P2-205 Cognitive decline is associated with progression of cerebral white matter hyperintensities. A population-based follow-up study

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Poster Session P2: Diagnosis and Disease Progression - Neuroimaging WHITE MATTER CORRELATES OF COGNITIVE I M P A I R M E N T S IN EARLY ALZHEIMER'S DISEASE

Voyko Kavcic*, Charles J. Duffy, Sven Ekholm, Jianhni Zhong. University of Rochester Medical Center, Rochester, NY, USA. Contact e-mail: voyko_kavcic@ urmc. rochester edu

Background: Based on our previous research on perceptual and attentional impairments in AD, we have developed a two-stage concurrent inhibition model which predicts that AD patients lack proper connectivity between perceptual and mnemonic modules. Objectives: We tested this prediction by using MR diffusion tensor imaging (DTI) to measure integrity of white matter (WM) fibers, known to be part of the mnemonic and attentional networks at the prefrontal, posterior parietal, cnigular, and medial temporal regions. In addition, we also assessed WM in the corpus callosum (CC), fiber connecting the two hemispheres Methods: After initial diagnostic evaluation at AD Clinic of University of Rochester Medical Center, 15 mildly impaired AD patients (M/VISE > 20) and 15 age-matched controls underwent extensive neuropsychological testing, including: 1) The Mini-Mental Status Examination; 2) The Road Map test; 3) Two subtests from the Wechsler Memory scale were used: the Verbal Paired Associates and the Figural Memory tests; 4) The Category Name Retrieval test; 5) The Judgement of Line Orientation test; 6) The Facial Recognition test. All participants also underwent perceptual testing for determining motion perception thresholds. MRI examinations were performed on a GE Signa 1.5 T MR scanner with a single-shot pulsed-gradient spin-echo (PGSE) EPI. Diffusion weighting were applied in 20 different orientations with b value = 0 and 1000 s/mm2. Results: Behaviorally, AD showed lower scores in all neuropsyehological tests, except the Facial Recognition test. AD patients also showed higher motion perceptual thresholds than controls. Neuroanatomically, in a subgroup of AD patients studied to date, we found significantly decreased fractional anisotropy (FA) values in WM in the anterior (genu) and posterior (splenium) CC and posterior cingulum. We also found significant correlations between FA values from different regions and performance on neuropsychological tests: better performance on the tests was correlated with higher integrity of WM. Conclusions: Overall, the results indicate a strong link of perceptual and attentional impairments to WM changes in early AD. Our initial pilot results are, thus, encouraging and promising in that with combining neuroanatomical and behavioral methods we may be able to reliably distinguish AD from normal aging at a relatively early stage.

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C O G N I T I V E D E C L I N E IS ASSOCIATED W I T H P R O G R E S S I O N OF CEREBRAL WHITE MATTER HYPERINTENSITIES. A POPULATION-BASED FOLLOW-UP STUDY

Ellen Garde* 1, Erik L. Mortensen 2, Egill Rostrup 3 . llnstitute of Neurology, London, United Kingdom; 2Institute of Public Health, Copenhagen University, Copenhagen, Denmark; 3Danish Research Center for Magnetic" Resonance, Copenhagen University Hospital, Hvidovre, Denmark. Contact e-mail: [email protected]

Background: White matter hyperintensities (WMH) are often observed in magnetic resonance imaging (MRI) of elderly individuals. It is generally presumed that WMH, when first present in MRI, progress over time. Few studies, however, have determined the time course and clinical implications of WMH. Objective(s): The objectives were to quantify the progression of WMH and determine whether changes in WMH are associated with cognitive decline from age 50 to 85 in community-dwelling octogenarians. Methods: From a Danish cohort of 698 people born in 1914, 75 communityliving individuals were tested with the complete Wechsler adult intelligence scale (WAIS) at ages 50, 60, 70, and 80, and agreed to a cerebral MRI at age 80-82 (82.3 years ± 10 months). At the 85-year follow-up, twenty-six of these individuals participated in both the neuropsychological (WAIS and M/VISE) and MRI study. All MRI was performed on the same 1.5T scanner. WMH quantification was based on both proton densityand T2-weighted images, and done with the help of a serni-antomated technique based on local thresholding (http://magnet'drcrmndk/s°ftware) (within-subject error 0.14ml, intra-class correlation (ICC) 0.99). Cross-

sectional correlations between WMH and cognitive tests from the 80 and 85 year studies were adjusted for sex and education, while both unadjusted and adjusted correlations were calculated between WMH volumes and cognitive decline between the 80 and 85 examinations. Results: mean WMH volume increased significantly from 10.4 ± 12.1 ml to 15.7 4- 14.2 ml, amounting to a mean annual progression of 1.4 (±1.7) ml per year and an annualized rate of progression of 19% (±14.5%). Increase in WMH volume was significantly correlated to a simultaneous decline in verbal IQ score (unadjusted r = -0.53, p = 0.005 and adjusted r = -0.61, p = 0.002). While larger baseline WMH volumes predicted larger decline in the Digit Symbol subtest (r = -0.56, p < 0.01) WMH at baseline were not associated with absolute increase in WMH. No associations could be detected in cross-sectional analysis or analysis of MMSE. Conclusions: Cerebral WMH have a detectable impact on function even in independently living non-demented elderly and could be a valuable MRI marker when evaluating patients with cognitive impairment.

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VIVO BRAIN IMAGING O F TAU AGGREGATION IN FRONTAL T E M P O R A L D E M E N T I A USING [F-18]FDDNP POSITRON E M I S S I O N TOMOGRAPHY

Gary W. Small*, Vladimir Kepe, Sung C. Huang, H.M. Wu, Prabha Siddarth, Linda Ercoli, Karen Miller, Helen Lavretsky, Benjamin C. Wright, Kooresh Shoghi-Jadid, Nagichettiar Satyamurthy, Michael E. Phelps, Jorge R. Barrio. David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Contact e-mail: [email protected]

Objective: Previous fluorescent microscopy studies of Alzheimer's disease (AD) brain specimens have shown that I, 1-dicyano-2-[6-(dimethylamino)-2naphthalenyl]propene or DDNP and its fluorinated analogue, [F- 18]FDDNP, provide excellent visualizations not only of [3-amyloid senile plaques (SPs), but also of intraneurnnal neurofibrillary tangles (NFTs). The ability of [F-18]FDDNP to label NF/'s suggests that it may be useful in imaging prominent tanopathies, such as frontal temporal dementia (FTD). In this study, we report the first in vivo [18]FDDNP PET human brain images of FTD patients. Methods: [F-18]FDDNP-PET scans were performed on 3 PTD patients (age: 85 d= 11 years [mean -4- SD], MMSE: 29, 26, and 0), and 10 controls (CTL; age: 63 ± 10 years, MMSE: all 30). Frontal, prefrontal, and cerebeflar regions of interest (ROIs) were drawn, and quantitation of regional binding for ROIs was performed using a relative standard uptake value evaluated at equilibrium (SUVR, normalized to cerebellum, 60-120 min). This analytic method has been validated previously using distribution volumes (Logan plot graphical analysis, cerebellum as reference region, 60-120 rain) and relative residence times (intercept of Logan plot with y-axis, cerebellum as reference). Nnnparamelric analyses of variance were used for group comparisons. [F-18]FDDNP-PET images of FFD, AD, and CTL were compared visually, and all subjects also received FDG-PET scans. Results: The SUVRs for frontal (FTD: 1.16 ± 0.13, CTL: 0.96 ± 0.07, p = 0.002) and prefrontal (FTD: 1.12 ± 0.07, CTL: 1.02 ± 0.05, p = 0.004) regions demonstrated significantly higher uptake in FED patients compared with controls. Visual comparisons of [F-18]FDDNP-PET images demonstrated a prominent frontal/temporal signal in FTD, in contrast to