Biology subjects

Betthauser, T. J.

Publications and source records attributed to Betthauser, T. J..

2 recordsLinked to original sources

bioRxiv2018

In vivo characterization and quantification of neurofibrillary tau PET radioligand [18F]MK-6240 in humans from Alzheimer’s disease dementia to young controls

Tau positron emission tomography (PET) imaging has potential for elucidating changes in the deposition of neuropathological tau aggregates that are occurring during the progression of Alzheimers disease (AD). This work investigates in vivo kinetics, quantification strategies and imaging characteristics of a novel tau PET radioligand [18F]MK-6240 in humans.\n\nMethodsFifty-one individuals ranging from cognitively normal young controls to persons with dementia underwent T1-weighted magnetic resonance imaging (MRI), and [11C]PiB and [18F]MK-6240 PET imaging. PET data were coregistered to the MRI and time-activity curves were extracted from regions of interest to assess [18F]MK-6240 kinetics. The pons and inferior cerebellum were investigated as potential reference regions. Reference tissue methods (Logan graphical analysis (LGA) and multilinear reference tissue method (MRTM2)) were investigated for quantification of [18F]MK-6240 distribution volume ratios (DVRs) in a subset of nineteen participants. Stability of DVR methods was evaluated using truncated scan durations. Standard uptake value ratio (SUVR) estimates were compared to DVR estimates to determine the optimal timing window for SUVR analysis. Parametric SUVR images were used to identify regions of potential off-target binding and to compare binding patterns with neurofibrillary tau staging established in neuropathology literature.\n\nResultsStandard uptake values in the pons and the inferior cerebellum indicated consistent clearance across all 51 subjects. LGA and MRTM2 DVR estimates were similar, with LGA slightly underestimating DVR compared to MRTM2. DVR estimates remained stable when truncating the scan duration to 60 minutes. SUVR determined 70-90 minutes post-injection of [18F]MK-6240 indicated linearity near unity when compared to DVR estimates and minimized potential spill-in from uptake outside of the brain. [18F]MK-6240 binding patterns in target regions were consistent with neuropathological neurofibrillary tau staging. Off-target binding regions included the ethmoid sinus, clivus, meninges, substantia nigra, but not the basal ganglia or choroid plexus.\n\nConclusions[18F]MK-6240 is a promising PET radioligand for in vivo imaging of neurofibrillary tau aggregates in AD with minimal off-target binding in the human brain.

neuroscience↗

bioRxiv2017

Modifiable risk factors moderate the relationship between amyloid and cognition in midlife

Although evidence suggests a relationship between elevated beta-amyloid and cognitive decline, approximately 30% of older adults with positive markers of amyloid remain cognitively healthy. Our objective was to test if the presence of modifiable risk factors (i.e., central obesity, hypertension, and depressive symptoms) moderated the relationship between amyloid and longitudinal cognitive performance. Data were from 207 adults (140 females; age range=40-70) enriched for Alzheimers disease risk (73% parental history of Alzheimers disease) enrolled in the Wisconsin Registry for Alzheimers Prevention study. Participants completed at least two neuropsychological evaluations and one biomarker visit ([C11] Pittsburgh Compound B PET scan or lumbar puncture). Participants were characterized as high or low on amyloid using cutoffs developed for [C11] Pittsburgh Compound B-PET distribution volume ratio or CSF amyloid beta 1-42 values. Participants were also coded as high or low risk on obesity, hypertension, and depressive symptoms. Linear mixed effects regression models examined three-way interactions between modifiable risk factor status x amyloid group x age at each study visit on longitudinal Verbal Learning & Memory and Speed & Flexibility factor scores. Results indicated that the relationship between beta-amyloid and Verbal Learning & Memory decline was associated with hypertension status (Likelihood ratio test for significance of hypertension status age x amyloid status x visit age interaction term;{chi} 2 (1) = 5.28, p = .02). The relationship between beta-amyloid and Speed & Flexibility decline was associated with depression status (Likelihood ratio test for significance of amyloid status x depression status x visit age interaction term;{chi} 2 (1) = 7.10, p = .03). The presence of obesity did not significantly moderate the relationship between beta-amyloid status and cognitive performance, although the direction of relationship was similar to above relationships (Likelihood ratio test for significance of obesity status x amyloid status x visit age interaction term;{chi} 2 (1) = 1.52, p = .21). In this at-risk for Alzheimers disease cohort, the modifiable risk factors of hypertension and depression significantly moderated the relationship between beta-amyloid and cognitive decline. Identification and modification of these risk factors in late middle age may slow the effect of amyloid on the progression of cognitive symptoms.

neuroscience↗