Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia after Alzheimer's disease (AD) in patients <65 years of age. Tau and TDP-43 pathology variants of FTLD (FTLD-Tau and FTLD-TDP, respectively) account for -90 of FTLD cases, but TDP-43 pathology occurs in >50% of patients with AD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Guam amyotrophic lateral sclerosis (ALS)/Parkinson Dementia Complex (ALS/PDC). Despite the fact that this neuropathology overlap is well known, it is unclear how comorbid Ap, tau and alpha-synuclein pathology modify TDP-43 mediated neurodegeneration in patients with frontotemporal dementia (FTD). Conversely, it is unknown how TDP-43 modifies Ap, tau and alpha-synuclein pathologies, but TDP-43 pathology is known to independently contribute to behavioral impairments in AD. Since these issues are tractable to investigate experimentally in transgenic (Tg) mouse models of TDP-43, tau, Ap and alpha-synuclein pathology. Project 4 tests the hypothesis that comorbid tau, Ap and alpha-synuclein pathologies in Tg mice independently modify TDP-43 mediated neurodegeneration and wee versa. This will be done by studying TDP-43 Tg mice which recapitulate the hallmark features of FTLD-TDP that we cross with our previously characterized mutant P301S tau Tg mice which show tau mediated neurodegeneration, behavioral impairments and premature death, Tg2576 Tg mice that model AD-like Ap pathology and our extensively studied M83 alpha-synuclien Tg mice that develop Lewy body pathology, motor impairments and lethal neurodegeneration. Implementing these Aims will elucidate how TDP-43 mediated neurodegenerative disease is modified by comorbid tau, Ap and alpha-synuclien pathologies and vice versa. These studies are highly significant because they will clarify mechanisms of TDP-43 proteinopathy and they have translational potential to improve both the diagnosis and the treatment of patients with TDP-43 proteinopathy.
Project 4 tests the hypothesis that frontotemporal dementia (FTD) patients with co-incident Alzheimer's disease (AD) pathology (tau tangles, Ap plaques), or Parkinson's disease (PD) pathology (alpha-synuclein Lewy bodies) may have a different disease course and responses to therapies than those without these comorbid pathologies and vice versa. Although tau, Ap and alphasynuclein lesions often co-occur with TDP-43 pathologies in the same patient, these issues are difficult to address in patients but they are readily addressed in studies of transgenic (Tg) mouse models of TDP-43 mediated neurodegeneration that are/are not crossed with Tg mouse models of AD or PD pathologies. Thus, the relevance of Project 4 to human health is that it will elucidate how TDP-43 mediated neurodegeneration is modified by comorbid tau, Ap and alpha-synuclien pathologies and vice versa. These studies are highly significant because they will clarify mechanisms of TDP-43 proteinopathy and have translational potential to improve the diagnosis and treatment of patients with FTD, AD, PD and related disorders.
|Besser, Lilah; Kukull, Walter; Knopman, David S et al. (2018) Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set. Alzheimer Dis Assoc Disord 32:351-358|
|Rennert, Lior; Xie, Sharon X (2018) Cox regression model with doubly truncated data. Biometrics 74:725-733|
|Sandelius, Åsa; Portelius, Erik; Källén, Åsa et al. (2018) Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology. Alzheimers Dement :|
|Adler, Daniel H; Wisse, Laura E M; Ittyerah, Ranjit et al. (2018) Characterizing the human hippocampus in aging and Alzheimer's disease using a computational atlas derived from ex vivo MRI and histology. Proc Natl Acad Sci U S A 115:4252-4257|
|Gibbons, Garrett S; Banks, Rachel A; Kim, Bumjin et al. (2018) Detection of Alzheimer Disease (AD)-Specific Tau Pathology in AD and NonAD Tauopathies by Immunohistochemistry With Novel Conformation-Selective Tau Antibodies. J Neuropathol Exp Neurol 77:216-228|
|Robinson, John L; Lee, Edward B; Xie, Sharon X et al. (2018) Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141:2181-2193|
|Shi, Min; Tang, Lu; Toledo, Jon B et al. (2018) Cerebrospinal fluid ?-synuclein contributes to the differential diagnosis of Alzheimer's disease. Alzheimers Dement 14:1052-1062|
|McGurk, L; Mojsilovic-Petrovic, J; Van Deerlin, V M et al. (2018) Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathol Commun 6:84|
|Lleó, Alberto; Irwin, David J; Illán-Gala, Ignacio et al. (2018) A 2-Step Cerebrospinal Algorithm for the Selection of Frontotemporal Lobar Degeneration Subtypes. JAMA Neurol 75:738-745|
|Grossman, Murray (2018) Linguistic Aspects of Primary Progressive Aphasia. Annu Rev Linguist 4:377-403|
Showing the most recent 10 out of 593 publications