Our Work

A major obstacle for the development of meaningful therapies in neurodegenerative disorders is the inability to accurately diagnose the specific underlying neuropathology causing disease in living patients. Indeed, there is a divergent set of nomenclature for clinical syndromes that describe patient symptoms during life and the gold-standard neuropathological diagnoses at autopsy that cause these syndromes (e.g. A clinical diagnosis of “Alzheimer’s disease” does not always predict underlying “Alzheimer’s disease neuropathologic change”). Moreover, traditional histopathological data are more qualitative in nature and involve relatively sparse sampling of the brain that limit detailed clinicopathological correlations needed to improve antemortem diagnosis of underlying neuropathology.

We address this gap using a unique and innovative approach utilizing validated and rigorous digital methods to measure microscopic neuropathology in extended sampling across hemispheres in the human brain and relate this data to postmortem ex vivo and antemortem in vivo imaging, as well as other biomarkers collected during life for “tissue-guided biomarker discovery.” This targeted approach to biomarker discovery is advantageous to non-hypothesis driven biomarker discovery methods which can lead to false-positives due to the complexity of underlying pathology found in non-autopsy-validated clinical cohorts.

We focus on two main diagnostic uncertainties in neurodegenerative disease (please click below to learn more):

  1. Clinically indistinguishable distinct proteinopathies in the frontotemporal dementia (FTD) spectrum.
  2. Clinical influence of mixed pathologies in the spectrum of Alzheimer’s disease (AD) and Lewy body disorders (LBD).
clinicopathological correlation
FIGURE 1. CLINICOPATHOLOGICAL CORRELATIONS IN NEURODEGENERATIVE DEMENTIAS. Schematic depicts each clinical diagnosis box color shaded by the relative frequency of neurodegenerative neuropathologies found in large autopsy studies. Mixed co-pathologies are common in: A) Alzheimer’s disease (AD), where less than half of clinical AD patients are found to have isolated amyloid-beta plaques and tau neurofibrillary tau pathology and (B) LBD, where, roughly half of patients have “pure” alpha-synuclein pathology while relatively equal numbers have sufficient additional AD co-pathology for a secondary neuropathological diagnosis of AD. C) Finally, the majority of FTD clinical syndromes poorly predict distinct pure FTLD-Tau and FTLD-TDP protienopathies. Additionally, non-amnestic forms of pure AD neuropathology in younger patients can mimic all clinical FTD. (adapted from Irwin, DJ, Journal of Applied Laboratory Medicine 2019).