Gender differences in non-motor fluctuations in Parkinson's disease.

Non-motor symptoms (NMS) and Non-motor fluctuations (NMF) in Parkinson's Disease (PD) are common, involving several domains and affecting quality of life. Aim of the study is to estimate the burden of NMF in PD patients and to evaluate the possible gender effect. PD patients fulfilling the MDS-PD diagnostic criteria attending the "Parkinson's Disease and Movement Disorders Centre" of the University of Catania were evaluated using the Non-Motor Fluctuations Assessment (NoMoFA) Questionnaire. NoMoFA items were also grouped into the following domains: cognitive, mood, sleep/fatigue, dysautonomia, hallucination/perception and miscellaneous domains were identified. One-hundred and twenty-one patients with PD (67 men, 55.4%; mean age 70.2 ± 8.9 years, disease duration 8.3 ± 4.6 years) were evaluated. All PD patients reported at least one NMS, whereas 87 (71.9%) also reported NMF. "Feel sluggish or had low energy levels" (47.2%) along with "Feel excessively sleepy during the day" (40.0%) were the most common NMF reported in the whole sample. The majority of PD patients reported the presence of NMF during the OFF state (79, 65.3%). At multivariate analysis, NMF were positively associated with the female gender (adjusted OR 3.13; 95%CI 1.21-8.11 p-value 0.01). Women with PD had higher NMF scores especially in depression/anxiety, sleep/fatigue and dysautonomia domains. Our study reported the presence of a gender-related pattern in the frequency of NMS and NMF in PD patients, with female gender associated with a higher risk of developing NMF, highlighting the need for personalized treatment strategies when addressing NMF.

Parkinson's Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson's Disease Progression.

BACKGROUND: Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge. OBJECTIVE: To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones. METHODS: Using data from the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we monitored 25 milestones across six domains ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living"). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression. RESULTS: Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at the next annual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p < 0.0001), greater MDS-UPDRS total scores (p < 0.0001), higher GDS-15 depression scores (p = 0.0341), lower dopamine transporter binding (p = 0.0043), and lower CSF total α-synuclein levels (p = 0.0030). Symptomatic treatment was not significantly associated with reaching a milestone (p = 0.1639). CONCLUSION: Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.

Orthostatic hypotension in dementia with Lewy bodies: a meta-analysis of prospective studies.

PURPOSE: Orthostatic hypotension (OH), one of the supportive clinical features in the diagnosis of dementia with Lewy bodies (DLB), is a significant problem in advanced age because of its severe negative consequences. The aim of this meta-analysis was to investigate the prevalence and risk of OH in patients with DLB. METHODS: The indexes and databases cited to identify relevant studies were PubMed, ScienceDirect, Cochrane, and Web of Science. The keywords for the search were "Lewy body dementia" and "autonomic dysfunction" or "dysautonomia" or "postural hypotension" or "orthostatic hypotension." English-language articles published from January 1990 to April 2022 were searched. The Newcastle-Ottawa scale was applied to evaluate the quality of the studies. Odds ratios (OR) and risk ratios (RR) were extracted with 95% confidence intervals (CI) and combined using the random effects model after logarithmic transformation. The prevalence in the patients with DLB was also combined using the random effects model. RESULTS: Eighteen studies (10 case controls and 8 case series) were included to evaluate the prevalence of OH in patients with DLB. Higher rates of OH were found to be associated with DLB (OR 7.71, 95% CI 4.42, 13.44; p < 0.001), and 50.8% of 662 patients had OH. CONCLUSION: DLB increased the risk of OH by 3.62- to 7.71-fold compared to healthy controls. Therefore, it will be useful to evaluate postural blood pressure changes in the follow-up and treatment of patients with DLB.

Heart rate variability responses to cognitive stress in fibromyalgia are characterised by inadequate autonomous system stress responses: a clinical trial.

Fibromyalgia (FM) is associated with sympathetically dominant dysautonomia, but the connection between dysautonomia and FM symptoms is unclear. Dysautonomia can be analysed with heart rate variability (HRV) and it has been proposed that FM patients comprise subgroups with differing profiles of symptom severity. In our study, 51 female FM patients aged 18 to 65 years and 31 age-matched healthy female controls followed a 20-min protocol of alternating relaxation and cognitive stress (mental arithmetic). Heart rates and electrocardiograms were registered. The HRV measures of heart rate (HR), mean interval between heart beats (RRmean), root mean squared interval differences of successive beats (RMSSD), and the standard deviation of intervals between normal heart beats (SDNN) were analysed with generalized linear modelling. Features in HRV reactivity which differed between FM patients and controls were used to cluster the FM patients and cluster characteristics were analysed. FM patients had higher baseline HR (72.3 [SD 12.7] vs 64.5 [7.80], p < 0.001) and lower RRmean (0.844 [0.134] vs 0.934 [0.118], p = 0.002), compared with controls. They also reacted to repeated cognitive stress with an attenuated rise in HR (- 4.41 [95% CI - 7.88 to - 0.93], p = 0.013) and attenuated decrease of RRmean (0.06 [95 CI 0.03 to 0.09], p < 0.001), compared with controls. Clustering of FM patients by HRV reactivity resulted in three clusters characterised by (1) normal levels of HRV and HRV reactivity with low levels of depressive mood and anxiety, (2) reduced levels of HRV and impaired HRV reactivity with increased levels of depressive mood and high levels of anxiety, and (3) lowest HRV and most impaired HRV reactivity with the highest scores for depressive mood and anxiety. Our results show that FM patients have lower HRV than healthy controls and their autonomous reactions to cognitive stress are attenuated. Dysautonomia in FM associates with mood disturbance. Trial registration ClinicalTrials.gov (NCT03300635). Registered October 3 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03300635 .

Dysautonomia in people with epilepsy: A scoping review.

BACKGROUND: Epilepsy is one of the most common neurological diseases and has high morbidity and mortality. Multiple methods for assessing dysautonomia have been reported; however, the patient characteristics and epilepsy features that drive any method selection are unclear. People with epilepsy (PWE) can experience sudden unexpected death in epilepsy (SUDEP) and one reason can be dysautonomia. If dysautonomia can be detected in PWE before a severe event, then it could complement and redirect patient treatment and monitoring. OBJECTIVE: To map the available literature on dysautonomia in PWE and describe patients' characteristics and methods used to evaluate dysautonomia. METHODS: We performed a scoping literature review. We searched PubMed, Scopus, Embase, and hand searched starting from the first registry in the literature until August 2019. Studies were independently assessed by three authors and two epileptologists. We present data in tables and summarize information according to the following structure: population, concepts, and context. RESULTS: Thirty-five studies were included in the analysis with epidemiological designs including case reports (23), cross-sectional studies (4), case‒controls (7), and cohort studies (1). A total of 618 patients were enrolled. Heart rate variability, arrhythmia, blood pressure, the tilt-table test, polysomnography, respiratory function, and magnetic resonance imaging were the methods most commonly used to assess dysautonomia in PWE. A detailed description of the heart rate variability assessment is presented. CONCLUSIONS: This review provides a broad description of the available literature identifying clinical findings, the most frequently reported assessment measurements of dysautonomia, in temporal lobe epilepsy and extratemporal epilepsies.

Body-First Subtype of Parkinson's Disease with Probable REM-Sleep Behavior Disorder Is Associated with Non-Motor Dominant Phenotype.

BACKGROUND: The hypothesis of body-first vs. brain-first subtype of PD has been proposed with REM-Sleep behavior disorder (RBD) defining the former. The body-first PD presumes an involvement of the brainstem in the pathogenic process with higher burden of autonomic dysfunction. OBJECTIVE: To identify distinctive clinical subtypes of idiopathic Parkinson's disease (iPD) in line with the formerly proposed concept of body-first vs. brain-first subtypes in PD, we analyzed the presence of probable RBD (pRBD), sex, and the APOEɛ4 carrier status as potential sub-group stratifiers. METHODS: A total of 400 iPD patients were included in the cross-sectional analysis from the baseline dataset with a completed RBD Screening Questionnaire (RBDSQ) for classifying as pRBD by using the cut-off RBDSQ≥6. Multiple regression models were applied to explore (i) the effect of pRBD on clinical outcomes adjusted for disease duration and age, (ii) the effect of sex on pRBD, and (iii) the association of APOEɛ4 and pRBD. RESULTS: iPD-pRBD was significantly associated with autonomic dysfunction (SCOPA-AUT), level of depressive symptoms (BDI-I), MDS-UPDRS I, hallucinations, and constipation, whereas significantly negatively associated with quality of life (PDQ-39) and sleep (PDSS). No significant association between sex and pRBD or APOE ɛ4 and pRBD in iPD was found nor did we determine a significant effect of APOE ɛ4 on the PD phenotype. CONCLUSION: We identified an RBD-specific PD endophenotype, characterized by predominant autonomic dysfunction, hallucinations, and depression, corroborating the concept of a distinctive body-first subtype of PD. We did not observe a significant association between APOE ɛ4 and pRBD suggesting both factors having an independent effect on cognitive decline in iPD.

Selected autonomic signs and symptoms as risk markers for phenoconversion and functional dependence in prodromal Parkinson's disease.

PURPOSE: To determine whether dysautonomia can stratify individuals with other prodromal markers of Parkinson's disease (PD) for risk of phenoconversion and functional decline, which may help identify subpopulations appropriate for experimental studies. METHODS: Data were obtained from Parkinson's Progression Markers Initiative. Cohorts without PD but with at-risk features were included (hyposmia and/or rapid-eye-movement-sleep behavior disorder, LRRK2 gene mutation, GBA gene mutation). Dysautonomia measures included Scales-for-Outcomes-in-Parkinson's-Disease Autonomic (SCOPA-AUT), seven SCOPA-AUT subscales, and cardiovascular dysfunction (supine hypertension, low pulse pressure, neurogenic orthostatic hypotension). Outcome measures were phenoconversion and Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤ 70, which indicates functional dependence. Cox proportional-hazards regression was used to evaluate survival to phenoconversion/SE-ADL ≤ 70 for each dysautonomia measure. If a significant association was identified, a likelihood-ratio test was employed to evaluate whether a significant interaction existed between the measure and cohort. If so, regression analysis was repeated stratified by cohort. RESULTS: Median follow-up was 30 months. On multivariable analysis, gastrointestinal and female sexual dysfunction subscales were associated with increased risk of phenoconversion, while the cardiovascular subscale and neurogenic orthostatic hypotension were associated with increased risk of SE-ADL ≤ 70; respective hazard ratios (95% confidence intervals) were 1.13 (1.01-1.27), 3.26 (1.39-7.61), 1.87 (1.16-2.99), 5.45 (1.40-21.25). Only the association between the cardiovascular subscale and SE-ADL ≤ 70 was modified by cohort. CONCLUSIONS: Symptoms of gastrointestinal and female sexual dysfunction predict phenoconversion in individuals with other risk markers for PD, while signs and symptoms of cardiovascular dysfunction may be associated with functional decline.

CT-Guided Celiac Ganglion Block for Neurogenic Gastrointestinal Dysmotility.

PURPOSE: To determine whether celiac ganglion block can serve as a diagnostic test for dysautonomia as the cause of gastrointestinal dysmotility-related symptoms. MATERIALS AND METHODS: This was an institutional review board-approved, prospective, single-arm, registered study, from January 2020 to May 2021, and included patients aged 14-85 years with gastrointestinal symptoms of food intolerance, abdominal pain, or angina. Patients with nonneurogenic causes (ie, chronic cholecystitis, peptic ulcer disease, gastroesophageal reflux, and malabsorption syndrome) were excluded. All 15 patients underwent computed tomography-guided celiac ganglion block with 100 mg of liposomal bupivacaine. Patients filled out the dysautonomia-validated questionnaire Composite Autonomic Symptom Score 31 (COMPASS-31) before and after intervention. Differences (before vs after) were compared with the exact permutation method. RESULTS: Fifteen women (median age, 17 years; range, 14-41 years) were included. Average COMPASS-31 score improved significantly, from baseline 11 (SD ± 2.8) to 4 (SD ± 1.9) (improvement, 7 points ± 2.8; P < .001). All patients reported significant reduction in abdominal angina. Fourteen of the 15 patients (93%) reported complete resolution, and 14 of 15 (93%) reported a significant reduction in non-postprandial abdominal pain (P < .01). Only 1 patient reported no improvement. Eight of those 14 patients (57%) reported complete resolution of abdominal pain. There was a significant improvement in functional scores (vomiting, P = .01; constipation frequency, P = .02; constipation severity, P < .01; and nausea, P < .01). The rate of minor and major adverse events was 13% and 0%, respectively, per the Society of Interventional Radiology adverse event classification. CONCLUSIONS: Celiac ganglion block is a safe diagnostic tool for confirming dysautonomia as the underlying condition in patients with gastrointestinal dysmotility-related symptoms. It could provide early diagnosis, lead to definitive treatment (ganglionectomy) earlier, or obviate unnecessary surgery.

Associations of cognitive dysfunction with motor and non-motor symptoms in patients with de novo Parkinson's disease.

The risk factors of mild cognitive impairment (MCI) in patients with de novo Parkinson's disease (PD) remain unclear. Therefore, the objective of this study was to compare motor and non-motor symptoms between de novo patients with PD with and without MCI. Moreover, detailed relationships between each cognitive deficit and other clinical characteristics in de novo patients with PD were investigated. Consecutive patients with de novo PD were retrospectively enrolled in this study. Motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part-III and the Hoehn and Yahr (HY) stage. Non-motor symptoms including depression, anxiety, fatigue, and autonomic dysfunction were measured using representative questionnaires. Motor symptoms, depression, and dysautonomia were associated with MCI in de novo patients with PD. Compared with the non-MCI group with PD, the MCI group with PD had higher scores of UPDRS-III, HY stage, depression, and dysautonomia, but not fatigue or anxiety. Both UPDRS-III and HY stage were significantly linked to all cognitive deficits except attention. Logistic regression analysis showed that depression was associated with memory, visuospatial, and executive impairment, and dysautonomia was related to visuospatial and executive impairment. The results of this study suggest that cognitive impairment in PD might have a different relationship pattern to the motor and some non-motor symptoms.

Diagnosis of colonic dysmotility associated with autonomic dysfunction in patients with chronic refractory constipation.

We report the first study assessing human colon manometric features and their correlations with changes in autonomic functioning in patients with refractory chronic constipation prior to consideration of surgical intervention. High-resolution colonic manometry (HRCM) with simultaneous heart rate variability (HRV) was performed in 14 patients, and the resulting features were compared to healthy subjects. Patients were categorized into three groups that had normal, weak, or no high amplitude propagating pressure waves (HAPWs) to any intervention. We found mild vagal pathway impairment presented as lower HAPW amplitude in the proximal colon in response to proximal colon balloon distention. Left colon dysmotility was observed in 71% of patients, with features of (1) less left colon HAPWs, (2) lower left colon HAPW amplitudes (69.8 vs 102.3 mmHg), (3) impaired coloanal coordination, (4) left colon hypertonicity in patients with coccyx injury. Patients showed the following autonomic dysfunction: (1) high sympathetic tone at baseline, (2) high sympathetic reactivity to active standing and meal, (3) correlation of low parasympathetic reactivity to the meal with absence of the coloanal reflex, (4) lower parasympathetic and higher sympathetic activity during occurrence of HAPWs. In conclusion, left colon dysmotility and high sympathetic tone and reactivity, more so than vagal pathway impairment, play important roles in refractory chronic constipation and suggests sacral neuromodulation as a possible treatment.

Reduction of proteinuria in patients with diabetes kidney disease and dysautonomia through measures aimed at controlling supine hypertension.

In diabetes kidney disease (DKD), orthostatic hypotension and supine hypertension often coexist, which, when uncontrolled, contributes to the progression of proteinuria and renal dysfunction. Chronotherapy and elevation of the head of the bed during sleep are feasible clinical measures and could contribute to the control of supine hypertension and proteinuria in this group of patients. This study consists of a series of cases, in which nine consecutive patients with DKD, dysautonomia and supine hypertension (intervention group) were instructed to use chronotherapy and inclination of the head of the bed in six degrees during sleep. These patients were compared with a historical control group. The primary outcome was proteinuria behavior. The intervention group had a significant drop in proteinuria levels, while there was an increase in proteinuria in the control group (variation in the proteinuria/creatininuria index in an isolated sample from the intervention group: -6.60 ± 3.90 g/g; variation in the group control: +1.70 ± 7.10 g/g, p = 0.008). Chronotherapy and six-degree inclination of the head of the bed during sleep were associated with a significant decrease in proteinuria in patients in the intervention group, with conversion of nephrotic into non-nephrotic proteinuria in most of these patients.

[Current concepts about autonomic dysfunction in patients with epilepsy]. / Sovremennye predstavleniya o vegetativnoi disfunktsii u patsientov s epilepsiei.

Autonomic dysfunction is frequently observed in people with epilepsy. Ictal and postictal dysautonomia is not only manifestation of autonomic seizures, but could be a life threatening condition in some cases and contribute to sudden unexpected death (SUDEP). Interictal decrease of autonomic activity is associated with duration and severity of epilepsy, it is the most prominent in focal and drug-resistant epilepsy. Progress in our understanding of the underlying mechanisms, development of the autonomic assessment methods, and its integration in novel technical solutions for seizure detection will improve the quality of care for people with epilepsy.

Thoracic VGluT2+ Spinal Interneurons Regulate Structural and Functional Plasticity of Sympathetic Networks after High-Level Spinal Cord Injury.

Traumatic spinal cord injury (SCI) above the major spinal sympathetic outflow (T6 level) disinhibits sympathetic neurons from supraspinal control, causing systems-wide "dysautonomia." We recently showed that remarkable structural remodeling and plasticity occurs within spinal sympathetic circuitry, creating abnormal sympathetic reflexes that exacerbate dysautonomia over time. As an example, thoracic VGluT2+ spinal interneurons (SpINs) become structurally and functionally integrated with neurons that comprise the spinal-splenic sympathetic network and immunological dysfunction becomes progressively worse after SCI. To test whether the onset and progression of SCI-induced sympathetic plasticity is neuron activity dependent, we selectively inhibited (or excited) thoracic VGluT2+ interneurons using chemogenetics. New data show that silencing VGluT2+ interneurons in female and male mice with a T3 SCI, using hM4Di designer receptors exclusively activated by designer drugs (Gi DREADDs), blocks structural plasticity and the development of dysautonomia. Specifically, silencing VGluT2+ interneurons prevents the structural remodeling of spinal sympathetic networks that project to lymphoid and endocrine organs, reduces the frequency of spontaneous autonomic dysreflexia (AD), and reduces the severity of experimentally induced AD. Features of SCI-induced structural plasticity can be recapitulated in the intact spinal cord by activating excitatory hM3Dq-DREADDs in VGluT2+ interneurons. Collectively, these data implicate VGluT2+ excitatory SpINs in the onset and propagation of SCI-induced structural plasticity and dysautonomia, and reveal the potential for neuromodulation to block or reduce dysautonomia after severe high-level SCI.SIGNIFICANCE STATEMENT In response to stress or dangerous stimuli, autonomic spinal neurons coordinate a "fight or flight" response marked by increased cardiac output and release of stress hormones. After a spinal cord injury (SCI), normally harmless stimuli like bladder filling can result in a "false" fight or flight response, causing pathological changes throughout the body. We show that progressive hypertension and immune suppression develop after SCI because thoracic excitatory VGluT2+ spinal interneurons (SpINs) provoke structural remodeling in autonomic networks within below-lesion spinal levels. These pathological changes can be prevented in SCI mice or phenocopied in uninjured mice using chemogenetics to selectively manipulate activity in VGluT2+ SpINs. Targeted neuromodulation of SpINs could prevent structural plasticity and subsequent autonomic dysfunction in people with SCI.

Heart rate variability and sympathetic skin response for the assessment of autonomic dysfunction in leucine-rich repeat kinase 2 associated Parkinson's disease.

OBJECTIVES: We aimed to assess and compare autonomic function in Parkinson's disease (PD) associated with the leucine-rich repeat kinase (LRRK2) G2019S mutation (LRRK2-PD) and non-LRRK2 PD, by the study of heart rate variability (HRV) and sympathetic skin responses (SSR). METHODS: In a cross-sectional three-year study, fifty LRRK2-PD and fifty clinically matched non-LRRK2 PD patients were included. Cardiac parasympathetic functions were assessed using heart rate variation to deep breathing (HR-DB), to the Valsalva maneuver (HR-V) and to standing (HR-S) and the sympathetic autonomic system by sympathetic skin responses (SSR). RESULTS: Neurophysiological, parasympathetic and sympathetic dysautonomia were found in 78%, 69% and 37% of all PD patients respectively. Rates of dysautonomia in the LRRK2-PD and non-LRRK2 PD patient subgroups were 76% vs 80% (p = 0.405) for neurophysiological, 62% vs 76% (p = 0.123) for parasympathetic and 38% vs 36% (p = 0.500) for sympathetic dysautonomia. HR-S was the most frequently altered parameter in both groups, and was significantly associated with the tremor-dominant (TD) motor phenotype of PD in the total cohort (p = 0.004) and in LRRK2-PD (p = 0.015). In LRRK2-PD patients, female gender was associated with parasympathetic dysfunction (p = 0.024), and with altered HR-DB (p = 0.022). Early-onset parkinsonism was also significantly associated with preserved neurophysiological autonomic functions (p = 0.044) in LRRK2-PD. In non-LRRK2 PD patients, male gender was associated with early parasympathetic (p = 0.043) and sympathetic dysfunction (p = 0.007). CONCLUSION: Our study showed a roughly similar neurophysiological autonomic profile in non-LRRK2 PD and LRRK2-PD. The latter had some peculiarities with more marked parasympathetic dysfunction and more altered HR-DB in females, more altered HR-S in the TD-motor phenotype, and preserved autonomic functions in early-onset parkinsonism. These preliminary findings would require further investigations on larger genetically homogeneous cohorts to explore the multiple facets of autonomic dysfunction in PD.

Dysautonomia Following Tetanus, Diphtheria, and Pertussis Vaccine (Tdap): The First Case of Extreme Cachexia Caused by Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA Syndrome) in a Human.

Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA; Shoenfeld's syndrome) comprehends a group of autoimmune conditions that flourish in genetically predisposed individuals, following an external stimulus by the so-called adjuvants. Many adjuvants were described, such as vaccines, aluminum and other metals, silicone, tattoos, among others. Those conditions entail defined diseases, such as sarcoidosis and Sjogren's syndrome, and generalized complex symptoms, for example, fatigue, sleep disturbance, orthostatic intolerance, and other dysautonomic manifestations. Those complaints were previously associated with autoantibodies against nervous system autonomic receptors, especially antibeta 1 adrenergic receptor antibodies, suggesting the autoimmune component of the condition. Here we report on a case of an 18-year-old woman who presented with extreme cachexia due to severe dysautonomia caused by the ASIA syndrome induced by the tetanus, diphtheria, and pertussis vaccine (Tdap).

Clinical and Dopamine Depletion Patterns in Hyposmia- and Dysautonomia-Dominant Parkinson's Disease.

BACKGROUND: Olfactory or autonomic dysfunction is one of the earliest prodromal symptoms of Parkinson's disease (PD). It has not been investigated whether PD patients have different phenotypes depending on the presence of these prodromal symptoms. OBJECTIVE: To investigate whether hyposmia-dominant and dysautonomia-dominant patients with early PD have different clinical manifestations and nigrostriatal degeneration. METHODS: This cross-sectional study recruited 168 drug-naive PD patients and 34 control subjects. PD patients were classified as patients without hyposmia and dysautonomia (PD-H-D-, n = 51), hyposmia-dominant patients (PD-H+D-, n = 36), dysautonomia-dominant patients (PD-H-D+, n = 33), and patients with hyposmia and dysautonomia (PD-H+D+, n = 48). We then compared the baseline clinical characteristics, striatal specific to non-specific binding ratio (SNBR), neuropsychological performance, and neuropsychiatric symptoms among the groups. RESULTS: The PD-H+D-group had a lower SNBR in the ventral striatum (p = 0.013), a greater asymmetric index of striatal SNBRs, and higher prevalence of apathy (p = 0.021) than the PD-H-D+ group. The PD-H-D+ group had older age at onset (p = 0.043) and a higher prevalence of REM sleep behavior disorder (p = 0.041) than the PD-H+D-group. The PD-H+D+ group had higher motor deficits, lower cognitive function, and lower SNBRs in all striatal subregions than the PD-H-D-group. Decreased SNBRs in the anterior caudate, posterior caudate, and ventral striatum were associated with the presence of apathy. CONCLUSION: The present study suggests that hyposmia-dominant and dysautonomia-dominant PD have different clinical characteristics and patterns of striatal dopamine depletion.

Clinical characterization of dysautonomia in long COVID-19 patients.

Increasing numbers of COVID-19 patients, continue to experience symptoms months after recovering from mild cases of COVID-19. Amongst these symptoms, several are related to neurological manifestations, including fatigue, anosmia, hypogeusia, headaches and hypoxia. However, the involvement of the autonomic nervous system, expressed by a dysautonomia, which can aggregate all these neurological symptoms has not been prominently reported. Here, we hypothesize that dysautonomia, could occur in secondary COVID-19 infection, also referred to as "long COVID" infection. 39 participants were included from December 2020 to January 2021 for assessment by the Department of physical medicine to enhance their physical capabilities: 12 participants with COVID-19 diagnosis and fatigue, 15 participants with COVID-19 diagnosis without fatigue and 12 control participants without COVID-19 diagnosis and without fatigue. Heart rate variability (HRV) during a change in position is commonly measured to diagnose autonomic dysregulation. In this cohort, to reflect HRV, parasympathetic/sympathetic balance was estimated using the NOL index, a multiparameter artificial intelligence-driven index calculated from extracted physiological signals by the PMD-200 pain monitoring system. Repeated-measures mixed-models testing group effect were performed to analyze NOL index changes over time between groups. A significant NOL index dissociation over time between long COVID-19 participants with fatigue and control participants was observed (p = 0.046). A trend towards significant NOL index dissociation over time was observed between long COVID-19 participants without fatigue and control participants (p = 0.109). No difference over time was observed between the two groups of long COVID-19 participants (p = 0.904). Long COVID-19 participants with fatigue may exhibit a dysautonomia characterized by dysregulation of the HRV, that is reflected by the NOL index measurements, compared to control participants. Dysautonomia may explain the persistent symptoms observed in long COVID-19 patients, such as fatigue and hypoxia. Trial registration: The study was approved by the Foch IRB: IRB00012437 (Approval Number: 20-12-02) on December 16, 2020.

Dysautonomia in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders is associated with exercise intolerance and cardiac atrophy.

Dysautonomia is a recognized manifestation in patients with joint hypermobility (JH) disorders. Symptoms can be highly debilitating and commonly include physical deconditioning and poor aerobic fitness. In this study, the prevalence of dysautonomia, range of associated symptoms, patient-reported physical activity levels, and echocardiographic features were assessed retrospectively in a cohort of 144 patients (94% female) with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD). Echocardiographic parameters of left ventricular size and function were compared between patients with and without dysautonomia as well as to reported values from healthy controls. Dysautonomia was identified in 65% of female and 44% of male subjects and was associated with a high burden of symptomatology, most commonly exercise intolerance (78%). Exercise capacity was limited by dysautonomia, often postural symptoms, in half of all patients. We observed a reduction in physical activity following the onset or significant flare of hEDS/HSD, most strikingly noting the proportion of dysautonomic patients with sedentary lifestyle, which increased from 44% to 85%. JH-related dysautonomia was associated with smaller cardiac chamber sizes, consistent with the previous reports in positional orthostatic tachycardia syndrome. Dysautonomia is prevalent in patients with hEDS/HSD, and exercise intolerance is a key feature and leads to drastic decline in physical activity. Unfavorable cardiac geometry may underlie dysautonomia symptoms and may be due to cardiac atrophy in the setting of aerobic deconditioning.

Cardiovascular dysautonomia in Achalasia Patients: Blood pressure and heart rate variability alterations.

Achalasia is a disease characterized by the inability to relax the esophageal sphincter due to a degeneration of the parasympathetic ganglion cells located in the wall of the thoracic esophagus. Achalasia has been associated with extraesophageal dysmotility, suggesting alterations of the autonomic nervous system (ANS) that extend beyond the esophagus. The purpose of the present contribution is to investigate whether achalasia may be interpreted as the esophageal manifestation of a more generalized disturbance of the ANS which includes alterations of heart rate and/or blood pressure. Therefore simultaneous non-invasive records of the heart inter-beat intervals (IBI) and beat-to-beat systolic blood pressure (SBP) of 14 patients (9 female, 5 male) with achalasia were compared with the records of 34 rigorously screened healthy control subjects (17 female, 17 male) in three different conditions: supine, standing up, and controlled breathing at 0.1 Hz, using a variety of measures in the time and spectral domains. Significant differences in heart rate variability (HRV) and blood pressure variability (BPV) were observed which seem to be due to cardiovagal damage to the heart, i.e., a failure of the ANS, as expected according to our hypothesis. This non-invasive methodology can be employed as an auxiliary clinical protocol to study etiology and evolution of achalasia, and other pathologies that damage ANS.