Peripheral Autonomic Nervous System Research Articles

Cardiovascular dysautonomia and cognitive impairment in Parkinson's disease (Review).

Cognitive impairment is a prevalent non-motor symptom of Parkinson's disease (PD), which can result in significant disability and distress for patients and caregivers. There is a marked variation in the timing, characteristics and rate at which cognitive decline occurs in patients with PD. This decline can vary from normal cognition to mild cognitive impairment and dementia. Cognitive impairment is associated with several pathophysiological mechanisms, including the accumulation of β-amyloid and tau in the brain, oxidative stress and neuroinflammation. Cardiovascular autonomic dysfunctions are commonly observed in patients with PD. These dysfunctions play a role in the progression of cognitive impairment, the incidents of falls and even in mortality. The majority of symptoms of dysautonomia arise from changes in the peripheral autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. Cardiovascular changes, including orthostatic hypotension, supine hypertension and abnormal nocturnal blood pressure (BP), can occur in both the early and advanced stages of PD. These changes tend to increase as the disease advances. The present review aimed to describe the cognitive changes in the setting of cardiovascular dysautonomia and to discuss strategies through which these changes can be modified and managed. It is a multifactorial process usually involving decreased blood flow to the brain, resulting in the development of cerebral ischemic lesions, an increased presence of abnormal white matter signals in the brain, and a potential influence on the process of neurodegeneration in PD. Another possible explanation is this association being independent observations of PD progression. Patients with clinical symptoms of dysautonomia should undergo 24-h ambulatory BP monitoring, as they are frequently subtle and underdiagnosed.

Alleviation of physiological stress response by apple aroma

ABSTRACT Objective The study evaluated the potential of apple aroma to alleviate physiological stress response induced by a short-term cognitive stressor. It investigated the effects of apple aroma on cardiac and peripheral autonomic nervous system activity under stressful conditions. Methods Within-subject experiments were conducted with 25 healthy male university students with a 30-minute calculation task under three conditions: Apple, Chamomile (CHA), and Di propylene glycol (DPG) (scentless air). The aroma administration was precisely controlled and counterbalanced. Cardiac activity on electrocardiograms and nose tip temperature were recorded throughout the experiment. A visual analog scale and a scent questionnaire were subjective measures. Results Apple aroma demonstrated a significantly smaller increase in heart rate (t [24] = 3.36, p = 0.008 vs. DPG, t [24] = 4.06, p = 0.001 vs. CHA), and a decrease in the high-frequency component of heart rate variability (t [24] = 2.81, p = 0.029 vs. DPG, t [24] = 3.48, p = 0.006 vs. CHA) compared to the other conditions, representing a smaller enhancement of cardiac sympathetic nervous system activity and smaller suppression of cardiac parasympathetic nervous system activity respectively. Conclusion Apple aroma showed efficacy in alleviating the physiological stress response in terms of cardiac activity. Apple was also considered significantly preferable and comfortable compared to the other conditions, which would be beneficial in the context of aromatherapy.

Investigating the Prevalence of Autonomic Neuropathy in Diabetic Patients with Urinary Irritation Symptoms Without a Known Cause.

Evaluating pseudomotor performance can be a valuable tool for investigating the peripheral autonomic nervous system in diabetic patients. Sudoscan, a simple and non-invasive method for assessing pseudomotor performance, has been developed in recent years. This study aimed to investigate autonomic neuropathy using Sudoscan in diabetic patients with lower urinary tract symptoms (LUTS) of unknown cause. In this cross-sectional study conducted from April 2022 to April 2023, we included 195 patients with type 2 diabetes who were referred to the urology clinic. We extracted demographic, clinical, and laboratory data from the patient files and evaluated urinary symptoms using the International Prostate Symptom Score (IPSS) questionnaire. Patients underwent Sudoscan testing to evaluate autonomic neuropathy in the physical medicine and rehabilitation clinic. To further assess urinary irritative symptoms, patients underwent urodynamic studies (UDS) and ultrasonography. The Sudoscan test results showed that autonomic neuropathy was present in 77 patients (40%), with 43 (22.1%) having moderate and 44 (22.6%) having severe neuropathy. Patients with autonomic neuropathy were found to be older, had longer diabetes durations, higher average blood glucose levels, and higher creatinine levels. Additionally, we found a significant correlation between autonomic neuropathy and signs of high post-void residue on ultrasound and detrusor contraction disorders on UDS (p-value < 0.05). Our study found a higher prevalence of autonomic neuropathy in diabetic patients with LUTS using Sudoscan (40%). Longer diabetes duration and poor glycemic control were associated with an increased risk of autonomic neuropathy linked with LUTS, such as urge incontinence.

Mechanisms Underlying the Propagation of α-Synuclein Seeds Derived from the Blood of Patients with α-Synucleinopathies

The aggregation of α-synuclein (α-syn), associated with Parkinson's disease (PD) extends from the peripheral autonomic nervous system to the cerebral cortex, indicating a neural circuit-based mechanism of spread. However, recent studies, have proposed alternative propagation routes beyond neural pathways, including transmission via bodily fluids, such as the blood. This notion expands our understanding of PD progression, underscoring the complexity of α-syn spread and its implications in disease management and therapeutic strategies.

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.

Chronic and acute exposure to rotenone reveals distinct Parkinson's disease-related phenotypes in human iPSC-derived peripheral neurons

Peripheral autonomic nervous system (P-ANS) dysfunction is a critical non-motor phenotype of Parkinson's disease (PD). The majority of PD cases are sporadic and lack identified PD-associated genes involved. Epidemiological and animal model studies suggest an association with pesticides and other environmental toxins. However, the cellular mechanisms underlying toxin induced P-ANS dysfunctions remain unclear. Here, we mapped the global transcriptome changes in human induced pluripotent stem cell (iPSC) derived P-ANS sympathetic neurons during inhibition of the mitochondrial respiratory chain by the PD-related pesticide, rotenone. We revealed distinct transcriptome profiles between acute and chronic exposure to rotenone. In the acute stage, there was a down regulation of specific cation channel genes, known to mediate electrophysiological activity, while in the chronic stage, the human P-ANS neurons exhibited dysregulation of anti-apoptotic and Golgi apparatus-related pathways. Moreover, we identified the sodium voltage-gated channel subunit SCN3A/Nav1.3 as a potential biomarker in human P-ANS neurons associated with PD. Our analysis of the rotenone-altered coding and non-coding transcriptome of human P-ANS neurons may thus provide insight into the pathological signaling events in the sympathetic neurons during PD progression.

Alleviation of acute stress response by black pepper aroma administration

BackgroundBlack pepper is one of the most popular spices globally. As black pepper essential oil has not yet been used in the context of aromatherapy, this study examined the effect of black pepper aroma on cardiac and peripheral autonomic nervous system (ANS) activity under stressful conditions using an olfactometer to administer aroma in a precise and controlled manner to ensure reproducibility.MethodsA within-participant design experiment was conducted with 20 male university students who performed a 30-min calculation task as a short-term stressor under three aroma conditions: black pepper, ginger, and dipropylene glycol (DPG) (scentless air as a control). Each aroma was sporadically delivered (first 20 s of each 1-min interval) with the olfactometer during the task. Electrocardiograms and skin conductance level (SCL) were measured to evaluate ANS's physiological acute stress response. Subjective evaluations for the given stressful task and impressions on the types of aromas were assessed.ResultsThe physiological acute stress response induced by the short-term stressor, which is characterized by the enhancement of the heart rate (HR) and SCL and decreases in the heart rate variability (HRV), was suppressed with black pepper: the increase in HR and reduction in HRV from the baseline were 38.9% (p = 0.048 when compared with DPG) and 32.9% smaller (p = 0.002 for multiple comparisons) than those in DPG, respectively, and the increase of SCL was 15.5% smaller (p = 0.005 for multiple comparisons) than that in ginger. However, there was no significant difference in subjective scores among the conditions.ConclusionAlthough black pepper is a stimulative agent, the study findings showed that black pepper aroma alleviated the physiological acute stress response, which can be beneficial in aromatherapy under stressful conditions.

Dysfunction of peripheral somatic and autonomic nervous system in patients with severe forms of Crohn's disease on biological therapy with TNFα inhibitors-A single center study.

Crohn's disease (CD) can be associated with a wide range of extraintestinal manifestations (EIMs), including neurological ones. Published studies differ in their conclusions about the epidemiology and etiopathogenesis of neurological EIMs. The aims of this study were to demonstrate the presence and find risk factors of peripheral (somatic and autonomic) neuropathy patients with severe CD on anti-TNFα biological therapy. A clinical examination focusing on detection of peripheral sensor-motor nervous dysfunction (including Sudoscan) and examination of autonomic nervous system dysfunction (using Ewing´s battery tests and spectral analysis) together with laboratory tests and collection of demographic data followed by administration of questionnaires were performed on a total of 30 neurologically asymptomatic outpatients with severe CD on anti-TNFα biological therapy. Peripheral sensor-motor nervous function via clinical neurological examination was pathological in 36.7% and Sudoscan in 33.3% of cases. Statistically significant associations between vibration perception test and age, CD and biological therapy duration, body mass index and Crohn's Disease Activity Index were proved while statistically significant associations between temperature perception test and age and BMI were proved as well. Additionally, a decrease of total protein in a patient´s serum below the physiological cut-off in the 6 months prior to measurement was associated with a pathological result of a Sudoscan. Cardiovascular autonomic neuropathy based on Ewing´s battery tests was present in 56.7% of patients, no statistically significant risk factors were found. Our peripheral neuropathy questionnaire correlated with the results of the Sudoscan test and some tests of the clinical examination of peripheral sensor-motor nervous function (discriminatory contact perception test, temperature perception test). This study demonstrated a relatively high prevalence of peripheral (especially autonomic) neuropathy and verified some risk factors for the development of peripheral somatic neuropathy in asymptomatic patients with severe form of CD on anti-TNFα biological therapy.

Complementary role of peripheral and central autonomic nervous system on insulin-like growth factor-1 activation to prevent fatty liver disease.

Insulin-like growth factor-1 (IGF-1) is involved in the pathology of non-alcoholic fatty liver disease (NAFLD) and ameliorates fatty infiltration in the liver. It is activated by growth hormone (GH); however, the role of GH-IGF-1 axis in NAFLD developmental phase has not been well identified. Therefore, in this study, we focused on the effect of IGF-1 in NAFLD pathology and GH excretion activation from the pituitary gland by peripheral autonomic neural pathways relaying liver-brain-gut pathway and by central neuropeptides. GH and IGF-1 levels were assessed in wild-type and melanocortin-4 receptor knockout mice upon the development of diet-induced NAFLD. The contribution of the peripheral autonomic nervous system connecting the liver-brain-gut axis was assessed by its blockade using capsaicin and that of the central nervous system was assessed by the expression of hypothalamic brain-derived neurotrophic factor (BDNF) and corticotropin-releasing factor (CRH), which activates GH release from the pituitary gland. In the NAFLD mouse models, the levels of GH and IGF-1 increased (p < .05). Further, hepatic fatty infiltration was suppressed even under peripheral autonomic nervous system blockade (p < .001), which inhibited gastric ghrelin expression. In mice with peripheral autonomic nervous blockade, hypothalamic BDNF and CRH were inhibited (p < .05), resulting in GH and IGF-1 excretion, whereas other neuropeptides of somatostatin and cortistatin showed no changes. These complementary effects were canceled in melanocortin-4 receptor knockout mice, which diminished BDNF and CRH release control. Our study demonstrates that the release of IGF-1 by the nervous system is a key factor in maintaining the pathological homeostasis of NAFLD, suggesting its therapeutic potential.

Relaxation and Performance During Microsurgical Learning

Introduction: Microsurgical learning is a difficult and stressful process, requiring self-control to achieve relaxation. The purpose of this study is to evaluate peripheral and central nervous system relaxation during microsurgical training. Methods: This cohort study included ten medical students with no previous experience in microsurgery. The somatic peripheral nervous system was evaluated by the force applied to a custom-designed microsurgical needle holder. The autonomic peripheral nervous system was assessed by a heart rate monitor. Central nervous system relaxation was evaluated by the State and Trait Anxiety Inventory scores. The quality of the anastomosis was graded by the Microsurgical Anastomosis Rating Scale (MARS10). These data were compared to a group of 5 senior microsurgeons who underwent a single assessment. Results: The time to complete the anastomosis and the force decreased significantly with training after only 2 weeks ( P &lt; .05). After 4 weeks of training, no statistical difference was observed between students and experts regarding force while the time of suture was still significantly different at 30 days ( P = .001). The maximum heart rate decreased significantly at 2 weeks ( P = .01). Anxiety scores decreased significantly between days 1 and 15 ( P = .002 and P = .036). The MARS10 score demonstrates that the quality of the suture increases significantly during the first 15 days ( P = .006). Conclusion: Peripheral and central nervous system relaxation as well as the quality of the microsurgical anastomosis increase significantly after only 15 days of learning. The force-sensing microsurgical needle holder offers a new tool for the evaluation of relaxation and can function as a learning aid.

Heart Rate Variability as a Translational Dynamic Biomarker of Altered Autonomic Function in Health and Psychiatric Disease.

The autonomic nervous system (ANS) is responsible for the precise regulation of tissue functions and organs and, thus, is crucial for optimal stress reactivity, adaptive responses and health in basic and challenged states (survival). The fine-tuning of central ANS activity relies on the internal central autonomic regulation system of the central autonomic network (CAN), while the peripheral activity relies mainly on the two main and interdependent peripheral ANS tracts, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). In disease, autonomic imbalance is associated with decreased dynamic adaptability and increased morbidity and mortality. Acute or prolonged autonomic dysregulation, as observed in stress-related disorders, affects CAN core centers, thereby altering downstream peripheral ANS function. One of the best established and most widely used non-invasive methods for the quantitative assessment of ANS activity is the computerized analysis of heart rate variability (HRV). HRV, which is determined by different methods from those used to determine the fluctuation of instantaneous heart rate (HR), has been used in many studies as a powerful index of autonomic (re)activity and an indicator of cardiac risk and ageing. Psychiatric patients regularly show altered autonomic function with increased HR, reduced HRV and blunted diurnal/circadian changes compared to the healthy state. The aim of this article is to provide basic knowledge on ANS function and (re)activity assessment and, thus, to support a much broader use of HRV as a valid, transdiagnostic and fully translational dynamic biomarker of stress system sensitivity and vulnerability to stress-related disorders in neuroscience research and clinical psychiatric practice. In particular, we review the functional levels of central and peripheral ANS control, the main neurobiophysiologic theoretical models (e.g., polyvagal theory, neurovisceral integration model), the precise autonomic influence on cardiac function and the definition and main aspects of HRV and its different measures (i.e., time, frequency and nonlinear domains). We also provide recommendations for the proper use of electrocardiogram recordings for HRV assessment in clinical and research settings and highlight pathophysiological, clinical and research implications for a better functional understanding of the neural and molecular mechanisms underlying healthy and malfunctioning brain-heart interactions in individual stress reactivity and psychiatric disorders.

Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord.

The development of effective disease-modifying therapies to halt Parkinson's disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression.

Effect of Proprioception Exercise versus Focused Regimen Exercise on Balance and Quality of Life in Subjects with Diabetic Neuropathy

Background: Diabetic peripheral neuropathy is a polyneuropathy that can cause damage to the peripheral nervefibers, sensorimotor and autonomic nervous system. Neuropathy causes somatosensory dysfunction of the lowerextremities, such as decreased ankle position and vibration sensations. The sensation of the skin on the feet andthe proprioceptive sense are two important factors in standing balance, postural control and coordination. As thiscondition progresses, this can lead to increased postural sway, gait disturbance, abnormal neuromuscular controland increased reaction time leading to falls in balance impaired patients.Objective: To determine the effect of proprioception exercise versus focused regimen exercise on balance andquality of life in subjects with diabetic neuropathy.Methods: 20 Subjects with diabetic neuropathy of both genders, in the age group of 40 – 60 years were convenientlyassigned into 2 groups. Group A (n = 10) received Proprioception exercise and Group B (n = 10) received Focusedregimen exercise, 3 sessions a week for 8 weeks. Balance and quality of life were evaluated with Berg Balance Scaleand SF – 36 Survey questionnaire.Results: The difference in the post-test mean scores of group A and group B in Berg Balance Scale was 32 and 28.3and SF – 36 Survey questionnaire was 61.4 and 56.6 respectively. The result showed a significant improvement inGroup A than in Group B at p &lt; 0.0001.Conclusion: Therefore, the study concludes that the Proprioception exercise training is better managementto improve balance and quality of life in subjects with diabetic neuropathy.

Physiological Effects of Using Citrus Mint Flavored Mouthwash

This study aimed to investigate the effect of flavored mouthwash on peripheral and cardiac autonomic nervous system activity. In a within-subject experimental design, 10 male and 10 female healthy adults went through two types of mouthwashes, one was with citrus mint flavor and another was with spice mint flavor, right after performing a 20-minute calculation task given as a cognitive stressor. Along with subjective evaluation, skin conductance and electrocardiogram was recorded throughout the experiment. Although there was no difference in the subjective stress levels between the two conditions, the level of skin conductance decreased more remarkably and significantly during the recovery period when the participants used citrus mint mouthwash. The findings suggest that a particular flavored mouthwash may provide physiological effect on user regardless of its subjective sensation and the citrus mint type mouthwash might be better suited for use in need of a relaxation.

Humans at the dawn of the in-body electrical nerve stimulation era.

The neuroprosthesis laparoscopic implantation technique for electric pelvic nerve stimulation was introduced to gynaecology over 15 years ago to treat intractable pelvic neuropathic pain. Following this first indication, other applications were developed, particularly in parapleology. The LION procedure developed to assist patients with paraplegia and common problems associated with inertia when confined to a wheelchair could find revolutionary applications in aging medicine and prevention. Spinal cord injured patients who have undergone the Possover's LION procedure. PubMed was systematically searched to identify peer-reviewed articles published in English that reported on LION procedure. Three independent studies published recently (100 patients worldwide) have shown revolutionary recovery of supra-spinal control in patients with chronic spinal cord injury following pelvic nerves stimulation, with 70% of them establishing a walker/crutches-assisted gait. The same studies have also shown significant whole-body muscle-mass building, peripheral vasodilatation, and an unexpected improvement in bone mineral density. These ground-breaking findings could find revolutionary applications in aging medicine and the prevention of osteoporosis, with a huge impact on global public health. Humanity is on the cusp of an exciting new era following the introduction of the in-body electrical nerve stimulation technique. In-body electrical nerve stimulation for recovery and/or control of human peripheral somatic and autonomic nervous systems.

A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease

The dual-hit hypothesis of Parkinson’s disease (PD) originally postulated that a neurotropic pathogen leads to formation of α-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with α-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in either the olfactory bulb or the ENS, but rarely in the olfactory bulb and gut simultaneously. More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.

Nontraumatic Spinal Cord Injury: Epidemiology, Etiology and Management.

The spinal cord is a conduit within the central nervous system (CNS) that provides ongoing communication between the brain and the rest of the body, conveying complex sensory and motor information necessary for safety, movement, reflexes, and optimization of autonomic function. After a traumatic spinal cord injury (SCI), supraspinal influences on the peripheral nervous system and autonomic nervous system (ANS) are disrupted, leading to spastic paralysis, sympathetic blunting, and parasympathetic dominance, resulting in cardiac dysrhythmias, systemic hypotension, bronchoconstriction, copious respiratory secretions, and uncontrolled bowel, bladder, and sexual dysfunction. This article outlines the pathophysiology of the less reported nontraumatic SCI (NTSCI), its classification, its influence on sensory/motor function, and introduces the probable comorbidities associated with SCI that will be discussed in more detail in the accompanying manuscripts of this special issue. Finally, management strategies for NTSCI will be provided.

Mortality patterns of soft-tissue sarcomas worldwide up to 2018, with predictions for 2025.

The epidemiological evidence on soft-tissue sarcoma (STS) mortality is inconsistent in geographic and time coverage. This study provides mortality trends for STSs in selected countries worldwide over the last 2 decades, together with predicted figures for 2025. We extracted official numbers of certified deaths coded as C47 (i.e. malignant neoplasm of peripheral nerves and autonomic nervous system) and C49 (i.e. malignant neoplasm of other connective and soft tissue) according to the 10th Revision of the International Classification of Disease and population estimates from the WHO and the Pan American Health Organization databases. We computed age-standardized (world standard population) mortality rates (ASMRs). We used joinpoint regression analysis to identify significant changes in trends and to predict death numbers and rates for 2025. The pattern emerging from the number of deaths and ASMRs up to 2018 shows an increase in most countries in both sexes. Around 2015 to 2018, ASMRs differed by 2.5-fold in both sexes with the highest rates being registered in Central-Eastern Europe, North America and Australia, while the lowest ones in Latin America, Japan, and Korea. In 2025, the number of STS deaths is predicted to increase in most countries and both sexes, and unfavourable rates are predicted in Central Europe in both sexes. In addition to improvements in STSs registration, unfavourable mortality rates reported in this study reflect inadequate referral of patients with STSs to high-volume multidisciplinary centres, as well as insufficient advancements in STS prevention, diagnosis, and treatments.