Abstract
Whereas early Alzheimer disease (AD) neuropathology and mild cognitive impairment are relatively common in aging, accurate prediction of patients that will progress to dementia requires new biomarkers. Recently, substantial work has focused on phospho-tau/MAPT (p-MAPT) neuropathology since its regional propagation correlates with the degree of cognitive impairment in AD. Recent diffusion tensor imaging studies in AD suggest that increased diffusion in the fornix secondary to p-MAPT-related axonal injury could serve as a predictive biomarker of the risk of disease progression. However, our knowledge of p-MAPT neuropathology in the fornix is limited. To address this gap in knowledge, we examined p-MAPT neuropathology in the fornix and basal forebrain nuclei via AT8 immunohistochemistry in 39 brain autopsies spanning the spectrum of AD neuropathologic changes. We found that the fornix and its precommissural efferent target nuclei (septum and nucleus accumbens) demonstrated neuronal and thread-like p-MAPT neuropathology only in National Institute on Aging/Alzheimer Association (NIA/AA) stages B2 and B3 of neurofibrillary degeneration, consistent with involvement after (and propagation from) the hippocampal formation. Interestingly, although tau astrogliopathy was frequently observed in the mammillary bodies in stage B2, neuronal tauopathy was not observed in the postcommissural targets (mammillary bodies and anterior thalamic nucleus) until stage B3. Tauopathy in the nucleus basalis of Meynert was strongly correlated with p-MAPT-positive axons in the fornix, suggesting that projections to the hippocampus also likely contribute to fornix tauopathy. Our cross-sectional autopsy findings indicate that the fornix is involved by p-MAPT neuropathology secondary to hippocampal involvement by AD neuropathology. Furthermore, our findings are compatible with the goal of in vivo detection of p-MAPT-related axonal pathology in the fornix in AD as a possible biomarker of p-MAPT progression from the hippocampal formation and underscore a need for additional clinical-radiologic-pathologic correlation studies.
Highlights
Alzheimer disease (AD) is a common age-related neurodegenerative disease that is typically characterized by an early stage of amnestic mild cognitive impairment which can progress to multi-domain cognitive deterioration and dementia
This possibility mandates a better understanding of early AD neuropathology as well as the discovery of novel biomarkers that herald disease onset and that accurately identify the risk for progression from mild cognitive impairment (MCI) to dementia in sporadic AD
The National Institute on Aging/Alzheimer Association (NIA/AA) AD staging system [12], which is based in part on the Braak staging system of neurofibrillary degeneration [2,3,4], delineates the typical progression of cerebral neurofibrillary degeneration in AD beginning in the transentorhinal and entorhinal cortices (B1), progression into the hippocampal formation (B2) and culminating in involvement of the association neocortices followed by the primary neocortices (B3)
Summary
Alzheimer disease (AD) is a common age-related neurodegenerative disease that is typically characterized by an early stage of amnestic mild cognitive impairment which can progress to multi-domain cognitive deterioration and dementia. One potential explanation for the inefficacy of new experimental treatments is that they have been studied in patients with advanced disease when a window for functional recovery has closed This possibility mandates a better understanding of early AD neuropathology as well as the discovery of novel biomarkers that herald disease onset and that accurately identify the risk for progression from mild cognitive impairment (MCI) to dementia in sporadic AD. Diffusion tensor imaging (DTI) has recently received attention as a modality to detect p-MAPT-related axonal injury in the fornix in AD [1, 18]
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