Neurodegenerative diseases are characterized by CNS accumulations of misfolded protein aggregates that define the neuropathology of each disorder, including frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in patients under the age of 65. There have been dramatic advances in research on FTLD that have revolutionized concepts about FTLD since this Program Project Grant (PPG) was renewed in 2005. Thus, tau, TDP-43 or FUS inclusions now are recognized as the defining CNS lesions in ~45%, ~50% and ~5% of FTLD, respectively, and these FTLD variants are designated FTLD-Tau, FTLD-TDP and FTLD-FUS, respectively. FTD may be sporadic or familial, and hereditary FTD with parkinsonism linked to chromosome 17q21-22 is caused by >30 M>APT mutations while >30 TARDBP and FUS mutations were discovered in the last 3 years that associate with amyotrophic lateral sclerosis (ALS), but TARDBP mutations also associate with FTLD plus ALS. Notably, although FTLD-Tau, FTLD-TDP and FTLD-FUS account for nearly all FTLD cases, Alzheimer's disease (AD) is the cause of FTD in ~25% of patients. Moreover, TDP-43 pathology co-occurs in 30-50% of patients with AD, Parkinson's disease and dementia with Lewy bodies. Given the heterogeneity of FTD and the clinical overlap of FTD with AD and other disorders, a thorough postmortem examination of FTD patients followed in Clinical Core of this PPG is essential to define the clinicopathologic phenotypes of FTD and link them to genetic, imaging and biomarker findings as well as to provide CNS samples for research. Further, the collection of biofluids is essential to identify FTD biomarkers for the early and reliable diagnosis of FTD. Accordingly, Core D acquires, characterizes, banks, distributes and studies CNS and biofluid samples from FTD patients and control subjects followed in the Clinical Core of this PPG.

Public Health Relevance

The relevance of the Neuropathology Core D is that it challenges and re-defines concepts and current understanding of frontotemporal lobar degeneration (FTLD), the second most common cause of dementia after Alzheimer's disease in persons under the age of 65. By utilizing novel concepts and approaches to implement the Aims of Core D we also will improve upon current research and clinical practice paradigms for FTLD. In this manner. Core D will improve the postmortem diagnosis of FTLD, enhance understanding of mechanisms underlying FTLD, contribute to developing FTLD biomarkers forthe reliable diagnosis of FTLD during life, and accelerate efforts to identify disease modifying therapies for FTLDs. Thus, Core D contributes to improving the health of middle age and older members of society.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-4)
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University of Pennsylvania
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Russ, Jenny; Liu, Elaine Y; Wu, Kathryn et al. (2015) Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129:39-52
Massimo, Lauren; Evans, Lois K (2014) Differentiating subtypes of apathy to improve person-centered care in frontotemporal degeneration. J Gerontol Nurs 40:58-65
Ferrari, Raffaele; Hernandez, Dena G; Nalls, Michael A et al. (2014) Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol 13:686-99
Olm, Christopher A; McMillan, Corey T; Spotorno, Nicola et al. (2014) The relative contributions of frontal and parietal cortex for generalized quantifier comprehension. Front Hum Neurosci 8:610
Serrano, Geidy E; Sabbagh, Marwan N; Sue, Lucia I et al. (2014) Positive florbetapir PET amyloid imaging in a subject with frequent cortical neuritic plaques and frontotemporal lobar degeneration with TDP43-positive inclusions. J Alzheimers Dis 42:813-21
Irwin, David J; McMillan, Corey T; Suh, EunRan et al. (2014) Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia. Neurology 83:502-9
Alfieri, Julio A; Pino, Natalia S; Igaz, Lionel M (2014) Reversible behavioral phenotypes in a conditional mouse model of TDP-43 proteinopathies. J Neurosci 34:15244-59
Walker, Adam K; Daniels, Christine M LaPash; Goldman, James E et al. (2014) Astrocytic TDP-43 pathology in Alexander disease. J Neurosci 34:6448-58
McCluskey, Leo F; Geser, Felix; Elman, Lauren B et al. (2014) Atypical Alzheimer's disease in an elderly United States resident with amyotrophic lateral sclerosis and pathological tau in spinal motor neurons. Amyotroph Lateral Scler Frontotemporal Degener 15:466-72
Bit-Ivan, Esther N; Suh, Eunran; Shim, Hyung-Sub et al. (2014) A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases. J Neuropathol Exp Neurol 73:467-73

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