Tau and ɑ-synucleinopathy co-pathology in military Veterans with parkinsonism: An autopsy study

Abstract:Background: Lewy bodies consisting of misfolded ɑ-synuclein accumulation and neurofibrillary tangles composed of hyperphosphorylated tau (p-tau) are common co-pathologies observed in parkinsonian syndromes, such as Parkinson's disease and progressive supranuclear palsy. The high frequency of these co-pathologies suggests that these proteins might synergistically impact disease progression and/or severity. Our goal is to examine potential interactions between these proteinopathies by analyzing the co-pathology inclusion distribution frequency of p-tau and ɑ-synuclein, correlating these with regional vulnerability and disease progression. Methods: We selected post-mortem tissue from brain donors (n=27) with a parkinsonian syndrome referred from the James J. Peters Veterans Affairs Medical Center Movement Disorders Clinic. Post-mortem examination included standardized neuropathological assessment protocols. The regional and frequency distribution of inclusions were identified using single and duplex immunohistochemistry (IHC) performed on the Ventana Discovery Ultra using primary antibodies p-tau (AT8) and ɑ-synuclein (LB509). Each slide was scanned on the Aperio GT-450, assessed for pathological severity, and given a semi-quantitative score. Results: Of the 27 cases studied, 23 (85.2%) were positive for p-tau, which included primary age-related tauopathy (n=3, 11.1%), progressive supranuclear palsy (n=4, 14.8%), and/or Alzheimer’s disease neuropathologic change (n=15, 55.6%). There were 17 cases (63.0%) immunopositive for ɑ-synuclein, brainstem predominant (n=2, 11.8%), limbic (n=1, 5.9%), and diffuse neocortical (n=14, 82.4%). Over half (n=14, 52.0%) were immunopositive for both p-tau and ɑ-synuclein. Duplex IHC demonstrated co-localization of p-tau and ɑ-synuclein in the same neurons and neuronal processes. Conclusions: This study demonstrates the prevalence of intracellular co-aggregation of tau and ɑ-synuclein in a distinct cohort of veterans with parkinsonian syndromes, providing a potential marker for regional vulnerability leading to a change in disease progression. Further studies are warranted to identify molecular and genetic factors that could contribute to these co-aggregation types in parkinsonian syndromes and other neurodegenerative disorders.