Helen Ling1,2, Yasmine T Asi1, Igor N Petrovic2,3, Zeshan Ahmed1, L K Prashanth4,5, Lili-Naz Hazrati4,5, Masatoyo Nishizawa6, Tetsutaro Ozawa6, Anthony Lang4,5, Andrew J Lees1,2, Tamas Revesz1, Janice L Holton1. 1. Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, UK. 2. Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK. 3. Institute of Neurology, School of Medicine, Belgrade, Serbia. 4. University of Toronto, Toronto, Canada. 5. Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Canada. 6. Department of Neurology, Niigata University, Japan.
Abstract
BACKGROUND: Glial cytoplasmic inclusions containing α-synuclein are the pathological hallmark of multiple system atrophy (MSA). Minimal change (MC-MSA) is an unusual MSA subtype with neuronal loss largely restricted to the substantia nigra and locus coeruleus. METHODS: Immunohistochemistry on selected brain regions and semiquantitative assessment were performed on six MC-MSA and eight MSA control cases. RESULTS: More neuronal cytoplasmic inclusions were seen in the caudate and substantia nigra in MC-MSA than in MSA controls (P = 0.002), without any statistical difference in glial cytoplasmic inclusion load in any region. Severe glial cytoplasmic inclusion load was found in the ventrolateral medulla (P = 1.0) and nucleus raphe obscurus (P = 0.4) in both groups. When compared with MSA controls, the three MC-MSA cases who had died of sudden unexpected death had an earlier age of onset (mean: 38 vs. 57.6 y, P = 0.02), a numerically shorter disease duration (mean: 5.3 vs. 8 y, P = 0.2) and a more rapid clinical progression with most of the clinical milestones reached within 3 y of presentation, suggesting an aggressive variant of MSA. Another three MC-MSA cases, who had died of unrelated concurrent diseases, had an age of onset (mean: 57.7 y) and temporal course similar to controls, had less severe neuronal loss and gliosis in the medial and dorsolateral substantia nigra subregions (P < 0.05) than in MSA controls, and could be considered as a unique group with interrupted pathological progression. Significant respiratory dysfunction and early orthostatic hypotension were observed in all MC-MSA cases. CONCLUSIONS: Our findings could suggest that α-synuclein-associated oligodendroglial pathology may lead to neuronal dysfunction sufficient to cause clinical symptoms before overt neuronal loss in MSA.
BACKGROUND: Glial cytoplasmic inclusions containing α-synuclein are the pathological hallmark of multiple system atrophy (MSA). Minimal change (MC-MSA) is an unusual MSA subtype with neuronal loss largely restricted to the substantia nigra and locus coeruleus. METHODS: Immunohistochemistry on selected brain regions and semiquantitative assessment were performed on six MC-MSA and eight MSA control cases. RESULTS: More neuronal cytoplasmic inclusions were seen in the caudate and substantia nigra in MC-MSA than in MSA controls (P = 0.002), without any statistical difference in glial cytoplasmic inclusion load in any region. Severe glial cytoplasmic inclusion load was found in the ventrolateral medulla (P = 1.0) and nucleus raphe obscurus (P = 0.4) in both groups. When compared with MSA controls, the three MC-MSA cases who had died of sudden unexpected death had an earlier age of onset (mean: 38 vs. 57.6 y, P = 0.02), a numerically shorter disease duration (mean: 5.3 vs. 8 y, P = 0.2) and a more rapid clinical progression with most of the clinical milestones reached within 3 y of presentation, suggesting an aggressive variant of MSA. Another three MC-MSA cases, who had died of unrelated concurrent diseases, had an age of onset (mean: 57.7 y) and temporal course similar to controls, had less severe neuronal loss and gliosis in the medial and dorsolateral substantia nigra subregions (P < 0.05) than in MSA controls, and could be considered as a unique group with interrupted pathological progression. Significant respiratory dysfunction and early orthostatic hypotension were observed in all MC-MSA cases. CONCLUSIONS: Our findings could suggest that α-synuclein-associated oligodendroglial pathology may lead to neuronal dysfunction sufficient to cause clinical symptoms before overt neuronal loss in MSA.
Authors: J Brettschneider; D J Irwin; S Boluda; M D Byrne; L Fang; E B Lee; J L Robinson; E Suh; V M Van Deerlin; J B Toledo; M Grossman; H Hurtig; R Dengler; S Petri; V M-Y Lee; J Q Trojanowski Journal: Neuropathol Appl Neurobiol Date: 2016-10-18 Impact factor: 8.090
Authors: Shunsuke Koga; Fuyao Li; Na Zhao; Shanu F Roemer; Tanis J Ferman; Anna I Wernick; Ronald L Walton; Ayman H Faroqi; Neill R Graff-Radford; William P Cheshire; Owen A Ross; Dennis W Dickson Journal: Brain Pathol Date: 2020-04-14 Impact factor: 6.508