LONGITUDINAL MRI AND NEUROPSYCHOLOGICAL CHANGES IN SYMPTOMATIC FRONTOTEMPORAL LOBAR DEGENERATION SUBJECTS WITH MUTATIONS IN MAPT, PGRN, AND C9ORF72

Oral Sessions: O3-03: Neuroimaging: Neuroimaging for Tracking Disease Progression and for Prognosis

O3-03-04

IN VIVO IMAGING OF BASAL FOREBRAIN ATROPHY: A POTENTIAL IMAGING MARKER OF PREDEMENTIA ALZHEIMER’S DISEASE

Stefan Teipel1, Helmut Heinsen2, Michel Grothe3, 1University Medicine Rostock and DZNE Rostock, Rostock, Germany; 2University of Wuerzburg, W€ urzburg, Germany; 3DZNE, Rostock, Germany. Contact e-mail: stefan. [email protected] Background: Alzheimer’s disease (AD) is characterized by a selective loss of cholinergic neurons in the basal forebrain cholinergic system (BFCS). We used stereotactic cytoarchitectonic maps with multimodal imaging to investigate the onset and temporal dynamics of BFCS degeneration in predementia and dementia stages of AD, its association with cortical amyloid accumulation and its potential use as diagnostic biomarker of AD. Methods: We assessed volumetric changes in the BFCS in a large number (N>800) of subjects, including AD patients, subjects with Mild Cognitive Impairment (MCI), predementia AD (CSF-positive MC) as well as cognitively normal controls. Volumetric measures of the BFCS were evaluated for their diagnostic utility in predementia and clinically manifest stages of AD. Using AV45- and FDG-PET scans from the ADNI2 database, we assessed associations between BFCS degeneration and cortical changes in amyloid deposition and hypometabolism, respectively, in the prodromal phase of AD. In a multicentre study, we determined the stability of BFCS volumetry for the detection of predementia stages of AD across 10 different scanners. Results: The findings suggest that BFCS volume is particularly vulnerable to degeneration in advanced age and the presence of prodromal AD has an additional effect on BFCS volume loss. In clinically manifest stages of AD the diagnostic accuracy of BFCS volume is comparable to that of hippocampus volume. However, subregional volume of the posterior BFCS is more accurate than hippocampus volume in the detection of predementia AD compared to healthy controls, both in single and multicentre settings. In addition, in the predementia phase of AD BFCS volume is significantly associated with AV45-PET measured cortical amyloid deposition, suggesting a high specificity for AD pathology in predementia subjects. BFCS atrophy correlates with performance decline in tests of both memory and attention/executive function in MCI. Regression analyses in FDG-PET scans indicate that the differential effect of BFCS atrophy on

Figure. Atrophy in MCI compared to controls: Atrophy of cortical gray matter (upper row) and basal forebrain (rows 2 to 4) in 69 MCI subjects compared to 95 healthy controls. The color bar indicates T-values for group differences.

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cognitive function is mediated by its association with hypometabolism in distinct cortical networks underlying these specific cognitive functions. Conclusions: In-vivo BFCS enables the assessment of BFCS changes in predementia AD, and determining the temporal dynamics of atrophic changes and their association with cortical amyloid deposition. O3-03-05

LONGITUDINAL MRI AND NEUROPSYCHOLOGICAL CHANGES IN SYMPTOMATIC FRONTOTEMPORAL LOBAR DEGENERATION SUBJECTS WITH MUTATIONS IN MAPT, PGRN, AND C9ORF72

Jonathan Graff-Radford1, David Jones2, Stephen Weigand1, Scott Przybelski1, Jennifer Louise Whitwell1, Mathew Senjem1, David S. Knopman1, Neill R. Graff-Radford3, Keith Josephs1, Zbigniew Wszolek3, Prashanthi Vemuri4, Julie A. Fields5, Tanis J. Ferman6, John Lucas7, Val J. Lowe2, Ralitza Gavrilova7, Karen Kuntz1, Mariely DeJesus Hernandez1, Matthew Baker8, Rosa Rademakers8, Ronald Carl Petersen2, Kejal Kantarci1, Clifford Jack1, Bradley F. Boeve1, 1 Mayo Clinic, Rochester, Minnesota, United States; 2Mayo Clinic Rochester, Rochester, Minnesota, United States; 3Mayo Clinic Jacksonville, Jacksonville, Florida, United States; 4Mayo Clinic, Rochester, Minnesota, United States; 5Mayo Clinic College of Medicine, Rochester, Minnesota, United States; 6Mayo Clinic, Jacksonville, Florida, United States; 7Mayo Clinic, Rochester, Minnesota, United States; 8Mayo Clinic, Jacksonville, Florida, United States. Contact e-mail: [email protected] Background: Familial frontotemporal lobar degeneration (f-FTLD) is commonly caused by mutations in MAPT, progranulin (PGRN) and C9ORF72. Our objectives were to compare imaging and neuropsychological progression among these three mutation groups to prepare for clinical trials. Methods: Available neuroimaging data on f-FTLD patients evaluated at Mayo Clinic were reviewed and analyzed. In order to compare longitudinal changes in frontotemporal volume (FTV) and ventricular volume (VV) in symptomatic MAPT, PGRN and C9ORF72 mutation carriers, the Symmetric Diffeomorphic Image Normalization method was used for normalization of serial scans to obtain Tensor Based Morphometry (TBMSyN) maps. We also compared baseline and longitudinal data on the Controlled Oral Word Association Test (COWAT), Trailmaking Test B (TMT B), Boston Naming Test (BNT) and Category Fluency (Cat Fl) in f-FTLD mutation carriers among subjects. We used linear mixed models with random slopes and intercepts to analyze longitudinal clinical and imaging data with years from baseline as the time scale. Results: MR data was available for 21 MAPT kindred subjects (age 50 6 12 years, 57% male), 11 PGRN subjects (age 64 6 9 years, 45% male) and 11 C9ORF72 subjects (age 62 6 10 years, 55% male). PGRN mutation carriers had a greater rate of change in FTV compared to MAPT (p¼0.01); with a trend compared to C9ORF72 (p¼0.07). (Figure 1) VV change was greater in PGRN subjects compared to MAPT (p<0.001); and C9ORF72 subjects (p¼0.003). While all mutation carriers declined on neuropsychological measures, there was no difference in baseline or rate of change on the COWAT or Cat Fl among the three groups. Rates of changes were greater in PGRN carriers on the BNT compared to MAPT carriers, and greater in MAPT carriers on the TMT B compared to C9ORF72 subjects. Conclusions: These findings suggest that among

Figure 1. Volume in frontotemporal region over time for individual subjects by group.

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Oral Sessions: O3-04: Genetics: Transcriptomic and Epigenetic Changes in Alzheimer’s Disease and Related Traits

symptomatic f-FTLD subjects with mutations in MAPT, PGRN and C9ORF72: 1) FTV decreases and VV increases in a measurable and relatively linear fashion using TBM-SyN maps, 2) the rate of volume change is greater for PGRN than for MAPT and C9ORF72 mutation carriers, 3) the rate of volume change is similar between MAPT and C9ORF72 mutation carriers, 4) all mutation carriers have declining performance on key neuropsychological measures. O3-03-06

REGIONAL FLUX ANALYSIS OF LONGITUDINAL ATROPHY IN ALZHEIMER’S DISEASE

Marco Lorenzi1, Nicholas Ayache2, Xavier Pennec3, 1Asclepios Research Project - INRIA Sophia Antipolis, Sophia Antipolis, France; 2Asclepios Group, INRIA Sophia Antipolis, Valbonne, France; 3Asclepios Group, INRIA Sophia Antipolis, Sophia Antipolis, Cedex, France. Contact e-mail: [email protected] Background: The longitudinal analysis of the brain morphology in Alzheimer’s disease (AD) is fundamental for discovering and quantifying the dynamics of the pathology. We can broadly identify two main paradigms for the analysis of time series of structural magnetic resonance images (MRIs): hypothesis-free and regional analysis. In the former case, the longitudinal atrophy is modeled at fine scales on the whole brain such as in the voxel/tensor based morphometry and cortical thickness analysis.These methods are useful for exploratory purposes, but usually lack robustness for a reliable quantification of the changes at the subject level. On the other hand, the regional analysis identifies volume changes in preliminary segmented regions. It is however limited to previously defined regions of interest, and therefore it might fail to detect the complex and spread pattern of changes which is likely to underlie the evolution of the pathology. In this study we propose the regional flux analysis, a new approach for the study of the brain longitudinal changes. The aim of regional flux analysis is twofold: consistently unify hypothesis-free and regional approaches to 1) reliably discovery the dynamics of brain morphological changes, and 2) at the same time provide statistically powered measures of longitudinal atrophy. Methods: We encode the morphological differences of follow-up images by longitudinal deformations estimated by non-linear image registration. We compute the scalar pressure potential associated to the non-linear deformations, and we identify the regions of maximal apparent volume change by the loci of extremal pressure. Maximum pressure points identify significant areas of volume loss (deformation sinks), while minimum pressure points identify significant areas of volume gain (deformation sources). We build an atlas of probabilistic regions of group-wise significant sources and sinks of longitudinal atrophy, which is used as reference for quantifying the volume changes of given patients as the flux of the longitudinal deformation across these regions. We tested our method on the discovery and measurement of the yearly longitudinal atrophy of 200 healthy controls, 150 subjects with mild congnitive impairment (MCI) and 142 AD patients. For each subject, baseline and 1-year images were non-linearly registered with the LCC-logDemons algorithm[ref1]. The probabilistic atlas was estimated from a subset of longitudinal deformations estimated for 20 AD patients, and the resulting regions were used for the quantification of the longitudinal atrophy in the remaining subjects. Statistical power of the resulting measures was assessed by sample size analysis.[ref1] M. Lorenzi, N. Ayache, G. Frisoni, X. Pennec, LCC-Demons: a robust and accurate symmetric diffeomorphic registration algorithm, Neuroimage,2013 ;81:470-83. Results: The estimated probabilistic atlas was composed by 44 and 18 regions of respectively deformation sink and sources (Figure 1A). The sink regions of apparent volume loss mapped to grey/withe matter regions, and included hippocampi (bilateral), temporal areas (Sup,Mid and Inf temporal gyrus), Insula and Parahippocampal gyrus. The source regions of apparent volume gain were localized exclusively in CSF areas, among the which Posterior, Anterior and Temporal horns of the ventricles. Longitudinal atrophy measured in hippocampi, temporal regions, and temporal horn of the ventricles was the most discriminative between controls and respectively MCI and AD (Figure 1B). Based on the whole set of longitudinal atrophy measurements, sample size analysis required 243 (95% CI: 151,441) and 556 (95% CI: 244,1273) subjects per arm when considering respectively AD and MCI for a randomized two-arm placebo controlled clin-

ical trial for detecting 25% atrophy reduction by controlling for normal aging (80% power, p¼0.05). On the head-to-head comparison, the proposed flux analysis outperformed in terms of reduced sample size previously validated quantification methods based on longitudinal hippocampal volumetry[ref2] (Table 1).[ref2] J. Haller, A. Banerjee, G. Christensen, M. Gado, S. Joshi, M. Miller, Y. Sheline, M. Vannier, J. Csernansky, Three-dimensional hippocampal MR morphometry with high-dimensional transformation of a neuroanatomic atlas, Radiology, 1997 ;202:504-510. Conclusions: Regional flux analysis of deformations is a novel approach to deformation based morphometry which combines the flexibility of voxel based methods (like tensor based morphometry) with the robustness of segmentation based methods for the quantification of longitudinal atrophy. We showed that regional flux analysis enables a fully automated and powered analysis of longitudinal atrophy in AD, and favorably compares with validated methods for the regional quantification of longitudinal atrophy. Flux analysis thus represents a promising candidate for detecting and robustly quantifying potential drugs effects in clinical trials.

Table Sample size analysis. Estimated sample size (mean(95%CI)) to detect a 25% difference of the progression measured by the regional flux with 80% power by controlling for normal aging. Regional Flux SNT1

AD

MCI

243 (125,441) 383 (211,810)

556 (244,1273) 1413 (565,7175)

1 J. Haller, A. Banerjee, G. Christensen, M. Gado, S. Joshi, M. Miller, Y. Sheline, M. Vannier, J. Csernansky, Three-dimensional hippocampal MR morphometry with high-dimensional transformation of a neuroanatomic atlas, Radiology 202 (1997) 504-510.

TUESDAY, JULY 15, 2014 ORAL SESSIONS O3-04 GENETICS: TRANSCRIPTOMIC AND EPIGENETIC CHANGES IN ALZHEIMER’S DISEASE AND RELATED TRAITS O3-04-01

NEXT-GENERATION RNA SEQUENCING IN ALZHEIMER’S DISEASE AND PROGRESSIVE SUPRANUCLEAR PALSY

Nilufer Ertekin-Taner1, Chen Wang2, Minerva M. Carrasquillo1, Mariet Allen3, Curtis Younkin4, Daniel Serie3, Xue Wang1, V. Shane Pancratz2, Thuy Nguyen1, Li Ma5, Kimberly Malphrus1, Sarah Lincoln5, Ronald Carl Petersen6, Neill R. Graff-Radford5, Dennis W. Dickson3, Steven Younkin7, Yan Asmann1, 1Mayo Clinic Florida, Jacksonville, Florida, United States; 2Mayo Clinic Minnesota,