Profile of cognitive impairment and underlying pathology in multiple system atrophy

Abstract

Objectives To elucidate any potential association between α-synuclein pathology and cognitive impairment, and to determine the profile of cognitive impairment in multiple system atrophy (MSA) patients, we analyzed the clinical and pathologic features in autopsy-confirmed MSA patients. Methods We retrospectively reviewed medical records, including neuropsychological test data, in 102 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank. The burden of glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were semi-quantitatively scored in the limbic regions and middle frontal gyrus. We also assessed concurrent pathologies potentially causing dementia including Alzheimer disease, hippocampal sclerosis, and cerebrovascular pathology. Results Of 102 patients, 33 (32%) patients were documented with cognitive impairment. Those that received objective testing, deficits primarily in processing speed and attention/executive functions were identified, which suggests a frontal-subcortical pattern of dysfunction. Of these 33 patients with cognitive impairment, eight patients had concurrent pathologies of dementia. MSA patients with cognitive impairment had a greater burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without cognitive impairment, both including and excluding patients with concurrent pathologies of dementia. Conclusions The cognitive deficits observed in this study were more evident on neuropsychological assessment compared to cognitive screens. Based on these findings, we recommend that clinicians consider more in-depth neuropsychological assessments if patients with MSA present with cognitive complaints. Although we did not identify the correlation between cognitive deficits and responsible neuroanatomical regions, greater burden of neuronal cytoplasmic inclusions in the limbic regions was associated with cognitive impairment in MSA.

Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy

“…Homma et al reported that frequent globular NCIs in the medial temporal regions are a pathological feature of dementia in MSA 63. Our previous study also showed that greater burden of NCI in hippocampal dentate gyrus was associated with cognitive impairment in MSA 34. More recently, a patient with MSA-dementia who had numerous NCIs in the perirhinal region without hippocampal involvement has been reported 76.…”

“…Similarly, 10% of MSA cases (10 of 102) from the Mayo Clinic Brain Bank had Lewy bodies 34. Intriguingly, Lewy body pathology was not observed in a series of 50 Japanese MSA cases 27.…”

Diagnosis of multiple system atrophy

“…There is increasing evidence, however, showing that cognitive impairment is an integral part of the disease (Koga et al, 2017b; Stankovic et al, 2014). Cognitive disturbances in MSA occur across a wide spectrum ranging from mild single domain deficits to impairments in multiple domains and even to frank dementia in rare cases.…”

TDP‐43 pathology in multiple system atrophy: colocalization of TDP‐43 and α‐synuclein in glial cytoplasmic inclusions

“…Immunohistochemistry for α-synuclein (NACP, 1:3000 rabbit polyclonal)[39] was performed on sections of the basal forebrain, striatum, midbrain, pons, medulla, and cerebellum to establish a neuropathologic diagnosis of MSA [6]. The severity of α-synuclein pathology, including GCIs, neuronal cytoplasmic inclusions (NCIs), and DNs was graded semi-quantitatively on a five-point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe) [3]. Neuropathological diagnosis of AD was based on the consensus criteria for the neuropathologic diagnosis of AD [40].…”

“…Clinical information in all MSA cases was assessed as previously described [3, 35, 45]. Antemortem clinical information for age at symptom onset, family history of dementia or parkinsonism, clinical diagnosis, and clinical symptoms and signs (autonomic dysfunctions, parkinsonism, cerebellar ataxia, cognitive impairment, etc.)…”