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Cardiac Electrophysiology Clinics Mar 2021Atrial fibrillation (AF) is the most commonly diagnosed arrhythmia and eludes an efficacious cure despite an increasing prevalence and a significant association with... (Review)
Review
Atrial fibrillation (AF) is the most commonly diagnosed arrhythmia and eludes an efficacious cure despite an increasing prevalence and a significant association with morbidity and mortality. In addition to an array of clinical sequelae, the origins and propagation of AF are multifactorial. In recent years, the contribution from the autonomic nervous system has been an area of particular interest. This review highlights the relevant physiology of autonomic and neurohormonal contributions to AF origin and maintenance, the current state of the literature on targeted therapies, and the path forward for clinical interventions.
Topics: Atrial Fibrillation; Autonomic Nervous System; Autonomic Nervous System Diseases; Heart Disease Risk Factors; Humans; Nervous System Diseases; Renin-Angiotensin System; Transcutaneous Electric Nerve Stimulation
PubMed: 33516396
DOI: 10.1016/j.ccep.2020.11.012 -
Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies.Brain : a Journal of Neurology Aug 2022Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear...
Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear palsy and corticobasal degeneration. However, pathological τ has also been observed in α-synucleinopathies like Parkinson's disease and multiple system atrophy. Based on the involvement of the peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibres in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 kDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both were more expressed in progressive supranuclear palsy/corticobasal degeneration by real-time PCR. Enzyme-linked immunosorbent assay demonstrated significantly higher levels of total τ protein in skin lysates of progressive supranuclear palsy/corticobasal degeneration compared to the other groups. Multivariate regression analysis and receiver operating characteristics curve analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for progressive supranuclear palsy/corticobasal degeneration versus Parkinson's disease (sensitivity 90%, specificity 69%) and progressive supranuclear palsy/corticobasal degeneration versus multiple system atrophy (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in progressive supranuclear palsy/corticobasal degeneration. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiological and pathological conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.
Topics: Biopsy; Humans; Multiple System Atrophy; Parkinson Disease; Supranuclear Palsy, Progressive; Synucleinopathies; Tauopathies; tau Proteins
PubMed: 35485527
DOI: 10.1093/brain/awac161 -
Stroke Jun 2021The autonomic nervous system has been implicated in stroke and dementia pathophysiology. High resting heart rate and low heart rate variability indicate the effect of... (Clinical Trial)
Clinical Trial
BACKGROUND AND PURPOSE
The autonomic nervous system has been implicated in stroke and dementia pathophysiology. High resting heart rate and low heart rate variability indicate the effect of autonomic imbalance on the heart. We examined the associations of resting heart rate and heart rate variability with incident stroke and dementia in a community-based cohort of middle- and old-aged adults.
METHODS
The study sample included 1581 participants aged >60 years and 3271 participants aged >45 years evaluated for incident dementia and stroke, respectively, who participated in the Framingham Offspring cohort third (1983–1987) examination and had follow-up for neurology events after the seventh (1998–2001) examination. Heart rate variability was assessed through the standard deviation (SD) of normal-to-normal RR intervals and the root mean square of successive differences between normal heartbeats from 2-hour Holter monitor. Participants were followed-up for stroke and dementia incidence from exam 7 to a maximum of 10 years. Cox regression models were used to assess the link of resting heart rate and heart rate variability with stroke and dementia risk while adjusting for potential confounders, and interactions with age and sex were assessed.
RESULTS
Of the dementia (mean age, 55±6 years, 46% men) and stroke (mean age, 48±9 years, 46% men) samples, 133 and 127 developed dementia and stroke, respectively, during the follow-up. Overall, autonomic imbalance was not associated with dementia risk. However, age modified the associations such that SD of normal-to-normal intervals and root mean square of successive differences were associated with dementia risk in older people (hazard ratio [HR] [95% CI] per 1SD, 0.61 [0.38–0.99] and HR [95% CI] per 1SD, 0.34 [0.15–0.74], respectively). High resting heart rate was associated with increased stroke risk (HR [95% CI] per 10 bpm, 1.18 [1.01–1.39]), and high SD of normal-to-normal intervals was associated with lower stroke risk in men (HR [95% CI] per 1SD, 0.46 [0.26–0.79]) but not women (HR [95% CI] per 1SD, 1.25 [0.88–1.79]; P for interaction=0.003).
CONCLUSIONS
Some measures of cardiac autonomic imbalance may precede dementia and stroke occurrence, particularly in older ages and men, respectively.
Topics: Adult; Autonomic Nervous System; Autonomic Nervous System Diseases; Dementia; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Stroke; Time Factors
PubMed: 33874747
DOI: 10.1161/STROKEAHA.120.030601 -
The Journal of Clinical Endocrinology... Sep 2023Hyperglycemia and autonomic dysfunction are bidirectionally related.
CONTEXT
Hyperglycemia and autonomic dysfunction are bidirectionally related.
OBJECTIVE
We investigated the association of longitudinal evolution of heart rate variability (HRV) with incident type 2 diabetes (T2D) among the general population.
METHODS
We included 7630 participants (mean age 63.7 years, 58% women) from the population-based Rotterdam Study who had no history of T2D and atrial fibrillation at baseline and had repeated HRV assessments at baseline and during follow-up. We used joint models to assess the association between longitudinal evolution of heart rate and different HRV metrics (including the heart rate-corrected SD of the normal-to-normal RR intervals [SDNNc], and root mean square of successive RR-interval differences [RMSSDc]) with incident T2D. Models were adjusted for cardiovascular risk factors. Bidirectional Mendelian randomization (MR) using summary-level data was also performed.
RESULTS
During a median follow-up of 8.6 years, 871 individuals developed incident T2D. One SD increase in heart rate (hazard ratio [HR] 1.20; 95% CI, 1.09-1.33), and log(RMSSDc) (HR 1.16; 95% CI, 1.01-1.33) were independently associated with incident T2D. The HRs were 1.54 (95% CI, 1.08-2.06) for participants younger than 62 years and 1.15 (95% CI, 1.01-1.31) for those older than 62 years for heart rate (P for interaction <.001). Results from bidirectional MR analyses suggested that HRV and T2D were not significantly related to each other.
CONCLUSION
Autonomic dysfunction precedes development of T2D, especially among younger individuals, while MR analysis suggests no causal relationship. More studies are needed to further validate our findings.
Topics: Humans; Female; Middle Aged; Male; Diabetes Mellitus, Type 2; Heart Rate; Atrial Fibrillation; Autonomic Nervous System Diseases; Risk Factors
PubMed: 37022971
DOI: 10.1210/clinem/dgad200 -
CNS Neuroscience & Therapeutics Feb 2024Autonomic dysfunction with central autonomic network (CAN) damage occurs frequently after intracerebral hemorrhage (ICH) and contributes to a series of adverse outcomes.... (Review)
Review
AIMS
Autonomic dysfunction with central autonomic network (CAN) damage occurs frequently after intracerebral hemorrhage (ICH) and contributes to a series of adverse outcomes. This review aims to provide insight and convenience for future clinical practice and research on autonomic dysfunction in ICH patients.
DISCUSSION
We summarize the autonomic dysfunction in ICH from the aspects of potential mechanisms, clinical significance, assessment, and treatment strategies. The CAN structures mainly include insular cortex, anterior cingulate cortex, amygdala, hypothalamus, nucleus of the solitary tract, ventrolateral medulla, dorsal motor nucleus of the vagus, nucleus ambiguus, parabrachial nucleus, and periaqueductal gray. Autonomic dysfunction after ICH is closely associated with neurological functional outcomes, cardiac complications, blood pressure fluctuation, immunosuppression and infection, thermoregulatory dysfunction, hyperglycemia, digestive dysfunction, and urogenital disturbances. Heart rate variability, baroreflex sensitivity, skin sympathetic nerve activity, sympathetic skin response, and plasma catecholamine concentration can be used to assess the autonomic functional activities after ICH. Risk stratification of patients according to autonomic functional activities, and development of intervention approaches based on the restoration of sympathetic-parasympathetic balance, would potentially improve clinical outcomes in ICH patients.
CONCLUSION
The review systematically summarizes the evidence of autonomic dysfunction and its association with clinical outcomes in ICH patients, proposing that targeting autonomic dysfunction could be potentially investigated to improve the clinical outcomes.
Topics: Humans; Autonomic Nervous System; Sympathetic Nervous System; Autonomic Nervous System Diseases; Vagus Nerve; Cerebral Hemorrhage; Heart Rate
PubMed: 38372446
DOI: 10.1111/cns.14544 -
Neurology India 2022For a favorable outcome, patients admitted to critical care units require continuous monitoring and swift decision-making ability regarding management. One of the... (Review)
Review
BACKGROUND
For a favorable outcome, patients admitted to critical care units require continuous monitoring and swift decision-making ability regarding management. One of the biggest challenges in neurocritical care units is the identification and management of autonomic dysfunction and in the worst-case scenario, autonomic storms.
OBJECTIVE
Most of the literature available focuses mainly on autonomic storms following traumatic brain injury. However, due to the myriad neurological presentations in a critical care setting, it is particularly important for physicians and intensivists to suspect and manage autonomic dysfunction in various neurological scenarios.
METHODS
Understanding the mechanism of paroxysmal sympathetic hyperactivity (PSH) is essential for early recognition and treatment. PSH-AM is an assessment measurement scale to diagnose and assess the severity of PSH in traumatic brain injury. However, this is not yet standardized across all neurological settings.
CONCLUSION
We present a comprehensive report on understanding the mechanism of autonomic storms across various neurological disorders and outline the management.
Topics: Autonomic Nervous System Diseases; Brain Injuries, Traumatic; Hospitalization; Humans; Intensive Care Units; Magnetic Resonance Imaging
PubMed: 35532608
DOI: 10.4103/0028-3886.344657 -
Clinical Autonomic Research : Official... Aug 2023
Topics: Humans; Hypertension; Autonomic Nervous System Diseases; Hypotension, Orthostatic; Blood Pressure
PubMed: 37389705
DOI: 10.1007/s10286-023-00961-x -
Pain Research & Management 2020The purpose of this review is to summarize the pathophysiology of complex regional pain syndrome (CRPS), the underlying molecular mechanisms, and potential treatment... (Review)
Review
The purpose of this review is to summarize the pathophysiology of complex regional pain syndrome (CRPS), the underlying molecular mechanisms, and potential treatment options for its management. CRPS is a multifactorial pain condition. CRPS is characterized by prolonged or excessive pain and changes in skin color and temperature, and/or swelling in the affected area, and is generally caused by stimuli that lead to tissue damage. An inflammatory response involving various cytokines and autoantibodies is generated in response to acute trauma/stress. Chronic phase pathophysiology is more complex, involving the central and peripheral nervous systems. Various genetic factors involved in the chronicity of pain have been identified in CRPS patients. As with other diseases of complex pathology, CRPS is difficult to treat and no single treatment regimen is the same for two patients. Stimulation of the vagus nerve is a promising technique being tested for different gastrointestinal and inflammatory diseases. CRPS is more frequent in individuals of 61-70 years of age with a female to male ratio of 3 : 1. Menopause, migraine, osteoporosis, and asthma all represent risk factors for CRPS and in smokers the prognosis appears to be more severe. The pathophysiological mechanisms underlying CRPS involve both inflammatory and neurological pathways. Understanding the molecular basis of CRPS is important for its diagnosis, management, and treatment. For instance, vagal nerve stimulation might have the potential for treating CRPS through the cholinergic anti-inflammatory pathway.
Topics: Aged; Complex Regional Pain Syndromes; Female; Humans; Male; Middle Aged
PubMed: 32351641
DOI: 10.1155/2020/7697214 -
Journal of Neural Transmission (Vienna,... Oct 2021Multiple system atrophy (MSA) is a challenging neurodegenerative disorder with a difficult and often inaccurate early diagnosis, still lacking effective treatment. It is... (Review)
Review
Multiple system atrophy (MSA) is a challenging neurodegenerative disorder with a difficult and often inaccurate early diagnosis, still lacking effective treatment. It is characterized by a highly variable clinical presentation with parkinsonism, cerebellar ataxia, autonomic dysfunction, and pyramidal signs, with a rapid progression and an aggressive clinical course. The definite MSA diagnosis is only possible post-mortem, when the presence of distinctive oligodendroglial cytoplasmic inclusions (GCIs), mainly composed of misfolded and aggregated α-Synuclein (α-Syn) is demonstrated. The process of α-Syn accumulation and aggregation within oligodendrocytes is accepted one of the main pathological events underlying MSA. However, MSA is considered a multifactorial disorder with multiple pathogenic events acting together including neuroinflammation, oxidative stress, and disrupted neurotrophic support, among others. The discussed here treatment approaches are based on our current understanding of the pathogenesis of MSA and the results of preclinical and clinical therapeutic studies conducted over the last 2 decades. We summarize leading disease-modifying approaches for MSA including targeting α-Syn pathology, modulation of neuroinflammation, and enhancement of neuroprotection. In conclusion, we outline some challenges related to the need to overcome the gap in translation between preclinical and clinical studies towards a successful disease modification in MSA.
Topics: Humans; Inclusion Bodies; Multiple System Atrophy; Oligodendroglia; alpha-Synuclein
PubMed: 34398313
DOI: 10.1007/s00702-021-02406-z -
Annals of Neurology Aug 2022Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting...
OBJECTIVE
Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD.
METHODS
Immunoglobulin G (IgG) from pediatric ROHHAD patients (n = 9), non-inflammatory individuals (n = 100) and relevant pediatric controls (n = 25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively.
RESULTS
Autoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed.
INTERPRETATION
Our results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291.
Topics: Autoantibodies; Autonomic Nervous System Diseases; Child; Endocrine System Diseases; Humans; Hypothalamic Diseases; Hypoventilation; Ligands; Paraneoplastic Syndromes, Nervous System; Syndrome
PubMed: 35466441
DOI: 10.1002/ana.26380