Search

Traditionally regarded to coordinate movement, the cerebellum also exerts non-motor functions including the regulation of cognitive and behavioral processing, suggesting a potential role in neurodegenerative conditions affecting cognition, such as Alzheimer's disease (AD). This study aims to investigate neuropathology and AD-related molecular changes within the neocerebellum using post-mortem human brain tissue microarrays (TMAs). Immunohistochemistry was conducted on neocerebellar paraffin-embedded TMAs from 24 AD and 24 matched control cases, and free-floating neocerebellar sections from 6 AD and 6 controls. Immunoreactivity was compared between control and AD groups for neuropathological hallmarks (amyloid-β, tau, ubiquitin), Purkinje cells (calbindin), microglia (IBA1, HLA-DR), astrocytes (GFAP) basement-membrane associated molecules (fibronectin, collagen IV), endothelial cells (CD31/PECAM-1) and mural cells (PDGFRβ, αSMA). Amyloid-β expression (total immunolabel intensity) and load (area of immunolabel) was increased by >4-fold within the AD cerebellum. Purkinje cell counts, ubiquitin and tau immunoreactivity were unchanged in AD. IBA1 expression and load was increased by 91% and 69%, respectively, in AD, with no change in IBA1-positive cell number. IBA1-positive cell process length and branching was reduced by 22% and 41%, respectively, in AD. HLA-DR and GFAP immunoreactivity was unchanged in AD. HLA-DR-positive cell process length and branching was reduced by 33% and 49%, respectively, in AD. Fibronectin expression was increased by 27% in AD. Collagen IV, PDGFRβ and αSMA immunoreactivity was unchanged in AD. The number of CD31-positive vessels was increased by 98% in AD, suggesting the increase in CD31 expression and load in AD is due to greater vessel number. The PDGFRβ/CD31 load ratio was reduced by 59% in AD. These findings provide evidence of molecular changes affecting microglia and the neurovasculature within the AD neocerebellum. These changes, occurring without overt neuropathology, support the hypothesis of microglial and neurovascular dysfunction as drivers of AD, which has implications on the neocerebellar contribution to AD symptomatology and pathophysiology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by variable motor and behavioral symptoms attributed to major neuropathology of mainly the basal ganglia and cerebral cortex. The role of the cerebellum, a brain region involved in the coordination of movements, in HD neuropathology has been controversial. This study utilizes postmortem human brain tissue to investigate whether Purkinje cell degeneration in the neocerebellum is present in HD, and how this relates to disease symptom profiles., Methods: Unbiased stereological counting methods were used to quantify the total number of Purkinje cells in 15 HD cases and 8 neurologically normal control cases. Based on their predominant symptoms, the HD cases were categorized into 2 groups: "motor" or "mood.", Results: The results demonstrated a significant 43% loss of Purkinje cells in HD cases with predominantly motor symptoms, and no cell loss in cases showing a major mood phenotype. There was no significant correlation between Purkinje cell loss and striatal neuropathological grade, postmortem delay, CAG repeat in the IT15 gene, or age at death., Interpretation: This study shows a compelling relationship between Purkinje cell loss in the HD neocerebellum and the HD motor symptom phenotype, which, together with our previous human brain studies on the same HD cases, provides novel perspectives interrelating and correlating the variable cerebellar, basal ganglia, and neocortical neuropathology with the variability of motor/mood symptom profiles in the human HD brain. ANN NEUROL 2019;85:396-405., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Traditionally regarded to coordinate movement, the cerebellum also exerts non-motor functions including the regulation of cognitive and behavioral processing, suggesting a potential role in neurodegenerative conditions affecting cognition, such as Alzheimer's disease (AD). This study aims to investigate neuropathology and AD-related molecular changes within the neocerebellum using post-mortem human brain tissue microarrays (TMAs).Immunohistochemistry was conducted on neocerebellar paraffin-embedded TMAs from 24 AD and 24 matched control cases, and free-floating neocerebellar sections from 6 AD and 6 controls. Immunoreactivity was compared between control and AD groups for neuropathological hallmarks (amyloid-β, tau, ubiquitin), Purkinje cells (calbindin), microglia (IBA1, HLA-DR), astrocytes (GFAP) basement-membrane associated molecules (fibronectin, collagen IV), endothelial cells (CD31/PECAM-1) and mural cells (PDGFRβ, αSMA).Amyloid-β expression (total immunolabel intensity) and load (area of immunolabel) was increased by >4-fold within the AD cerebellum. Purkinje cell counts, ubiquitin and tau immunoreactivity were unchanged in AD. IBA1 expression and load was increased by 91% and 69%, respectively, in AD, with no change in IBA1-positive cell number. IBA1-positive cell process length and branching was reduced by 22% and 41%, respectively, in AD. HLA-DR and GFAP immunoreactivity was unchanged in AD. HLA-DR-positive cell process length and branching was reduced by 33% and 49%, respectively, in AD. Fibronectin expression was increased by 27% in AD. Collagen IV, PDGFRβ and αSMA immunoreactivity was unchanged in AD. The number of CD31-positive vessels was increased by 98% in AD, suggesting the increase in CD31 expression and load in AD is due to greater vessel number. The PDGFRβ/CD31 load ratio was reduced by 59% in AD.These findings provide evidence of molecular changes affecting microglia and the neurovasculature within the AD neocerebellum. These changes, occurring without overt neuropathology, support the hypothesis of microglial and neurovascular dysfunction as drivers of AD, which has implications on the neocerebellar contribution to AD symptomatology and pathophysiology.