Abstract Olfactory dysfunction is common in multiple sclerosis ( MS ). Olfactory bulb and tract pathology in MS and other demyelinating diseases remain unexplored. A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease ( MS ; n = 17), neuromyelitis optica [( NMO ); n = 3] and acute disseminated encephalomyelitis [( ADEM ); n = 7] was compared to neuroinflammatory [herpes simplex virus encephalitis ( HSE ); n = 3], neurodegenerative [ A lzheimer's disease ( AD ); n = 4] and non‐neurologic (n = 8) controls. For each case, olfactory bulbs and/or tracts were stained for myelin, axons and inflammation. Inferior frontal cortex and hippocampus were stained for myelin in a subset of MS and ADEM cases. Olfactory bulb/tract demyelination was frequent in all demyelinating diseases [ MS 12/17 (70.6%); ADEM 3/7 (42.9%); NMO 2/3 (66.7%)] but was absent in HSE , AD and non‐neurologic controls. Inflammation was greater in the demyelinating diseases compared to non‐neurologic controls. Olfactory bulb/tract axonal loss was most severe in MS where it correlated significantly with the extent of demyelination ( r = 0.610, P = 0.009) and parenchymal inflammation ( r = 0.681, P = 0.003). The extent of olfactory bulb/tract demyelination correlated with that found in the adjacent inferior frontal cortex but not hippocampus. We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early and is highly inflammatory, and is specific to demyelinating disease.
OBJECTIVE: To identify and characterise olfactory bulb/tract pathology in central nervous system demyelinating diseases. BACKGROUND: Olfactory dysfunction is a common feature of multiple sclerosis. Previous radiographic and pathological studies have attributed olfactory disturbance in multiple sclerosis to demyelination of the olfactory brain with the olfactory bulb and tract thought to be relatively spared. DESIGN/METHODS: A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease (multiple sclerosis (n=17), neuromyelitis optica (n=3), and acute disseminated encephalomyelitis (n=7)) was compared to neuroinflammatory (herpes simplex virus encephalitis; n=3), neurodegenerative (Alzheimer's disease; n=3), and non-neurologic (n=8) controls. For each case, olfactory bulbs and/or tracts were stained for myelin, axons, and inflammation. RESULTS: Olfactory bulb/tract demyelination was frequent in all demyelinating diseases (multiple sclerosis 12/17 (70.6%); acute disseminated encephalomyelitis 3/7 (42.9%); neuromyelitis optica 2/3 (66.7%)) but was absent in herpes simplex encephalitis, Alzheimer's disease, and non-neurologic controls. Inflammation was significantly greater in the demyelinating diseases compared to non-neurologic controls. Olfactory bulb/tract axonal loss was detected in all demyelinating diseases, being most severe in multiple sclerosis where it correlated significantly with the extent of demyelination (r = 0.610, p = 0.009) and parenchymal inflammation (r = 0.681, p = 0.003). The extent of olfactory bulb/tract demyelination and inflammation mirrored that found in superficial cortical layers where subpial demyelination and inflammation was observed. CONCLUSIONS: We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early, is highly inflammatory and specific to demyelinating disease. These novel findings shed insight into the pathogenesis of demyelinating diseases and fuel support for further exploration of the nose to brain hypothesis. Study Supported by: GCD is supported by the AANF/CMSC John F. Kurtzke Clinician-Scientist Development Award and a Goodger Scholarship (University of Oxford). GCD and MME receive support from the NIHR Biomedical Research Centre, Oxford. RY is supported a Medical Research Council PhD Studentship.
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