University of Wisconsin–Madison

Bradley T Christian, PhD

Brad Christian Slide of the Week

Title: PET Neuroimaging of Pathology Related to Alzheimer’s Disease

Legend:  Investigators in the Christian Lab use positron emission tomography to detect and monitor Alzheimer’s disease beta-amyloid and tau pathologies in the human brain in collaboration with Waisman investigator Sterling Johnson. Graduate student Tobey Betthauser works in the Christian Lab to characterize radiotracers and detection methodology. Current research projects involve the longitudinal tracking of AD related pathology in adults with Down syndrome.

Citation: Betthauser TJ, Lao PJ, Murali D, Barnhart TE, Furumoto S, Okamura N, Stone C, Johnson SC, Christian BT. Imaging tau and beta amyloid using 11C-PiB, 18F-THK-5117, and 18F-THK-5351 in Alzheimer’s Disease. 10th Human Amyloid Imaging Conference, Miami, FL, Jan. 13-15, 2016.

Abstract:  Introduction – Alzheimer’s disease is characterized by accumulation of beta amyloid (Aβ) and hyperphosphorylated tau proteins, which neuropathology suggests follow distinct spatiotemporal patterns. 11C-PiB, 18F-THK-5117, and 18FTHK-5351 are PET radioligands for fibrillar Aβ (PiB), and neurofibrillary tau (THK) aggregates. Tau, more so than Aβ, is thought to correlate with cognitive decline in AD. This cross-sectional study observes spatial patterns of aggregated tau and Aβ in individuals ranging in age, AD risk factors, and cognitive status. Methods – N=16 subjects (4 cognitively normal, 5 cognitive declining, 4 MCI, 2 AD, 1 non-AD dementia) underwent T1-weighted MRI, 11C-PiB (70min dynamic), and 18F-THK-5117 (n=14) and/or 18F-THK-5351 (n=3) (90min dynamic) scans. PET time series were coregistered to T1w MRI, and FreeSurfer segmented. Distribution volumes ratios were calculated (Logan 1996) using a cerebellar gray matter reference region. Subjects were grouped and rank ordered by disease severity based on longitudinal neuropsychological assessment and clinical diagnosis upon study enrollment. Spearman’s rank analyses were performed to assess monotonic relationships between PiB, THK, and cognitive status. THK kinetics were also assessed. Results – Significant spatial intercorrelation of PiB and THK DVRs and affected volumes were observed globally, and regionally in temporal, parietal, occipital and frontal cortices, and the fusiform gyrus, but not medial temporal lobe, independent of cognitive status. These regions also showed correlations between Aβ and tau measures and cognitive decline, though, only tau measures in the ventral and lateral temporal, lateral parietal, and occipital cortices survived multiple comparisons correction. In WM, THK compounds exhibited slow uptake and clearance, with THK-5351 showing a 1.5-fold reduction compared to THK-5117 at t>40 min. In GM, THK-5351 and THK-5117 demonstrated rapid kinetics and linearization of Logan plots (t*=30 min). Conclusion – These data indicate combined regional Aβ and tau accumulation may play a role in cognitive dysfunction. Additional studies of paired PiB/THK-5351 are ongoing.

About the investigator:  Christian’s research focuses on the use of positron emission tomography (PET) to interrogate molecular pathways involved in various brain processes. [11C]PiB imaging is used to detect Aβ plaques in elderly participants with and without Alzheimer’s disease, as well as young adults with Down syndrome. A variety of radiolabelled tracers such as [18F]THK5351, [18F]nifene, [18F]mefway, [11C]PBR28, and [11C]clozapine are also used to understand tauopathies, addiction, and neuroinflammation.

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