Ubiquitin positive inclusions are found in amyotrophic lateral sclerosis (ALS), a prototypic motor neuron disease and frontotemporal lobar degeneration (FTLD), the second most common dementia after Alzheimer's disease in patients <65. Recently, investigators at the University of Pennsylvania (PENN) identified TDP-43 as the disease protein ubiquitinated in both disorders. Since motor neuron disease and dementia are found in ALS and FTLD, and since the same disease protein accumulates in both disease entities, this suggests that ALS and FTLD represent the same clinicopathological spectrum of a neurodegenerative syndrome. Thus, the major goals of this Program Project Grant (PPG) is to develop a vigorous research program focused on elucidating the etiology and pathogenesis of TDP-43 proteinopathies in ALS without or with cognitive impairment or dementia (designated as ALS, ALS-Cog and ALS-FTLD, respectively) and compare them to FTLD with and without ALS. The investigators of this new PPG are a close-knit and highly integrated multidisciplinary group of PENN physicians and basic scientists who have formed a productive collaborative alliance and established a very comprehensive clinical and basic science research program at PENN to study ALS, ALS-Cog and ALS-FTLD in patients, in human postmortem tissues and in model systems. These investigators propose a set of bold objectives for ALS and FTLD research that will be implemented through 4 Cores and 3 Projects. Specifically, they will: 1) recruit ALS, ALS-Cog and ALS-FTLD patients;2) develop new algorithms to characterize the cognitive impairments and dementia in ALS patients;3) test the hypothesis that there is a tight link between language and motor systems in the representation of action verbs;4) further characterize the spectrum of TDP-43 neuropathologies in ALS, ALS-Cog and ALS-FTLD brains and compare them with FTLD with and without ALS;5) identify hyperphosphorylated residues and N-terminal cleavage sites that generate C-terminal fragments in pathological TDP-43 and determine their significance in mechanisms of TDP-43 proteinopathies;6) establish cell culture and transgenic mouse models of TDP-43;7) use these models to elucidate the pathogenic mechanisms of neurodegeneration in TDP-43;8) determine if genetic variants in TDP-43 found in patients with ALS, ALS-Cog and ALS-FTLD are disease risk factors or pathogenic disease causing mutations;These and other studies will lead to improved understanding of the cognitive impairments and dementia in ALS as well as provide insights on the diagnosis and treatment of these disorders.
The basic, Clinical and translational studies proposed in the 4 Cores and 3 Projects here in this Program Project Grant represent an interdisciplinary, synergistic and complementary team effort to increase understanding of the cognitive impairments and dementia in amyotrophic lateral sclerosis (ALS) as well as provide insights on the diagnosis and treatment of ALS and its different clinical manifestations, especially those that affect cognition. Thus, this PPG addresses important questions in the field of ALS research.
|Alcolea, Daniel; Irwin, David J; Illán-Gala, Ignacio et al. (2018) Elevated YKL-40 and low sAPP?:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD. J Neurol Neurosurg Psychiatry :|
|Barupal, Dinesh Kumar; Fan, Sili; Wancewicz, Benjamin et al. (2018) Generation and quality control of lipidomics data for the alzheimer's disease neuroimaging initiative cohort. Sci Data 5:180263|
|Olm, Christopher A; McMillan, Corey T; Irwin, David J et al. (2018) Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers. Neuroimage Clin 19:497-506|
|Dong, Aoyan; Toledo, Jon B; Honnorat, Nicolas et al. (2017) Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers. Brain 140:735-747|
|Wisse, L E M; Adler, D H; Ittyerah, R et al. (2017) Comparison of In Vivo and Ex Vivo MRI of the Human Hippocampal Formation in the Same Subjects. Cereb Cortex 27:5185-5196|
|Irwin, David J; Lleó, Alberto; Xie, Sharon X et al. (2017) Ante mortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration. Ann Neurol 82:247-258|
|Taskesen, E; Mishra, A; van der Sluis, S et al. (2017) Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS. Sci Rep 7:8899|
|St John-Williams, Lisa; Blach, Colette; Toledo, Jon B et al. (2017) Targeted metabolomics and medication classification data from participants in the ADNI1 cohort. Sci Data 4:170140|
|Lee, Yune-Sang; Min, Nam Eun; Wingfield, Arthur et al. (2016) Acoustic richness modulates the neural networks supporting intelligible speech processing. Hear Res 333:108-117|
|Irwin, David J; Brettschneider, Johannes; McMillan, Corey T et al. (2016) Deep clinical and neuropathological phenotyping of Pick disease. Ann Neurol 79:272-87|
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