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  • 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. S6 ( 2021-12)
    Abstract: Recent work has found that memorability, an intrinsic image property predictive of memory, shows consistency across healthy controls (HC), subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Looking at memorability pattern differences between groups, certain images in which HC outperform MCI or SCD individuals can also better predict group membership with a reduced number of images. A key question is whether these diagnostic images reflect a strong link between behavioral performance and biomarker status. Method Behavioral and biomarker data was collected from 232 participants (64 HC, 99 SCD, 48 MCI, 21 AD) from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. Participants were tested for recognition of images from a pool of 835 scene images. Aβ42, total tau, phospho‐tau, Aβ42/Aβ40, and Aβ42/phospho‐tau were collected as biomarkers. We computed linear models predicting corrected recognition with each biomarker as a separate regressor. Using hold‐out cross‐validation (80% training) across 1000 iterations, we also identified three subsets of 50 images in which performance differences between HC and MCI were the highest (“top subset”), lowest (“bottom subset”), or close to zero (“middle subset”). We tested these subsets on the remaining 20% test data, by correlating each biomarker and the average hit rate for that image subset, and comparing their performance with independent t‐tests. Result All five biomarkers significantly predicted corrected recognition (p 〈 10 ‐5 ) in the linear models (Table 1). For all biomarkers, the correlation coefficients acquired from the top subsets were significantly larger than those acquired from the middle subsets or bottom subsets (Fig. 1). In contrast, the middle and bottom subsets showed small differences that were inconsistent across biomarkers. Conclusion Our results reveal that images with larger memorability differences between HC and patient groups provide stronger links between behavioral performance and biomarker status. These images are more indicative of neuropathologic changes relevant to AD and are thus more diagnostic. Future study may provide more evidence with functional imaging data.
    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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  • 3
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: The new consensus definition of cognitive reserve (CR) provides a framework to study individual differences in cognitive functioning relative to aging and disease. CR denotes a property of the brain that allows for better than expected cognitive performance given the degree of age‐related brain changes or disease. More specifically, individual differences in patterns of brain activity during fMRI tasks might explain the differential susceptibility to pathological burden. Method According to the consensus definitions, we sought to identify and quantify CR from fMRI novelty‐contrast maps in a large multi‐centric sample (DELCODE) consisting of 215 participants with SCD, 79 with MCI, 30 with AD dementia, 56 AD relatives and 156 cognitively normal controls (CN). CSF amyloid‐42/40 ratio, CSF p‐tau and hippocampal volume (ATN) were reduced to a single number, representing a (Alzheimer’s) disease progression (DP) score. To identify a CR network, voxel‐wise linear regression models determined where functional task‐activation moderates the relationship between DP and cognition. Finally, task‐related activity within the CR network was extracted to obtain individual fMRI‐based CR scores. Result The DP score showed a strong negative quadratic association with baseline memory scores. CR voxels, in which higher or lower activation were associated with better cognition, weakening the effect of DP, were mainly located within the novelty network. They included lateral‐occipital and superior‐parietal regions, lingual and fusiform gyrus, cuneus and small parts of cingulate. While there was no association between the CR score and cognition in CNs, higher CR scores in MCI and AD patients were related to higher PACC5 scores. Conclusion We established a DP score that collapses the ATN measures into a single number, while retaining its deleterious effect on an individual’s memory score. Furthermore, a newly identified task‐dependent CR network could be used to establish a CR score, which was related to higher PACC5 scores in MCI and AD patients, suggesting a functional compensation mechanism at later stages of AD that is not yet present in CN. Thus, targeted alteration of brain activity might be a promising route to modify cognitive trajectories in MCI and AD patients. Further, detailed examination of individuals with high CR might reveal additional disease‐modifying factors.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 4
    In: Alzheimer's & Dementia, Wiley, Vol. 13, No. 7S_Part_12 ( 2017-07)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    Language: English
    Publisher: Wiley
    Publication Date: 2017
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  • 5
    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
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  • 6
    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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