.org/lists/ into two groups: those who underwent exercise training (n = 12) and those who continued their usual activities (n = 12). Eight patients completed the exercise training protocol, and 10 patients were clinically followed up for 4months. Muscular sympathetic nerve activity was measured by microneurography and muscle blood flow (MBF) using venous occlusion plethysmography. The low-frequency component of heart rate variability in normalized units (LFnuHR) reflects sympathetic activity in the heart, and the low-frequency component of systolic blood pressure variability in normalized units reflects sympathetic activity in the vessels. The infusion of vasoactive drugs (phenylephrine and sodium nitroprusside) was used to evaluate cardiac baroreflex sensitivity, and a vastus lateralis muscle biopsy was performed to evaluate atrogin-1 and MuRF-1 gene expression. The baroreflex sensitivity for increases (p = 0.002) and decreases (p = 0.02) in systolic blood pressure increased in the ET group. Muscle blood flow also increased only in the ET group (p = 0.004). Only the ET group had reduced resting muscular sympathetic nerve activity levels (p = 0.008) and sympathetic activity in the heart (LFnu; p = 0.004) and vessels (p = 0.04) after 4months. Regarding skeletal muscle, after 4months, participants in the exercise training group presented with lower atrogin-1 gene expression than participants who continued their activities as usual (p = 0.001). The reduction in muscular sympathetic nerve activity was positively associated with reduced atrogin-1 (r = 0.86; p = 0.02) and MuRF-1 gene expression (r = 0.64; p = 0.06); it was negatively associated with improved baroreflex sensitivity both for increases (r = -0.72; p = 0.020) and decreases (r = -0.82; p = 0.001) in blood pressure. ET improved cardiac and peripheral autonomic function in patients with subclinical chagasic cardiomyopathy. ET reduced MSNA and sympathetic activity in the heart and vessels and increased cardiac parasympathetic tone and baroreflex sensitivity. Regarding peripheral muscle, after 4months, patients who underwent exercise training had an increased cross-sectional area of type I fibers and oxidative metabolism of muscle fibers, and decreased atrogin-1 gene expression, compared to participants who continued their activities as usual. In addition, the reduction in MSNA was associated with improved cardiac baroreflex sensitivity, reduced sympathetic cardiovascular tone, and reduced atrogin-1 and MuRF-1 gene expression. ID: NCT02295215. Registered in June 2013.

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.

Heart Rate Estimation From Wrist-Worn Photoplethysmography: A Review

Photoplethysmography (PPG) is a low-cost, non-invasive, and optical technique used to detect blood volume changes in the microvascular tissue bed, measured from the skin surface. It has traditionally been used in commercial medical devices for oxygen saturation, blood pressure monitoring, and cardiac activity for assessing peripheral vascular disease and autonomic function. There has been a growing interest to incorporate PPG sensors in daily life, capable of use in ambulatory settings. However, inferring cardiac information (e.g. heart rate) from PPG traces in such situations is extremely challenging, because of interferences caused by motion. Following the IEEE Signal Processing Cup in 2015, numerous methods have been proposed for estimating particularly the average heart rate using wrist-worn PPG during physical activity. Details on PPG technology, sensor development, and applications have been well documented in the literature. Hence, in this paper, we have presented a comprehensive review of state-of-the-art research on heart rate estimation from wrist-worn PPG signals. Our review also encompasses brief theoretical details about PPG sensing and other potential applications-biometric identification, disease diagnosis using wrist PPG. This paper will set a platform for future research on pervasive monitoring using wrist PPG.

Structure‐Activity Relationships of Selective Pyrimidine Agonists on α7‐nAChRs

Nicotinic acetylcholine receptors (nAChRs) are prototypic pentameric ligand‐gated ion channels (pLGIC), activated by the endogenous neurotransmitter acetylcholine. nAChRs are present in the peripheral and central nervous systems, where they modulate central, peripheral autonomic and neuromuscular functions. One of the most abundant neuronal nAChRs is the homopentameric α7. This subtype comprises of five identical α7 subunits with five binding sites, located between the subunit interfaces. The α7‐nAChR has a relatively low affinity for nicotine and acetylcholine, and a high permeability for Ca+2. Activation occurs on sub‐millisecond time scale; desensitization occurs upon prolonged application of agonist. nAChRs are found on presynaptic terminals in brain mediating the release of other neurotransmitters.We previously synthesized a family of 4,6 substituted 2‐aminopyrimidines; our lead candidate, AC‐171A2, activates selectively the α7‐nAChRswith an EC50 of 70nM in the presence of PNU‐120596, diverging from classical agonist on binding interaction as well as chemical components. This compound has an EC50 of 360nM when fast activation was evaluated in a Xenopus oocyte system without PNU‐120596. When recovery of the receptor was assessed, AC‐171A2 allowed full recovery at 3mM concentration after 12 min. One of the goals of our current study is to better understand the molecular determinants of these ligands in these different time frames. We have developed an expanded library of compounds, based on previous leads, by combining the pyrimidine system with the di‐picolyl substitution at the 4‐position. To distinguish receptor interactions on nAChRs and related pentameric ligand‐gated ion channels, we employ HEK cells transfected with cDNA's encoding one of three requisite receptor subtypes: α7‐nAChR, α4β2‐nAChR and 5HT3AR, along with a fluorescent reporter, TN‐XXL. To assess fast activation of lead candidates, we use a Xenopus oocyte system expressing α7‐nAChR. This approach has enabled us to define the molecular determinants of the selective activation of α7‐nAChR's and offer more selective and potent lead candidates with EC50's extending to 30nM in the presence of PNU‐120596.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Widespread Cardiac and Vasomotor Autonomic Dysfunction in Non-Val30Met Hereditary Transthyretin Amyloidosis.

Objective The autonomic functions of hereditary transthyretin (ATTRm) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, have primarily been investigated in patients with Val30Met mutations, and information regarding non-Val30Met patients is scarce. The aim of this study was to systematically investigate the cardiac and peripheral vasomotor autonomic functions in non-Val30Met patients. Methods The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test results, noradrenaline infusion test results, and the (123)I-metaiodobenzylguanidine (MIBG) uptake on myocardial scintigraphy were assessed in five patients. The predominant manifestations were neuropathy in three patients (Val94Gly, Val71Ala, and Pro24Ser), cardiomyopathy in one (Thr60Ala), and oculoleptomeningeal involvement in one (Tyr114Cys). Results Although one patient with predominant cardiomyopathy did not manifest orthostatic hypotension during the head-up tilt test, the CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated the presence of cardiac sympathetic and parasympathetic dysfunction in all patients. The total peripheral resistance at 60° tilt did not increase from the baseline values in any of the examined patients. An infusion of low-dose noradrenaline induced an increase in the systolic blood pressure, except in one patient with mild neuropathy. Conclusion Cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in non-Val30Met patients, irrespective of their phenotype, suggesting a common pathology of autonomic involvement. However, the vasoconstrictor function was preserved, even in a patient with advanced neuropathy.

The relationship of one-leg standing time with peripheral nerve function and clinical neuropathy in patients with type 2 diabetes.

This study aimed at exploring physical fitness including postural stability in relation to peripheral nerve function and clinical neuropathy in patients with type 2 diabetes across a wide range of ages. We analyzed data collected from 139 patients with type 2 diabetes aged between 19 and 81years, which included the peripheral nerve conduction parameters and coefficient of variation for normal R-R intervals (CVRR) at rest and during deep breathing. The results of neurological examinations to diagnose probable and confirmed diabetic neuropathies based on the minimal criteria proposed by the Toronto diabetic neuropathy expert group and a battery of physical fitness tests including one-leg standing time with eyes open were also assessed. Multiple linear and logistic regressions were used to estimate the relationships of the physical fitness measures with the parameters of peripheral and cardiac autonomic nerve functions and clinical neuropathies, respectively. Receiver operating characteristic curves were generated to depict the relation between sensitivity and specificity of one-leg standing time for probable and confirmed neuropathies. After adjustment for age and other potential confounders, one-leg standing time correlated with peripheral and cardiac autonomic nerve functions as well as with probable and confirmed neuropathies. The one-leg standing time of 23s was found to be 66 and 63% sensitive and 81 and 77% specific for diagnosing probable and confirmed neuropathies, respectively. Short one-leg standing time was associated with peripheral and cardiac autonomic nerve dysfunction and clinical neuropathy in patients with type 2 diabetes, independent of age.

Analysis of peripheral nerve and autonomic nervous system function and the stage of microangiopathy in patients with secondary Raynaud's phenomenon in the course of connective tissue diseases.

The pathogenesis of secondary Raynaud's phenomenon (SRP) associated with connective tissue diseases (CTD) is not entirely understood. Nervous system dysfunction and microangiopathy are considered to be causes of this pathology. Peripheral and autonomic nervous system function, the stage of microangiopathy, and the relationships between these in patients with SRP were analyzed. In the study, 20 patients with CTD-related SRP and 30 healthy controls were subject to capillaroscopy, standard conduction velocity tests and conduction velocity distribution (CVD) tests in ulnar and peroneal nerves, heart rate variability (HRV), and sympathetic skin response (SSR) tests. There were no significant differences in the standard motor and sensory conduction velocity tests, or in CVD tests in the ulnar and peroneal nerves in SRP patients compared with the controls. The patients with SRP had a significantly lower SSR amplitude and longer latency in hands and feet. The patients with CTD-related SRP had a significantly lower mean HRV with higher low frequency (LF) values in the spectral analysis and expiration/inspiration ratio (E/I) during deep breathing. There was no correlation between the stage of microangiopathy and neurophysiological test results. Correct standard conduction velocity and CVD testing in patients with SPR suggest that vasomotor disturbances may occur in CTD regardless of peripheral neuropathy. The lack of relationship between SSR and microangiopathy could confirm that these 2 processes occur independently in patients with CTD-related SRP. Autonomic nervous system impairment together with normal peripheral nerve function suggest the central origin of CTD-related SRP.

Cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy.

The objective of this study was to systematically investigate cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy (FAP ATTR Val30Met) patients from non-endemic areas. The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test with impedance cardiography, noradrenaline infusion test, and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy were assessed in eight patients. Although only four patients manifested orthostatic hypotension during the head-up tilt test, CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated a higher prevalence of cardiac sympathetic and parasympathetic dysfunction. Total peripheral resistance at 60° tilt did not increase from baseline values in five of six examined patients. An infusion of low-dose noradrenaline induced an increase in systolic blood pressure in all patients. The extent of the change in systolic blood pressure negatively correlated to that in total peripheral resistance (p<0.05). Patients with poor vasoconstrictor responses to orthostatic stress tended to exhibit severe reduction of unmyelinated fibres in sural nerve biopsy specimens. In conclusion, both cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in late-onset FAP ATTR Val30Met patients from non-endemic areas, even in those without orthostatic intolerance. However, vasoconstriction by alpha-adrenoceptor agonists was preserved even after denervation, carrying important implications for the management of orthostatic hypotension in FAP.

Clinical characteristics and risk factors for retinal diabetic neurodegeneration in type 2 diabetes.

To identify clinical characteristics and risk factors of retinal neurodegeneration represented by macular ganglion cell/inner plexiform layer (mGCIPL) thinning in patients with long-standing type 2 diabetes mellitus (T2DM). Patients who had T2DM for >15years were prospectively recruited from September 2014 to July 2015. Clinical data and samples were collected according to the Common Data Element and Standards of Procedure developed by the Korean Diabetes Association research council. Baseline characteristics included age, gender, family history, medical record of comorbidity, and microvascular complications. All patients underwent optical coherence tomography with automatic segmentation of the mGCIPL in six parafoveal regions. Multivariable regression analysis identified factors associated with mGCIPL thinning. Of 220 registered patients, 162 were included after ophthalmologic examination. The mean (SD) age was 65.0 (9.3) years, the mean duration of T2DM was 20.5 (4.0) years; mGCIPL thickness was 76.2 (8.5) µm. Hypertension, diabetic retinopathy, statin medication, estimated glomerular filtration rate, conduction velocity of the posterior tibial, peroneal, and sural nerves, and cardiac autonomic neuropathy (CAN) score were significantly correlated with mGCIPL thickness. Multivariate regression analysis showed that the CAN score (coefficient=-1.78, p=0.001) and sural nerve velocity (coefficient=0.458, p=0.035) yielded a significant high regression correlation with mGCIPL thickness (overall R 2=0.46). This study demonstrated that various clinical features were associated with retinal neurodegeneration in T2DM. In particular, peripheral nerve conduction and autonomic nerve function were confirmed to be strong risk factors for mGCIPL thinning in patients with T2DM.

Osteopontin and clusterin levels in type 2 diabetes mellitus: differential association with peripheral autonomic nerve function.

Osteopontin (OPN) and clusterin are secreted glycoproteins potentially associated with nerve function. Sudomotor dysfunction is associated with the development of foot ulcerations. The purpose of this study was to investigate the potential relationship of OPN and clusterin with sudomotor function (i.e., autonomic nerves that control sweating) in participants with type 2 diabetes mellitus (T2DM). Sudomotor function was assessed using SUDOSCAN® which measures electrochemical skin conductance (ESC) of the hands and feet. Demographics (e.g., age, gender, race, body mass index (BMI)), HbA1c, 25-hydroxyvitamin D, creatinine, OPN, and clusterin were also determined for the participants. Fifty individuals with T2DM (age=59±11years; 23/27 male/female; 13 African Americans) participated in this study. Lower ESC for the hands and feet were observed in African Americans versus Caucasians/Asians (p<0.05). No significant ESC differences were observed for good [HbA1c <7%] versus poor [HbA1c ≥7%] glycemic control. With regard to gender, ESC values were lower for the hands for females (p<0.05). In linear regression with ESC for the hands or feet as the dependent variable, increased OPN levels, but not clusterin, were independently associated with reduced sudomotor function while adjusting for age, gender, race, BMI, and glycemic control (ESC hands model R 2=0.504, p<0.001; ESC feet model R 2=0.534, p<0.001). The association between OPN and reduced sudomotor function found in our study warrants further investigation to delineate the underlying mechanisms and determine if OPN is neuroprotective, involved in the pathogenesis of sudomotor dysfunction, or simply a bystander.

Predictors of autonomic neuropathy in rheumatoid arthritis.

Autonomic dysfunction occurs in rheumatoid arthritis (RA). However, the association between the autonomic dysfunction and inflammation has not been investigated in RA. We investigated the relationship between inflammation and ANS function in RA. In this cross-sectional study, 25 RA patients and 25 age and sex-matched healthy controls were recruited. Autonomic function assessed by five cardiovascular reflex tests according to Ewing. Parasympathetic dysfunction established by applying three tests: heart rate response to deep breath (HRD) and standing (HRS) and Valsalva tests. Sympathetic dysfunction examined by applying two tests: BP response to standing and handgrip test. Peripheral sympathetic autonomic function assessed by Sudoscan through measurement of electrochemical skin conductance of hands and feet. Sudoscan investigates the sweat gland activity and used as a surrogate to study the damage of sympathetic sudomotor nerves in neuropathy. It is an indirect assessment tool of sudomotor function. Disease-specific and inflammatory measures (DAS 28, ESR, CRP, TNF-α, IL-6 and IL-1) were determined. RA patients had significantly impaired HRD, HRS, BP response to hand grip and sudomotor function as compared to healthy controls. Pro-inflammatory cytokines were significantly higher in RA as compared to healthy controls (p<0.05). DAS 28 significantly correlated with HRD in RA. ESR significantly correlated with HRD and HRS. TNF-α significantly correlated with HRD, HRS, BP response to standing and sudomotor function. Significant correlation was found between IL-6 and HRS. Seropositive patients had more pronounced CAN and sudomotor dysfunction. Autonomic dysfunction in RA is related to disease activity, seropositivity and pro-inflammatory cytokines.