| 1. |
- Hansson, Oskar, et al.
(författare)
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CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression : A study of fully automated immunoassays in BioFINDER and ADNI cohorts
- 2018
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:11, s. 1470-1481
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort. Methods: Cutoffs for Elecsys amyloid-β1–42 (Aβ), total tau/Aβ(1–42), and phosphorylated tau/Aβ(1–42) were defined against [18F]flutemetamol PET in Swedish BioFINDER (n = 277) and validated against [18F]florbetapir PET in Alzheimer's Disease Neuroimaging Initiative (n = 646). Clinical progression in patients with mild cognitive impairment (n = 619) was studied. Results: CSF total tau/Aβ(1–42) and phosphorylated tau/Aβ(1–42) ratios were highly concordant with PET classification in BioFINDER (overall percent agreement: 90%; area under the curve: 94%). The CSF biomarker statuses established by predefined cutoffs were highly concordant with PET classification in Alzheimer's Disease Neuroimaging Initiative (overall percent agreement: 89%–90%; area under the curves: 96%) and predicted greater 2-year clinical decline in patients with mild cognitive impairment. Strikingly, tau/Aβ ratios were as accurate as semiquantitative PET image assessment in predicting visual read–based outcomes. Discussion: Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis.
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| 2. |
- Sadaghiani, Shokufeh, et al.
(författare)
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Associations of phosphorylated tau pathology with whole-hemisphere ex vivo morphometry in 7 tesla MRI
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2355-2364
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neurodegenerative disorders are associated with different pathologies that often co-occur but cannot be measured specifically with in vivo methods. Methods: Thirty-three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2-weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere. Results: Partial Spearman correlation of phosphorylated tau and cortical thickness with TAR DNA-binding protein 43 (TDP-43) and α-synuclein scores, age, sex, and postmortem interval as covariates showed significant relationships in entorhinal and primary visual cortices, temporal pole, and insular and posterior cingulate gyri. Linear models including Braak stages, TDP-43 and α-synuclein scores, age, sex, and postmortem interval showed significant correlation between Braak stage and thickness in the parahippocampal gyrus, entorhinal cortex, and Broadman area 35. Conclusion: We demonstrated an association of measures of AD pathology with tissue loss in several AD regions despite a limited range of pathology in these cases. Highlights: Neurodegenerative disorders are associated with co-occurring pathologies that cannot be measured specifically with in vivo methods. Identification of the topographic patterns of these pathologies in structural magnetic resonance imaging (MRI) may provide probabilistic biomarkers. We demonstrated the correlation of the specific patterns of tissue loss from ex vivo brain MRI with underlying pathologies detected in postmortem brain hemispheres in patients with Alzheimer's disease (AD) spectrum disorders. The results provide insight into the interpretation of in vivo structural MRI studies in patients with AD spectrum disorders.
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| 3. |
- Young, Alexandra L., et al.
(författare)
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Empirical pathological staging and subtyping of TDP-43 proteinopathies
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pathological aggregation of tar DNA-binding protein 43 (TDP-43) in the brain is the primary cause of many cases of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE). It is therefore imperative to establish empirical staging systems to characterize and distinguish stereotypical patterns and commonplace deviations of different TDP-43 proteinopathies. Method: We use ordinal ratings of TDP-43 burden from 19 brain regions to perform data-driven disease progression modeling (SuStaIn) to find the most likely trajectories for FTLD-TDP (n = 108), ALS (n = 137) and LATE (n = 283) from the CNDR Brain Bank at the University of Pennsylvania. Subtype number was defined using cross-validated information criterion. Each individual was assigned a subtype and stage. Multivariate OLS models tested differences between subtypes. Stages were compared to age and existing staging schemes. Cross-validated logistic regression was used for 3-way classification using SuStaIn information only. Result: SuStaIn provided data-driven staging of TDP-43 proteinopathies complementing previously described human-defined staging schema, further providing additional detail (Fig1A-C; Fig3A-C). SuStaIn also identified two distinct subtypes within FTLD-TDP and a further two within ALS (Fig1D). FTLD-TDP subtypes differed in TDP-43 type and Alzheimer’s disease pathology (Table1); ALS subtypes were differentiated by age (Table 2) and by antemortem clinical characteristics. No subtypes were observed for the LATE group. Progression along data-driven stages was positively associated with age in LATE individuals, but negatively associated with age in individuals with FTLD-TDP (Fig2). Using only regional TDP-43 severity, our data driven model could distinguish individuals diagnosed with ALS, FTD or LATE with a cross-validated balanced precision of 0.93 and balanced recall of 0.92, and these metrics improved to 0.95 and 0.96 when combined with a logistic regression model (Fig3). Very little stage overlap was found between FTLD-TDP and LATE, but stages that did overlap showed subtly different patterns (Fig4). Conclusion: We provide an empirical pathological staging system for ALS, FTLD-TDP and LATE, which is sufficient for staging and accurate classification. We demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns, whilst LATE exhibits a homogeneous progression pattern.
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