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  • 1
    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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  • 2
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 99, No. 8 ( 2022-08-23), p. e775-e788
    Abstract: We assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy. Methods We studied 499 participants aged 60–88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of β-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel 〉 highly familiar scenes) in entorhinal cortex, hippocampus, and precuneus as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, sex, study site, and education. Results In the precuneus, we observed an inverted U-shaped pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared with HC, but not in patients with AD who showed relatively lower activity than MCI. This nonlinear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to the precuneus, hippocampal activity was reduced in AD dementia compared with all other groups and related to AD biomarkers. Discussion Novelty-related activity in the precuneus follows a nonlinear pattern across the clinical spectrum of increased AD risk. Although the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the nonlinearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 3
    In: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Wiley, Vol. 11, No. 1 ( 2019-12), p. 610-618
    Abstract: Impaired long‐term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently memorable. Methods We conducted item‐based analyses of long‐term visual recognition memory. Three hundred ninety‐four participants (healthy controls, subjective cognitive decline [SCD], and MCI) in the multicentric DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs. Results We observed consistent memorability for images in healthy controls, SCD, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set. Discussion Individuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.
    Type of Medium: Online Resource
    ISSN: 2352-8729 , 2352-8729
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2832898-X
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  • 4
    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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  • 5
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 4 ( 2022-05-24), p. 1473-1485
    Abstract: We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A−) of amyloid pathology was defined by CSF amyloid-β42 (Aβ42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A− individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau ( & gt;700 pg/ml) and phospho-tau ( & gt;100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aβ42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A− groups. After classifying this matched sample for phospho-tau pathology (T−/T+), individuals with A+/T+ were significantly more memory-impaired than A−/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer’s disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer’s disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 6
    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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  • 7
    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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  • 8
    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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