Cognitive Endophenotype Associated with the C9ORF72 GGGGCC Expansion in FTD/ALS (P05.063)

Objective: To investigate the cognitive endophenotype associated with the GGGGCC repeat in C9ORF72 in subjects with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) compared to FTD subjects with no known mutations in C9ORF72, MAPT, or PGRN . Background We have previously shown that the cognitive profile in subjects with the GGGGCC expansion in C9ORF72 is characterized by slowed processing speed, executive dysfunction, and impairment in phonemic word fluency. However, this phenotype is not unique to C9ORF72 and resembles the well-known phenotypic characteristics of FTD. Thus, it remains unclear how the cognitive deficits associated with C9ORF72 may differ from the FTD phenotype in subjects without any known mutation. Design/Methods: Subjects were enrolled in Mayo Clinic Alzheimer9s Disease Research Center (ADRC) or Alzheimer9s Disease Patient Registry (ADPR). FTD/ALS subjects with the C9ORF72 mutation (“ C9ORF72 subjects,” n=25) and FTD subjects without any known mutations in C9ORF72, MAPT , and PGRN (n=65) who had neuropsychological data were identified. The neuropsychological battery included tests of attention/executive functions (Digit Span, Trailmaking-B, Stroop), processing speed (Trailmaking-A), language (phonemic and semantic word fluency, Boston Naming), and memory (Logical Memory and Auditory Verbal Learning Test, AVLT). All test scores were converted into age-corrected z-scores. Results: C9ORF72 subjects were younger (57.2 ± 9.1) than FTD subjects without any mutation (66.9 ± 9.8) (p C9ORF72 subjects showed marked deficits in executive functions, speed, and phonemic fluency, but not delayed recall. Compared to those without any known mutations, C9ORF72 subjects performed worse on Trailmaking-B (p = .002), Stroop (p = .04), and phonemic fluency (p = .05), yet significantly better on Logical Memory (p Conclusions: Although a common phenotype exists characterized by impairment in speed, executive functions, and phonemic fluency, subjects with the C9ORF72 mutation demonstrate significantly worse cognitive impairment compared to FTD subjects without any known mutations. Disclosure: Dr. Pedraza has nothing to disclose. Dr. Boeve has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rush has nothing to disclose. Dr. Lucas has nothing to disclose. Dr. Fields has received personal compensation for activities with Medtronic, Inc., as a consultant. Dr. Machulda has nothing to disclose. Dr. Graff-Radford has received personal compensation for activities with Codman as a participant on a scientific advisory board. Dr. Graff-Radford has received personal compensation in an editorial capacity for the Neurologist. Dr. Graff-Radford has received research support from Janssen Pharmaceuticals, Inc., Pfizer Inc, Medivation, Inc., Forrest Laboratories and Allon Therapeutics Inc. Dr. Knopman has received personal compensation for activities with Lilly Pharmaceuticals as a data safety monitoring board member. Dr. Knopman has received personal compensation in an editorial capacity for Neurology. Dr. Knopman has received research support from Elan, Forest, and Baxter. Dr. Josephs has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Ferman has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Ivnik has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Boylan has nothing to disclose. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, and GE Healthcare. Dr. Rademakers has nothing to disclose.