Multiple system atrophy: using clinical pharmacology to reveal pathophysiology.

Oral L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic catechol amino acid, increases standing blood pressure and improves standing ability in patients with neurogenic orthostatic hypotension, by conversion of L-DOPS to norepinephrine (NE) outside the brain. This study assessed the pharmacokinetics of L-DOPS, NE, and dihydroxyphenylglycol (DHPG), the main neuronal metabolite of NE, in patients with primary chronic autonomic failure from pure autonomic failure (PAF) or multiple system atrophy (MSA). In 5 MSA and 4 PAF patients, antecubital venous blood was drawn during supine rest and plasma levels of catechols measured at various times for 48 hours after a single oral dose of 400 mg of L-DOPS. Plasma L-DOPS peaked at 1.9 microg/ml (9 micromol/L) about 3 hours after drug administration, followed by a monoexponential decline with a half-time of 2-3 hours in both patient groups. Plasma NE and DHPG also peaked at about 3 hours, but at much lower concentrations (4 and 42 nmol/L). Compared to the MSA group, the PAF group had a smaller calculated volume of distribution of L-DOPS and up to 10-fold lower plasma NE levels at all time points. Plasma NE was above baseline in MSA even at 48 hours after L-DOPS. The relatively long half-time for disappearance of L-DOPS compared to that of NE explains their very different attained plasma concentrations. The similar NE and DHPG responses in PAF and MSA suggests production of NE from LDOPS mainly in non-neuronal cells. Persistent elevation of plasma NE in MSA suggests residual release of NE from sympathetic nerves.

Differential patterns of central synucleinopathy and catecholaminergic abnormalities in Lewy body diseases and multiple system atrophy.

18F-dopa and S-11C-nomifensine (NMF) are positron emitting tracers whose caudate and putamen uptake reflects striatal dopamine storage capacity and the integrity of dopamine reuptake sites, respectively. Using these two tracers, the integrity of the presynaptic striatal dopaminergic system has been studied with positron emission tomography (PET) in 10 subjects with multiple system atrophy (MSA, Shy-Drager syndrome) who had an akinetic-rigid syndrome that was poorly responsive to L-dopa, autonomic failure, and cerebellar ataxia. PET findings for the 10 MSA patients were compared with those for 13 age-matched controls, 8 subjects with L-dopa responsive Parkinson's disease (PD), and 7 subjects with pure autonomic failure (PAF). Influx constants, Ki, reflecting specific 18F-dopa uptake into striatal tissue, were severely reduced in the putamen and caudate of the 10 MSA subjects (mean putamen Ki 0.005 min-1 MSA vs 0.013 min-1 controls; mean caudate Ki 0.007 min-1 MSA vs 0.013 min-1 controls). Reduction of putamen, but not caudate, 18F-dopa uptake correlated with severity and duration of locomotor disability. Eight patients with PD, and a similar degree and duration of locomotor disability to the patients with MSA, demonstrated equal impairment of mean putamen 18F-dopa uptake, but significant preservation of mean caudate function. The 7 PAF patients had normal mean levels of putamen and caudate 18F-dopa uptake, although 1 individual PAF patient had significantly impaired striatal function. The MSA and PD groups of subjects both showed significantly reduced levels of specific striatal S-11C-NMF binding, again caudate function being relatively preserved in PD. It is concluded that in both MSA and PD there is a parallel decline of striatal dopamine storage capacity and reuptake site integrity, probably reflecting a loss of nigrostriatal nerve terminals. Caudate function is relatively preserved in PD compared with MSA. The majority of PAF patients have an intact nigrostriatal dopaminergic system, suggesting that PAF is a condition distinct from PD and MSA in spite of some pathological similarities. PET is capable of detecting subclinical nigrostriatal involvement in PAF patients when this is present.

To explore the role of alpha-synuclein (αSyn) oligomers and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) of patients with pure autonomic failure (PAF) as markers of future phenoconversion to multiple system atrophy (MSA). Well-characterized patients with PAF (n=32) were enrolled between June 2016 and February 2019 at Mayo Clinic Rochester and followed prospectively with annual visits to determine future phenoconversion to MSA, Parkinson's disease (PD), or dementia with Lewy bodies (DLB). ELISA was utilized to measure NfL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF collected at baseline. Patients were followed for a median of 3.9 years. Five patients converted to MSA, 2 to PD, and 2 to DLB. NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters. ASyn-PMCA was positive in all but two cases (94%). The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA. αSyn-PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α-synucleinopathy. Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA. This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop. ANN NEUROL 2021;89:1212-1220.

We investigated the effect of a balanced liquid meal on blood pressure (BP) and heart rate (with patients supine and during head-up tilt), and on levels of plasma catecholamines, glucose, and insulin, in patients with idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA), pure autonomic failure (PAF), and in healthy subjects (controls). After food, supine BP fell in IPD, but to a greater extent in MSA and PAF. In controls, BP was unchanged. Head-up tilt did not lower BP in IPD and controls, but there was a postprandial fall to lower levels in both MSA and PAF. Plasma norepinephrine levels rose in IPD pre- and postprandially during tilt, but were unchanged in MSA and PAF. These data suggest that in IPD, food causes a smaller fall in supine BP than in MSA and PAF. In IPD, as in controls, food does not induce or unmask postural hypotension, unlike in MSA and PAF, in which BP falls to even lower levels. There are therefore differences in the responses to food ingestion between these groups. This may be of value in separation of these disorders at an early stage.

On head down tilt to the supine horizontal position (tilt reversal) after head up tilt (HUT), patients with orthostatic hypotension may show an increase in blood pressure (BP) relative to baseline readings. We assessed this BP overshoot in 8 patients with pure autonomic failure (PAF, 64+/-13 years) and 8 patients with multiple system atrophy (MSA, 66+/-10 years). BP was intermittently measured during pre-tilt supine, HUT (60 degrees , 10 min), and post-tilt supine periods. In addition, beat-to-beat BP was measured continuously using the Portapres model 2 device to calculate stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR). There was systolic BP overshoot of > or = 15 mmHg after tilt reversal in 5 out of 8 PAF, but in only one of 8 MSA. A mean increase of systolic BP in PAF was significantly higher than that in MSA (p<0.01). TPR increased over baseline level after tilt reversal, although there was no significant difference. SV and CO levels during the post-tilt supine period were similar to baseline levels. In conclusion, BP overshoot was prominent in the PAF group but not in the MSA group. The phenomenon of BP overshoot while supine, especially in PAF, may have implications for long term cardiac and vascular damage in such patients.

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...

Synucleinopathies are neurodegenerative diseases pathologically characterized by aggregates of α-synuclein protein in selectively vulnerable neurons and/or glia.1 These include neuronal Lewy bodies (LB) and Lewy neurites in Parkinson's disease (PD), dementia with LB, and PD dementia, and predominantly oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA).1 Isolated rapid eye movement sleep behavior disorder (iRBD) and pure autonomic failure (PAF) are often underpinned by α-synuclein pathology, sometimes revealing themselves as prodromal stages of the aforementioned disorders in retrospect.2, 3 The self-propagation of misfolded proteins assembling into seeds that induce normal-like proteins to misshape and aggregate was first recognized as mechanism of neurotoxicity in prion diseases. Increasing evidence supports the prion-like behavior of other proteins in neurodegeneration, including amyloid-β, tau, and α-synuclein.4 Therefore, detecting protein aggregates in easily accessible biospecimens represents a promising diagnostic avenue,5 especially in synucleinopathies, which can be difficult to clinically differentiate in early stages and lack specific positron emission tomography radiotracers. Moreover, because the prion-like process may precede their clinical onset by years or decades, iRBD and PAF are potential targets for an early biochemical diagnosis of synucleinopathies.2, 3, 5 Real-time quaking-induced conversion (RT-QuIC) is a high-sensitive amplification assay to detect the seeding activity of protein aggregates in biospecimens at the expense of a substrate (ie, the recombinant protein) under shaking conditions, which is monitored by thioflavin T fluorescence. RT-QuIC was first validated in sporadic Creutzfeldt-Jacob disease and is now included in its diagnostic criteria.6 Recently, it has also been explored in synucleinopathies.7 Following an established protocol,8 Rossi and colleagues9 performed cerebrospinal fluid α-synuclein RT-QuIC in a large cohort of (1) neuropathologically verified cases of LB-positive and LB-negative dementia, atypical parkinsonism, and LB-negative controls and (2) clinically diagnosed cases of PD, atypical parkinsonism, dementia, iRBD, and PAF. The assay accurately detected α-synuclein seeding activity across LB-related synucleinopathies (ie, PD, dementia with LB, iRBD, and PAF), with an overall sensitivity of 95.3% (100% in definite dementia with LB and iRBD) and an overall specificity of 98% against cases lacking LB on neuropathology.9 Intriguingly, negative RT-QuIC results were found in almost all MSA cases, 1 iRBD case with subsequent phenoconversion to MSA, and 1 PAF case showing normal adrenergic cardiac innervation on iodine-123 meta-iodobenzylguanidine single photon emission computed tomography, as observed in MSA.9 Finally, quantification of α-synuclein seeding activity through fluorescence analysis did not discriminate among LB-related clinical syndromes.9 Besides supporting the prion-like nature of LB-related synucleinopathies, this study demonstrates that α-synuclein RT-QuIC provides an accurate and reliable biomarker for these disorders in the largest cohort hitherto investigated.9 It also proves that RT-QuIC detects α-synuclein seeding activity in prodromal syndromes, allowing early diagnosis of synucleinopathy and identification of candidates for disease-modifying trials.9 Interpretation of negative assay results in most MSA cases is arguable. Although it might confirm that MSA and LB-related syndromes are associated with different conformational α-synuclein strains,10 further research needs to clarify whether different RT-QuIC set-ups may detect α-synuclein seeding activity in MSA, thus differentiating synucleinopathies. In conclusion, these findings endorse the inclusion of an RT-QuIC-based biomarker in diagnostic criteria for LB-related synucleinopathies and promote studies to test the α-synuclein RT-QuIC analysis of other biospecimens and its potential as a progression/prognostic tool. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Data Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. F.M.: 1A, 2A, 2B, 3A M.T.: 2C, 3B K.P.B.: 1A, 2C, 3B We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. The authors confirm that no patient consent was required for this work. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. F.M. is supported by the European Academy of Neurology Research Fellowship 2020. M.T. reports no disclosures. K.P.B. has received grant support from Welcome/Medical Research Council, National Institute for Health Research, Parkinsons's UK, and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), Marsden's Book of Movement Disorders (Oxford University Press, 2012), and Case Studies in Movement Disorders–Common and Uncommon Presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, and Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals, and the American Academy of Neurology, and the International Parkinson's Disease and Movement Disorders Society.

IntroductionPure Autonomic Failure (PAF) is a rare synucleinopathy characterized by chronic neurogenic orthostatic hypotension (OH), often with bladder/bowel dysfunction and anhidrosis. Many phenoconvert to Parkinson’s Disease (PD), Dementia with Lewy...

Neurogenic orthostatic hypotension (NOH) usually results from deficient release of the sympathetic neurotransmitter norepinephrine (NE) when the patient stands up. In pure autonomic failure (PAF) and PD with NOH, sympathetic denervation can explain this deficiency, whereas in multiple-system atrophy (MSA), deficient baroreflex regulation of sympathetic traffic to intact terminals probably causes the NOH. From the concept of a unitary sympathoadrenomedullary system, one might predict parallel sympathoneural and adrenomedullary abnormalities in NOH. To test the concept of parallel sympathoneural and adrenomedullary abnormalities in NOH by simultaneous measurements of plasma levels of catechols and metanephrines. Antecubital venous blood drawn via an indwelling cannula with the subject supine was assayed for catecholamines (NE, epinephrine [EPI]), dihydroxyphenylglycol (DHPG), and metanephrines (normetanephrine [NMN] and metanephrine [MN]) in patients with PAF, PD + NOH, or MSA + NOH. Control subjects had PD lacking NOH or were normal volunteers at least 35 years old. Cardiac sympathetic innervation was assessed by 6-[18F]fluorodopamine PET scanning. The three NOH groups differed clearly in patterns of plasma catechols and metanephrines. The PAF group had low NE, DHPG, NMN, EPI, and MN levels, the group with MSA + NOH had generally normal levels, and the PD + NOH group low NMN levels and low DHPG levels for given NE levels but normal mean NE, EPI, and MN levels. All patients with PAF or PD + NOH had markedly decreased 6-[18F]fluorodopamine-derived radioactivity throughout the left ventricular myocardium; all patients with MSA + NOH had normal radioactivity. PAF involves generalized loss of sympathoadrenomedullary cells, MSA + NOH intact sympathoadrenomedullary cells, and PD + NOH intact adrenomedullary cells but organ-selective sympathetic denervation, especially in the heart.

Pure autonomic failure (PAF) is an idiopathic sporadic disorder characterized by orthostatic hypotension with evidence of more widespread autonomic failure. It has been suggested that PAF belongs to the group of synucleinopathies, as autopsy studies showed α-synuclein-positive Lewy bodies in sympathetic neurons of patients with PAF.1 REM sleep behavioral disorder (RBD) appears to be an almost universal feature of synucleinopathies. Whereas initial studies suggested that RBD specifically occurs in multiple system atrophy (MSA), subsequent studies showed that it is also a frequent feature of Parkinson disease (PD) and dementia with Lewy bodies (DLB).2 Furthermore, patients with isolated RBD often later develop PD.3 We here present a consecutive unselected series of three patients with PAF (M/F: 2/1, …

Pure autonomic failure (PAF) is a rare disease in which chronic neurogenic orthostatic hypotension (nOH) dominates the clinical picture. Longitudinal studies have reported that PAF can phenoconvert to a central synucleinopathy with motor or cognitive involvement-i.e., to Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). These studies have classified patients clinically as having PAF based on nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration. This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA. Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA. Conversely, PAF without these features leaves open the possibility of premotor MSA.

Treatment with L-threo-3,4-dihydroxyphenylserine (L-threo-dops), a synthetic precursor of norepinephrine, significantly increased upright blood pressure in patients with multiple system atrophy but had no effect on the upright blood pressure of patients with pure autonomic failure. These results suggest that the site of action of L-threo-dops is central and that its pressor effect requires intact peripheral sympathetic neurons.

A scintigraphical qualitative analysis of peripheral vascular sympathetic function with meta-[ 123I]iodobenzylguanidine in neurological patients with autonomic failure

Postmortem examination of a patient with pure autonomic failure showed loss of intermediolateral column cells and of sympathetic ganglionic neurons; there were Lewy bodies in sympathetic neurons. No neuronal loss or Lewy bodies were seen in pigmented brainstem nuclei. This case indicates that pure autonomic failure can occur in the absence of presymptomatic Parkinson's disease. Furthermore, it supports the view that in pure autonomic failure the lesion is more distal than in autonomic failure associated with multiple system atrophy.