Frontotemporal
variety
lobar degeneration (FTLD) i s a neurodegenerative disease found at autopsy that underlies a
of clinical dementia syndromes, and is the second most common cause of dementia under age 65 [1].
Patients with FTLD-related dementias are underserved in part because the complex relationship between
dementias and underlying pathology is not well understood. Much of the complexity lies in the fact that the
same pathology
can
between
can cause different dementia syndromes and, conversely, dementia syndrome
be caused by multiple pathologies. The goal of this proposal is relationship
dementia syndromes, anatomic atrophy, cell death, and a specific form of FTLD, known as FTLD-tau.
that
a
single
to disentangle the complex
In doing so, this work will help identify the putative substrates of neurodegeneration in FTLD-tau.
This study focuses on a robust cohort of postmortem human specimens that show the most common forms
of FTLD-tau: Pick's disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).
These tauopathies can underlie primary progressive aphasia (PPA), a clinical dementia syndrome
characterized
clinical
specific targets and cellular features of a single tauopathy (Pick's disease) in
with
respectively)
clinical
responsible
pathologies
(PPA-G
between
also
distributions
atrophy
of PPA and bvFTD,
specifically, offer exciting opportunities for exploring the organization and pathologic targets of anatomic
networks in neurodegenerative diseases. Outcomes of this multidisciplinary study will clarify
by progressive language impairment, and behavioral variant frontotemporal dementia (bvFTD), a
dementia syndrome characterized by progressive changes in comportment. Aim 1 will determine the
cases diagnosed antemortem
different dementia syndromes: the semantic and agrammatic variants of PPA (PPA-S and PPA-G,
and bvFTD. These dementia syndromes are each associated with distinct patterns of atrophy and
profiles, an model to explore the vulnerabilities of anatomic regions
for cognition or behavior. Aim 2 will study the converse relationship by investigating multiple
( Pick's disease, CBD, and PSP ) in cases diagnosed antemortem with a single dementia syndrome
or bvFTD). Histological and unbiased stereological methods will be used to determine relationships
FTLD-tau pathology, not only to detailed clinical profiles and quantitative MRI atrophy patterns, but
to neuronal, glial, and synaptic abnormalities. A central hypothesis of this work is that regional
of FTLD-tau — and related cellular features — will show concordance with anatomic patterns of
and istinct clinical profiles.
This is one of the first works of its kind that aims to establish clinical, anatomic, and pathologic concordance
high specificity between clinical dementia syndromes and the tauopathies that cause them.
providing ideal selective
d
the
pathologic
underpinningsof clinical heterogeneity in dementias,sharpen our understanding of the principles of selective
vulnerability, and are highly relevant for the development of tauopathy-specific diagnostic tools and treatments.
