Quantification of pathology in Lewy body: the impact of multiple pathologies

Abstract

Introduction: Pathologies characteristic of Alzheimer’s disease (i.e. hyperphosphorylated tau (HP-T) and β amyloid (Aβ) plaques) often co-exist in patients with dementia with Lewy bodies and Parkinson’s disease dementia, in addition to lesions positive for α-synuclein. Post-translational modifications of Aβ and α-synuclein, namely pyroglutamylated amyloid-β (pE(3)-Aβ) and α- synuclein phosphorylated at serine-129 (pSer129 α-syn) have also been implicated in disease pathogenesis, and with recent studies pointing to a synergistic relationship between HP-T, Aβ and α-synuclein, interactions between these protein aggregations may have clinical implications. The aim of this study was to determine whether quantitative neuropathological assessment can be a useful tool in detecting subtle changes in pathology load in cases with mixed Alzheimer’s disease (AD) and Lewy body disease (LBD) (mixed AD/LBD) presenting with either AD or LBD. In addition, the impact that multiple pathological lesions have on the pathological profile and clinical phenotype of cases with LBD was investigated. Methods: Post-mortem brain tissue from cases that fulfilled neuropathological criteria for mixed AD/LBD was analysed by immunohistological staining and quantitative image analysis, measurements of cortical thickness were taken and APOE status determined to detect differences between different clinical phenotypes, with ‘pure’ AD, DLB and control samples for comparison. HP-T, Aβ, pE(3)-Aβ and pSer129 α-syn pathology loads were quantitatively measured in a cohort of LBD cases and the influence of individual and combined pathology loads on end stage motor dysfunction, as measured by part III of the Unified Parkinson’s Disease Rating Scale (UPDRS), was determined. Key findings: In neuropathologically mixed AD/LBD cases, both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Aβ, individually and in combination with α- syn, may be associated with UPDRS scores in DLB cases, and both pE(3)-Aβ and HP-T correlated positively with pSer129 α-syn in multiple regions in LBD cases.Conclusions: This study demonstrated the potential importance of quantitative neuropathological assessment in clinico-pathological studies and suggests coexisting pathologies may play a role in neurodegeneration. In addition to supporting studies that suggest a synergistic relationship between Aβ and HP-T with pSer129 α-syn, this study also introduces pE(3)-Aβ as a potential contributor, making it an interesting target for future study and therapeutic design.