George Mawko

Early Detection of Cerebral Glucose Uptake Changes in the 5XFAD Mouse

Brain glucose hypometabolism has been observed in Alzheimer’s disease (AD) patients, and is detected with 18F radiolabelled glucose, using positron emission tomography. A pathological hallmark of AD is deposition of brain β-amyloid plaques that may influence cerebral glucose metabolism. The five times familial AD (5XFAD) mouse is a model of brain amyloidosis exhibiting AD-like phenotypes. This study examines brain β-amyloid plaque deposition and 18FDG uptake, to search for an early biomarker distinguishing 5XFAD from wild-type mice. Thus, brain 18FDG uptake and plaque deposition was studied in these mice at age 2, 5 and 13 months. The 5XFAD mice demonstrated significantly reduced brain 18FDG uptake at 13 months relative to wild-type controls but not in younger mice, despite substantial β-amyloid plaque deposition. However, by comparing the ratio of uptake values for glucose in different regions in the same brain, 5XFAD mice could be distinguished from controls at age 2 months. This method of measuring altered glucose metabolism may represent an early biomarker for the progression of amyloid deposition in the brain. We conclude that brain 18FDG uptake can be a sensitive biomarker for early detection of abnormal metabolism in the 5XFAD mouse when alternative relative uptake values are utilized.

Synthesis and Preliminary Evaluation of Piperidinyl and Pyrrolidinyl Iodobenzoates as Imaging Agents for Butyrylcholinesterase

PurposeThe purpose of this study is to synthesize and evaluate specific agents for molecular imaging of butyrylcholinesterase (BuChE), known to be associated with neuritic plaques and neurofibrillary tangles in Alzheimer’s disease (AD). In this study, these agents were tested in a normal rat model. The distribution of radiolabel was compared with known BuChE histochemical distribution in the rat brain.ProceduresIodobenzoate esters were synthesized and tested, through spectrophotometric analysis, as specific substrates for BuChE. These compounds were converted to the corresponding 123I esters from tributyltin intermediates and purified for studies in the rat model. Whole body dynamic scintigraphic images were obtained for biodistribution studies. Autoradiograms of brain sections were obtained and compared to histochemical distribution of the enzyme in this model system.ResultsThe three iodobenzoate esters studied were specific substrates for BuChE. Whole body biodistribution studies with 123I-labeled compounds showed rapid disappearance from the body while radioactivity was retained in the head region. Brain section autoradiography of animals injected with these labeled compounds indicated that most areas known to contain BuChE corresponded to areas of radioactivity accumulation.ConclusionBuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.

Butyrylcholinesterase-knockout reduces fibrillar β-amyloid and conserves 18FDG retention in 5XFAD mouse model of Alzheimer’s disease

Alzheimers disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of β-amyloid (Aβ) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Aβ pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Aβ plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Aβ than 5XFAD mice at the same age. Therefore, BChE may have a role in Aβ pathogenesis. Furthermore, in AD, diminished glucose metabolism in the brain can be detected in vivo with positron emission tomography (PET) imaging following 2-deoxy-2-(18F)fluoro-D-glucose (18FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Aβ burden, whole brain and regional uptake of 18FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT5XFAD and WTBChE-KO) strains at 5months. Diminished fibrillar Aβ burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brain 18FDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction in 18FDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT5XFAD. Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WTBChE-KO, while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Aβ, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice.

Cerebral glucose metabolism, pathology and behaviour in the 5XFAD mouse model of Alzheimer's disease

IC-P-045 CEREBRAL GLUCOSE METABOLISM, PATHOLOGYAND BEHAVIOR IN THE 5XFAD MOUSE MODEL OFALZHEIMER’S DISEASE Ian Macdonald, Drew DeBay, Tim O’Leary, Andrew Reid, Meghan Cash, Courtney Jollymore, George Mawko, Steve Burrell, Chris Bowen, Earl Martin, Richard Brown, Sultan Darvesh, Dalhousie University, Halifax, Nova Scotia, Canada; National Research Council, Halifax, Nova Scotia, Canada; Mount Saint Vincent University, Halifax, Nova Scotia, Canada. Contact e-mail: Ian.Macdonald@dal.ca

Visualization of 90Yttrium Colloid Within a Cystic Craniopharyngioma Using PET/CT/MRI Fusion

Untreated expansion of cystic craniopharyngiomas can have significant consequences from mass effect including worsening headache, vision loss, and obstructive hydrocephalus. Conventional surgical treatments include attempted resection, typically via craniotomy. Less invasive aspiration of cystic contents only provides a temporary solution, with cysts tending to refill and expand after a single drainage. The beneficial effects of intracavitary irradiation for treatment of cystic craniopharyngiomas as a means to abolish the secretory capability of the cyst’s epithelial lining, while sparing nearby critical brain structures, has been previously reported. Yttrium colloid is considered a suitable isotope for treatment of cystic craniopharyngiomas because of its short half-life and pure β emission. Intracavitary irradiation with stereotactically implanted yttrium colloid has been shown to be effective in longterm shrinkage of the cystic portion of recurrent craniopharyngiomas. A retrospective review of 78 patients over a 36-year period showed sustained cyst reduction in 63% of patients following yttrium colloid treatment, with 33% of cysts disappearing completely. The administered dose is calculated based on delivering 200 Gy to the inner wall of the cyst. Although radiation delivery into the cyst using a stereotactically guided needle had been previously outlined in Pollack et al, imaging techniques to demonstrate the ongoing intracystic radiation have not been previously described. Although Bremsstrahlung single-photon emission computed tomography/computed tomography (CT) can be used to image the activity distribution after administration of yttrium colloid, positron emission tomography (PET)-CT has become the preferred modality in the brain because of higher spatial and energy resolution . In this report, we demonstrate the use of PET-CT imaging, fused to anatomic CT and magnetic resonance imaging (MRI), as a means of documenting the actual distribution of yttrium colloid delivered to the cystic craniopharyngioma.

ALTERNATIVE CEREBRAL GLUCOSE UPTAKE METRICS DETECT EARLY METABOLIC CHANGES IN THE 5XFAD MOUSE MODEL OF ALZHEIMER'S DISEASE

Background: Changes in visual and auditory function have been reported in patients with clinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI), but the relationship of these measures to known biomarkers of AD neuropathology is unknown. Thus, the goal of this study was to test the hypothesis that sensory measures, including visual (contrast sensitivity) and auditory function (pure tone audiometry), are associated with neuroimaging biomarkers of AD, including amyloid deposition (measured with [11 C]PiB PET) and hippocampal volume. Methods: 31 participants, including 13 healthy age-matched controls (HC), 6 euthymic older adults with subjective cognitive decline (SCD) but no neuropsychological deficits, and 12 patients with MCI, were included in the present analysis. All participants underwent a test of contrast sensitivity, measured using frequency doubling technology (FDT-2) as previously described [1], pure tone audiometry to test tonal hearing, and structural MRI. A subset of participants also underwent [11 C]PiB PET imaging (n1⁄412 [3 HC, 3 SCD, 6 MCI]). Structural MRI scans were processed using FreeSurfer version 5.1. [11 C]PiB PET scans were processed using standard techniques in SPM8. Mean PiB standardized uptake value ratio (SUVR) was extracted from a global cortical grey matter region of interest. Contrast sensitivity (duration of FDT-2 exam) and tonal hearing at high frequency (mean tonal intensity at 8000Hz) were compared between diagnostic groups. The relationship of these sensory measures to global PiB uptake and hippocampal atrophy was evaluated using a linear regression model. Results: No significant difference between diagnostic groups was observed for either visual function or tonal hearing at 8000 Hz in this small sample (Fig. 1A & 1B). However, visual function (duration of FDT-2 exam) was significantly associated with amyloid deposition (p1⁄40.001, Fig. 1C). Tonal hearing and hippocampal volume were also significantly associated (p1⁄40.001, Fig. 1D). Conclusions: Visual and auditory changes in individuals at risk and during prodromal stages of AD are associated with neuroimaging biomarkers of AD pathology, including amyloid deposition and neurodegeneration. Non-invasive and inexpensive measures of visual and auditory sensory function warrant further investigation as potential biomarkers of early stage AD pathology. [1] Risacher et al. (2013) Neurobiol Aging. IC-P-098 ALTERNATIVE CEREBRAL GLUCOSE UPTAKE METRICS DETECT EARLY METABOLIC CHANGES IN THE 5XFAD MOUSE MODEL OFALZHEIMER’S DISEASE Drew R. DeBay, Ian R. Macdonald, G. Andrew Reid, Tim P. O’Leary, Courtney T. Jollymore, Meghan K. Cash, GeorgeMawko, Steve Burrell, Earl Martin, Chris V. Bowen, Richard E. Brown, Sultan Darvesh, Dalhousie University, Halifax, Nova Scotia, Canada; Mount Saint Vincent University, Halifax, Nova Scotia, Canada. Contact e-mail: drdebay@dal.ca