CSF STREM2, BUT NOT YKL-40, IS ASSOCIATED WITH LONGITUDINAL MORPHOLOGICAL BRAIN CHANGES IN PRECLINICAL ALZHEIMER’S DISEASE

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Poster Presentations: Monday, July 17, 2017

MA, USA; 2University of Leuven, Leuven, Belgium; 3 Massachusetts General Hospital, Boston, MA, USA; 4Martinos Center for Biomedical Imaging, Charlestown, MA, USA. Contact e-mail: [email protected] Background: Recent diagnostic criteria for Primary Progressive

Aphasia (PPA) include neuroimaging as a supportive feature [Gorno-Tempini et al., 2011]. The regional overlap between atrophy (measured by structural MRI) and hypometabolism (measured by FDG-PET) may vary throughout the PPA spectrum. Comparison of territories affected by atrophy and hypometabolism will shed light on the sequence of pathophysiological changes in the disease. We hypothesized that subtle hypometabolism is detectable in the PPA affected language regions which do not yet show cortical atrophy. Methods: 30 right-handed PPA patients (10 logopenic, 11 nonfluent agrammatic, 9 semantic) underwent FDG-PET scan within 12 months from structural MRI scan. PET was co-registered to MRI and glucose uptake was quantified by standardized uptake value ratios (SUVR) with pons as reference region. MRI scans were analyzed according to FreeSurfer pipeline. SUVR and cortical thickness values were projected to surfaces in fsaverage space. Hypometabolism and atrophy Z-maps were calculated based on a set of 30 age and sex matched controls from Harvard Aging Brain Study [Dagley et al., 2015]. Results: Hypometabolism and cortical atrophy were localized to mainly left hemispheric regions involved in language dysfunction in PPA. In frontal and parietal language areas, regions with cortical atrophy were smaller and contained within regions displaying hypometabolism. Temporal areas were affected by hypometabolism and atrophy to comparable extent. Quantitatively, FDG Z-scores were lower than cortical thickness

Figure 1. Proposed roadmap to discovering multi-omics AD biomarkers. Despite diagnostic labels. Alzheimer’s disease and related dementias are inherently heterogeneous entities both in clinical presentation and underlying pathophysiology. We reviewed recent techniques to discover multiomics biomarkers of AD. Biotypes derived from the integration of multi-omics data using semi-supervised machine learning techniques will better identify individuals on an AD spectrum trajectory. Abbreviations: Alzheimer’s Disease (AD). FrontoTemporal Dementia spectrum (FTD), Lewy Body Disease (LBD), Vascular Cognitive Impairment (VCI), Mixed etiology dementia (Mixed), Healthy Controls (HC), Subjective Cognitive Impairment (SCI). Mild Cognitive Impairment (MCI).

Z-scores in frontal and parietal language areas on the left and right. In temporal areas cortical thickness Z-scores were lower than FDG Z-scores, only on the left. Control region and other regions did not show significant differences. The pattern of regional differences between FDG and cortical thickness Z-scores in logopenic and nonfluent agrammatic subtypes resembled the pattern of differences in the whole PPA group. Semantic PPA patients had lower cortical thickness Z-scores than FDG Z-scores in temporal areas in both hemispheres. Conclusions: Our data suggest that hypometabolism is present without co-occurring atrophy in parts of the PPA affected language regions, which likely indicate future disease spread. Hypometabolism reflects synaptic and neuronal dysfunction, therefore, may occur earlier than cortical atrophy which represents neuronal death.

P2-355

CSF STREM2, BUT NOT YKL-40, IS ASSOCIATED WITH LONGITUDINAL MORPHOLOGICAL BRAIN CHANGES IN PRECLINICAL ALZHEIMER’S DISEASE

Carles Falcon1, Gemma C. Monte2, Marc Suarez-Calvet3, Gernot Kleinberger4, Lorena Rami5, Albert Llado6, Raquel Sanchez-Valle7, Juan Domingo Gispert8, Jose Luis Molinuevo1,9, 1Barcelonabeta Brain Research Center, Barcelona, Spain; 2Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clınic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 3German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; 4 Ludwig-Maximilians-University Munich, Munich, Germany; 5Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clınic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 6Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clınic, Institut d’Investigacions Biom ediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 7Institut d’Investigacio Biomedica August Pi i Sunyer, Barcelona, Spain; 8Barcelonabeta Brain Research Center, Barcelona, Spain; 9Alzheimer’s Disease Unit and Other Cognitive Disorders Unit, Hospital Clinic de Barcelona, Barcelona, Spain. Contact e-mail: [email protected] Background: Cerebrospinal fluid YKL-40 and sTREM2 are biomarkers of astroglial and microglial activity, respectively, with an important role in neuroinflammation. We assessed whether YKL40 and sTREM2 levels are associated to structural longitudinal changes in preclinical patients of Alzheimer’s disease. Methods: Brain MRI scans of 40 participants (29 Control; 11 Preclinical due to Alzheimer) were acquired at baseline and after a 2 year follow-up. Cerebrospinal fluid YKL-40 and sTREM2 concentrations determined. A Two-sample T-Test analysis was employed to detect differences in glial cerebrospinal fluid biomarkers according to diagnostic, and structural longitudinal changes were explored using Pairwise Longitudinal Registration (SPM12) to search for interactions in the cerebral patterns associated to the glial biomarkers. Results: No relevant changes in brain morphology were found associated with YKL-40 in controls, nor in preclinical AD. Preclinical AD subjects showed significant volumetric changes in association with CSF sTREM2 in temporal inferior and parahippocampal, cuneus and calcarine. Controls did not show structural changes associated with CSF sTREM2 concentrations. Conclusions: Our findings are indicative of increased microglial response at early stages of Alzheimer’s disease.