Selective vulnerability of subcortical nuclei in atypical Alzheimer’s Disease

Abstract

AbstractBackgroundRecent evidence suggests that sleep‐wake dysregulation in Alzheimer’s disease (AD) is an early event and parallels the tau accumulation in the arousal system spefically noted in the locus coeruleus (LC) as well as other subcortical nuclei as the Pedunculopontine Tegmental Nucleus (PPTg), Laterodorsal Tegmental Nucleus (LDTg), and the Dorsal Raphe (DR). We have previously demonstrated that the pattern of sleep‐wake dysfunction is different among AD clinical variants. This existence of specific sleep‐wake profiles suggest differential degeneration patterns of the arousal system within differing AD presentations. This study continues this investigation at the cellular/molecular level to uncover the selective vulnerability of subcortical structures to AD specific tau accumulation. That remains elusive to‐date.MethodHuman postmortem brainstem samples were sourced from the Neurodegenerative Disease Brain Bank (NDBB) at UCSF. 24 subjects were selected based on primary diagnosis, including 6 amnestic AD, 17 non‐amnestic AD (5 EOAD, 3 PCA, 5 lvPPA, 4 CBS) and 1 control. Paraffin blocks containing the areas of interest were cut into 8‐lm‐thick sections that underwent double‐labeled immunohistochemistry (IHC) and brightfield imaging. The images were then overlayed to created mutlidimentaional maps and neurons were classified in 4 subgroups: (1) positive for the neurotransmitter of interest (NEU‐positive), (2) bearing hyperphosphorylated tau neuronal cytoplasmic inclusions (tau‐positive), (3) positive for the neurotransmitter of interest and bearing tau‐positive (NEU‐positive/tau‐positive colocalized neurons), and (4) negative for NEU and tau.ResultIn the LC, lvPPA had the highest had the highest percentage of tau postive neurons (40%), followed by amnestic AD (31.1%), PCA (29.3%), EOAD (27.1%), and finally CBS (24.3%). EOAD had the highest percentage of colocalized neurons (34.7%) as well as LOAD (31%) compared to PCA (0.02%), lvPPA (0.18%), CBS (0.09%).ConclusionMultidimensional quantitative analysis suggests differences in vulnerabliblity of sleep‐wake subcortical nuclei to AD, EOAD, PCA, lvPPA, and CBS. For instance the neuronal loss in EOAD was so extreme in the LC that few neurons remained to develop aggregates whereas in PCA, CBS, and lvPPA the high percentage of tau accumulation presents a neuropathological framework underlying atypical clinical manifestations and possible insight into therapeutic targets.