Longitudinal Cognitive Performance and Cerebrospinal Fluid Biomarkers in Sporadic and Hereditary Frontotemporal Lobar Degeneration (P05.102)

OBJECTIVE: To compare longitudinal cognitive performance and cerebrospinal fluid (CSF) biomarkers in hereditary and sporadic forms of frontotemporal lobar degeneration (FTLD). BACKGROUND: Clinical trials of disease-modifying therapies in FTLD will require careful patient selection for homogeneous samples. While hereditary cases provide a useful surrogate for underlying neuropathology (i.e. tau or TDP-43), differences in rates of progression or biomarker profiles relative to sporadic cases could influence trial outcomes. DESIGN/METHODS: 26 autopsy-confirmed (FTLD-TDP=12, FTLD-Tau=14) and 27 hereditary FTLD cases (C9orf72=12, GRN=10, MAPT=5) with available neuropsychological testing within 3 months of CSF collection were studied. Follow-up testing obtained between 9 and 20 months after baseline assessment were used for longitudinal analysis (n=19 sporadic;n=11 hereditary). RESULTS: Groups did not differ in education, gender, APOE genotype or MAPT haplotype, onset-CSF collection interval, CSF collection-baseline cognitive assessment interval and interval between cognitive assessments (p>0.05). Mean CSF phosphorylated-tau (ptau) level (pg/ml) was higher in hereditary FTLD (12.2) than sporadic cases (10.5; MWU=236,p=0.04). Annualized-decline for Mini-mental status (t=2.12,p=0.04) and category fluency (t=2.19,p=0.08) was greater in hereditary (7.9 points/year;5.5 words/year) than sporadic cases (2.4 points/year; 1.5 words/year). Repeated-measure ANOVAs found significant interactions of hereditary status with MMSE (F(1,28)=4.5, p=0.04) and with category fluency (F(1,24)=4.23, p=0.05) scores between visits, suggesting more rapid decline on these measures for hereditary than sporadic FTLD. CONCLUSIONS: Hereditary forms of FTLD may have more rapid cognitive decline and differing CSF ptau profile compared with sporadic cases that could influence clinical trial outcome measures. Due to the large hereditary component of FTLD, careful consideration of study populations will be necessary. These results will require confirmation in larger samples sufficient for comparison between specific genetic and neuropathological FTLD subtypes. Supported by: Grants: P30AG010124-20, P01 AG017586, R01 NS44266, R01 AG15116, P01 AG32953, and P01 NS53488 from the National Institutes of Health and grants from the Wyncote Foundation. Dr Irwin9s work is supported by training grant T32-AG000255 from the National Institutes of Health, and Dr Toledo9s work is supported by a grant from the Alfonso Martin Escudero Foundation. Disclosure: Dr. Irwin has nothing to disclose. Dr. Weinberg has nothing to disclose. Dr. McMillan has nothing to disclose. Dr. Toledo has nothing to disclose. Dr. Arnold has received personal compensation for activities from Bristol-Myers Squibb and Cowan Group for consulting services. Dr. Arnold has received research support fromPenn-Pfizer Alliance, National Philanthropic Trust, Johnson & Johnson, Baxter, American College of Radiology Imaging Network, Pfizer, and Eli Lilly. Dr. Shaw has nothing to disclose. Dr. Lee has received personal compensation for activities with Pfizer, J&J, MetLife, and BMS as a consultant. Dr. Lee has received payments from PENN, Eli Lilly, and the University of Pennsylvania. Dr. Lee has received research support from AstraZeneca and Bristol-Myers Squibb. Dr. Trojanowski has received personal compensation for activities with Pfizer, Johnson & Johnson, MetLife, and Bristol-Myers Squibb Company. Dr. Trojanowski has received royalty payments from PENN licenses. Dr. Trojanowski has received research support from AstraZeneca Pharmaceuticals, Inc., and Bristol-Myers Squibb Company. Dr. Grossman has nothing to disclose.