Beth C. Mormino

TAU AND HIPPOCAMPAL VOLUME REFLECT DISTINCT PROCESSES IN PRECLINICAL ALZHEIMER’S DISEASE

cognitively normal (with CDR1⁄40) and 14 cognitively impaired (CDR> 0, 9 CDR 0.5, 3 CDR 1, and 2 CDR 2) participants were drawn from studies on aging at Washington University in St. Louis. Participants had one or more MRI sessions preceding a visit where they acquired both a MRI scan and underwent PET imaging with AV-1451, with mean follow-up from first MRI of 5.3 (sd 2.3) yrs. A subset (n1⁄4 93) also underwent florbetapir beta-amyloid imaging. MRIs were processed using FreeSurfer to generate mean cortical thickness in each region of interest (ROI). PET data was converted to standardized uptake value ratios (SUVRs) normalized to the cerebellum and partial volume corrected. Global tau burden was estimated by the mean SUVR from entorhinal cortex, amygdala, inferior temporal cortex, and lateral occipital cortex ROIs. For each person, a slope estimating structural atrophy in each ROI was quantified by fitting all longitudinal MRI measurements in a generalized linear model (GLM). These slope estimates were then used to predict tau burden in a GLMwhile controlling for baseline age and gender. Participants who also had beta-amyloid imaging were fit into a second GLM, with an additional covariate of florbetapir mean cortical SUVR. Multiple comparisons were controlled using a false discovery rate. Results:Antecedent cortical thinning was significantly associated with tau deposition throughout the cortex in the entire cohort (Figure 1). The effects were most prominent in the lateral temporal lobe and inferior parietal areas. These associations remained even after controlling for florbetapir levels (Figure 2) and were evident even in cognitively normal cohorts alone (Figure 3). Conclusions:Antecedent cortical thinning predicts current PET Tau in preclinical AD and symptomatic AD. This relationship holds in AD even after controlling for PET beta-amyloid burden. This may be useful for participant selection for tau PET imaging or clinical trials.

QUANTIFYING STAGES OF SUBTLE MEMORY IMPAIRMENT IN PRECLINICAL ALZHEIMER’S DISEASE

underlying neural mechanisms associated with mobility is fundamental to developing targeted, effective, and timely strategies to mitigate loss of independence in older adults at risk for dementia. References: [1] J. Verghese, M. Robbins, R. Holtzer, et al. Gait dysfunction in mild cognitive impairment syndromes. J Am Geriatr Soc 2008;56:1244-1251. [2] J.Verghese, C. Wang, R.B. Lipton, R. Holtzer. Motoric cognitive risk syndrome and the risk of dementia. J Gerontol A Biol Sci Med Sci 2013;68:412-418. [3 M.L. Callisaya, C.P. Launay, V.K. Srikanth, J. Verghese, G. Allali, O. Beauchet. Cognitive status, fast walking speed and walking speed reserve-the Gait and Alzheimer Interactions Tracking (GAIT) study. Geroscience 2017;39:231-239. [4] H.Makizako, H. Shimada, T. Doi, et al. The association between decline in physical functioning and atrophy of medial temporal areas in community-dwelling older adults with amnestic and nonamnestic mild cognitive impairment. Arch Phys Med Rehabil 2011 ;92:19921999. [5] R. Holtzer, N. Epstein, J.R. Mahoney, M. Izzetoglu, H.M. Blumen. Neuroimaging of mobility in aging: a targeted review. J Gerontol A Biol SciMed Sci 2014;69:1375-1388. [6] Buchman, D.A.Bennett. Loss ofmotor function in preclinical Alzheimer’s disease. Expert Rev Neurother 2011;11:665-676. [7] C.R. Jack, Jr., P. Vemuri, H.J. Wiste, et al. Evidence for ordering of Alzheimer disease biomarkers. Arch Neurol 2011;68:1526-1535.

LATENT ATROPHY FACTORS IN POSTERIOR CORTICAL ATROPHY RELATE TO SPECIFIC COGNITIVE IMPAIRMENTS

tex. Voxel-wise SUVR images were nonlinearly aligned onto the MNI152 atlas. Voxel-wise analyses relating flortaucipir uptake to age while controlling for gender were performed using permutation testing implemented using Randomise. Additionally, partial volume corrected SUVR values from Freesurer ROIs of interested (choroid plexus, inferior temporal, caudate, putamen) were extracted and analyzed in parallel. Results:Voxel-wise analyses found significant positive associations with age throughout the temporal lobe, basal ganglia, precuneus, and cerebellar white matter (Figures 1-4). Data extracted from corresponding Freesurfer ROIs (Figures 5 and 6) characterize the robust associations with age across the population. These results suggest that there are age-related increases in flortaucipir binding already beginning in 30 and 40-year olds. Conclusions:We found significant associations between increasing age and flortaucipir uptake in a population of cognitively normal adults without significant AD pathology. Results in the medial and lateral temporal lobe suggest that flortaucipir is sensitive to primary agerelated tau accumulation in middle and older age. The results in the choroid plexus and basal ganglia indicate that previously noted off-target binding in these regions is highly related to biological changes occurring with advancing age.

APOE AND ALZHEIMER'S DISEASE IMAGING BIOMARKERS

not available. S3-01-02 APOE AND ALZHEIMER’S DISEASE IMAGING BIOMARKERS Beth C. Mormino, Massachusetts General Hospital, Boston, MA, USA. Contact e-mail: bmormino@stanford.edu Abstract not available.not available. S3-01-03 APOE AND SEX DIFFERENCES ON ALZHEIMER’S DISEASE RISK Arthur W. Toga, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Contact e-mail: toga@loni.usc.edu Abstract not available.not available. S3-01-04 THERAPEUTIC STRATEGIES: APOE IN TRAUMATIC BRAIN INJURY Cheryl Wellington, University of British Columbia, Vancouver, BC, Canada. Contact e-mail: cheryl.wellington@ubc.ca Abstract not available.not available. SYMPOSIA S3-02 MECHANISMS OF NEURONAL DEATH S3-02-01 NECROPTOSIS ACTIVATION IN ALZHEIMER’S DISEASE Antonella Caccamo, Caterina Branca, Salvatore Oddo, Arizona StateUniversity, Tempe,AZ,USA.Contact e-mail: caccamo@asu.edu Background: Neuronal loss is a major pathological feature of Alzheimer’s disease (AD). Nevertheless, the mechanisms underlying this key event in the disease pathogenesis are not clear. Methods:Necroptosis, a programmed form of necrosis, is performed by the mixed lineage kinase domain-like (MLKL) protein, which is activated by receptor-interactive protein kinases (RIPK) 1 and 3. Necroptosis is activated in various neurodegenerative disorders including multiple sclerosis and amyotrophic lateral sclerosis. However, it remains to be determined whether necroptosis plays a role in AD. Results:We show that necroptosis is activated in human AD brains and its activation correlates with brain weight and cognitive scores. We also show that necroposis is also activated in 5xFAD mice, which are characterized by marked neuronal loss. Using complementary in vitro and in vivo approaches, we found that reducing necroptosis activation rescues AD-related neuronal loss. Conclusions: Overall, these data provide the first direct evidence that necroptosis is a mechanism involved in neurodegeneration in AD. S3-02-02 STRESS GRANULE FORMATION AND NEURONAL DEATH Ben Wolozin, Boston University School of Medicine, Boston, MA, USA. Contact e-mail: bwolozin@bu.edu Abstract not available.not available. S3-02-03 NEUROINFLAMMATORY PROCESSES AND NEURODEGENERATION Roisin M. McManus, Michael T. Heneka, German Center for Neurodegenerative Diseases, Bonn, Germany. Contact e-mail: roisin. mcmanus@dzne.de Abstract not available.not available. S3-02-04 MICROGLIAL ACTIVATION IN NEURODEGENERATIVE DISEASES: OPPORTUNITIES FOR THERAPEUTIC INTERVENTION Diego Gomez-Nicola, University of Southampton, Southampton, United Kingdom. Contact e-mail: d.gomez-nicola@soton.ac.uk Background:Microglial cells are the resident immune cells of the brain andplay crucial roles in the regulation of normal andpathological neural functions. Our lab aims at studying the balance of the numbers of microglial cells from development to ageing, to better understand the roles of these cells in the brain, through a multidisciplinary approach using invivomodels, geneticmolecular tools and behavioural analysis of brain function. We aim to define how microglial cells control their numbers and phenotype during not only healthy ageing, but also disease. Microglial cells play a key role in the development and maintenance of the inflammatory response characteristic of several neurodegenerative disorders, showing enhanced proliferation and morphological activation. Methods:We are using a multidisciplinary approach combining the study of laboratory models of chronic neurodegeneration, including prion disease, Alzheimer’s disease (AD) and ALS,with the study of post-mortem samples from patients, to describe the time-course and regulation of microglial proliferation.Results:Our results demonstrate thatmicroglial proliferation is an important feature of the evolution of chronic neurodegenerative disease, with direct implications for understanding the contribution of the CNS innate immune response to disease progression. We have shown that the control of microglial numbers in prion, AD and ALS is regulated by the activation of the Colony Stimulating Factor 1 Receptor (CSF1R). Conclusions: Pharmacological inhibition of CSF1R leads to a diminished proliferation of microglia and the amelioration of the behavioural and neuropathological symptoms of chronic neurodegeneration. FEATURED RESEARCH SESSIONS F3-01 PERIOPERATIVE NEUROCOGNITIVE DISORDERS AND VASCULAR RISK F3-01-01 POSTOPERATIVE CHANGES IN CSF BIOMARKERS AND RESTING-STATE FUNCTIONAL NEUROIMAGING SIGNAL CHARACTERISTICS Jeffrey Browndyke, Mary Cooter, Joseph P. Mathew, Miles Berger and MADCO-PC Investigators, Duke University Medical Center, Durham, NC, USA; Duke Brain Imaging & Analysis Center, Durham, NC, USA; Duke Institute for Brain Sciences, Durham, NC, USA. Contact e-mail: j.browndyke@duke.edu

THE CONTRIBUTION OF EARLY ALZHEIMER’S DISEASE MARKERS TO INDIVIDUAL DIFFERENCES IN EPISODIC MEMORY IN COGNITIVELY NORMAL OLDER ADULTS

P4-322 THE CONTRIBUTION OF EARLY ALZHEIMER’S DISEASE MARKERS TO INDIVIDUAL DIFFERENCES IN EPISODIC MEMORY IN COGNITIVELY NORMAL OLDER ADULTS Alexandra N. Trelle, Jeffrey Bernstein, Valerie A. Carr, Gayle Deutsch, Carolyn A. Fredericks, Scott A. Guerin, Wanjia Guo, Marc Harrison, Manasi Jayakumar, Jiefeng Jiang, Geoffrey A. Kerchner, Anna Khazhenzon, Celia Litovsky, Beth C. Mormino, Ayesha Nadiadwala, Sharon Sha, Natalie Tanner, Monica Thieu, Anthony D. Wagner, Stanford University, Stanford, CA, USA; University of California San Diego, San Diego, CA, USA; San Jose State University, San Jose, CA, USA; Stanford Hospital and Clinics, Palo Alto, CA, USA; Genentech, Inc, South San Francisco, CA, USA; Johns Hopkins University, Baltimore, MD, USA; Massachusetts General Hospital, Boston, MA, USA; University of California at Irvine, Irvine, CA, USA; Stanford University, Palo Alto, CA, USA; Columbia University, New York, NY, USA. Contact e-mail: atrelle@stanford.edu

COMPARING HIPPOCAMPAL EFFECT SIZE BETWEEN ALZHEIMER’S DISEASE AND HEALTHY CONTROLS USING OLDER AND NEWER VERSIONS OF SPM AND FREESURFER

Background: Cerebral microinfarcts (CMI) have been commonly observed in Alzheimer’s Disease (AD) and associated with cognitive impairment (vanVeluw et al., 2017). Previous animal studies demonstrated that CMI may impair white matter pathways and affect brain function that extends beyond lesion boundaries (Summers et al., 2017). Nevertheless, how CMI influences brain structural connectivity in living humans remains largely unknown. Hence, we for the first time aimed to investigate topological features of brain structural networks in relation to CMI presence. We hypothesized that patients with CMI would show disrupted structural network topology in higher-order cognitive networks (the default mode (DMN) and executive networks (ECN)) (Chong et al., 2017). Methods:We examined the structural connectivity based on diffusionMRI data of 92 AD (26 with CMI), 83 cognitive-impairment-no-dementia (CIND, 28 with CMI) and 28 healthy controls without CMI (Table 1). CMIs were

TAU PET IN A4: PRELIMINARY REPORT

ASHS volume measurements (mm), standard deviation in parentheses Number of subjects 178 90 139 103 116 Anterior hippocampus 1722.0 (223.6) 1707.4 (205.3) 1662.7 (236.9) 1517.2 (260.0) 1414.7 (207.7) % Diff 0.8 3.4 11.9 17.8 t value <2 2.3 6.9 11.8 p value >0.1 0.023 2.4e-11 1.1e-26 Posterior hippocampus 1652.3 (159.8) 1664.3 (163.1) 1575.6 (180.3) 1400.4 (205.9) 1336.1 (179.3) % Diff -0.7 4.6 15.2 19.1 t value <2 4.0 10.7 15.8 p value >0.1 7.6e-5 8.1e-21 4.6e-41 Whole hippocampus 3374.4 (300.2) 3371.6 (302.9) 3238.3 (353.6) 2917.6 (414.1) 2750.8 (337.4) % Diff 0.1 4.0 13.5 18.5 t value <2 3.6 9.8 16.6 p value >0.1 3.4e-4 3.7e-18 6.4e-44 Entorhinal cortex 593.9 (76.2) 585.4 (69.5) 575.4 (82.1) 518.4 (93.0) 462.1 (84.1) % Diff 1.4 3.1 12.7 22.2 t value <2 2.1 7.0 13.9 p value >0.1 0.039 5.2e-11 4.2e-34 Brodmann area 35 617.8 (82.6) 608.9 (82.8) 586.4 (94.9) 542.0 (98.4) 483.3 (89.1) % Diff 1.4 5.1 12.3 21.8 t value <2 3.1 6.9 13.2 p value >0.1 1.8e-3 3.5e-11 1.2e-31 Brodmann area 36 1824.9 (254.2) 1844.1 (245.7) 1789.4 (219.8) 1683.0 (257.3) 1551.5 (234.9) % Diff -1.1 1.9 7.8 15.0 t value <2 <2 4.5 9.3 p value >0.1 >0.1 l.le-5 3.8e-18 Parahippocampal cortex 869.6 (120.9) 893.3 (125.0) 885.4 (145.9) 831.5 (129.4) 773.3 (121.9) % Diff -2.7 -1.8 4.4 11.1 t value <2 <2 2.5 6.7 p value >0.1 >0.1 0.014 1.4e-10

THE RELATIONSHIP BETWEEN RECALL OF RECENTLY VERSUS REMOTELY ENCODED FAMOUS FACES AND AMYLOID AND TAU BURDEN IN CLINICALLY NORMAL OLDER ADULTS

covariates.Models included all participants so thatWMH/cognition relationships could be explored independently from diagnostic category. Results:Right dorsolateral WMH volumes were negatively associated with Rey copy score (b1⁄4-2.6, p<.001); left dorsolateral WMH volumes were negatively associated with WCST total correct trials (b1⁄40.9, p1⁄4.036). Post-hoc analyses showed that WMH/Rey associations were driven primarily by AD participants, whileWMH/WCSTassociations were driven by CIND participants. Conclusions:Results indicate that not all executive functions are affected equally by SVD, and regional distribution of WMH may be selectively associated with different tests. Determining specific associations between SVD/executive processes at different stages of AD is the first step in developing targeted process-specific treatments, which may improve other areas of cognition downstream. This study increases understanding of brain-behavior relationships in SVD, a potentially modifiable risk factor for dementia, in the context of cognitive symptoms in persons with or at risk for AD.

HETEROGENEITY IN NEUROIMAGING PATTERNS PRESENT THROUGHOUT THE CLINICAL SPECTRUM OF TYPICAL LATE-ONSET AMNESTIC AD

Here, we studied the cognitive and emotional effectiveness of caregiver-implemented musical activities in persons with mild-moderate dementia (PWDs). Methods: In a three-arm randomized controlled trial (RCT), 89 PWD-caregiver dyads received a 10week singing intervention, a 10-week music listening intervention, or a usual care. Outcomewas assessed with neuropsychological tests and questionnaires on mood, quality of life (QOL) and caregiver burden at baseline, after the intervention (3-month stage, n 1⁄4 84), and 6 months later (9-month stage, n 1⁄4 74). Results:Compared to usual care, both singing and music listening enhanced general cognition and executive function and reduced depression at 3 months and enhanced orientation and autobiographical memory at 9 months. Singing also enhanced working memory at 3 months as well as reduced caregiver burden at 9 months. The positive effects of singing on working memory and of both musical activities on mood were larger in mild vs. moderate dementia. The musical background of the PWD did not influence the efficacy of the music interventions. Conclusions:PWD-caregivermusical activities have long-term cognitive, emotional, and social benefits in PWDs and could potentially be widely used in dementia care and rehabilitation.