BACKGROUND: Quantitative amyloid-beta (A{beta})-PET is increasingly used in AD prevention trials. Although the Centiloid (CL) framework provides a common scale, variability persists across processing pipelines, including differences in template/native space, partial volume correction (PVC), and reference region. These choices may influence cut-points, and in turn positivity rates, as well as longitudinal accumulation rates. We examined cut-point estimates and inter-pipeline discordance in a community cohort where many are expected to have early A{beta} deposition. METHODS: We analysed [18F]florbetapir PET/MR data from predominantly cognitively unimpaired (~95%) individuals aged ~71 years at baseline (n=433) and at follow-up (n=328; ~2.4-year interval) in Insight 46 (1946 British birth cohort). Centiloids were derived using the standard pipeline and ten in-house pipelines employing alternative reference regions and PVC in native space. Gaussian mixture modelling estimated cut-points with bootstrapped uncertainty. We assessed A{beta}-discordance across pipelines as a function of standard CLs and examined follow-up CSF A{beta}42/A{beta}40 (n=120) and PET in individuals with discordant baseline classifications. RESULTS: Baseline cut-points were 10-23 CL across pipelines, classifying 16-25% as A{beta}-positive. Reliable accumulation cut-points were 3.5-6 CL/year, identifying 16-22% as accumulators. Uncertainty varied across pipelines. At baseline, 18% were discordant across PET measures, predominantly between 11-35 standard CLs. The discordant group showed higher A{beta}-PET accumulation and lower CSF A{beta}42/A{beta}40 than concordant negatives. CONCLUSIONS: Disagreement between A{beta}-PET methods was highest between 11-35 standard Centiloids and was frequently associated with accumulating A{beta}. These findings highlight the importance of considering cut-point uncertainty and methodological influences when interpreting early-stage amyloidosis.
W. Coath, A. Bollack, C. Scott et al.· medRxiv· 0 citations
Background and Objectives Early dementia risk-stratification is crucial for timely intervention. Brain-predicted age difference (brain-PAD) derived from structural MRI reflects the gap between computer-estimated age and chronological age and has been linked to clinical progression to dementia. We evaluate whether brain-PAD has prognostic value for progression to dementia in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) and whether brain-PAD provides added value beyond visual rating scales. Methods This retrospective cohort study included patients with SCD and MCI with up to 10-year follow-up assessments from the Amsterdam Dementia Cohort and SCIENCe project. Brain-PAD was computed from baseline MRI using 2 pretrained methods. Cox proportional hazards models assessed the association between brain-PAD and risk of progression to dementia, controlling for age, sex, Mini Mental State Examination, and visual rating scales. We tested interactions between brain-PAD and baseline diagnosis to assess stage-specific value and evaluated the added value beyond amyloid status in a biomarker-available subset. Results The study included 799 patients (SCD 412, MCI 387; 39.4% female, 63.3 ± 8.0 years). During a median follow-up of 3.2 years, 235 (29.4%) progressed to dementia. Higher brain-PAD was associated with an increased risk of progression to dementia (hazard ratio [HR] 1.04, 95% CI 1.02–1.06) and improved model fit beyond visual ratings (χ2 = 12.24, p = 0.003). Following a significant interaction between brain-PAD and baseline diagnosis (p = 0.013), stratified analyses demonstrated brain-PAD was a stronger predictor in SCD (HR 1.09, 95% CI 1.03–1.15) than in MCI (HR 1.01, 95% CI 0.99–1.04). In SCD, brain-PAD improved model fit beyond visual rating scales (χ2 = 10.17, p = 0.003) and modestly increased discrimination (C-index +0.02). A data-driven brain-PAD cutoff of −2.6 years corresponded to a high negative predictive value (0.91–0.99) over 2–10 years. Although brain-PAD improved model fit beyond amyloid status (χ2 = 6.44, p = 0.018), it did not improve discrimination. In MCI, brain-PAD provided no additional value (χ2 = 0.88, p = 0.351). Discussion MRI-derived brain-PAD predicts progression to dementia in memory clinic patients with SCD or MCI. In particular, brain-PAD provided additional predictive value to visual rating scales in patients with SCD.
Stefan de Vries, Katalin Farkas, H. Rhodius-Meester et al.· Neurology· 0 citations
Grey matter network topology is altered in Alzheimer’s disease and these alterations are related to cognitive decline, which suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to tau.
Diederick M. de Leeuw, F. Duits, E. Dicks et al.· Brain Communications· 0 citations
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