Search

Background: The role of peripheral phosphorylated-α-Synuclein (p-α-syn) deposition on nerve degeneration in synucleinopathies is still unknown.Objective: To assess the cutaneous neural distribution of p-α-Syn deposits and its correlation with clinical data and with morphology and function of cutaneous sensory and autonomic nerves in early Parkinson’s disease (PD) and multiple system atrophy-parkinson type (MSA-p).Methods: We recruited 57 PD (F/M = 21/36; age 63.5±9.4 years) and 43 MSA-p (F/M = 16/27; age 62.3±9.0 years) patients within 2 years from motor symptoms. We applied questionnaires and clinical scales, sensory thresholds, and sudomotor testing to assess severity of motor and non-motor involvement and sensory and autonomic dysfunction. We quantified, in skin biopsy from thigh, leg, and fingertip, epidermal, pilomotor, and sudomotor nerve fibers, Meissner corpuscles and intrapapillary myelinated endings and the neural distribution of p-α-syn deposits.Results: Compared to controls, we found a cutaneous denervation paralleling functional and clinical impairment. Sensory and autonomic denervation was more severe in MSA-p than in PD. Deposits of p-α-syn were found in the majority of patients, with no significant differences among sites in both groups. Higher occurrence of p-α-syn deposits in autonomic nerves differentiated (p< 0.01) PD from MSA-p. p-α-syn deposits correlated positively with sudomotor function, epidermal, pilomotor and sudomotor nerve densities, and inversely with non-motor symptoms and disease progression.Conclusion: Our work demonstrated an early peripheral sensory and autonomic involvement in synucleinopathies, more severe in MSA-p than in PD. Higher p-α-syn deposits in autonomic nerves differentiated PD from MSA-p. p-α-syn deposits were associated with preserved innervation and slower disease progression.

The role of peripheral phosphorylated-α-Synuclein (p-α-syn) deposition on nerve degeneration in synucleinopathies is still unknown. To assess the cutaneous neural distribution of p-α-Syn deposits and its correlation with clinical data and with morphology and function of cutaneous sensory and autonomic nerves in early Parkinson’s disease (PD) and multiple system atrophy-parkinson type (MSA-p). We recruited 57 PD (F/M = 21/36; age 63.5±9.4 years) and 43 MSA-p (F/M = 16/27; age 62.3±9.0 years) patients within 2 years from motor symptoms. We applied questionnaires and clinical scales, sensory thresholds, and sudomotor testing to assess severity of motor and non-motor involvement and sensory and autonomic dysfunction. We quantified, in skin biopsy from thigh, leg, and fingertip, epidermal, pilomotor, and sudomotor nerve fibers, Meissner corpuscles and intrapapillary myelinated endings and the neural distribution of p-α-syn deposits. Compared to controls, we found a cutaneous denervation paralleling functional and clinical impairment. Sensory and autonomic denervation was more severe in MSA-p than in PD. Deposits of p-α-syn were found in the majority of patients, with no significant differences among sites in both groups. Higher occurrence of p-α-syn deposits in autonomic nerves differentiated (p < 0.01) PD from MSA-p. p-α-syn deposits correlated positively with sudomotor function, epidermal, pilomotor and sudomotor nerve densities, and inversely with non-motor symptoms and disease progression. Our work demonstrated an early peripheral sensory and autonomic involvement in synucleinopathies, more severe in MSA-p than in PD. Higher p-α-syn deposits in autonomic nerves differentiated PD from MSA-p. p-α-syn deposits were associated with preserved innervation and slower disease progression.

Background: According to Braak staging of Parkinson's disease (PD), detection of autonomic dysfunction would help with early diagnosis of PD. Objective: To determine whether the autonomic nervous system is involved in the early stage of PD, we evaluated cardiovascular and sudomotor function in early untreated PD patients. Methods: Orthostatic blood pressure regulation, heart rate variability, skin vasomotor function, and palmar sympathetic sweat responses were examined in 50 early untreated PD patients and 20 healthy control subjects. Results: The mean decrease in systolic blood pressure during head-up tilt in PD patients was mildly but significantly larger than in controls (p = 0.0001). There were no differences between the 2 groups in heart rate variability, with analysis of low frequency (LF; mediated by baroreflex feedback), and high frequency (HF; mainly reflecting parasympathetic vagal) modulation. However, LF/HF, an index of sympatho-parasympathetic balance, was lower in the PD group than in controls (p = 0.02). Amplitudes of palmar sweat responses to deep inspiration (p = 0.004), mental arithmetic (p = 0.01), and exercise (p = 0.01) in PD patients were lower than in controls, with negative correlations with motor severity. Amplitudes of palmar skin vasomotor reflexes in PD patients did not differ from controls. Conclusions: Our study indicates impairment of sympathetic cardiovascular and sudomotor function with orthostatic dysregulation of blood pressure control, reduced LF/HF and reduction in palm sweat responses even in early untreated PD patients.

IntroductionOrthostatic hypotension (OH) and supine hypertension (SH) are prevalent in alpha-synucle- inopathies, posing a therapeutic dilemma as OH treatment may worsen SH. We aimed to characterise SH in pure autonomic failure (PAF), multiple system atrophy (MSA), and Lewy body disorders (LBD: Parkinson’s disease and Dementia with Lewy bodies).Methods166 patients (72 PAF, 59 MSA, 35 LBD) underwent cardiovascular autonomic testing and 24hr- ambulatory blood pressure monitoring (24hr-ABPM). Demographic, clinical features, medications and cardiovascular autonomic biomarkers were compared.ResultsSH was present in more than half of patients with PAF, MSA and LBD (56%, 51% and 50%, respec- tively) without anti-hypotensive medications. Supine pre-stand BP during 24hr-ABPM detected SH with 60% sensitivity and 86% specificity [area under the curve 0.73 (95%CI 0.66-0.81)]. Supine noradrenaline levels were significantly higher in MSA vs PAF and LBD (268 vs 183 and 210 pg/ml, p<0.01). There was a strong correlation between OH, SH and nocturnal hypertension after adjusting for age, anti-hypotensive medications and supine noradrenaline levels (R2=0.48, p<0.01).ConclusionsSH and nocturnal hypertension commonly co-exist and are independently associated with OH in alpha-synucleinopathies. 24hr-ABPM is useful in detecting SH in these patients. The pathophysiology of SH is likely to be heterogeneous and not entirely explained by residual sympathetic tone.

IntroductionCardiovascular autonomic failure is the hallmark finding in Pure autonomic failure (PAF) however other autonomic functions are likely to be affected. This study aims to characterise genitourinary dysfunction in PAF patients and explore their relationship with cardiovascular autonomic dysfunction.MethodsPAF patients who underwent cardiovascular autonomic testing completed self-administered questionnaires evaluating urinary and sexual symptoms and a 3-day bladder diary measuring fluid intake and urine output. Demographic, clinical features, disease duration and related medical comorbidities were assessed.Results25 PAF patients (10 males) were recruited (mean age 71+8 years; disease duration 13+8 years). 96% (24/25) reported lower urinary tract symptoms, most commonly overactive bladder symptoms (92%) followed by low stream (80%) and stress incontinence (52%). 4(16%) patients required catheterisation. 19/22 (86%) had nocturnal polyuria (NP), defined as NP index >0.3 (nocturnal urine volume/24-hour urine volume), mean NP index 0.45 (range, 0.20-0.73). There were no significant correlations between BP drops on head-up tilt, supine hypertension, respiratory sinus arrhythmia, Valsalva ratio or disease duration with the degree of nocturnal polyuria and need for catheterisation (p>0.05).ConclusionsNP and genitourinary symptoms are common in PAF. The pathophysiology of NP in PAF is likely to be multifactorial and may not only be explained by cardiovascular autonomic failure.

Post-coronavirus disease 19 (COVID-19) syndrome has substantial health and economic implications. It is multi-systemic, with prevalent autonomic symptoms. Understanding presentations and potential autonomic causes may help guide treatment strategies and recovery.All patients with a suspected or confirmed history of COVID-19 infection who underwent autonomic testing between May 2020 and October 2021 were reviewed retrospectively.We evaluated 62 patients (20 male, 42 female, mean age of 41.38 ±11.52). COVID-19 was PCR confirmed in 15 patients (26%), and five (8%) required acute hospital intervention. Most common symptoms included palpitations (81%), light-headedness/dizziness (62%), dyspnoea (48%), fatigue (46%), or cognitive symptoms(33%)Autonomic testing showed normal blood pressure responses to pressor stimuli, a mean respiratory sinus arrhythmia of 18.89b/m, and Valsalva ratio of 2.09. Postural tachycardia syndrome (PoTS) was diagnosed in 12 patients, autonomically mediated syncope (AMS) in 11, neurogenic orthostatic hypotension (NOH) in two, and initial orthostatic hypotension (IOH) in seven.Normal supine and upright plasma noradrenaline levels were measured in 34 patients (mean 283.38 pg/ml supine; 472.43pg/ml tilted).Autonomic testing was reassuring (PoTS and syncope) in the majority with abnormal testing (n=32, or 52%). Further phenotyping of PoTS to exclude neuropathic pathology may be needed. IOH and OH are important considerations.

BackgroundSurvivors of moderate-severe traumatic brain injury (msTBI) frequently experience trouble- some unexplained somatic symptoms, which may be attributable to autonomic dysfunction.MethodsWe conducted two cohort studies. Cohort 1 comprises msTBI patients (with controls) prospec- tively recruited from a regional referral TBI outpatient clinic, in whom we assessed subjective burden of autonomic symptoms using the Composite Autonomic Symptom Score (COMPASS31) questionnaire. Cohort 2 comprises msTBI patients who had clinical autonomic function testing, retrospectively identified from referrals to a national referral autonomics unit.ResultsCohort 1 comprises 39 msTBI patients (10F:20M, median age 40 years, range 19-76), with median time since injury 19 months (range 6-299), and 44 controls (22F:22M, median age 45, range 25-71). Patients had significantly higher mean scores than controls in the weighted total COMPASS-31 score (p<0.001), and also gastrointestinal, orthostatic and secretomotor subscores (corrected p<0.05). Total COMPASS31 score inversely correlated with subjective rating of general health (p<0.001, rs=-0.84). Cohort 2 comprises 18 msTBI patients (7F:11M, median age 44 years, range 21-64), with median time between injury and testing 57.5 months (range 2-416). Clinical autonomic function testing revealed a broad spectrum of autonomic dysfunction in 13/18 patients.DiscussionOur results provide evidence for clinically relevant autonomic dysfunction after msTBI, even at the chronic stage. We advocate for routine enquiry about potential autonomic symptoms, and demons- trate the utility of formal autonomic testing in providing diagnoses.

IntroductionCardiovascular autonomic failure and neurogenic orthostatic hypotension (nOH) are common and disabling features of Parkinson’s disease (PD) and multiple system atrophy (MSA). Compared to PD, MSA is considered a primarily central alpha-synucleinopathy.AimTo characterise the relationship between cardiovascular autonomic failure and cutaneous autonomic and somatic innervation in early PD and MSA.MethodsFifty-five patients (37 PD, 18 MSA) within 2 years of motor onset underwent: 1) cardiovascular autonomic testing 2) plasma catecholamines 3) distal leg skin biopsies for quantification of intraepider- mal (IENF), pilomotor (PNF), and sudomotor nerve fibres (SNF), and 4) COMPASS-31 autonomic symptom questionnaires.Results75% with MSA and 36% with PD had OH ≥20/10mmHg. Supine noradrenaline was significantly higher in MSA vs PD with OH (264[241-304] vs 158[154-190] pg/ml, P=.03). Compared to patients without OH, patients with OH had significantly reduced cutaneous innervation (3.1[1.3-6.0] vs 7.4[5.3-8.7] IENF/mm, P=.008; 2.8[0-8.2] vs 11.8[6.5-23.4] PNF/mm, P=.007; and 0.9[0.1-1.4] vs 1.6[1.4-1.8] nm SNF/µm3,P=.002), with no significant differences between MSA and PD with OH subgroups. Markers of cardiovas- cular autonomic failure, including severity of OH, correlated significantly with cutaneous denervation (IENF: ρ=-0.47, P=.007; PNF: ρ=-0.51, P=.004; SNF: ρ=-0.51, P=.006), and patient symptoms (COMPASS-31: ρ=0.57, P=.002).ConclusionCardiovascular autonomic failure was associated with cutaneous denervation in both MSA and PD. Postganglionic denervation may contribute to the pathophysiology of cardiovascular autonomic failure and nOH, and influence response to therapeutic agents for nOH.

BackgroundNon-motor features can be presenting symptoms and often precede the motor features in patients with multiple system atrophy (MSA). However there have been no studies specifically looking at the conversion time, clinical features and survival rate in autopsy-confirmed MSA patients.MethodsMedical records of 47 autopsy-confirmed MSA cases at the Queen Square Brain Bank who underwent clinical examination and cardiovascular autonomic testing at the National Hospital for Neurology were reviewed.Results15/47 (32%, M:F/9:6) MSA patients had non-motor autonomic features as an initial presentation before developing motor symptoms. Mean pre-motor phase duration was 3 (range 1–6) years. Among these 15 patients, the most common pre-motor features (87%) were genitourinary (erectile dysfunction in 7, bladder dysfunction in 6 patients); pre-motor symptomatic orthostatic hypotension (OH) and REM sleep behavioural disorder (RBD) occurred in one patient each. 5/15 patients developed cardiovascular autonomic failure and were initially diagnosed with pure autonomic failure (PAF). There was no difference in age of onset between patients presenting with motor and pre-motor autonomic features (p=0.67) or between different pre-motor presenting features and disease duration (p>0.05).ConclusionsPre-motor autonomic features, including genitourinary, cardiovascular autonomic failure and RBD, are common presenting symptoms in MSA, accounting for almost one-third of patients. These features can predate motor symptoms by up to 6 years, or longer.

Slowly progressive autonomic failure in adults presents a diagnostic challenge. Here we describe a patient with slowly progressive autonomic failure present for many years before any other clinically significant symptoms or signs appeared, who underwent detailed autonomic function testing, MR brain imaging and other neurological investigations on several occasions. After she developed bulbar dysfunction (causing two life-threatening choking episodes), pyramidal and sensory dysfunction, and characteristic brain imaging abnormalities were noted, a diagnosis of adult onset Alexander disease was made. GFAP sequencing demonstrated a heterozygous missense mutation (F199S) which has not been previously reported. Relatives affected by similar symptoms (orthostatic syncope and dysphagia) suggest autosomal dominant inheritance. On retrospective review, the imaging abnormalities were present from an early stage of her illness, when autonomic symptoms were present in isolation. We propose that a diagnosis of adult onset Alexander disease should be considered in cases of slowly progressive autonomic failure even in the absence of other clinical manifestations, and that awareness of the characteristic brain imaging abnormalities should allow early diagnosis which can be confirmed with genetic testing.