Christina Dheel

In vivo 18F-AV-1451 tau-PET signal in MAPT mutation carriers varies by expected tau isoforms

Objective To evaluate 18F-AV-1451 tau PET binding among microtubule-associated protein tau (MAPT) mutation carriers. Methods Using a case-control study, we quantitatively and qualitatively compared tau PET scans in 10 symptomatic and 3 asymptomatic MAPT mutation carriers (n = 13, age range 42–67 years) with clinically normal (CN) participants (n = 241, age range 42–67 years) and an Alzheimer disease (AD) dementia cohort (n = 30, age range 52–67 years). Eight participants had MAPT mutations that involved exon 10 (N279K n = 5, S305N n = 2, P301L n = 1) and tend to form 4R tau pathology, and 5 had mutations outside exon 10 (V337M n = 2, R406W n = 3) and tend to form mixed 3R/4R tau pathology. Results Tau PET signal was qualitatively and quantitatively different between participants with AD, CN participants, and MAPT mutation carriers, with the greatest signal intensity in those with AD and minimal regional signal in MAPT mutation carries with mutations in exon 10. However, MAPT mutation carriers with mutations outside exon 10 had uptake levels within the AD range, which was significantly higher than both MAPT mutation carriers with mutations in exon 10 and controls. Conclusions Tau PET shows higher magnitude of binding in MAPT mutation carriers who harbor mutations that are more likely to produce AD-like tau pathology (e.g., in our series, the non–exon 10 families tend to accumulate mixed 3R/4R aggregates). Exon 10 splicing determines the balance of 3R and 4R tau isoforms, with some mutations involving exon 10 predisposing to a greater proportion of 4R aggregates and consequently a lower level of AV-1451 binding, as seen in this case series, thus supporting the notion that this tau PET ligand has specific binding properties for AD-like tau pathology.

ACCELERATED NEUROCHEMICAL CHANGES PRIOR TO PHENOCONVERSION TO FRONTOTEMPORAL LOBAR DEGENERATION IN PRESYMPTOMATIC MICROTUBULE-ASSOCIATED PROTEIN TAU (MAPT) MUTATION CARRIERS: A LONGITUDINAL MRS STUDY

Sandra Weintraub, Zbigniew Wszolek and LEFFTDS Consortium, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Charlestown, MA, USA; Massachusetts General Hospital, Boston, MA, USA; The Harvard Clinical and Translational Science Center, Boston, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA; Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA; Mayo Clinic, Rochester, MN, USA; University of California San Francisco, San Francisco, CA, USA; University of Pennsylvania, Philadelphia, PA, USA; University of California, Los Angeles School of Medicine, Los Angeles, CA, USA; The AFTD, Radnor, PA, USA; National Cell Repository for Alzheimer’s Disease (NCRAD), Indianapolis, IN, USA; Indiana University School of Medicine, Indianapolis, IN, USA; Washington University, St. Louis, MO, USA; Columbia University, New York, NY, USA; Mayo Clinic, Jacksonville, FL, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; NIH, Bethesda, MD, USA; Univ of Penn, Philadelphia, PA, USA; Washington University, St. Louis, MO, USA; Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; UCSF, San Francisco, CA, USA; National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA; University of British Columbia, Vancouver, BC, Canada; Gertrude H. Sergievsky Center at Columbia University, New York, NY, USA; The Bluefield Project, San Francisco, CA, USA; Penn FTD Center, University of Pennsylvania, Philadelphia, PA, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Northwestern University, Chicago, IL, USA. Contact e-mail: atouroutoglou@mgh.harvard.edu

NONLINEAR N-SCORE ESTIMATION FOR ESTABLISHING COGNITIVE NORMS FROM THE NATIONAL ALZHEIMER’S COORDINATING CENTER (NACC) DATASET

Background: The cerebrospinal fluid (CSF) Ab42/Ab40 ratio has been proposed a better biomarker for cerebral b-amyloidosis than CSFAb42 alone. Since 2014, the test has been available in our clinical laboratory practice upon request. Here, we evaluated the distribution of the CSF Ab42/Ab40 ratio, as well as its diagnostic accuracy in relation amyloid PET. Methods:The CSF Ab42/Ab40 ratio was measured on a weekly basis in clinical laboratory practice on consecutive samples from 3647 patients (1853 men, 1794 women, mean age 6 standard deviation, 71.5 6 8.2 years) over 3 years using the MSD Abeta Triplex assay according the manufacturer’s instructions (Meso Scale Discovery, Rockville, MD). Longitudinal stability in the measurements was maintained using an elaborate QC system. One thousand nineteen of the patients were from the specialized memory clinic at Sk ane University Hospital. One hundred and forty three of these had undergone amyloid ([18]F-flutemetamol) PET. Optimal cut-points to discriminate bimodally distributed groups were determined by mixture modelling. The optimal cut-point for differentiating Ab-positive from -negative patients according to amyloid PET was determined as the one that generated the highest Youden index. Results: The CSF Ab42/Ab40 ratio (all data) showed a bimodal normal distribution. The mixture modelling-derived optimal cut-point for differentiating the two groups was 0.076. More patients (56%) were found in the low (Ab-positive) group. When examining patients from the specialized memory clinic separately, a similar bimodal distribution was seen; the optimal cut-point for distinguishing the two groups was 0.080 and 49% of the patients had ratios below this limit. In patients who had undergone amyloid PET, the optimal mixture modelling-derived cut-point was 0.077, which was a little lower than the Youden index-derived cut-point (0.083) that best discriminated Ab-positive from -negative cases (diagnostic accuracy 97%). Conclusions: The CSF Ab42/Ab40 ratio is a bimodal biomarker. The striking lack of individuals with grey zone CSF Ab42/Ab40 ratios suggests that people change Ab status according to the ratio quite rapidly. It is not a gradual increase of Ab plaque pathology over years that slowly changes the ratio; rather, the ratio appears to reflect a switch-like shift in Ab homeostasis in the CSF.

QUALITY OF LIFE AMONG SUBJECTS AND INFORMANTS IN FAMILIAL FRONTOTEMPORAL DEMENTIA: PRELIMINARY DATA IN THE LEFFTDS COHORT

P1-317 QUALITY OF LIFE AMONG SUBJECTS AND INFORMANTS IN FAMILIAL FRONTOTEMPORAL DEMENTIA: PRELIMINARY DATA IN THE LEFFTDS COHORT Kendrick J. Calvert, Brad F. Boeve, Howard J. Rosen, Adam L. Boxer, Christina Dheel, Bradford C. Dickerson, Julie A. Fields, Ralitza H. Gavrilova, Nupur Ghoshal, Jill Goldman, Neill R. GraffRadford, Murray Grossman, Hilary Heuer, Ging-Yuek Robin Hsiung, Edward D. Huey, Samantha R. Hughes, David J. Irwin, David S. Knopman, John Kornak, Ruth A. Kraft, Joel H. Kramer, Maria I. Lapid, Ian R. Mackenzie, Bruce L. Miller, Matt R. Miller, Katherine Rankin, Jeremy Syrjanen, Sandra Weintraub, Zbigniew Wszolekon Behalf of the LEFFTDS Consortium, Mayo Clinic, Rochester, MN, USA; University of California San Francisco, San Francisco, CA, USA; University of California, San Francisco, San Francisco, CA, USA; Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Washington University School of Medicine, St. Louis, MO, USA; Gertrude H. Sergievsky Center at Columbia University, New York, NY, USA; Mayo Clinic, Jacksonville, FL, USA; Penn FTD Center, University of Pennsylvania, Philadelphia, PA, USA; UCSF, San Francisco, CA, USA; University of British Columbia, Vancouver, BC, Canada; Northwestern University, Chicago, IL, USA. Contact e-mail: calvert.kenny@mayo.edu

CHARACTERISTICS AND PROGRESS ON THE INITIAL 209 SUBJECTS IN THE LONGITUDINAL EVALUATION OF FAMILIAL FRONTOTEMPORAL DEMENTIA SUBJECTS (LEFFTDS) PROTOCOL

O2-14-01 CHARACTERISTICS AND PROGRESS OF 320 SUBJECTS IN THE LONGITUDINAL EVALUATION OF FAMILIAL FRONTOTEMPORAL DEMENTIA SUBJECTS (LEFFTDS) PROTOCOL LeahK. Forsberg, Bradley F. Boeve, Howard J. Rosen, AdamL. Boxer, Jessica Bove, Danielle Brushaber, Giovanni Coppola, Christina Dheel, Brad C. Dickerson, Susan Dickinson, Kelley Faber, Julie A. Fields, Jamie Fong, Tatiana M. Foroud, Ralitza H. Gavrilova, Debra Gearhart, Nupur Ghoshal, Jill Goldman, Jonathan Graff-Radford, Neill R. GraffRadford, Murray Grossman, Dana Haley, Hilary W. Heuer, John Hsiao, Ging-Yuek Robin Hsiung, Edward D. Huey, David J. Irwin, David T. Jones, Lynne Jones, Kejal Kantarci, Anna M. Karydas, David S. Knopman, John Kornak, Joel H. Kramer, Walter K. Kremers, Walter A. Kukull, Maria I. Lapid, Diane Lucente, Ian R. Mackenzie, Masood Manoochehri, Scott M. McGinnis, Bruce L. Miller, Rodney Pearlman, Leonard Petrucelli, Madeline Potter, Rosa Rademakers, Katherine Rankin, Katya Rascovsky, Pheth Sengdy, Leslie M. Shaw, Marg Sutherland, Jeremy Syrjanen, Nadine Tatton, Joanne Taylor, Arthur W. Toga, John Q. Trojanowski, Sandra Weintraub, Bonnie Wong, Zbigniew Wszolek, Mayo Clinic, Rochester, MN, USA; University of California San Francisco, San Francisco, CA, USA; Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, USA; University of California, Los Angeles School of Medicine, Los Angeles, CA, USA; Massachusetts General Hospital, Boston, MA, USA; Association of Frontotemporal Degeneration, Radnor, PA, USA; Indiana University School of Medicine, Indianapolis, IN, USA; Washington University, Saint Louis,MO, USA; ColumbiaUniversity, New York, NY, USA; MayoClinic, Jacksonville, FL, USA; National Institutes of Health, Bethesda, MD, USA; University of British Columbia, Vancouver, BC, Canada; National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA; The Harvard Clinical and Translational Science Center, Boston, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA; The Bluefield Project, San Francisco, CA, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Northwestern University, Chicago, IL, USA. Contact e-mail: Forsberg.Leah@mayo.edu

PHENOCONVERSION FROM ASYMPTOMATIC TO MINIMALLY SYMPTOMATIC FTLD: PRELIMINARY DATA IN THE LEFFTDS COHORT

Family history revealed her son also suffered from schizophrenia. At the age of 55, she had an exacerbation of psychotic symptoms and exhibited grandiosity. She progressively became very disorganised and apathetic which impacted considerably her activities of daily living; nursing home placement was necessary. She also started to have new perseverative behaviours such as wiping her saliva for hours. Brain MRI showed mild bifrontal and temporal atrophy. F-fluorodeoxyglucose positron emission tomography showed bifrontal hypometabolism particularly in orbitofrontal and medial frontal regions, predominantly left, and anterior temporal hypometabolism. A diagnosis of bvFTD was made. Genetic analysis revealed C9orf72 repeat expansion with >80 repeats. Conclusions: This case report suggests that analysis of C9orf72 repeat expansion may be considered in young patients showing schizophreniform disorders with neuroleptic hypersensitivity or in the context of positive family history of neurodegenerative disease. We hypothesize that early functional synaptic and neurotransmitter changes, preceding neurodegeneration, may explain the time gap between schizophreniform manifestations and bvFTD typical features.

CAREGIVER BURDEN IN FAMILIAL FRONTOTEMPORAL DEMENTIA SUBJECTS: PRELIMINARY DATA IN THE LEFFTDS COHORT

Background: There is a relationship between presbycusis and cognitive impairment. To study the relation between cognitive impairment and auditory sensorial input we performed Auditory Brainstem Response (ABR), which provides information on the peripheral hearing status through amplitude and time of response from auditory nerve (wave I) to the inferior colliculus (wave V) and a cognitive evaluation, with emphasis on auditory verbal working memory (WM). Objective: To determine if the electrophysiological response of the Peripheral auditory pathway is associated with the performance in WM tests. Methods: Participants (N 1⁄4 55): subjects over 65 years, without dementia. They were evaluated with a comprehensive battery of neuropsychological test including visual and verbal WM, and a complete auditory evaluation including ABR and Pure Tone Audiometry (PTA). Subject included with normal hearing (PTA <20dB) or with mild (PTA 20-40dB) to moderate (PTA >40dB) presbycusis. The auditory material for testing WM was created from the Speech Perception in Noise Test (SPIN), including phrases with two variables: background noise (on /off) and predictability of the last word in relation to the content of the sentence. Results: Performance on SPIN was better with no background noise (p <0.01) and with greater predictability (p <0.01). As a whole, SPIN is associated with the PTA (p <0.001). WM task was associated with other cognitive test: MMSE (p <0.05), indirect span of the Corsi Test (p<0.05), indirect digit span (p <0.05) and the Grobber & Buschke test (P <0.05). Using Median Regression and controlling for covariates, the WM score was negatively associated

ADVANCING RESEARCH AND TREATMENT IN FRONTOTEMPORAL LOBAR DEGENERATION (ARTFL) NORTH AMERICAN RARE DISEASE CLINICAL RESEARCH CONSORTIUM: PROGRESS AND CHARACTERIZATION OF INITIAL PARTICIPANTS

Author(s): Boxer, Adam L; Rosen, Howard J; Boeve, Brad F; Heuer, Hilary; Grossman, Murray; Coppola, Giovanni; Dickerson, Bradford C; Bordelon, Yvette M; Dheel, Christina; Faber, Kelley; Fields, Julie A; Fong, Jamie; Foroud, Tatiana M; Ghoshal, Nupur; Graff-Radford, Neil; Robin Hsiung, Ging-Yuek; Huey, Edward D; Irwin, David J; Kantarci, Kejal; Kaufer, Daniel; Karydas, Anna; Knopman, David S; Kramer, Joel H; Kukull, Walter A; Litvan, Irene; Lungu, Codrin; Mackenzie, Ian R; Mendez, Mario F; Miller, Bruce L; Miller, Matt R; Onyike, Chiadi U; Pantelyat, Alex; Potter, Madeline; Rademakers, Rosa; Roberson, Erik D; Sutherland, Margaret; Tartaglia, Maria Carmela; Toga, Arthur W; Weintraub, Sandra; Wszolek, Zbigniew

PET TAU IMAGING WITH AV-1451 IN MICROTUBULE ASSOCIATED PROTEIN TAU (MAPT) MUTATION CARRIERS RELATIVE TO ALZHEIMER’S DISEASE DEMENTIA AND CONTROLS

lecular pathologies: cerebral beta-amyloidosis (amyloid-beta [Ab] plaques) and tauopathy (neurofibrillary tangles, neuritic plaques and neuropil threads). Until recently, only Ab topographies could be studied in vivo in humans owing to a lack of tau positron emission tomography (PET) imaging agents. Current clinic-pathological studies link tau pathology closely to the onset and progression of cognitive symptoms AD.Methods:This study reports on PET tau and Ab imaging results in a cohort of cognitively normal older adults and those with very mild AD. Multivariate analyses were used to identify unique disease-related spatial topographies in both tau and Ab deposition. Results: PET tau and Ab topographies were spatially unique but strongly related. Cerebrospinal fluid measures of tau, often used to stage preclinical AD, were strongly correlated with tau deposition in the temporal lobe. Tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than Ab deposition in any region of the brain. Conclusions:These data support models of AD where tau pathology closely tracks changes in brain function responsible for the onset of early symptoms.