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  • Brosseron, Frederic  (4)
  • Buerger, Katharina  (4)
  • Ramirez, Alfredo  (4)
  • 1
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: The NIA‐AA proposed ATN (Amyloid/Tau/Neurodegeneration) as a classification system for AD pathology. The Amyloid Cascade Hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (Amyloid‐conversion first, Tau‐conversion second, N‐conversion last; therefore ‘ATN’) and alternative progressions (ANT, TAN, TNA, NAT, NTA) using Voxel‐based Morphometry (VBM) of brain anatomy in a large MRI sample. Method We used the DELCODE cohort of 437 subjects (49% female) which underwent lumbar puncture, MRI scanning and neuropsychological assessment. ATN classification was performed using (A+/‐) CSF‐Abeta42over40, (T+/‐) CSF‐phospho‐Tau, and (N+/‐) adjusted hippocampal volume. We compared voxel‐based model evidence for monotonic decline of gray matter volume across various sequences over ATN groups accounting for age, sex, education, TIV and WMH. The evidence of each progression was assessed using the Bayesian Information Criterion on voxel‐ and ROI‐level. First, face validity of the ACH transition trajectory A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+ for VBM was compared against 23 biologically less plausible (permuted) sequences among AD‐continuum ATN groups. Then we evaluated the evidence for 6 brain volume progressions from A‐T‐N‐ towards A+T+N+ (ATN, ANT, TAN, TNA, NAT, NTA) including also non‐AD continuum ATN groups. Result The ACH‐based progression A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+ is in line with cognitive decline and clinical diagnosis (Figure 1 & 2). It also has highest evidence in 9% of the gray matter voxels (especially MTL; Figure 3 & 4). Many (especially cortical) regions were compatible with alternative non‐monotonic volume progressions (‘AP 1’: 16%, ‘AP 2’: 14%; see Figure 3) over ACH progression sequence, compatible with early amyloid‐related tissue expansion or sampling effects due to brain‐reserve (Figure 5). Volume decline in 65% of voxels was more compatible with ATN/ANT progression (A flips first) when compared to alternative sequences (TAN, TNA, NAT, NTA). Conclusion Early Amyloid status conversion (before Tau and Neurodegeneration) is compatible with brain volume loss observed during AD progression. The ATN classification and the ACH are compatible with monotonic progress of MTL atrophy.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 2
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Neuroimaging markers based on MRI often provide better prediction than traditional neuropsychological scores. With advancements of machine learning, data patterns may offer opportunities to personalize clinical practice that leads to better outcomes for patients at risk of dementia such as Alzheimer’s disease (AD) (Davatzikos et al., 2019). AD is a multifactorial process associated with ageing, brain atrophy, genes, proteins, vascular risk, and brain state activity (Frisoni et al., 2010). These processes do covary and interact in a complex fashion which needs to be accounted when aiming at predicting clinical outcomes for staging and stratification of disease‐modifying treatments. Method In our probabilistic predictive framework we focus on data from the DZNE DELCODE cohort (Jessen et al., 2018) consisting of T1‐weighted and FLAIR images to assess distributed patterns of Voxel‐based Morphometry (VBM) and White Matter Lesions for 929 subjects; subject‐specific demographics (age, sex, education) and available CSF biomarkers for 438 subjects. We developed a machine learning framework for brain‐based predictions of (A) memory performance (Wolfsgruber et al., 2020) and (B) CSF Amyloid 42/40 and p‐tau biomarker status using a Gaussian process multi‐kernel (GP‐MKL) learning approach (Rasmussen & Williams, 2006). The proposed GP‐MKL model combines multiple features (atrophy patterns, demographics age, sex, education, white matter lesions volume & apoe4) expected to characterize the transition from healthy ageing towards dementia in terms of cognitive symptoms and biomarker status (Figure 1). We evaluate predictive models and different feature combinations using 10‐fold cross‐validation. Result The framework enabled optimal individual prediction of memory performance (highest correlation true vs. predicted of r = 0.751 ± 0.082, R 2 = 0.56, Fig. 2) using a combination of demographics, brain tissue segments (GM & CSF) & CSF biomarkers (Aß42/40 & p‐tau). When estimating the CSF biomarker positivity, the AUC‐ROC score achieved 0.735 for Aß42/40 (Fig. 4A) and 0.802 for p‐tau (Fig. 4B) using a combination of brain tissue segments (GM & CSF), demographics, and cognitive testing. Conclusion In conclusion, multiple domains and imaging facets contribute to reliable estimation of individual cognitive memory performance and biomarker positivity in dementia and enable promising predictive technologies for staging and treatment stratification.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
    Location Call Number Limitation Availability
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  • 3
    In: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Wiley, Vol. 10, No. 1 ( 2018-01), p. 782-790
    Abstract: We examined the association between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, neural novelty responses, and brain volume in predementia old age. Methods We conducted a cross‐sectional analysis of the observational, multicentric DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Seventy‐six participants completed task functional magnetic resonance imaging and provided CSF (40 cognitively unimpaired, 21 experiencing subjective cognitive decline, and 15 with mild cognitive impairment). We assessed the correlation between CSF biomarkers and whole‐brain functional magnetic resonance imaging novelty responses to scene images. Results Total tau levels were specifically and negatively associated with novelty responses in the right amygdala and right hippocampus. Mediation analyses showed no evidence that these associations were dependent on the volume of hippocampus/amygdala. No relationship was found between phosphorylated‐tau or Aβ 42 levels and novelty responses. Discussion Our data show that CSF levels of total tau are associated with anatomically specific reductions in novelty processing, which cannot be fully explained by atrophy.
    Type of Medium: Online Resource
    ISSN: 2352-8729 , 2352-8729
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2832898-X
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  • 4
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2023-02-28)
    Abstract: In preclinical Alzheimer’s disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions. Methods We tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol. Results In asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly ( p  = 0.014) larger in stage 1 compared with HCs. Conclusions These data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline.
    Type of Medium: Online Resource
    ISSN: 1758-9193
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2506521-X
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