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  • 1
    Online Resource
    Online Resource
    Investigating white matter connectomes in amnestic and non‐amnestic Alzheimer's disease clinical variants
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S5 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S5 ( 2021-12)
    Abstract: Recent models propose that spread of Alzheimer's disease (AD) pathology may be mediated by white matter connectivity. AD clinical variants exhibit partially distinct patterns of gray matter atrophy. However, it is less clear whether phenotypic differences extend to patients' white matter connectomes. We hypothesized that white matter connectivity would differ between healthy controls, amnestic AD (aAD), and non‐amnestic AD (naAD), including behavioral variant Alzheimer's disease (bvAD), logopenic‐variant primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). Method We examined white matter connectomes in 194 participants (controls=60, aAD=42, bvAD=25, lvPPA=39, PCA=28). All participants with dementia had evidence of AD pathologic change based on autopsy, Aβ 1–42 from cerebrospinal fluid, or [18] F‐florbetaben positron emission tomography. T1‐weighted and diffusion tensor images were collected using a 3 Tesla scanner. We calculated gray matter volume for cortical regions of interest and median fractional anisotropy (FA) for the tract connecting every pair of regions. Tracts with the most variable FA values across participants were excluded to yield graphs with 30% density. Linear regressions adjusted for sex and age were used to investigate group differences in degree and betweenness centrality as well as the relationship between gray matter volume and FA measures. Phenotypic differences in tractwise FA were evaluated using t‐tests. Result Both node and edge metrics indicated significant (p 〈 .05, corrected) widespread differences between patient groups and controls. In contrasts between disease groups, aAD patients had reduced degree in multiple occipital and inferior temporal regions; and higher betweenness centrality in bilateral frontal and parietal regions relative to naAD phenotypes. Tractwise FA values did not differ between patient groups. Across groups, endpoint gray matter volume was correlated with tractwise FA measures. Conclusion Both node‐ and edge‐based metrics suggested patients’ white matter connectomes exhibited degeneration relative to controls. Phenotypic differences between patient populations were few, suggesting that AD clinical variants with distinct patterns of gray matter disease nevertheless had broadly similar patterns of white matter degeneration. Gray matter atrophy was closely associated with lower values of FA of white matter tracts connecting atrophied regions, consistent with Wallerian degeneration of white matter.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S5
    DOI: 10.1002/alz.054401
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 2
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    Amyloid‐associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S1 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S1 ( 2022-12)
    Abstract: For optimal design of anti‐amyloid‐β (Aβ) and anti‐tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p‐tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Method We included 327 participants from the Swedish BioFINDER‐2 cohort with cerebrospinal fluid (CSF) p‐tau217, Aβ‐PET, longitudinal tau‐PET, and longitudinal cognition. The main groups of interest were Aβ‐positive non‐demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p‐tau217 and regional Aβ‐PET were associated with tau‐PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p‐tau217 between Aβ‐PET and tau‐PET change. Second, we investigated how soluble p‐tau217 and tau‐PET change related to change in cognition, and mediation between these variables. Result In early AD stages (non‐demented participants), increased concentration of soluble p‐tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau‐PET rate of change), beyond the effect of regional Aβ‐PET and baseline tau‐PET (Figure 2A‐C). Further, averaged across all regions, soluble p‐tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p‐tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p‐tau levels have plateaued, soluble p‐tau217 was not associated with accumulation of tau aggregates beyond baseline tau‐PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p‐tau217 (Figure 4B‐C). Conclusion Soluble p‐tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p‐tau levels might be most favorable in early AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S1
    DOI: 10.1002/alz.065080
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 3
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    Online Resource
    Tau pathology associates with in vivo cortical thinning in Lewy body disorders
    Wiley ; 2020
    In:  Annals of Clinical and Translational Neurology Vol. 7, No. 12 ( 2020-12), p. 2342-2355
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 7, No. 12 ( 2020-12), p. 2342-2355
    Abstract: To investigate the impact of Alzheimer’s disease (AD) co‐pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD). Methods We studied 72 LBD patients (Parkinson disease (PD) = 2, PD‐MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co‐pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co‐pathology (t‐tau/A β 1‐42   〉  0.3) (LBD+AD, N  = 19), and those without AD co‐pathology (LBD−AD, N  = 53). We also included a reference group of 25 patients with CSF biomarker‐confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD−AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post‐mortem burdens of tau, A β , and alpha‐synuclein using digital histopathology in five representative neocortical regions. Results The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions ( P   〈  0.05 FWE‐corrected) relative to LBD−AD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post‐mortem tau pathology, while cortical thickness was not significantly associated with A β or alpha‐synuclein pathology. Interpretation LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post‐mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.v7.12
    DOI: 10.1002/acn3.51183
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2740696-9
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  • 4
    Online Resource
    Online Resource
    Amyloid‐associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S6 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: For optimal design of anti‐amyloid‐β (Aβ) and anti‐tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p‐tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Method We included 327 participants from the Swedish BioFINDER‐2 cohort with cerebrospinal fluid (CSF) p‐tau217, Aβ‐PET, longitudinal tau‐PET, and longitudinal cognition. The main groups of interest were Aβ‐positive non‐demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p‐tau217 and regional Aβ‐PET were associated with tau‐PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p‐tau217 between Aβ‐PET and tau‐PET change. Second, we investigated how soluble p‐tau217 and tau‐PET change related to change in cognition, and mediation between these variables. Result In early AD stages (non‐demented participants), increased concentration of soluble p‐tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau‐PET rate of change), beyond the effect of regional Aβ‐PET and baseline tau‐PET (Figure 2A‐C). Further, averaged across all regions, soluble p‐tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p‐tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p‐tau levels have plateaued, soluble p‐tau217 was not associated with accumulation of tau aggregates beyond baseline tau‐PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p‐tau217 (Figure 4B‐C). Conclusion Soluble p‐tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p‐tau levels might be most favorable in early AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S6
    DOI: 10.1002/alz.061624
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 5
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    Online Resource
    The mean diffusion propagator model revealed cortical microstructural changes associated with both amyloid‐β and tau pathology and astroglial activation
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S1 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S1 ( 2022-12)
    Abstract: Markers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Morphometric metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect Aβ‐related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes that could complement morphometric macrostructural measures. Method We applied the mean apparent diffusion propagator model (MAP‐MRI) to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐2 cohort. MAP‐MRI extends diffusion tensor imaging and provides metrics sensitive to subtle changes in the cortex. Participants were stratified in Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on Aβ‐ and tau‐PET uptake. Cortical regional values of both MAP‐MRI metrics and CT were compared across groups. Associations between regional values of MAP‐MRI metrics and both Aβ‐ and tau‐PET uptake were also investigated as well as the association between MAP‐MRI metrics and plasma level of GFAP, a marker of astroglial activation (available in 292 participants). Result Mean square displacement (MSD) from MAP‐MRI revealed widespread microstructural differences already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness appeared to be more limited (figure 1). MSD was also highly correlated with both Aβ‐ and tau‐PET uptake even independently from one another (figure 2). Regional MSD values were associated with GFAP with a pattern that resemble Aβ accumulation, and GFAP partially mediated the association between Aβ and MSD. A sensitivity analysis controlling for cortical thickness revealed that the associations between MSD and Aβ‐PET, tau‐PET and GFAP were largely independent from macrostructural changes (figures 2‐3). Conclusion Metrics of cortical microstructural alteration derived from MAP‐MRI are highly sensitive to multiple aspects of the AD pathological cascade. Of particular interest is the link between MSD, Aβ‐PET and GFAP which suggests MSD might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, MSD could help monitoring the response to anti‐Aβ treatments in clinical trials.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S1
    DOI: 10.1002/alz.064928
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 6
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    Online Resource
    The mean diffusion propagator model revealed cortical microstructural changes associated with both amyloid‐β and tau pathology and astroglial activation
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. S3 ( 2023-06)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. S3 ( 2023-06)
    Abstract: Markers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Morphometric metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect Aβ‐related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes that could complement morphometric macrostructural measures. Method We applied the mean apparent diffusion propagator model (MAP‐MRI) to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐2 cohort. MAP‐MRI extends diffusion tensor imaging and provides metrics sensitive to subtle changes in the cortex. Participants were stratified in Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on Aβ‐ and tau‐PET uptake. Cortical regional values of both MAP‐MRI metrics and CT were compared across groups. Associations between regional values of MAP‐MRI metrics and both Aβ‐ and tau‐PET uptake were also investigated as well as the association between MAP‐MRI metrics and plasma level of GFAP, a marker of astroglial activation (available in 292 participants). Result Mean square displacement (MSD) from MAP‐MRI revealed widespread microstructural differences already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness appeared to be more limited (figure 1). MSD was also highly correlated with both Aβ‐ and tau‐PET uptake even independently from one another (figure 2). Regional MSD values were associated with GFAP with a pattern that resemble Aβ accumulation, and GFAP partially mediated the association between Aβ and MSD. A sensitivity analysis controlling for cortical thickness revealed that the associations between MSD and Aβ‐PET, tau‐PET and GFAP were largely independent from macrostructural changes (figures 2‐3). Conclusion Metrics of cortical microstructural alteration derived from MAP‐MRI are highly sensitive to multiple aspects of the AD pathological cascade. Of particular interest is the link between MSD, Aβ‐PET and GFAP which suggests MSD might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, MSD could help monitoring the response to anti‐Aβ treatments in clinical trials. aging after age 90.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.S3
    DOI: 10.1002/alz.064912
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2201940-6
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