The Experts below are selected from a list of 1920 Experts worldwide ranked by ideXlab platform
Christopher J. Mathias - One of the best experts on this subject based on the ideXlab platform.
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Incidence of cerebrovascular lesions in Pure Autonomic Failure.
Autonomic neuroscience : basic & clinical, 2013Co-Authors: Walter Struhal, Heinz Lahrmann, Christopher J. MathiasAbstract:In Pure Autonomic Failure (PAF) - a rare form of primary dysautonomia - some patients show cerebrovascular lesions usually found in hypertensive subjects. In an Autonomic laboratory records of patients with a definitive diagnosis of PAF having had cerebral imaging (cMRI, cCT) were analysed retrospectively. Tilt table data (supine/tilted), 24 hour blood pressure recordings (day/night) and serum catecholamine levels were correlated with cerebrovascular lesions and also compared to published normal values. 50 PAF patients (23 female, 27 male) were identified, mean age 67 years (sd 9.5). Out of these 35 (70%) had pathologic cerebral scans showing white matter lesions (WML) in 30, lacunar strokes in 5 and hemispheric stroke and microbleeds each in 1. Age and supine systolic blood pressure were significantly elevated in patients with pathologic scans (70 compared to 61 years [p=0.007], and 170 compared to 154 mmHg [p=0.045]). Out of 28 patients with WML and ambulatory blood pressure recordings available 24 were non-dippers. The data show that the frequency of WML is lower in PAF patients aged 60 to 80 years compared to age matched community based samples. Although PAF usually results in hypotension, a frequent complication is supine hypertension. Although the overall frequency of WML seems to be reduced in PAF, a number of patients with elevated supine systolic blood pressure (>160 mmHg) develop WML and some of these suffer stroke.
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Pure Autonomic Failure with cold induced sweating.
Autonomic neuroscience : basic & clinical, 2013Co-Authors: Christopher J. Mathias, Juan Idiaquez, Ricardo Fadic, Renato Verdugo, Valeria Iodice, David A Low, Raffaela Lombardi, Giuseppe LauriaAbstract:Pure Autonomic Failure (PAF) is a progressive Autonomic neurodegenerative disorder. Cold induced sweating occurred in syndromes with mutations in CRLF1 and CLCF1 genes and in a case of cervical dissection. A patient with PAF developed sweating induced by cool ambient temperatures. He had severe orthostatic hypotension, abnormal cardiovagal reflexes, and paradoxical sweating in the upper trunk at a room temperature of 18°C. Skin biopsy showed involvement of somatic epidermal unmyelinated nerve fibers. Quantitative sensory testing showed abnormal thresholds to all thermal modalities. Possible mechanisms include cold induced noradrenaline release in remaining Autonomic innervation and a supersensitive sudomotor response.
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Hyposmia in Pure Autonomic Failure.
Neurology, 2009Co-Authors: Laura Silveira-moriyama, Christopher J. Mathias, L. Mason, C. Best, Np Quinn, Aj LeesAbstract:Background: Parkinson disease (PD), multiple system atrophy (MSA), and Pure Autonomic Failure (PAF) all present with varying degrees of dysautonomia and are pathologically characterized by accumulation of α-synuclein. Hyposmia and olfactory pathway pathology are found in PD and MSA. We tested odor identification in 16 patients with PAF and compared the results with those found in patients with PD, patients with MSA, and control subjects. Methods: The University of Pennsylvania Smell Identification Test (UPSIT) was used to evaluate the sense of smell in 16 patients with PAF, 14 patients with MSA, 191 patients with PD, and 145 control subjects. Multiple linear regression analyses were used to evaluate the effect of the diseases on the mean UPSIT score when adjusted for age, sex, and smoking habit. Results: The mean UPSIT score was higher in the controls than in patients with PAF ( p p p = 0.005) or patients with MSA ( p = 0.006); and no difference was found between patients with MSA and patients with PAF ( p = 0.9) when adjusted for age, gender, and smoking habits. Conclusions: Hyposmia may be a feature of Pure Autonomic Failure (PAF), but to a lesser degree than that found in Parkinson disease. Further research into the olfactory pathways in patients with PAF is warranted.
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Effects of water drinking on cardiovascular responses to supine exercise and on orthostatic hypotension after exercise in Pure Autonomic Failure
Journal of neurology neurosurgery and psychiatry, 2008Co-Authors: Andrea M Humm, Lydia Mason, Christopher J. MathiasAbstract:Objective: Patients with Pure Autonomic Failure (PAF) have an abnormal fall in blood pressure (BP) with supine exercise and exacerbation of orthostatic hypotension (OH) after exercise. This study assessed the pressor effect of water on the cardiovascular responses to supine exercise and on OH after exercise. Methods: 8 patients with PAF underwent a test protocol consisting of standing for 5 min, supine rest for 10 min, supine exercise by pedalling a cycle ergometer at workloads of 25, 50 and 75 W (each for 3 min), supine rest for 10 min and standing for 5 min. The test protocol was performed without water ingestion and on a separate occasion after 480 ml of distilled water immediately after pre-exercise standing. Beat to beat cardiovascular indices were measured with the Portapres II device with subsequent Modelflow analysis. Results: All patients had severe OH pre-exercise (BP fall systolic 65.0 (26.1) mm Hg, diastolic 22.7 (13.5) mm Hg), with prompt recovery of BP in the supine position. 5 min after water drinking, there was a significant rise in BP in the supine position. With exercise, there was a clear fall in BP (systolic 42.1 (24.4) mm Hg, diastolic 25.9 (10.0) mm Hg) with a modest rise in heart rate; this occurred even after water ingestion (BP fall systolic 49.8 (18.9) mm Hg, diastolic 26.0 (9.1) mm Hg). BP remained low after exercise but was significantly higher after water intake, resulting in better tolerance of post-exercise standing. Conclusions: Water drinking did not change the abnormal cardiovascular responses to supine exercise. However, water drinking improved orthostatic tolerance post-exercise.
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Pure Autonomic Failure followed by amyotrophy.
Neurology, 2007Co-Authors: Sarosh R. Irani, Christopher J. Mathias, Richard W. OrrellAbstract:Features of Autonomic dysfunction may develop late in amyotrophic lateral sclerosis (ALS), but Pure Autonomic Failure with subsequent amyotrophy has not been recognized. We report the rare combination of Pure Autonomic Failure followed by gradually progressive, isolated anterior horn cell disease. The patient initially presented at age 40 years with orthostatic dizziness and pain in her cervico-occipital and shoulder (coat hanger) region (appendix E-1 on the Neurology Web site at www.neurology.org). There were no additional neurologic symptoms. No relevant family or medical history was noted. Nocturia, dysphagia, and postprandial hypotensive symptoms developed 5 years later. Symptoms slowly progressed over 20 years. Orthostatic hypotension was ameliorated by a combination of fludrocortisone, midodrine, and octreotide. Detailed serial Autonomic function tests1 indicated Pure Autonomic Failure. She had severe orthostatic hypotension (205/119 mm Hg supine, to 74/52 mm Hg standing) on head-up tilt to 60o1 (table E-1). Pressor responses to sustained handgrip, mental arithmetic, and cutaneous cold were impaired. She had postprandial and post-exercise hypotension. There was no heart …
Vincenzo Donadio - One of the best experts on this subject based on the ideXlab platform.
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93. Phosphorylated α-synuclein biomarker in skin nerves is differently expressed in Pure Autonomic Failure and idiopathic Parkinson disease
Clinical Neurophysiology, 2016Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Alex Incensi, Cristina Piccinini, A. Baruzzi, Rocco LiguoriAbstract:The aim of this study was to characterize the expression in skin nerves of native (n-syn) and misfolded or phosphorylated (p-syn) α-synucleins in Pure Autonomic Failure (PAF) and idiopathic Parkinson disease (IPD). We studied 30 patients, including 16 well-characterized IPD, 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from cervical, thigh and leg sites to study small nerve fibers and intraneural n-syn and p-syn. PAF and IPD both showed a skin denervation, more severely expressed in patients with higher p-syn load. N-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not found in controls, but it was disclosed in all PAF and IPD patients with different skin innervation. In addition, abnormal α-syn deposits were found in all analysed skin samples in PAF, but in 49% of samples only with higher positivity rate in the cervical site in IPD. In conclusion: (1) intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF, but it is critical in IPD.
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Skin nerve misfolded α-synuclein in Pure Autonomic Failure and Parkinson disease.
Annals of neurology, 2015Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Cristina Piccinini, Rocco LiguoriAbstract:OBJECTIVE To characterize the expression in skin nerves of native (n-syn) and misfolded phosphorylated (p-syn) α-synucleins in Pure Autonomic Failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to (1) define the importance of n-syn and p-syn as disease biomarkers and (2) ascertain differences in abnormal synuclein skin nerve deposits. METHODS We studied 30 patients, including 16 well-characterized IPD patients and 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from proximal (ie, cervical) and distal (ie, thigh and leg) sites to study small nerve fiber and intraneural n-syn and p-syn. RESULTS PAF and IPD showed length-dependent somatic and Autonomic small fiber loss, more severely expressed in patients with higher p-syn load. n-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not evident in any skin sample of controls but was found in all PAF and IPD patients, although with different skin innervation. In addition, abnormal α-synuclein deposits were found in all analyzed skin samples in PAF but in only 49% of samples with a higher positivity rate at the proximal site in IPD. INTERPRETATION (1) Intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) when searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF but it is critical in IPD.
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skin sympathetic fiber α synuclein deposits a potential biomarker for Pure Autonomic Failure
Neurology, 2013Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Masen Abdel Jaber, Rocco LiguoriAbstract:Objective: This study aimed to test whether peripheral α-synuclein staining might be useful for Pure Autonomic Failure (PAF) diagnosis, helping to differentiate degenerative from acquired peripheral Autonomic neuropathy. Methods: We studied 21 patients with chronic peripheral Autonomic neuropathy showing sympathetic and parasympathetic involvement as confirmed by cardiovascular reflexes and microneurography from the peroneal nerve. Twelve patients showed a specific cause of neuropathy (acquired Autonomic neuropathy) whereas 9 had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons. Results: Somatic and Autonomic skin innervations were significantly decreased in patients with peripheral Autonomic neuropathy compared to controls. No differences were found between acquired Autonomic neuropathy and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative Autonomic peripheral neuropathy: all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired Autonomic neuropathy. Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers. Conclusions: Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral Autonomic neuropathy and may shed more light on the pathogenesis of PAF.
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Skin sympathetic fiber α-synuclein deposits: a potential biomarker for Pure Autonomic Failure.
2013Co-Authors: Vincenzo Donadio, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Masen Abdel Jaber, P. Cortelli, Rocco LiguoriAbstract:This study aimed to test whether peripheral α-synuclein staining might be useful for Pure Autonomic Failure (PAF) diagnosis, helping to differentiate degenerative from acquired peripheral Autonomic neuropathy.We studied 21 patients with chronic peripheral Autonomic neuropathy showing sympathetic and parasympathetic involvement as confirmed by cardiovascular reflexes and microneurography from the peroneal nerve. Twelve patients showed a specific cause of neuropathy (acquired Autonomic neuropathy) whereas 9 had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons.Somatic and Autonomic skin innervations were significantly decreased in patients with peripheral Autonomic neuropathy compared to controls. No differences were found between acquired Autonomic neuropathy and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative Autonomic peripheral neuropathy: all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired Autonomic neuropathy. Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers.Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral Autonomic neuropathy and may shed more light on the pathogenesis of PAF
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Autonomic INNERVATION IN MULTIPLE SYSTEM ATROPHY AND Pure Autonomic Failure
Journal of Neurology Neurosurgery and Psychiatry, 2010Co-Authors: Vincenzo Donadio, Pietro Cortelli, Pasquale Montagna, Mikael Elam, Vitantonio Di Stasi, Björn Holmberg, Maria Pia Giannoccaro, Enrico Bugiardini, Patrizia Avoni, Agostino BaruzziAbstract:Background. Pure Autonomic Failure (PAF) and multiple system atrophy (MSA) are both characterized by chronic dysautonomia although presenting different disability and prognosis. Skin Autonomic function evaluation by indirect tests has disclosed conflicting results in these disorders. Here we report the first direct analysis of skin sympathetic fibers including structure and function in PAF and MSA to ascertain different underlying Autonomic lesion sites which may help differentiate the two conditions. Methods. We studied 8 patients with probable MSA (mean age 60±5 years) and 9 patients fulfilling diagnostic criteria for PAF (64±8 years). They underwent head-up tilt test (HUTT), extensive microneurographic search for muscle and skin sympathetic nerve activities from peroneal nerve and punch skin biopsies from finger, thigh and leg to evaluate cholinergic and adrenergic Autonomic dermal annexes innervation graded by a semiquantitative score presenting a high level of reliability. Results. MSA and PAF patients presented a comparable neurogenic orthostatic hypotension during HUTT and high Failure rate of microneurographic trials to record sympathetic nerve activity, suggesting a similar extent of chronic dysautonomia. In contrast, they presented different skin Autonomic innervation in the immunofluorescence analysis. MSA patients showed a generally preserved skin Autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation. In MSA patients with long disease duration morphological abnormalities and/or a slightly decreased Autonomic score could be found in the leg reflecting a mild postganglionic involvement. Conclusion. Autonomic innervation study of skin annexes is a reliable method which may help differentiate MSA from PAF.
Rocco Liguori - One of the best experts on this subject based on the ideXlab platform.
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93. Phosphorylated α-synuclein biomarker in skin nerves is differently expressed in Pure Autonomic Failure and idiopathic Parkinson disease
Clinical Neurophysiology, 2016Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Alex Incensi, Cristina Piccinini, A. Baruzzi, Rocco LiguoriAbstract:The aim of this study was to characterize the expression in skin nerves of native (n-syn) and misfolded or phosphorylated (p-syn) α-synucleins in Pure Autonomic Failure (PAF) and idiopathic Parkinson disease (IPD). We studied 30 patients, including 16 well-characterized IPD, 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from cervical, thigh and leg sites to study small nerve fibers and intraneural n-syn and p-syn. PAF and IPD both showed a skin denervation, more severely expressed in patients with higher p-syn load. N-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not found in controls, but it was disclosed in all PAF and IPD patients with different skin innervation. In addition, abnormal α-syn deposits were found in all analysed skin samples in PAF, but in 49% of samples only with higher positivity rate in the cervical site in IPD. In conclusion: (1) intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF, but it is critical in IPD.
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Skin nerve misfolded α-synuclein in Pure Autonomic Failure and Parkinson disease.
Annals of neurology, 2015Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Cristina Piccinini, Rocco LiguoriAbstract:OBJECTIVE To characterize the expression in skin nerves of native (n-syn) and misfolded phosphorylated (p-syn) α-synucleins in Pure Autonomic Failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to (1) define the importance of n-syn and p-syn as disease biomarkers and (2) ascertain differences in abnormal synuclein skin nerve deposits. METHODS We studied 30 patients, including 16 well-characterized IPD patients and 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from proximal (ie, cervical) and distal (ie, thigh and leg) sites to study small nerve fiber and intraneural n-syn and p-syn. RESULTS PAF and IPD showed length-dependent somatic and Autonomic small fiber loss, more severely expressed in patients with higher p-syn load. n-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not evident in any skin sample of controls but was found in all PAF and IPD patients, although with different skin innervation. In addition, abnormal α-synuclein deposits were found in all analyzed skin samples in PAF but in only 49% of samples with a higher positivity rate at the proximal site in IPD. INTERPRETATION (1) Intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) when searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF but it is critical in IPD.
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skin sympathetic fiber α synuclein deposits a potential biomarker for Pure Autonomic Failure
Neurology, 2013Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Masen Abdel Jaber, Rocco LiguoriAbstract:Objective: This study aimed to test whether peripheral α-synuclein staining might be useful for Pure Autonomic Failure (PAF) diagnosis, helping to differentiate degenerative from acquired peripheral Autonomic neuropathy. Methods: We studied 21 patients with chronic peripheral Autonomic neuropathy showing sympathetic and parasympathetic involvement as confirmed by cardiovascular reflexes and microneurography from the peroneal nerve. Twelve patients showed a specific cause of neuropathy (acquired Autonomic neuropathy) whereas 9 had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons. Results: Somatic and Autonomic skin innervations were significantly decreased in patients with peripheral Autonomic neuropathy compared to controls. No differences were found between acquired Autonomic neuropathy and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative Autonomic peripheral neuropathy: all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired Autonomic neuropathy. Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers. Conclusions: Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral Autonomic neuropathy and may shed more light on the pathogenesis of PAF.
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Skin sympathetic fiber α-synuclein deposits: a potential biomarker for Pure Autonomic Failure.
2013Co-Authors: Vincenzo Donadio, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Masen Abdel Jaber, P. Cortelli, Rocco LiguoriAbstract:This study aimed to test whether peripheral α-synuclein staining might be useful for Pure Autonomic Failure (PAF) diagnosis, helping to differentiate degenerative from acquired peripheral Autonomic neuropathy.We studied 21 patients with chronic peripheral Autonomic neuropathy showing sympathetic and parasympathetic involvement as confirmed by cardiovascular reflexes and microneurography from the peroneal nerve. Twelve patients showed a specific cause of neuropathy (acquired Autonomic neuropathy) whereas 9 had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons.Somatic and Autonomic skin innervations were significantly decreased in patients with peripheral Autonomic neuropathy compared to controls. No differences were found between acquired Autonomic neuropathy and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative Autonomic peripheral neuropathy: all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired Autonomic neuropathy. Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers.Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral Autonomic neuropathy and may shed more light on the pathogenesis of PAF
David S. Goldstein - One of the best experts on this subject based on the ideXlab platform.
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Cardiac sympathetic innervation and vesicular storage in Pure Autonomic Failure.
Annals of clinical and translational neurology, 2020Co-Authors: David S. Goldstein, Risa Isonaka, Courtney Holmes, Yu‐shin Ding, Yehonatan SharabiAbstract:OBJECTIVE Pure Autonomic Failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using 11 C-methylreboxetine (11 C-MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using 18 F-dopamine (18 F-DA) to assess intraneuronal vesicular storage in the same subjects. METHODS Seven comprehensively tested PAF patients and 11 controls underwent 11 C-MRB PET scanning for 45 minutes (dynamic 5X1', 3X5', 1X10', static 15 minutes) and 18 F-DA scanning for 30 minutes (same dynamic imaging sequence) after 3-minute infusions of the tracers on separate days. RESULTS In the PAF group septal 11 C-MRB-derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of 11 C-MRB, the PAF group had a 41.1% mean decrease in myocardial 11 C-MRB-derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of 18 F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p
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cardiac sympathetic innervation and vesicular storage in Pure Autonomic Failure
Annals of clinical and translational neurology, 2020Co-Authors: David S. Goldstein, Risa Isonaka, Courtney Holmes, Yushin Ding, Yehonatan SharabiAbstract:OBJECTIVE Pure Autonomic Failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using 11 C-methylreboxetine (11 C-MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using 18 F-dopamine (18 F-DA) to assess intraneuronal vesicular storage in the same subjects. METHODS Seven comprehensively tested PAF patients and 11 controls underwent 11 C-MRB PET scanning for 45 minutes (dynamic 5X1', 3X5', 1X10', static 15 minutes) and 18 F-DA scanning for 30 minutes (same dynamic imaging sequence) after 3-minute infusions of the tracers on separate days. RESULTS In the PAF group septal 11 C-MRB-derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of 11 C-MRB, the PAF group had a 41.1% mean decrease in myocardial 11 C-MRB-derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of 18 F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001). At all time points after infusion of 18 F-DA and 11 C-MRB mean 18 F/11 C ratios in septal myocardium were lower in the PAF than control group. INTERPRETATION PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves.
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Pure Autonomic Failure without synucleinopathy
Clinical Autonomic Research, 2017Co-Authors: Risa Isonaka, Courtney Holmes, Glen A. Cook, Patti Sullivan, Yehonatan Sharabi, David S. GoldsteinAbstract:Pure Autonomic Failure is a rare form of chronic Autonomic Failure manifesting with neurogenic orthostatic hypotension and evidence of sympathetic noradrenergic denervation unaccompanied by signs of central neurodegeneration. It has been proposed that Pure Autonomic Failure is a Lewy body disease characterized by intra-neuronal deposition of the protein alpha-synuclein in Lewy bodies and neurites. A middle-aged man with previously diagnosed Pure Autonomic Failure experienced a sudden, fatal cardiac arrest. He was autopsied, and tissues were harvested for neurochemical and immunofluorescence studies. Post-mortem microscopic neuropathology showed no Lewy bodies, Lewy neurites, or alpha-synuclein deposition by immunohistochemistry anywhere in the brain. The patient had markedly decreased immunofluorescent tyrosine hydroxylase in sympathetic ganglion tissue without detectable alpha-synuclein even in rare residual nests of tyrosine hydroxylase-containing ganglionic fibers. In Pure Autonomic Failure, sympathetic noradrenergic denervation can occur without concurrent Lewy bodies or alpha-synuclein deposition in the brain or sympathetic ganglion tissue.
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The Natural History of Pure Autonomic Failure: a U.S. Prospective Cohort
Annals of neurology, 2017Co-Authors: Horacio Kaufmann, David S. Goldstein, Wolfgang Singer, Phillip A. Low, Lucy Norcliffe-kaufmann, Jose-alberto Palma, Italo Biaggioni, Amanda Peltier, Cyndia A. Shibao, Christopher H. GibbonsAbstract:Objective: To define the clinical features and biomarkers that predict which patients with Pure Autonomic Failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. Methods: One hundred patients who presented with Pure Autonomic Failure were recruited at 5 medical centers in the U.S. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular Autonomic function tests. Results: At enrollment, patients were 68(12) years old [(median (interquartile range)] and had had Autonomic Failure for 5(7) years. Within 4-years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (in 13), Parkinson disease (in 6), or multiple system atrophy (in 6). The presence of probable REM sleep behavior disorder was strongly associated with the development of a manifest CNS synucleinopathy (odds ratio=7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of Autonomic Failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotrophic response upon tilt >10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotrophic response to tilt, and a longer duration of illness. The small group of patients retaining the Pure Autonomic Failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell. Interpretation: Patients presenting with Pure Autonomic Failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. This article is protected by copyright. All rights reserved.
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natural history of Pure Autonomic Failure a united states prospective cohort
Annals of Neurology, 2017Co-Authors: Horacio Kaufmann, David S. Goldstein, Wolfgang Singer, Phillip A. Low, Jose-alberto Palma, Italo Biaggioni, Amanda Peltier, Cyndia A. Shibao, Lucy Norcliffekaufmann, Christopher H. GibbonsAbstract:Objective To define the clinical features and biomarkers that predict which patients with Pure Autonomic Failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. Methods One hundred patients who presented with Pure Autonomic Failure were recruited at 5 medical centers in the United States. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular Autonomic function tests. Results At enrollment, patients were 68 ± 12 years old (median ± interquartile range) and had had Autonomic Failure for 5 ± 7 years. Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of Autonomic Failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt > 10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the Pure Autonomic Failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell. Interpretation Patients presenting with Pure Autonomic Failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287-297.
Maria Pia Giannoccaro - One of the best experts on this subject based on the ideXlab platform.
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93. Phosphorylated α-synuclein biomarker in skin nerves is differently expressed in Pure Autonomic Failure and idiopathic Parkinson disease
Clinical Neurophysiology, 2016Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Alex Incensi, Cristina Piccinini, A. Baruzzi, Rocco LiguoriAbstract:The aim of this study was to characterize the expression in skin nerves of native (n-syn) and misfolded or phosphorylated (p-syn) α-synucleins in Pure Autonomic Failure (PAF) and idiopathic Parkinson disease (IPD). We studied 30 patients, including 16 well-characterized IPD, 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from cervical, thigh and leg sites to study small nerve fibers and intraneural n-syn and p-syn. PAF and IPD both showed a skin denervation, more severely expressed in patients with higher p-syn load. N-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not found in controls, but it was disclosed in all PAF and IPD patients with different skin innervation. In addition, abnormal α-syn deposits were found in all analysed skin samples in PAF, but in 49% of samples only with higher positivity rate in the cervical site in IPD. In conclusion: (1) intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF, but it is critical in IPD.
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Skin nerve misfolded α-synuclein in Pure Autonomic Failure and Parkinson disease.
Annals of neurology, 2015Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Cristina Piccinini, Rocco LiguoriAbstract:OBJECTIVE To characterize the expression in skin nerves of native (n-syn) and misfolded phosphorylated (p-syn) α-synucleins in Pure Autonomic Failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to (1) define the importance of n-syn and p-syn as disease biomarkers and (2) ascertain differences in abnormal synuclein skin nerve deposits. METHODS We studied 30 patients, including 16 well-characterized IPD patients and 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from proximal (ie, cervical) and distal (ie, thigh and leg) sites to study small nerve fiber and intraneural n-syn and p-syn. RESULTS PAF and IPD showed length-dependent somatic and Autonomic small fiber loss, more severely expressed in patients with higher p-syn load. n-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not evident in any skin sample of controls but was found in all PAF and IPD patients, although with different skin innervation. In addition, abnormal α-synuclein deposits were found in all analyzed skin samples in PAF but in only 49% of samples with a higher positivity rate at the proximal site in IPD. INTERPRETATION (1) Intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) when searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF but it is critical in IPD.
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skin sympathetic fiber α synuclein deposits a potential biomarker for Pure Autonomic Failure
Neurology, 2013Co-Authors: Vincenzo Donadio, Pietro Cortelli, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Masen Abdel Jaber, Rocco LiguoriAbstract:Objective: This study aimed to test whether peripheral α-synuclein staining might be useful for Pure Autonomic Failure (PAF) diagnosis, helping to differentiate degenerative from acquired peripheral Autonomic neuropathy. Methods: We studied 21 patients with chronic peripheral Autonomic neuropathy showing sympathetic and parasympathetic involvement as confirmed by cardiovascular reflexes and microneurography from the peroneal nerve. Twelve patients showed a specific cause of neuropathy (acquired Autonomic neuropathy) whereas 9 had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons. Results: Somatic and Autonomic skin innervations were significantly decreased in patients with peripheral Autonomic neuropathy compared to controls. No differences were found between acquired Autonomic neuropathy and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative Autonomic peripheral neuropathy: all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired Autonomic neuropathy. Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers. Conclusions: Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral Autonomic neuropathy and may shed more light on the pathogenesis of PAF.
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Skin sympathetic fiber α-synuclein deposits: a potential biomarker for Pure Autonomic Failure.
2013Co-Authors: Vincenzo Donadio, Maria Pia Giannoccaro, Agostino Baruzzi, Alex Incensi, Masen Abdel Jaber, P. Cortelli, Rocco LiguoriAbstract:This study aimed to test whether peripheral α-synuclein staining might be useful for Pure Autonomic Failure (PAF) diagnosis, helping to differentiate degenerative from acquired peripheral Autonomic neuropathy.We studied 21 patients with chronic peripheral Autonomic neuropathy showing sympathetic and parasympathetic involvement as confirmed by cardiovascular reflexes and microneurography from the peroneal nerve. Twelve patients showed a specific cause of neuropathy (acquired Autonomic neuropathy) whereas 9 had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons.Somatic and Autonomic skin innervations were significantly decreased in patients with peripheral Autonomic neuropathy compared to controls. No differences were found between acquired Autonomic neuropathy and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative Autonomic peripheral neuropathy: all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired Autonomic neuropathy. Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers.Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral Autonomic neuropathy and may shed more light on the pathogenesis of PAF
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Autonomic INNERVATION IN MULTIPLE SYSTEM ATROPHY AND Pure Autonomic Failure
Journal of Neurology Neurosurgery and Psychiatry, 2010Co-Authors: Vincenzo Donadio, Pietro Cortelli, Pasquale Montagna, Mikael Elam, Vitantonio Di Stasi, Björn Holmberg, Maria Pia Giannoccaro, Enrico Bugiardini, Patrizia Avoni, Agostino BaruzziAbstract:Background. Pure Autonomic Failure (PAF) and multiple system atrophy (MSA) are both characterized by chronic dysautonomia although presenting different disability and prognosis. Skin Autonomic function evaluation by indirect tests has disclosed conflicting results in these disorders. Here we report the first direct analysis of skin sympathetic fibers including structure and function in PAF and MSA to ascertain different underlying Autonomic lesion sites which may help differentiate the two conditions. Methods. We studied 8 patients with probable MSA (mean age 60±5 years) and 9 patients fulfilling diagnostic criteria for PAF (64±8 years). They underwent head-up tilt test (HUTT), extensive microneurographic search for muscle and skin sympathetic nerve activities from peroneal nerve and punch skin biopsies from finger, thigh and leg to evaluate cholinergic and adrenergic Autonomic dermal annexes innervation graded by a semiquantitative score presenting a high level of reliability. Results. MSA and PAF patients presented a comparable neurogenic orthostatic hypotension during HUTT and high Failure rate of microneurographic trials to record sympathetic nerve activity, suggesting a similar extent of chronic dysautonomia. In contrast, they presented different skin Autonomic innervation in the immunofluorescence analysis. MSA patients showed a generally preserved skin Autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation. In MSA patients with long disease duration morphological abnormalities and/or a slightly decreased Autonomic score could be found in the leg reflecting a mild postganglionic involvement. Conclusion. Autonomic innervation study of skin annexes is a reliable method which may help differentiate MSA from PAF.
