Midlife adiposity predicts earlier onset of Alzheimer’s dementia, neuropathology, and presymptomatic cerebral amyloid accumulation

Developing Topics

voxel-wise. Results: Peak SUV values were approximately 3, 1.5 and 3.5 for [11C]RO6924963, [11C]RO6931643, and [18F] RO6958948, respectively. The retention of [11C]RO6931643 and [18F]RO6958948 in HS was much lower than that of [11C] RO6924963. For [11C]RO6931643 and [18F]RO6958948 (in AD), highest uptake was seen in the frontal (Fr), temporal (Tp), parietal (Pa), occipital (Oc), and fusiform (Fs) cortices, and the entorhinal area (ER). SUVR60-90 values ranged from 1.22 (L. Fr) to 1.55 (L. Oc) for [11C]RO6931643, and 1.39 (R.Fr) to 2.25 (L. Fs) for [18F]RO6958948, and VT ranged from 2.28 (R. ER) to 3.14 (L. Tp), and 3.98 (R. ER) to 5.62 (L. Tp), respectively. Regional analysis of SUVR and VT for [11C]RO6931643 and [18F]RO6958948 clearly allowed AD and HS to be distinguished. When compared to HS, the two tracers showed robust group effects (F>90; p¼<10-6; two-way ANOVA) on SUVR and VT, and significant group differences (p<0.05 with Bonferroni correction; without overlap) in 6 of 12 regions for [11C]RO6931643 and 4 of 12 for [18F]RO6958948 (using SUVR). Voxel-wise analysis of SUVR revealed clusters of significantly higher uptake in AD compared to HS in Fs for [11C]RO6931643 (7 AD vs. 5 HS), and [18F] RO6958948 (5 AD vs. 5 HS). There were no radiolabelled metabolites nor defluorination of [18F]RO6958948. Conclusions: Our data supports further evaluation of [18F]RO6958948. Kinetic analysis is reported in detail in Kuwabara, AAIC 2015.

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KINETIC EVALUATION OF THREE NEWLY DEVELOPED RADIOLIGANDS FOR HUMAN TAU IMAGING

Hiroto Kuwabara1, Robert A. Comley2, Edilio Borroni2, Michael Honer2, Dean F. Wong1, 1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Contact e-mail: [email protected] Background: Neuroimaging of aggregated tau may be useful for

monitoring progression of tauopathies such as in Alzheimer’s disease (AD). Three new PET radioligands for tau imaging were evaluated quantitatively in healthy subjects (HS) and patients with AD. Methods: Seven amyloid PET positive AD patients (4M:2F; 67-86 y; MMSE: 16-24), and 7 young HS (5M:2F; 25-38 y) each received 2 different tau tracers. Dynamic 90 min scans were obtained after bolus injection of [11C]RO6924963 (4HS:2AD), [11C]RO6931643 (5HS:7AD), or [18F]RO6958948 (5HS:5AD). Arterial blood sampling was performed in 8/14 AD, and 13/14 HS. Time-activity curves (TAC) were obtained for a total of 41 MRI-derived brain regions. Results: [11C]RO6924963 alone

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showed some regional variation of TACs in HS, and rapid metabolism in plasma (parent fraction: 30% at 5 min; <5% at 90 min). Therefore, only [11C]RO6931643 and [18F]RO6958948 (parent fractions: w30% at 15 min; w10% at 90 min) are reported further. The kinetics of both radioligands can be described by a twotissue compartmental model, and the plots reached asymptotes by 20 min for the plasma-reference graphical analysis (PRGA; Logan et al., 1990) for both groups. Target-cerebellum ratios (¼TRR, a.k.a. SUVR) became stable by 60 min in AD and HS for both radioligands. Regional TRR (¼y) correlated with BPND of PRGA (BPND ¼ target-cerebellum distribution volume ratio less 1) for RO6931643 (y ¼ 0.91∙x + 1.04; R2¼0.963) as well as for RO6958948 (y ¼ 1.8∙x + 1.1; R2¼0.944), using AD data alone. In AD subjects, regional TRR of RO6931643 (n¼7) ranged from 1.22 to 1.55 among high TRR regions including the frontal (Fr), temporal (Tp), parietal (Pa), occipital (Oc), and fusiform (Fs) cortices, and the entorhinal area(ER) (12 regions per side) while TRR of RO6958948 (n¼5) ranged from 1.39 to 2.55. TRR correlated between the two radioligands (RO6958948 ¼ 2∙x 0.96; R2¼0.801; p<10-6). AD subjects showed higher TRR values without overlap in 6/12 regions for RO6931643 and 4/12 regions for RO6958948; p<0.0042 for Bonferroni correction. Conclusions: Of the three candidate radioligands, [11C]RO6931643 and [18F] RO6958948 appeared to be promising radioligands for tau imaging.

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MIDLIFE ADIPOSITY PREDICTS EARLIER ONSET OF ALZHEIMER’S DEMENTIA, NEUROPATHOLOGY, AND PRESYMPTOMATIC CEREBRAL AMYLOID ACCUMULATION

Madhav Thambisetty1, Yi-Fang Chuang1, Yang An1, Murat Bilgel1, Dean F. Wong2, Juan C. Troncoso2, Richard O’Brien3, John C.S. Breitner4, Susan M. Resnick1, 1National Institute on Aging, Baltimore, MD, USA; 2 Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Duke University, Durham, NC, USA; 4McGill University Faculty of Medicine, Montreal, QC, Canada. Contact e-mail: [email protected] Background: Understanding how midlife risk factors influence ageat-onset (AAO) of Alzheimer’s disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer’s neuropathology. Methods: Using a prospective population-based cohort, the Baltimore Longitudinal Study of Aging (BLSA), we sought to examine the relationships between midlife body mass index (BMI) and: (1) AAO of AD; (2) severity of Alzheimer’s neuropathology; and (3) fibrillar brain amyloid deposition during aging. We analyzed data from 1,394 cognitively normal individuals at baseline (8643 visits; average follow up interval 13.9 years), 142 of whom developed incident AD. In two sub-samples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging by 11C-PiB PET. Midlife adiposity was derived from BMI data at 50 years of age. Results: Each unit increase in midlife BMI predicted earlier onset of AD by 6.7 months (P¼0.013). Higher midlife BMI was associated with greater Braak neurofibrillary tangle but not CERAD neuritic plaque scores at autopsy overall. Higher midlife BMI was associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio and within the precuneus. Conclusions: Midlife overweight predicts earlier onset of AD and

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Developing Topics

increased burden of Alzheimer’s neuropathology. Accordingly, a healthy BMI in midlife may delay the onset of AD. P4-188

BIPHASIC CHANGES IN CEREBROSPINAL FLUID LEVELS OF TAU IN TG4510 MICE

Mansuo Hayashi, Eli Lilly and Co., Indianapolis, IN, USA. Contact e-mail: [email protected] Background: Increased Tau pathology is a major hallmark in

Alzheimer’s disease and tauopathies. However, it is unclear how the increase in Tau pathology might relate to the accumulation of CSF Tau, and what other factors may influence CSF Tau. To investigate this, we utilized the forebrain-inducible Tg4510 mice and conducted a longitudinal study to fine map the changes in Tau pathology, brain atrophy and CSF Tau. Methods: Tg4510 mice at various ages were analyzed for Tau pathology and brain atrophy by ELISA and immunohistochemistry. CSF was collected from the same animals and subjected to ELISA to measure Tau and pT181 Tau. Results: In the younger mice of 14 to 18 weeks of age, we observed a strong correlation between CSF levels of Tau and brain levels of insoluble Tau, but not total Tau. We also observed a strong correlation between levels of CSF Tau and CSF pT181 Tau. Surprisingly, in mice of older age (19 and 20 weeks), even though their insoluble Tau levels nearly doubled in a weekly basis, their CSF Tau levels reached plateau and did not increase further. Notably, this coincided with brain atrophy, which became significant from 20 weeks of age. Conclusions: Our data demonstrated biphasic changes in CSF levels of Tau in the Tg4510 mice, where the initial increase in CSF Tau may attribute to increased Tau pathology while the subsequent plateau of CSF Tau in older mice may reflect a reduced Tau release from atrophied neurons.

Figure 1. Immunostaining of tau phosphorylation by BRSK2. The brains of flies expressing: (A) Canton-S under the control of the G1118 Gal4 driver (control line); and (B) both 0N4R tau and BRSK2, were stained with the BP102 antibody to label axons in the Drosophila central nervous system, and counterstained with the DAPI and GFP fluorescent antibodies.

in sleep-like episodes, but recorded reduced average sleep length and total amount of sleep. Average longest sleep episode was highest in flies expressing both tau and BRKS2, but decreased in those expressing only tau or BRSK2 compared to control. Daytime sleep patters (up to 3 hours zeitgeber time) were more affected in aged flies compared to younger ones. Conclusions: Our findings demonstrate that close similarities exist between tauopathy-related sleep disturbances reported in humans and those observed in Drosophila. The established genetic systems in fruit flies can therefore be used to study the genetic and molecular links between tau phosphorylation, toxicity and sleep defects. P4-190

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EFFECT OF BRAIN-SPECIFIC KINASEDEPENDENT TAU PHOSPHORYLATION ON TAUOPATHY-ASSOCIATED SUNDOWNING SLEEP BEHAVIOUR

Thomas K. Karikari, Richard Osgood, Sophie Poppy Crighton, Kevin G. Moffat, University of Warwick, Coventry, United Kingdom. Contact e-mail: [email protected] Background: Previous studies have linked sleep disturbances to Alzheimer’s disease (AD) and other tauopathies. However, the molecular and genetic basis of this linkage remains enigmatic. Hyper-phosphorylation of tau, by BRSK2 and other kinases, reduces the protein’s ability to promote microtubule assembly, although little is known about how this might lead to sleep problems. In this study, we sought to ascertain whether tau hyper-phosphorylation by BRSK2 disturbs sleep-like behaviours in a Drosophila tauopathy model. Methods: The 0N4R human tau isoform was expressed with or without the brain-specific kinase BRSK2 in the fly brain circadian network. Using Trikinetic Activity Monitors, sleep-like behaviours were monitored for F1 offspring carrying the G1118GAL4 driver in the presence or absence of tau and/or BRSK2. Data analysis was conducted using BeFly and PySolo. Results: Sleep-like defects were observed in flies expressing tau alone and those expressing both tau and BRSK2. These defects were most pronounced in flies expressing both tau and BRSK2, suggesting that tau phosphorylation by BRSK2 enhances toxicity leading to sleep-like behavioural changes. This was also observed in immunostaining and fluorescence microscopy studies where flies expressing tau and BRSK2 showed reduced axon intensity in specific brain regions compared to control (Figure 1). Furthermore, flies expressing tau and/or BRSK2 showed increases

CO-EXPRESSION OF APP AND TAU ACCELERATES COGNITIVE DECLINE IN A NEW TRIPLE TRANSGENIC MODEL THAT ALLOWS FOR ACCOUNTING FOR THE EFFECT OF AGE AS A RISK FACTOR FOR ALZHEIMER’S DISEASE

Tatiana Melnikova1, Da Min Park1, Stephanie Porter1, Natalie Christie1, David R. Borchelt2, Alena Savonenko1, 1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2University of Florida, Gainesville, FL, USA. Contact e-mail: [email protected] Background: Studies of cognitive effects of tau in the setting of APP co-expression are surprisingly rare. In addition, expression of APP and tau in AD models usually starts during pre- or early post-natal development resulting in initiation of pathological processes at a young age, a characteristic that are not relevant to AD. Accumulation of Ab and/or tau during young age that has high resilience to any toxic agents might skew correlations between cognitive deficits and pathological markers. Methods: We used a new triple transgenic model (CaMKII-tTa:APPsi:rTg4510) with co-existing Ab and tau pathologies. Inducible expression from both APPsi and tauP301L transgenes allowed for the flexibility temporally to control expression via systemically delivered doxycycline. We delayed expression of APP and tau until middle age to model initiation of both pathologies in humans in the 4th decade of life and analyzed the dynamics of cognitive decline and developing pathologies. Results: We show that tTa:APPsi mice with middle-age onset (MAO) of APP expression develop cognitive deficits at much earlier stages of Ab accumulation than mice with an earlyadulthood onset. Our studies in the MAO tTa:APPsi:rTg4510 model confirmed Ab-induced aggravation of tau phosphorylation/ pathology observed in previous studies. Mice with expression of both transgenes had earlier onset and more severe cognitive deficits