Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder that typically presents as behavioral changes and dementia, sometimes also associated with parkinsonism and/or amyotrophic lateral sclerosis. FTLD is at least as common as Alzheimer's disease in people under the age of 65, and is devastating for affected individuals and their relatives. These features reinforce the importance of current effort to develop treatments for this disorder, particularly in the presymptomatic phase. FTLD is caused by dysfunction of two major proteins-microtubule associated protein tau and TAR DNA binding protein molecular weight 43. FTLD often presents as a dominantly inherited familial disorder (f-FTLD), usually due to mutations in the microtubule associated protein tau (MAPT), progranulin (PGRN), or chromosome 9 open reading frame 72 (C9ORF72) genes, which together account for at least 50% of f-FTLD. Several agents which impact tau or progranulin/TDP-43 protein pathophysiology have been identified, but it is not clear how efficacy of drugs can be assessed, particularly in presymptomatic individuals. Importantly, f- FTLD is currently the only practical context in which people in presymptomatic or very early symptomatic stages can be studied, making it the best context for testing drugs aimed at delaying symptom onset. Based on data from other familial neurodegenerative syndromes, we expect that the rates of clinical and biomarker change in f-FTLD are complex, with slower rates of decline in the early presymptomatic phase, followed by acceleration several years prior to development of symptoms and continuing through the symptomatic phase. The proposed study will enroll 300 members of f-FTLD families with a known mutation in MAPT, PGRN, or C9ORF72 (100 symptomatic mutation carriers, 100 asymptomatic mutation carriers, and 100 non-carriers) across 8 centers [Mayo Clinic Rochester (n=70 subjects), University of California at San Francisco (n=70), University of Pennsylvania (n=70), Mayo Clinic Florida (n=18), Harvard University (n=18), Columbia University (n=18), Washington University (n=18) and University of British Columbia (n=18)] to obtain annual assessments including key magnetic resonance imaging (MRI) measures, cerebrospinal fluid analysis, blood, behavioral, neuropsychological and functional assessment, for a total of four assessments per participant. Several aims will be addressed which focus on biofluid and neuroimaging biomarkers, with the ultimate goal of identifying which measures are optimal for assessing efficacy of potential disease-modifying or preventative therapies.

Public Health Relevance

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder that typically presents as behavioral changes and dementia, sometimes also associated with parkinsonism and/or amyotrophic lateral sclerosis. FTLD is at least as common as Alzheimer's disease in people under the age of 65, and is devastating for affected individuals and their relatives. These features reinforce the importance of current effort to develop treatments for this disorder, particularly in the presymptomatic phase.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AG045390-01A1
Application #
8760412
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Hsiao, John
Project Start
2014-09-30
Project End
2019-05-31
Budget Start
2014-09-30
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Townley, Ryan A; Boeve, Bradley F; Benarroch, Eduardo E (2018) Progranulin: Functions and neurologic correlations. Neurology 90:118-125
Jones, David T; Knopman, David S; Graff-Radford, Jonathan et al. (2018) In vivo 18F-AV-1451 tau PET signal in MAPT mutation carriers varies by expected tau isoforms. Neurology 90:e947-e954
Konno, T; Yoshida, K; Mizuta, I et al. (2018) Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation. Eur J Neurol 25:142-147
Konno, Takuya; Wszolek, Zbigniew K (2018) Diaphragmatic Pacemaker for Perry Syndrome. Mayo Clin Proc 93:263
Miura, Takeshi; Mezaki, Naomi; Konno, Takuya et al. (2018) Identification and functional characterization of novel mutations including frameshift mutation in exon 4 of CSF1R in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. J Neurol 265:2415-2424
Tian, Jun; Vemula, Satya R; Xiao, Jianfeng et al. (2018) Whole-exome sequencing for variant discovery in blepharospasm. Mol Genet Genomic Med :
Mandelli, Maria Luisa; Welch, Ariane E; Vilaplana, Eduard et al. (2018) Altered topology of the functional speech production network in non-fluent/agrammatic variant of PPA. Cortex 108:252-264
Deutschländer, Angela B; Boeve, Bradley F; Rosen, Howard J et al. (2018) Tau Mutations as a Novel Risk Factor for Cancer-Letter. Cancer Res 78:6523-6524
Pottier, Cyril; Zhou, Xiaolai; Perkerson 3rd, Ralph B et al. (2018) Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol 17:548-558
Roe, Catherine M; Barco, Peggy P; Head, Denise M et al. (2017) Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals. Alzheimer Dis Assoc Disord 31:69-72

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