Coon, Elizabeth A.

Abstract The synucleinopathies—Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure—result from distinct patterns of abnormal α‐synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinson's disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy‐related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction. © 2018 International Parkinson and Movement Disorder Society

AbstractBackgroundThe objective of this study was to characterize the degree, pattern, lesion site, and temporal evolution of sudomotor dysfunction in multiple system atrophy (MSA) and to evaluate differences by parkinsonian (MSA‐parkinsonism) and cerebellar (MSA‐cerebellar) subtypes.MethodsAll cases of MSA evaluated at Mayo Clinic Rochester between 2005 and 2010 with postganglionic sudomotor testing and thermoregulatory sweat test were reviewed. Pattern and lesion site (preganglionic, postganglionic, or mixed) were determined based on thermoregulatory sweat test and postganglionic sudomotor testing.ResultsThe majority of the 232 patients were MSA‐parkinsonism (145, 63%). Initial postganglionic sudomotor testing was abnormal in 59%, whereas thermoregulatory sweat test was abnormal in 95% of all patients. MSA‐parkinsonism patients were more likely to have an abnormal thermoregulatory sweat test compared with MSA‐cerebellar (98% versus 90%, P = 0.006) and had a higher mean percentage of anhidrosis (57%) compared with MSA‐cerebellar (48%; P = 0.033). Common anhidrosis patterns were regional (38%) and global (35%). The site of the lesion was preganglionic in 47% and mixed (preganglionic and postganglionic) in 41%. The increase in anhidrosis per year was 6.2% based on 70 repeat thermoregulatory sweat tests performed on 29 patients. The frequency of postganglionic sudomotor abnormalities increased over time.ConclusionsOur findings suggest: (1) sudomotor dysfunction is almost invariably present in MSA and even more common and severe in MSA‐parkinsonism than MSA‐cerebellar; (2) a preganglionic pattern of sweat loss is common in MSA; however, pre‐ and postganglionic abnormalities may coexist; and (3) the increasing frequency of postganglionic sudomotor dysfunction over time suggests involvement of postganglionic fibers or sweat glands later in the disease course. © 2016 International Parkinson and Movement Disorder Society

ABSTRACT Background Accumulation of α‐synuclein in multiple system atrophy (MSA) affects medullary autonomic and respiratory control areas, including the rostral ventrolateral medulla and raphe nuclei. Relative neuronal vulnerability and its relationship to α‐synuclein accumulation in these areas are unknown. The aim of this study was to determine the extent of loss of adrenergic neurons in the rostral ventrolateral medulla and serotonergic neurons in the ventrolateral medulla and raphe nuclei and its relationship with α‐synuclein accumulation. Methods Medullary sections from 7 MSA and 6 control subjects were processed for tyrosine hydroxylase, tryptophan hydroxylase, and α‐synuclein immunoreactivity. Neuronal counts were performed stereologically, whereas α‐synuclein burden in oligodendrocytes and neurons was quantified using object detection density (area/mm2). Results All MSA cases had orthostatic hypotension; 5 had laryngeal stridor. There was marked neuronal loss in the rostral ventrolateral medulla and medullary raphe in all cases. Most severely affected were tyrosine hydroxylase ventrolateral medulla (C1) neurons (83% reduction), followed by tryptophan hydroxylase neurons in the ventrolateral medulla (70%), raphe obscurus (56%), pallidus (57%), and magnus (47%). α‐Synuclein accumulation occurred predominantly as glial cytoplasmic inclusions with rare α‐synuclein accumulation occurring within the remaining neurons. Density of α‐synuclein did not correlate with neuronal loss in any of the areas analyzed, and there was no correlation between α‐synuclein density and disease duration for any regions of interest. Conclusions These findings indicate that in MSA adrenergic neurons are more susceptible than serotonergic neurons in the medulla. Further, loss of medullary monoaminergic neurons may progress independently from α‐synuclein accumulation in MSA. © 2016 International Parkinson and Movement Disorder Society.