Medullary neuronal loss and alpha-synuclein burden in Multiple System Atrophy

      Background: Multiple system atrophy (MSA) is characterized by α-synuclein accumulation as glial cytoplasmic inclusions (GCIs) and affects medullary autonomic and respiratory control areas, including the rostral ventrolateral medulla (VLM) and raphe nuclei. The relative neuronal vulnerability and its relationship to GCI accumulation in these areas are unknown. Aim: To determine the extent of loss of adrenergic (C1) neurons in the rostral VLM and serotonergic neurons in the VLM, raphe pallidus, raphe obscurus and raphe magnus, and its relationship with GCI accumulation. Methods: Sections of the medulla from 5 MSA (3 MSA-P and 2 MSA-C) and 6 control subjects were processed for tyrosine hydroxylase (TH), tryptophan hydroxylase (TrOH), and α-synuclein immunoreactivity. Neuronal counts were performed stereologically. GCI burden was quantified using object detection density (area/mm2). Results: All MSA cases had orthostatic hypotension; 3 had laryngeal stridor. There was marked neuronal loss in the rostral VLM and medullary raphe in all cases. This most severely affected the TH-VLM (C1) neurons (84% reduction), followed by TrOH-neurons in the VLM (70%), raphe obscurus (56%), pallidus (54%), and magnus (46%). GCI density was highest in the raphe pallidus (0.0056), followed by the VLM (0.0051), raphe obscurus (0.0046) and magnus (0.0026). GCI density did not correlate with neuronal loss. Conclusions: 1) Neuronal loss in the VLM and medullary raphe is consistent with previous studies and contributes to cardiovascular and respiratory dysfunction. 2) C1 may be more vulnerable than serotonergic VLM neurons. 3) Neuronal loss and oligodendrocyte (GCI) pathology may progress independently in medullary cardiorespiratory regions.
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