| 1. |
- Arvidsson, Ida, et al.
(författare)
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Comparing a pre-defined versus deep learning approach for extracting brain atrophy patterns to predict cognitive decline due to Alzheimer’s disease in patients with mild cognitive symptoms
- 2024
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Predicting future Alzheimer’s disease (AD)-related cognitive decline among individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) is an important task for healthcare. Structural brain imaging as measured by magnetic resonance imaging (MRI) could potentially contribute when making such predictions. It is unclear if the predictive performance of MRI can be improved using entire brain images in deep learning (DL) models compared to using pre-defined brain regions. Methods: A cohort of 332 individuals with SCD/MCI were included from the Swedish BioFINDER-1 study. The goal was to predict longitudinal SCD/MCI-to-AD dementia progression and change in Mini-Mental State Examination (MMSE) over four years. Four models were evaluated using different predictors: (1) clinical data only, including demographics, cognitive tests and APOE ε4 status, (2) clinical data plus hippocampal volume, (3) clinical data plus all regional MRI gray matter volumes (N = 68) extracted using FreeSurfer software, (4) a DL model trained using multi-task learning with MRI images, Jacobian determinant images and baseline cognition as input. A double cross-validation scheme, with five test folds and for each of those ten validation folds, was used. External evaluation was performed on part of the ADNI dataset, including 108 patients. Mann-Whitney U-test was used to determine statistically significant differences in performance, with p-values less than 0.05 considered significant. Results: In the BioFINDER cohort, 109 patients (33%) progressed to AD dementia. The performance of the clinical data model for prediction of progression to AD dementia was area under the curve (AUC) = 0.85 and four-year cognitive decline was R2 = 0.14. The performance was improved for both outcomes when adding hippocampal volume (AUC = 0.86, R2 = 0.16). Adding FreeSurfer brain regions improved prediction of four-year cognitive decline but not progression to AD (AUC = 0.83, R2 = 0.17), while the DL model worsened the performance for both outcomes (AUC = 0.84, R2 = 0.08). A sensitivity analysis showed that the Jacobian determinant image was more informative than the MRI image, but that performance was maximized when both were included. In the external evaluation cohort from ADNI, 23 patients (21%) progressed to AD dementia. The results for predicted progression to AD dementia were similar to the results for the BioFINDER test data, while the performance for the cognitive decline was deteriorated. Conclusions: The DL model did not significantly improve the prediction of clinical disease progression in AD, compared to regression models with a single pre-defined brain region.
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| 2. |
- Borland, Emma, et al.
(författare)
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The age-related effect on cognitive performance in cognitively healthy elderly is mainly caused by underlying AD pathology or cerebrovascular lesions : implications for cutoffs regarding cognitive impairment
- 2020
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: As research in treatments for neurocognitive diseases progresses, there is an increasing need to identify cognitive decline in the earliest stages of disease for initiation of treatment in addition to determining the efficacy of treatment. For early identification, accurate cognitive tests cutoff values for cognitive impairment are essential. METHODS: We conducted a study on 297 cognitively healthy elderly people from the BioFINDER study and created subgroups excluding people with signs of underlying neuropathology, i.e., abnormal cerebrospinal fluid [CSF] β-amyloid or phosphorylated tau, CSF neurofilament light (neurodegeneration), or cerebrovascular pathology. We compared cognitive test results between groups and examined the age effect on cognitive test results. RESULTS: In our subcohort without any measurable pathology (n = 120), participants achieved better test scores and significantly stricter cutoffs for cognitive impairment for almost all the examined tests. The age effect in this subcohort disappeared for all cognitive tests, apart from some attention/executive tests, predominantly explained by the exclusion of cerebrovascular pathology. CONCLUSION: Our study illustrates a new approach to establish normative data that could be useful to identify earlier cognitive changes in preclinical dementias. Future studies need to investigate if there is a genuine effect of healthy aging on cognitive tests or if this age effect is a proxy for higher prevalence of preclinical neurodegenerative diseases.
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| 3. |
- Janelidze, Shorena, et al.
(författare)
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Towards a unified protocol for handling of CSF before β-amyloid measurements
- 2019
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Widespread implementation of Alzheimer's disease biomarkers in routine clinical practice requires the establishment of standard operating procedures for pre-analytical handling of cerebrospinal fluid (CSF). Methods: Here, CSF collection and storage protocols were optimized for measurements of β-amyloid (Aβ). We investigated the effects of (1) storage temperature, (2) storage time, (3) centrifugation, (4) sample mixing, (5) blood contamination, and (6) collection gradient on CSF levels of Aβ. For each study participant, we used fresh CSF directly collected into a protein low binding (LoB) tube that was analyzed within hours after lumbar puncture (LP) as standard of truth. Aβ42 and Aβ40 were measured in de-identified CSF samples using EUROIMMUN and Mesoscale discovery assays. Results: CSF Aβ42 and Aβ40 were stable for at least 72 h at room temperature (RT), 1 week at 4 °C, and 2 weeks at - 20 °C and - 80 °C. Centrifugation of non-blood-contaminated CSF or mixing of samples before the analysis did not affect Aβ levels. Addition of 0.1-10% blood to CSF that was stored at RT without centrifugation led to a dose- and time-dependent decrease in Aβ42 and Aβ40, while Aβ42/Aβ40 did not change. The effects of blood contamination were mitigated by centrifugation and/or storage at 4 °C or - 20 °C. Aβ levels did not differ between the first to fourth 5-ml portions of CSF. Conclusions: CSF can be stored for up to 72 h at RT, 1 week at 4 °C, or at least 2 weeks at either - 20 °C or - 80 °C before Aβ measurements. Centrifugation of fresh non-blood-contaminated CSF after LP, or mixing before analysis, is not required. In case of visible blood contamination, centrifugation and storage at 4 °C or - 20 °C is recommended. After discarding the first 2 ml, any portion of up to 20 ml of CSF is suitable for Aβ analysis. These findings will be important for the development of a clinical routine protocol for pre-analytical handling of CSF.
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| 4. |
- Mattsson, Niklas, et al.
(författare)
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Greater tau load and reduced cortical thickness in APOE ε4-negative Alzheimer’s disease : a cohort study
- 2018
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer’s disease is characterized by aggregated β-amyloid and tau proteins, but the clinical presentations and patterns of brain atrophy vary substantially. A part of this heterogeneity may be linked to the risk allele APOE ε4. The spread of tau pathology is related to atrophy and cognitive decline, but little data exist on the effects of APOE ε4 on tau. The objective of this preliminary study was therefore to test if tau load and brain structure differ by APOE ε4 in Alzheimer’s disease. Methods: Sixty-five β-amyloid-positive patients at the prodromal and dementia stages of Alzheimer’s disease were enrolled, including APOE ε4-positive (n = 46) and APOE ε4-negative (n = 19) patients. 18F-AV-1451 positron emission tomography was used to measure tau and brain magnetic resonance imaging (MRI) was used to measure cortical thickness. Results: Compared with their APOE ε4-positive counterparts, APOE ε4-negative patients had greater tau load and reduced cortical thickness, with the most pronounced effects for both in the parietal cortex. Relative to the overall cortical tau load, APOE ε4-positive patients had greater tau load in the entorhinal cortex. APOE ε4-positive patients also had slightly greater cortical β-amyloid load. There was an interaction between APOE ε4 and 18F-AV-1451 on cortical thickness, with greater effects of 18F-AV-1451 on cortical thickness in APOE ε4-negative patients. APOE ε4 and 18F-AV-1451 were independent predictors of cognition, but showed distinct associations with different cognitive tests. Conclusions: APOE genotype may be associated with differences in pathways in Alzheimer’s disease, potentially through differential development and spread of tau, as well as through effects on cognitive outcomes involving non-tau-related mechanisms.
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| 5. |
- Stomrud, Erik, et al.
(författare)
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Alterations of matrix metalloproteinases in the healthy elderly with increased risk of prodromal Alzheimer's disease
- 2010
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 2:3, s. 20-20
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Matrix metalloproteinases (MMP) are believed to be involved in the pathologic processes behind Alzheimer's disease (AD). In this study, we aimed to examine the cerebrospinal fluid (CSF) levels of MMPs and tissue inhibitors of metalloproteinase-1 (TIMP-1) in individuals with AD dementia and cognitively healthy elderly individuals, and to investigate their relationship with established CSF biomarkers for Alzheimer's disease.METHODS: CSF was collected from 38 individuals with AD dementia and 34 cognitively healthy elderly individuals. The CSF was analyzed for MMP-1, MMP-3, MMP-9, TIMP-1, beta-amyloid1-42 (Abeta42), total tau protein (T-tau) and phosphorylated tau protein (P-tau). MMP/TIMP-1 ratios were calculated. APOE genotype was determined for the participants.RESULTS: AD patients had higher MMP-9/TIMP-1 ratios and lower TIMP-1 levels compared to cognitively healthy individuals. In AD patients, the MMP-9/TIMP-1 ratio correlated with CSF T-tau, a marker of neurodegeneration. Interestingly, the cognitively healthy individuals with risk markers for future AD, i.e. AD-supportive CSF biomarker levels of T-tau, P-tau and Abeta42 or the presence of the APOE epsilon4 allele, had higher CSF MMP-3 and MMP-9 levels and higher CSF MMP-3/TIMP-1 ratios compared to the healthy individuals without risk markers. The CSF levels of MMP-3 and -9 in the control group also correlated with the CSF T-tau and P-tau levels.CONCLUSIONS: This study indicates that MMP-3 and MMP-9 might be involved in early pathogenesis of AD and that MMPs could be associated with neuronal degeneration and formation of neurofibrillary tangles even prior to development of overt cognitive dysfunction.
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| 6. |
- Svenningsson, Anna Linnéa, et al.
(författare)
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Axonal degeneration and amyloid pathology predict cognitive decline beyond cortical atrophy
- 2022
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cortical atrophy is associated with cognitive decline, but the association is not perfect. We aimed to identify factors explaining the discrepancy between the degree of cortical atrophy and cognitive decline in cognitively unimpaired elderly. Methods: The discrepancy between atrophy and cognitive decline was measured using the residuals from a linear regression analysis between change in whole brain cortical thickness over time and change in a cognitive composite measure over time in 395 cognitively unimpaired participants from the Swedish BioFINDER study. We tested for bivariate associations of this residual measure with demographic, imaging, and fluid biomarker variables using Pearson correlations and independent-samples t-tests, and for multivariate associations using linear regression models. Mediation analyses were performed to explore possible paths between the included variables. Results: In bivariate analyses, older age (r = −0.11, p = 0.029), male sex (t = −3.00, p = 0.003), larger intracranial volume (r = −0.17, p < 0.001), carrying an APOEe4 allele (t = −2.71, p = 0.007), larger white matter lesion volume (r = −0.16, p = 0.002), lower cerebrospinal fluid (CSF) β-amyloid (Aβ) 42/40 ratio (t = −4.05, p < 0.001), and higher CSF levels of phosphorylated tau (p-tau) 181 (r = −0.22, p < 0.001), glial fibrillary acidic protein (GFAP; r = −0.15, p = 0.003), and neurofilament light (NfL; r = −0.34, p < 0.001) were negatively associated with the residual measure, i.e., associated with worse than expected cognitive trajectory given the level of atrophy. In a multivariate analysis, only lower CSF Aβ42/40 ratio and higher CSF NfL levels explained cognition beyond brain atrophy. Mediation analyses showed that associations between the residual measure and APOEe4 allele, CSF Aβ42/40 ratio, and CSF GFAP and p-tau181 levels were mediated by levels of CSF NfL, as were the associations with the residual measure for age, sex, and WML volume. Conclusions: Our results suggest that axonal degeneration and amyloid pathology independently affect the rate of cognitive decline beyond the degree of cortical atrophy. Furthermore, axonal degeneration mediated the negative effects of old age, male sex, and white matter lesions, and in part also amyloid and tau pathology, on cognition over time when accounting for cortical atrophy.
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