PET imaging of cholinergic-receptor–binding in the healthy elderly and those with Alzheimer's disease or mild cognitive impairment: Preliminary findings

PET imaging of cholinergic-receptor–binding in the healthy elderly and those with Alzheimer's disease or mild cognitive impairment: Preliminary findings

P94 IC-P-158 Alzheimer’s Imaging Consortium Poster Presentations: IC-P IN VIVO PATTERN OF TAU AND BETA-AMYLOID DEPOSITION IN THE BRAIN MIGHT DISTINGU...

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P94 IC-P-158

Alzheimer’s Imaging Consortium Poster Presentations: IC-P IN VIVO PATTERN OF TAU AND BETA-AMYLOID DEPOSITION IN THE BRAIN MIGHT DISTINGUISH HEALTHY INDIVIDUALS FROM THOSE WITH PRECLINICAL ALZHEIMER’S DISEASE

Victor Villemagne1, Shozo Furumoto2, Michelle Fodero-Tavoletti3, Rachel S. Mulligan1, Ryuichi Harada4, Paul Yates5, Svetlana Pejoska5, Kazuhiko Yanai2, Colin Masters6, Yukitsuka Kudo7, Christopher Rowe8, Nobuyuki Okamura9, 1Austin Health, Melbourne, Australia; 2Tohoku University School of Medicine, Sendai, Japan; 3University of Melbourne, Melbourne, Australia; 4Tohoku University School of Medicine, Sendai, Japan; 5Austin Health, Heidelberg, VIC, Australia; 6University of Melbourne, Melbourne, VIC, Australia; 7Tohoku University, Sendai, Japan; 8 Austin Health, Melbourne, Australia; 9Tohoku University School of Medicine, Sendai, Japan. Contact e-mail: [email protected] edu.au Background: Tau deposition in Alzheimer’s disease (AD) follows a stereotypical pattern. The introduction of tau imaging with 18 F-THK523, a novel tau imaging ligand displaying high selectivity and specificity for PHF-tau pathology, has allowed the in vivo evaluation of the regional distribution of PHF-tau in the brain. Methods: Twenty participants -10 elderly healthy controls (HC) and 10 AD patients- underwent neuropsychological examination, MRI, 18 F-THK523 and 11 C-PiB PET. Standard uptake value ratios (SUVR) at 60-90 min and 40-70 min post injection were calculated for 18 F-THK523 and 11 C-PiB respectively, using the cerebellar cortex as the reference region. Images were corrected for partial volume effects. Results: Significantly higher 18 F-THK523 cortical retention was observed in the temporal, parietal, orbitofrontal and hippocampus of AD patients when compared to HC. The pattern of 18 F-THK523 retention followed the known distribution of PHF-tau in the AD brain (higher in posterior areas than frontal) and it did not correlate with the cortical retention of 11 C-PiB. Furthermore, 18 F-THK5233 retention was correlated with cognitive parameters and unlike 11 C-PiB, 18 F-THK523 hippocampal retention was highly correlated with hippocampal atrophy. Cognitively unimpaired individuals with high Ab in neocortical areas, already presented AD-like levels of tau deposition in the mesial temporal cortex, but not in isocortex. Conclusions: 18 FTHK523 retention follows the known distribution of PHF-tau in the brain and does not bind to Ab in vivo. Significantly higher cortical 18 FTHK523 retention in association with cognitive parameters and hippocampal volume indicates that 18 F-THK523 selectively binds to PHF-tau in the AD brain. Futhermore, our results suggest cognitively unimpaired individuals with high hippocampal tau and high neocortical Ab deposition might truly represent preclinical AD and may benefit most from disease-specific therapies aimed at reducing or eliminating Ab and/or tau from the brain before irreversible neuronal or synaptic loss occurs. Longitudinal follow up studies will allow o determine the sequence of cortical tau deposition associated with progressive cognitive impairment. IC-P-159

PET IMAGING OF CHOLINERGIC-RECEPTOR– BINDING IN THE HEALTHY ELDERLY AND THOSE WITH ALZHEIMER’S DISEASE OR MILD COGNITIVE IMPAIRMENT: PRELIMINARY FINDINGS

David Sultzer1, Rebecca Melrose1, Jessica Brommelhoff2, Arthur Brody1, Dylan Harwood1, Theresa Narvaez2, Michelle Tulac2, Mark Mandelkern3, 1 UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, California, United States; 2VA Greater Los Angeles Healthcare System, Los Angeles, California, United States; 3UC-Irvine and VA Greater Los Angeles Healthcare System, Los Angeles, California, United States. Contact e-mail: [email protected] Background: Dysfunction of the cholinergic system is well-known in Alzheimer’s disease (AD), but specific alterations in cholinergic neurotransmission, their regional distribution, and their relationship to specific cognitive or behavioral symptoms are not clear. 18F-2-FA is a radiotracer for PET imaging that binds to alpha4beta2 nicotinic receptor subunits in the brain and

measures regional cholinergic receptor binding in vivo. Methods: Twentythree patients with probable AD (mean age 76; mean MMSE 18.9), 15 with mild cognitive impairment (MCI), and 25 healthy elderly controls (EC) participated. Clinical assessments included measures of cognition, psychiatric symptoms, and functional skills. The PET imaging procedure utilized a 2FA bolus-plus-infusion technique. In this preliminary analysis, regional cholinergic binding was measured in thalamus and five cortical regions, bilaterally, using manually-placed spherical ROIs and plasma levels of unbound, nonmetabolized 2-FA to calculate volume of distribution (V T) values on the PET images. Results: In AD, mean cholinergic receptor binding (V T) in bilateral medial temporal cortex (MTL) was lower than in the EC group (left: p¼.002; right: p<.001). Although not significant, V T in the thalamus, lateral temporal cortex, and inferior parietal cortex was also lower in AD. Mean binding in the frontal and occipital cortices was similar in AD and EC. In the MCI group, mean V T in MTL was midway beween the mean V T in the AD and EC groups. In other cortical regions, mean V T in the MCI and AD groups were similar. In the combined group (n¼53), V T in medial temporal cortex was correlated with MMSE score (left: r¼.27, p¼.04; right: r¼.36, p¼.004). Conclusions: Reduced cholinergic receptor binding in AD varies by brain region. Lower binding in medial temporal cortex is most prominent. In MCI, preservation of cholinergic binding in medial temporal cortex may maintain cognitive and functional skills in the longitudinal process of neurodegeneration. In vivo measurement of cholinergic receptor binding in AD is feasible, can demonstrate relationships with specific clinical symptoms, can improve understanding of the sequence and interactions among critical AD neuropathologies, and in the future may reveal cholinergic efects of treatment and essential links to clinical improvement. IC-P-160

PET RADIOLIGAND BINDING TO TRANSLOCATOR PROTEIN MAY MARK CONVERSION FROM MILD COGNITIVE IMPAIRMENT TO ALZHEIMER’S DISEASE

William Kreisl1, Chul Hyoung Lyoo1, Meghan McGwier1, Joseph Snow1, Kimberly Jenko1, Nobuyo Kimura1, Winston Corona1, Cheryl Morse1, Sami Zoghbi1, Victor Pike1, Francis McMahon1, Raymond Turner2, Robert Innis1, The Foundation for NIH Biomarkers Consortium PET Radioligand Project Team3, 1National Institute of Mental Health, Bethesda, Maryland, United States; 2Georgetown University, Washington, District of Columbia, United States; 3FNIH, Bethesda, Maryland, United States. Contact e-mail: [email protected] Background: While neuroinflammation is thought to play a pathogenic role in Alzheimer’s disease (AD), exactly when inflammatory brain changes occur during disease progression is controversial. Mild cognitive impairment (MCI) may represent a prodromal stage of AD, and studying these patients may shed light on whether inflammation is an early contributor to AD progression. To determine the relationship between inflammation and AD severity, we used positron emission tomography (PET) with [11 C]PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Methods: Patients with AD and MCI and older controls were scanned with [11 C]Pittsburgh Compound B to measure amyloid burden. Twenty-nine "amyloid-positive" patients (19 AD, 10 MCI) and 13 "amyloid-negative" controls underwent brain MRI, neuropsychological testing, and [11 C]PBR28 PET. Group differences in [11 C]PBR28 binding (total distribution volume, corrected for free fraction of radioligand in plasma) were determined for 16 brain regions using univariate ANOVA, adjusted for age, education, and TSPO genotype. Linear correlative analysis was performed to determine associations between [11 C]PBR28 binding and performance on Folstein Mini Mental State Exam, Logical Memory - Immediate, Block Design, Trail Making part B, and Wisconsin Card Sort Test - total errors. Associations between [11 C]PBR28 binding and gray matter volume were also determined. Results: AD patients had greater [11 C]PBR28 binding than both MCI patients and controls in cortical regions associated with amyloid pathology, most notably in inferior parietal lobule, middle and inferior temporal cortex, and precuneus (p < 0.005 vs. controls). MCI patients did not differ from controls in any region. [11 C]PBR28 binding inversely correlated with performance on all cognitive measures except for Wisconsin