| 1. |
- Groot, Colin, et al.
(författare)
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Tau Positron Emission Tomography for Predicting Dementia in Individuals With Mild Cognitive Impairment
- 2024
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Ingår i: JAMA Neurology. - 2168-6149. ; 81:8, s. 845-856
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE An accurate prognosis is especially pertinent in mild cognitive impairment (MCI), when individuals experience considerable uncertainty about future progression. OBJECTIVE To evaluate the prognostic value of tau positron emission tomography (PET) to predict clinical progression from MCI to dementia. DESIGN, SETTING, AND PARTICIPANTS 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 Tau PET, Aβ PET, and MRI. MAIN OUTCOMES AND MEASURES 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. RESULTS 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. CONCLUSIONS AND RELEVANCE 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.
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| 2. |
- Mastenbroek, Sophie E., et al.
(författare)
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Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer’s disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
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| 3. |
- Collij, Lyduine E., et al.
(författare)
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Spatial-Temporal Patterns of beta-Amyloid Accumulation A Subtype and Stage Inference Model Analysis
- 2022
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 98:17, s. E1692-E1703
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives beta-amyloid (A beta) staging models assume a single spatial-temporal progression of amyloid accumulation. We assessed evidence for A beta accumulation subtypes by applying the data-driven Subtype and Stage Inference (SuStaIn) model to amyloid-PET data. Methods Amyloid-PET data of 3,010 participants were pooled from 6 cohorts (ALFA+, EMIF-AD, ABIDE, OASIS, and ADNI). Standardized uptake value ratios were calculated for 17 regions. We applied the SuStaIn algorithm to identify consistent subtypes in the pooled dataset based on the cross-validation information criterion and the most probable subtype/stage classification per scan. The effects of demographics and risk factors on subtype assignment were assessed using multinomial logistic regression. Results Participants were mostly cognitively unimpaired (n = 1890 [62.8%]), had a mean age of 68.72 (SD 9.1) years, 42.1% were APOE epsilon 4 carriers, and 51.8% were female. A 1-subtype model recovered the traditional amyloid accumulation trajectory, but SuStaIn identified 3 optimal subtypes, referred to as frontal, parietal, and occipital based on the first regions to show abnormality. Of the 788 (26.2%) with strong subtype assignment (>50% probability), the majority was assigned to frontal (n = 415 [52.5%]), followed by parietal (n = 199 [25.3%]) and occipital subtypes (n = 175 [22.2%]). Significant differences across subtypes included distinct proportions of APOE epsilon 4 carriers (frontal 61.8%, parietal 57.1%, occipital 49.4%), participants with dementia (frontal 19.7%, parietal 19.1%, occipital 31.0%), and lower age for the parietal subtype (frontal/occipital 72.1 years, parietal 69.3 years). Higher amyloid (Centiloid) and CSF p-tau burden was observed for the frontal subtype; parietal and occipital subtypes did not differ. At follow-up, most participants (81.1%) maintained baseline subtype assignment and 25.6% progressed to a later stage. Discussion Whereas a 1-trajectory model recovers the established pattern of amyloid accumulation, SuStaIn determined that 3 subtypes were optimal, showing distinct associations with Alzheimer disease risk factors. Further analyses to determine clinical utility are warranted.
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| 4. |
- Visser, D., et al.
(författare)
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Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study
- 2023
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 50:8, s. 2409-19
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Tidskriftsartikel (refereegranskat)abstract
- PurposeTau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF.MethodsWe included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 +/- 7.5 years, 44% female, 57% amyloid-beta positive [A beta +], 26 cognitively impaired [CI]) who underwent dynamic [F-18]flortaucipir PET and structural MRI at baseline and 25 +/- 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [F-18]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [F-18]flortaucipir PET binding potential (BPND) and R-1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R-1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in A beta- cognitively normal (CN) individuals and A beta+ (CN and CI) individuals separately.ResultsIn A beta+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either A beta+ or A beta- individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in A beta + individuals.ConclusionWe showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal.
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