Engineering topics

Ossenkoppele, Rik

Publications and source records attributed to Ossenkoppele, Rik.

7 records

DOE OSTI2024

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model

Abstract INTRODUCTION Tau‐positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS Using head‐to‐head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed “CenTauR” [CTR]). JPM is a statistical model that simultaneously models the relationships between head‐to‐head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION Preliminary findings using the JPM support the development and adoption of a universal scale for tau‐PET quantification. Highlights Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed “CenTauRs”. Tested a Centiloid‐like linear regression approach. Using five cohorts with head‐to‐head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Neurosciences & Neurology↗

DOE OSTI2024

Tau Positron Emission Tomography for Predicting Dementia in Individuals With Mild Cognitive Impairment

An accurate prognosis is especially pertinent in mild cognitive impairment (MCI), when individuals experience considerable uncertainty about future progression. To evaluate the prognostic value of tau positron emission tomography (PET) to predict clinical progression from MCI to dementia. This was a multicenter cohort study with external validation and a mean (SD) follow-up of 2.0 (1.1) years. Data were collected from centers in South Korea, Sweden, the US, and Switzerland from June 2014 to January 2024. Participant data were retrospectively collected and inclusion criteria were a baseline clinical diagnosis of MCI; longitudinal clinical follow-up; a Mini-Mental State Examination (MMSE) score greater than 22; and available tau PET, amyloid-β (Aβ) PET, and magnetic resonance imaging (MRI) scan less than 1 year from diagnosis. A total of 448 eligible individuals with MCI were included (331 in the discovery cohort and 117 in the validation cohort). None of these participants were excluded over the course of the study. Exposures included Tau PET, Aβ PET, and MRI. Positive results on tau PET (temporal meta–region of interest), Aβ PET (global; expressed in the standardized metric Centiloids), and MRI (Alzheimer disease [AD] signature region) was assessed using quantitative thresholds and visual reads. Clinical progression from MCI to all-cause dementia (regardless of suspected etiology) or to AD dementia (AD as suspected etiology) served as the primary outcomes. The primary analyses were receiver operating characteristics. In the discovery cohort, the mean (SD) age was 70.9 (8.5) years, 191 (58%) were male, the mean (SD) MMSE score was 27.1 (1.9), and 110 individuals with MCI (33%) converted to dementia (71 to AD dementia). Only the model with tau PET predicted all-cause dementia (area under the receiver operating characteristic curve [AUC], 0.75; 95% CI, 0.70-0.80) better than a base model including age, sex, education, and MMSE score (AUC, 0.71; 95% CI, 0.65-0.77; P = .02), while the models assessing the other neuroimaging markers did not improve prediction. In the validation cohort, tau PET replicated in predicting all-cause dementia. Compared to the base model (AUC, 0.75; 95% CI, 0.69-0.82), prediction of AD dementia in the discovery cohort was significantly improved by including tau PET (AUC, 0.84; 95% CI, 0.79-0.89; P < .001), tau PET visual read (AUC, 0.83; 95% CI, 0.78-0.88; P = .001), and Aβ PET Centiloids (AUC, 0.83; 95% CI, 0.78-0.88; P = .03). In the validation cohort, only the tau PET and the tau PET visual reads replicated in predicting AD dementia. In this study, tau-PET showed the best performance as a stand-alone marker to predict progression to dementia among individuals with MCI. This suggests that, for prognostic purposes in MCI, a tau PET scan may be the best currently available neuroimaging marker.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Cognitively defined Alzheimer's dementia subgroups have distinct atrophy patterns

We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging-defined subgroups. We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid-negative controls. We used voxel-based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD-Memory. There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD-Memory, lower left hemisphere GMV for AD-Language, anterior lower GMV for AD-Executive, and posterior lower GMV for AD-Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD-Language group than any other group (p = 1.15 × 10 -10 ). For overlap between imaging-defined and cognitively defined subgroups, AD-Memory matched up with an imaging-defined limbic predominant group. MRI findings differ across cognitively defined AD subgroups.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease: A Head-to-Head Comparison Against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging

Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 ( 18 F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, setting, and participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [ 18 F]Flortaucipir PET in the discovery cohort (n = 1135) or [ 18 F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main outcomes and measures: Baseline [ 18 F]flortaucipir/[ 18 F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [ 18 F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R 2 , 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R 2 , 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [ 18 F]RO948 PET cohort. MRI mediated the association between [ 18 F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [ 18 F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

The impact of demographic, clinical, genetic, and imaging variables on tau PET status

Purpose: A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) are tau PET–negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET–positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status. Methods: We included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [ 18 F]flortaucipir ( n = 1944) or [ 18 F]RO948 ( n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOE ε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model. Results: Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan. Conclusion: We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer disease

We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer’s disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. We retrospectively included 150 participants, including 29 bvAD, 28 “typical” amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [ 18 F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvAD bvFTD, area under the curve [AUC] range 0.85–0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD<tAD), FDG anterior-DMN-ratios (bvAD<tAD, AUC range 0.71–0.84, all p < 0.05). Subtle frontoinsular hypometabolism and anterior DMN involvement may underlie the prominent behavioral phenotype in bvAD.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease

Importance: Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective: To examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, setting, an participants: In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures: Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET. Main outcomes and measures: Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results: A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P < .001) and global cortical thickness (standardized β = 0.23, P < .001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] = -0.235 [0.111], P = .03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and relevance: Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.

60 APPLIED LIFE SCIENCES↗