Faculty Bibliography

Objective: To compare ESC in patients with autonomic synucleinopathies and healthy controls and to evaluate its relationship to sympathetic adrenergic function. Background: Disorders of the autonomic nervous system may affect sweat production and result in abnormally low electrochemical skin conductance (ESC). ESC can be evaluated by applying a low direct voltage to the skin of the palms and soles, which generate a current based on sweat chloride concentrations. Methods: We assessed ninety-nine subjects: 59 patients with synucleinopathies (15 patients with multiple system atrophy [MSA], 20 patients with pure autonomic failure [PAF], 17 patients with Parkinson's disease [PD] and 7 patients with REM sleep behavior disorder [RBD]) and 40 healthy controls. ESC was measured in micro-Siemens (muS) and categorized into normal (>60 muS); moderately decreased (60-40 muS); and severely decreased (<40 muS). Percent of asymmetry between the right and left ESC was also calculated. All subjects underwent medical assessments, neurological examination, and standardized autonomic testing with plasma measurements of norepinephrine in the supine and tilted positions. Results: ESC in both the palms and soles was significantly lower in MSA, PAF and RBD patients compared to controls (p=0.04). Asymmetry between right and left ESC measurements of palms and soles were significantly higher in MSA, PAF and PD than in controls. ESC in palms was positively correlated with the increase in norepinephrine from supine to head-up tilt (r= 0.363; p=0.005). ESC below 73.5 muS in the soles identified accurately 85[percnt] of patients with synucleinopathies. Asymmetry in ESC in the soles above 1.5 [percnt] identified 92[percnt] of patients with syncleinopathies, while asymmetry above 2.5[percnt] in the palms identified 87[percnt] of patients with syncleinopathies. Conclusions: ESC measured in palms and soles was both decreased and asymmetric in patients with synucleinopathies compared to controls. Decreased ESC is associated with impaired sympathetic adrenergic function

Objectives: Although dementia is still considered as non-supporting diagnostic feature by current consensus diagnostic criteria, several studies reported that MSA patients experience cognitive deficits (1-3). Our aim is to identify the anatomical pattern of cognitive impairment (CI) inMSA patients. Methods: A multi-center-cohort of seventy-two MSA patients was collected from 5 international centers. CI was assessed by the MMSE score (< 26) [4]. We identified twenty-two MSA with CI (MSAeCI) [mean age 66.4(6.5), education 8.4(4.1)], and fifty MSA without CI (MSAeCNT) [mean age 62.6(6.6), education 12.4(4.5)]. VBM was run using FSLeVBM tool. GLM analysis comparison between MSAeCI and MSAeCNT subgroups was run controlling for intracranial volume, age, education, UPDRS-III and centers. Results: VBM analysis revealed significant wide gray-matter densities decrease in the MSAeCI group mainly in frontal, temporal, occipital, parietal areas and left cerebellum (Table 1). Moreover, an increase cortex density area was found on the left middle temporal area (Figure 1), which might be due to a compensative cognitive mechanism in a group of patients characterized by a not severe cognitive status [mean MMSE 22.8(2.7)]. All these areas survived after Alphasym correction (p<0.01; cluster threshold >22). Conclusions: Our study suggests that CI is associated with wide cortical and sub-cortical changes in MSA group. These findings support similar VBM evidence of graymatter loss in MSA cognitively impaired patients (1). (Table Presented)

Takotsubo cardiomyopathy (TC) often occurs after emotional or physical stress. Norepinephrine levels are unusually high in the acute phase, suggesting a hyperadrenergic mechanism. Comparatively little is known about parasympathetic function in patients with TC. We sought to characterize autonomic function at rest and in response to physical and emotional stimuli in 10 women with a confirmed history of TC and 10 age-matched healthy women. Sympathetic and parasympathetic activity was assessed at rest and during baroreflex stimulation (Valsalva maneuver and tilt testing), cognitive stimulation (Stroop test), and emotional stimulation (event recall, patients). Ambulatory blood pressure monitoring and measurement of brachial artery flow-mediated vasodilation were also performed. TC women (tested an average of 37 months after the event) had excessive pressor responses to cognitive stress (Stroop test: p <0.001 vs baseline and p = 0.03 vs controls) and emotional arousal (recall of TC event: p = 0.03 vs baseline). Pressor responses to hemodynamic stimuli were also amplified (Valsalva overshoot: p <0.05) and prolonged (duration: p <0.01) in the TC women compared with controls. Plasma catecholamine levels did not differ between TC women and controls. Indexes of parasympathetic (vagal) modulation of heart rate induced by respiration and cardiovagal baroreflex gain were significantly decreased in the TC women versus controls. In conclusion, even long after the initial episode, women with previous episode of TC have excessive sympathetic responsiveness and reduced parasympathetic modulation of heart rate. Impaired baroreflex control may therefore play a role in TC.

Hereditary sensory and autonomic neuropathy type III features disturbed proprioception and a marked ataxic gait. We recently showed that joint-angle matching error at the knee is positively correlated with the degree of ataxia. Using intraneural microelectrodes, we also documented that these patients lack functional muscle spindle afferents but have preserved large-diameter cutaneous afferents, suggesting that patients with better proprioception may be relying more on proprioceptive cues provided by tactile afferents. We tested the hypothesis that enhancing cutaneous sensory feedback by stretching the skin at the knee joint using unidirectional elasticity tape could improve proprioceptive accuracy in patients with a congenital absence of functional muscle spindles. Passive joint angle matching at the knee was used to assess proprioceptive accuracy in 25 patients with HSAN III and 9 age-matched control subjects, with and without taping. Angles of the reference and indicator knees were recorded with digital inclinometers, and the absolute error, gradient and correlation coefficient between the two sides calculated. Patients with HSAN III performed poorly on the joint angle-matching test (mean matching error +/- SE 8.0 +/- 0.8 degrees , controls 3.0 +/- 0.3 degrees ). Following application of tape bilaterally to the knee in an X-shaped pattern, proprioceptive performance improved significantly in the patients (mean error 5.4 +/- 0.7 degrees ) but not in the controls (3.0 +/- 0.2 degrees ). Across patients, but not controls, significant increases in gradient and correlation coefficient were also apparent following taping. We conclude that taping improves proprioception at the knee in HSAN III, presumably via enhanced sensory feedback from the skin.

Here we report the case of a patient with familial dysautonomia (a genetic form of afferent baroreflex failure), who had severe hypertension (230/149 mmHg) induced by the stress of his mother taking his blood pressure. His hypertension subsided when he learnt to measure his blood pressure without his mother's involvement. The case highlights how the reaction to maternal stress becomes amplified when catecholamine release is no longer under baroreflex control.

Background: Cognitive deficits in MSA have been observed, although dementia is still considered as non-supporting diagnostic feature by current consensus diagnostic criteria. MMSE is commonly used in clinical practice with atypical parkinsonism, but its neuroanatomical correlates have never been investigated. Objective: The aim of this study is to investigate the MRI structural correlates of the Mini-Mental State Examination (MMSE) in Multiple System Atrophy (MSA) patients compared with a Parkinson's disease (PD) sample. Methods: Multicenter cohort of 69 MSA patients [mean age 63.8 (7.3) and education of 11.1 (4.7)], collected from four international centers and 70 PD [mean age 63.9 (7.3) and education of 10.5(4.4)] subjects matched for age and MMSE score. Freesurfer software was used to evaluate intergroup differences in cortical thickness (CTh) and subcortical areas, in relationship with MMSE scores. Results: In MSA group MMSE scores did not correlate with cortical or subcortical areas. In PD, significant positive correlations were observed between MMSE scores and cortical thickness of the left medial and lateral orbitofrontal areas, caudal middle frontal area, superior frontal area, supramarginal region and superior temporal area. More focal right hemisphere significant correlations were found in the temporal pole and pars orbitalis. Subcortical analysis showed significant positive correlation in the right hippocampus and in the middle anterior side of corpus callosum. All these areas survived after Montecarlo correction. Conclusions: Our findings in PD corroborate previous studies showing correlations between cortical areas and MMSE scores. The predominance of the left hemisphere is likely due to the presence of several verbal items included in the cognitive scale. Lack of cortical correlates of cognitive deficits in MSA suggests a different nature of cognitive decline in MSA patients

Familial dysautonomia (FD) features a unique combination of cardiovascular disturbances not seen in patients with any other chronic disorder of the autonomic nervous system. While blood pressure falls and both heart rate and plasma noradrenaline fail to increase during standing in FD, patients demonstrate significant increases in blood pressure and plasma noradrenaline during episodes of emotional arousal. This indicates that vasoconstrictor neurones can be activated during states of emotional arousal, and that noradrenaline is released. Because constriction of arterioles in skeletal muscle vascular beds is one of the primary determinants of total peripheral resistance and hence of blood pressure, we would expect that muscle sympathetic nerve activity (MSNA) -which is vasoconstrictor in function - would be present in patients with FD. However, given the absence of functional baroreflex afferents we predicted that MSNA would not appear as cardiac-locked bursts. We tested this hypothesis using tungsten microelectrodes inserted percutaneously into muscle or cutaneous fascicles of the nerve in 12 patients with FD. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during baroreceptor unloading. Conversely, skin sympathetic nerve activity (SSNA) appeared normal. We conclude that the loss of baroreflex modulation of MSNA contributes to the poor control of blood pressure in FD, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement