| 1. |
- Momozawa, Y, et al.
(författare)
-
IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
- 2018
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2427-
-
Tidskriftsartikel (refereegranskat)abstract
- GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
|
|
| 2. |
- Burisch, J., et al.
(författare)
-
Health-related quality of life improves during one year of medical and surgical treatment in a European population-based inception cohort of patients with Inflammatory Bowel Disease : An ECCO-EpiCom study
- 2014
-
Ingår i: Journal of Crohn's & Colitis. - Oxford, United Kingdom : Oxford University Press. - 1873-9946 .- 1876-4479. ; 8:9, s. 1030-1042
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Health-related quality of life (HRQoL) is impaired in patients with Inflammatory Bowel Disease (IBD). The aim was prospectively to assess and validate the pattern of HRQoL in an unselected, population-based inception cohort of IBD patients from Eastern and Western Europe.Methods: The EpiCom inception cohort consists of 1560 IBD patients from 31 European centres covering a background population of approximately 10.1 million. Patients answered the disease specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and generic Short Form 12 (SF-12) questionnaire at diagnosis and after one year of follow-up.Results: In total, 1079 patients were included in this study. Crohn's disease (CD) patients mean SIBDQ scores improved from 45.3 to 55.3 in Eastern Europe and from 44.9 to 53.6 in Western Europe. SIBDQ scores for ulcerative colitis (UC) patients improved from 44.9 to 57.4 and from 48.8 to 55.7, respectively. UC patients needing surgery or biologicals had lower SIBDQ scores before and after compared to the rest, while biological therapy improved SIBDQ scores in CD. CD and UC patients in both regions improved all SF-12 scores. Only Eastern European UC patients achieved SF-12 summary scores equal to or above the normal population.Conclusion: Medical and surgical treatment improved HRQoL during the first year of disease. The majority of IBD patients in both Eastern and Western Europe reported a positive perception of disease-specific but not generic HRQoL. Biological therapy improved HRQoL in CD patients, while UC patients in need of surgery or biological therapy experienced lower perceptions of HRQoL than the rest.
|
|
| 3. |
- Burisch, J, et al.
(författare)
-
Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study
- 2019
-
Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:3, s. 423-433
-
Tidskriftsartikel (refereegranskat)abstract
- The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn’s disease (CD).DesignPatients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.ResultsIn total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5).ConclusionDespite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.
|
|
| 4. |
- Ennis, G. E., et al.
(författare)
-
Insulin resistance is related to cognitive decline but not change in CSF biomarkers of Alzheimer's disease in non-demented adults
- 2021
-
Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction We investigated whether insulin resistance (IR) was associated with longitudinal age-related change in cognition and biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration in middle-aged and older adults who were non-demented at baseline. Methods IR was measured with homeostatic model assessment of insulin resistance (HOMA2-IR). Core AD-related cerebrospinal fluid (CSF) biomarkers and cognition were assessed, respectively, on n = 212 (1 to 5 visits) and n = 1299 (1 to 6 visits). Linear mixed models tested whether HOMA2-IR moderated age-related change in CSF biomarkers and cognition. Linear regressions tested whether HOMA2-IR x apolipoprotein E epsilon 4 allele (APOE epsilon 4) carrier status predicted amyloid beta [A beta] chronicity (estimated duration of amyloid positron emission tomography [PET] positivity) (n = 253). Results Higher HOMA2-IR was associated with greater cognitive decline but not with changes in CSF biomarkers. HOMA2-IR x APOE4 was not related to A beta chronicity but was significantly associated with CSF phosphorylated tau (P-tau)(181)/A beta(42) level. Discussion In non-demented adults IR may not be directly associated with age-related change in AD biomarkers. Additional research is needed to determine mechanisms linking IR to cognitive decline.
|
|
| 5. |
- Panyard, D. J., et al.
(författare)
-
Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease
- 2023
-
Ingår i: Alzheimers & Dementia. - 1552-5260.
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONA hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODSWe conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTSWe identified 61 proteins significantly associated with the AT category (P < 5.46 x 10(-5)) and 636 significant protein-biomarker associations (P < 6.07 x 10(-6)). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSIONThese results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTSCerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing.Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins.Key glucose/carbon metabolism protein associations independently replicated.CSF proteome outperformed other omics data in predicting amyloid/tau positivity.CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.
|
|
| 6. |
- Deming, Y., et al.
(författare)
-
Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk
- 2023
-
Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:8, s. 3406-3416
-
Tidskriftsartikel (refereegranskat)abstract
- IntroductionApolipoprotein E (APOE) epsilon 4-carrier status or epsilon 4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE epsilon 2 or heterogeneous effect of epsilon 2, epsilon 3, and epsilon 4 haplotypes. MethodsWe leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI). ResultsThe APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE epsilon 4-carrier status and epsilon 4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. DiscussionThe APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.
|
|
| 7. |
- Erickson, Pontus, et al.
(författare)
-
Prevalence and Clinical Implications of a β-Amyloid-Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease.
- 2023
-
Ingår i: JAMA neurology. - 2168-6157. ; 80:9, s. 969-979
-
Tidskriftsartikel (refereegranskat)abstract
- Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile.To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications.This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023.Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240).Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET.A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile.Results suggest that the CSF A-T+ biomarker profile was found inapproximately5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.
|
|
| 8. |
- Jonaitis, E. M., et al.
(författare)
-
Crosswalk study on blood collection-tube types for Alzheimer's disease biomarkers
- 2022
-
Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Blood-based Alzheimer's disease (AD) biomarkers show promise, but pre-analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta [A beta]42${\rm{A\beta }}]{_{42}}$, A beta 40${\rm{A}}{{{\beta}}_{40}}$, phosphorylatedtau[p-tau181${\rm{phosphorylated\;tau\;[p - ta}}{{\rm{u}}_{181}}$, total tau [t-tau], neurofilament light chain [NfL], A beta 4240,${\rm{A}}{{{\beta}}_{\frac{{42}}{{40}}}},$ and p-tau181A beta 42$\frac{{{\rm{p - ta}}{{\rm{u}}_{181}}}}{{{\rm{A}}{{{\beta}}_{42}}}}$) in three collection tube types (ethylenediaminetetraacetic acid [EDTA] plasma, heparin plasma, serum). Methods Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography-positive and -negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis. Results Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL (R2${{\rm{R}}<^>2}\;$= 0.94), adequate for amyloid (R2${{\rm{R}}<^>2}\;$= 0.40-0.69), and weaker for t-tau (R2${{\rm{R}}<^>2}\;$= 0.04-0.42) and p-tau181${\rm{p - ta}}{{\rm{u}}_{181}}$ ( R2${{\rm{R}}<^>2}\;$= 0.22-0.29). Brain amyloidosis differentiated several measures, especially EDTA plasma pTau181A beta 42$\frac{{{\rm{pTa}}{{\rm{u}}_{181}}}}{{{\rm{A}}{\beta _{42}}}}$ (d$d\;$= 1.29). Discussion AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood.
|
|
| 9. |
- Ma, Y., et al.
(författare)
-
Measurement batch differences and between-batch conversion of Alzheimer's disease cerebrospinal fluid biomarker values
- 2021
-
Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Batch differences in cerebrospinal fluid (CSF) biomarker measurement can introduce bias into analyses for Alzheimer's disease studies. We evaluated and adjusted for batch differences using statistical methods. Methods A total of 792 CSF samples from 528 participants were assayed in three batches for 12 biomarkers and 3 biomarker ratios. Batch differences were assessed using Bland-Altman plot, paired t test, Pitman-Morgan test, and linear regression. Generalized linear models were applied to convert CSF values between batches. Results We found statistically significant batch differences for all biomarkers and ratios, except that neurofilament light was comparable between batches 1 and 2. The conversion models generally had high R-2 except for converting P-tau between batches 1 and 3. Discussion Between-batch conversion allows harmonized CSF values to be used in the same analysis. Such method may be applied to adjust for other sources of variability in measuring CSF or other types of biomarkers.
|
|
| 10. |
- Allison, S. L., et al.
(författare)
-
Comparison of different MRI-based morphometric estimates for defining neurodegeneration across the Alzheimer's disease continuum
- 2019
-
Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 23
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Several neurodegeneration (N) metrics using structural MRI are used for the purpose of Alzheimer's disease (AD)-related staging, including hippocampal volume, global atrophy, and an “AD signature” composite consisting of thickness or volumetric estimates derived from regions impacted early in AD. This study sought to determine if less user-intensive estimates of global atrophy and hippocampal volume were equivalent to a thickness-based AD signature from FreeSurfer for defining N across the AD continuum (i.e., individuals who are amyloid-positive (A+)). Methods: Cognitively unimpaired (CU) late middle-aged and older adults, as well as A+ mild cognitive impairment (MCI) and A+ AD dementia individuals, with available CSF and structural MRI scan <1.5 years apart, were selected for the study (n = 325, mean age = 62). First, in a subsample of A+ AD dementia and matched biomarker-negative (i.e., A- and tau tangle pathology (T)-) CU controls (n = 40), we examined ROC characteristics and identified N cut-offs using Youden's J for neurofilament light chain protein (NfL) and each of three MRI-based measures: a thickness-based AD signature from FreeSurfer, hippocampal volume (using FIRST), and a simple estimate of global atrophy (the ratio of intracranial CSF segmented volume to brain tissue volume, using SPM12). Based on the results from the ROC analyses, we then examined the concordance between NfL N positivity and N positivity for each MRI-based metric using Cohen's Kappa in the remaining subsample of 285 individuals. Finally, in the full sample (n = 325), we examined the relationship between the four measures of N and group membership across the AD continuum using Kruskal-Wallis tests and Cliff's deltas. Results: The three MRI-based metrics and CSF NfL similarly discriminated between the A-T- CU (n = 20) and A+ AD (n = 20) groups (AUCs ≥0.885; ps < 0.001). Using the cut-off values derived from the ROCs to define N positivity, there was weak concordance between NfL and all three MRI-derived metrics of N in the subsample of 285 individuals (Cohen's Kappas ≤0.429). Finally, the three MRI-based measures of N and CSF NfL showed similar associations with AD continuum group (i.e., Kruskal-Wallis ps < 0.001), with relatively larger effect sizes noted when comparing the A-T- CU to the A+ MCI (Cliff's deltas ≥0.741) and A+ AD groups (Cliff's deltas ≥0.810) than to the A+T- CU (Cliff's deltas = 0.112–0.298) and A + T+ CU groups (Cliff's deltas = 0.212–0.731). Conclusions: These findings suggest that the three MRI-based morphometric estimates and CSF NfL similarly differentiate individuals across the AD continuum on N status. In many applications, a simple estimate of global atrophy may be preferred as an MRI marker of N across the AD continuum given its methodological robustness and ease of calculation when compared to hippocampal volume or a cortical thickness AD signature. © 2019
|
|
| 11. |
- Hale, Madeline R, et al.
(författare)
-
Associations between recall of proper names in story recall and CSF amyloid and tau in adults without cognitive impairment.
- 2024
-
Ingår i: Neurobiology of aging. - 1558-1497. ; 133, s. 87-98
-
Tidskriftsartikel (refereegranskat)abstract
- Neuropsychological measures sensitive to decline in the preclinical phase of Alzheimer's diseaseare needed. We previously demonstrated that higher amyloid-beta (Aβ) assessed by positron emission tomography in adults without cognitive impairment was associated with recall of fewer proper names in Logical Memory story recall. The current study investigated the association between proper names and cerebrospinal fluidbiomarkers (Aβ42/40, phosphorylated tau181 [pTau181], neurofilament light) in 223 participants from the Wisconsin Registry for Alzheimer's Prevention. We assessed associations between biomarkers and delayed Logical Memory total score and proper names using binary logistic regressions. Sensitivity analyses used multinomial logistic regression and stratified biomarker groups. Lower Logical Memory total score and proper names scores from themost recent visit were associated with biomarker positivity. Relatedly, there was a 27% decreased risk of being classified Aβ42/40+/pTau181+for each additional proper name recalled. A linear mixed effects model found that longitudinal change in proper names recall was predicted by biomarker status. These results demonstrate a novel relationship between proper names and Alzheimer's disease-cerebrospinal fluid pathology.
|
|
| 12. |
- Johnson, S. C., et al.
(författare)
-
Identifying clinically useful biomarkers in neurodegenerative disease through a collaborative approach: the NeuroToolKit
- 2023
-
Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background Alzheimer's disease (AD) is a complex and heterogeneous disease, which requires reliable biomarkers for diagnosis and monitoring disease activity. Preanalytical protocol and technical variability associated with biomarker immunoassays makes comparability of biomarker data across multiple cohorts difficult. This study aimed to compare cerebrospinal fluid (CSF) biomarker results across independent cohorts, including participants spanning the AD continuum.Methods Measured on the NeuroToolKit (NTK) prototype panel of immunoassays, 12 CSF biomarkers were evaluated from three cohorts (ALFA+, Wisconsin, and Abby/Blaze). A correction factor was applied to biomarkers found to be affected by preanalytical procedures (amyloid-beta(1-42), amyloid-beta(1-40), and alpha-synuclein), and results between cohorts for each disease stage were compared. The relationship between CSF biomarker concentration and cognitive scores was evaluated.Results Biomarker distributions were comparable across cohorts following correction. Correlations of biomarker values were consistent across cohorts, regardless of disease stage. Disease stage differentiation was highest for neurofilament light (NfL), phosphorylated tau, and total tau, regardless of the cohort. Correlation between biomarker concentration and cognitive scores was comparable across cohorts, and strongest for NfL, chitinase-3-like protein-1 (YKL40), and glial fibrillary acidic protein.Discussion The precision of the NTK enables merging of biomarker datasets, after correction for preanalytical confounders. Assessment of multiple cohorts is crucial to increase power in future studies into AD pathogenesis.
|
|
| 13. |
- Jonaitis, Erin M, et al.
(författare)
-
Measuring longitudinal cognition: Individual tests versus composites.
- 2019
-
Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 11, s. 74-84
-
Tidskriftsartikel (refereegranskat)abstract
- Longitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aβ).Analyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aβ modified cognitive trajectories.Global and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aβ interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics.These results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.
|
|
| 14. |
- Merluzzi, A. P., et al.
(författare)
-
Differential effects of neurodegeneration biomarkers on subclinical cognitive decline
- 2019
-
Ingår i: Alzheimer's and Dementia: Translational Research and Clinical Interventions. - : Wiley. - 2352-8737. ; 5, s. 129-138
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neurodegeneration appears to be the biological mechanism most proximate to cognitive decline in Alzheimer's disease. We test whether t-tau and alternative biomarkers of neurodegeneration—neurogranin and neurofilament light protein (NFL)—add value in predicting subclinical cognitive decline. Methods: One hundred fifty cognitively unimpaired participants received a lumbar puncture for cerebrospinal fluid and at least two neuropsychological examinations (mean age at first visit = 59.3 ± 6.3 years; 67% female). Linear mixed effects models were used with cognitive composite scores as outcomes. Neurodegeneration interactions terms were the primary predictors of interest: age × NFL or age × neurogranin or age × t-tau. Models were compared using likelihood ratio tests. Results: Age × NFL accounted for a significant amount of variation in longitudinal change on preclinical Alzheimer's cognitive composite scores, memory composite scores, and learning scores, whereas age × neurogranin and age × t-tau did not. Discussion: These data suggest that NFL may be more sensitive to subclinical cognitive decline compared to other proposed biomarkers for neurodegeneration. © 2019
|
|
| 15. |
- Morrow, A., et al.
(författare)
-
Cerebrospinal Fluid Sphingomyelins in Alzheimer's Disease, Neurodegeneration, and Neuroinflammation
- 2022
-
Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:2, s. 667-680
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available. Objective: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation. Methods: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models. Results: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, alpha-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs. Conclusion: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.
|
|
| 16. |
- Ashton, Nicholas J., et al.
(författare)
-
Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology
- 2024
-
Ingår i: JAMA NEUROLOGY. - 2168-6149 .- 2168-6157.
-
Tidskriftsartikel (refereegranskat)abstract
- ImportancePhosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. ObjectiveTo determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid beta (A beta) and longitudinal change across 3 selected cohorts. Design, Setting, and ParticipantsThis cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. ExposuresMagnetic resonance imaging, A beta positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (A beta 42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Main Outcomes and MeasuresAccuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated A beta (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal A beta pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in A beta-positive individuals, with the highest increase observed in those with tau positivity. Conclusions and RelevanceThis study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.
|
|
| 17. |
- Clark, Lindsay R, et al.
(författare)
-
Age-accelerated cognitive decline in asymptomatic adults with CSF β-amyloid.
- 2018
-
Ingår i: Neurology. - 1526-632X. ; 90:15
-
Tidskriftsartikel (refereegranskat)abstract
- Compare cognitive and hippocampal volume trajectories in asymptomatic middle-aged and older adults with positive CSF markers of β-amyloid (Aβ) or tau to adults without an Alzheimer disease (AD)-associated biomarker profile.Three hundred ninety-two adults enrolled in a longitudinal cohort study (Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research Center) completed a lumbar puncture and at least 2 biennial or annual neuropsychological evaluations. Cutoffs for Aβ42, total tau, and phosphorylated tau were developed via receiver operating characteristic curve analyses on a sample of 78 participants (38 dementia, 40 controls). These cutoffs were applied to a separate sample of 314 cognitively healthy adults (mean age at CSF collection = 61.5 years), and mixed-effects regression analyses tested linear and quadratic interactions of biomarker group × age at each visit on cognitive and hippocampal volume outcomes.Two hundred fifteen participants (69%) were biomarker negative (preclinical AD stage 0), 46 (15%) were Aβ+ only (preclinical AD stage 1), 25 (8%) were Aβ+ and tau+ (preclinical AD stage 2), and 28 (9%) were tau+ only. Both stage 1 and stage 2 groups exhibited greater rates of linear decline on story memory and processing speed measures, and nonlinear decline on list-learning and set-shifting measures compared to stage 0. The tau+ only group did not significantly differ from stage 0 in rates of cognitive decline.In an asymptomatic at-risk cohort, elevated CSF Aβ (with or without elevated tau) was associated with greater rates of cognitive decline, with the specific pattern of decline varying across cognitive measures.
|
|
| 18. |
- Mattsson-Carlgren, Niklas, et al.
(författare)
-
Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers
- 2023
-
Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 80:4, s. 360-369
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Alzheimer disease (AD) pathology starts with a prolonged phase of beta-amyloid (A beta) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.OBJECTIVE To evaluate combinations of different plasma biomarkers for predicting cognitive decline in A beta-positive cognitively unimpaired (CU) individuals.DESIGN, SETTING, AND PARTICIPANTS This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain A beta pathology defined by cerebrospinal fluid (CSF) A beta 42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible A beta-positive and A beta-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 A beta-positive participants were included in the main analyses.EXPOSURES Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.MAIN OUTCOMES AND MEASURES The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E epsilon 4 allele status, and baseline cognition. Multivariable models were compared based on model R-2 coefficients and corrected Akaike information criterion.RESULTS Among 171 A beta-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R-2 = 0.41) and the MMSE (model R-2 = 0.34) and was superior to the covariates-only models (mPACC: R-2 = 0.23; MMSE: R-2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R-2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R-2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.CONCLUSIONS AND RELEVANCE In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.
|
|
| 19. |
- Salvadó, Gemma, et al.
(författare)
-
Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study
- 2023
-
Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:7, s. 2943-2955
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases.Methods: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of A beta 42, A beta 40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, alpha-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit).Results: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/A beta 42 alone (R-2 >= 0.31) or together with NfL (R-2 = 0.25), while p-tau/A beta 42 (R-2 >= 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/A beta 42 (AUC >= 0.87) and p-tau/A beta 42 together with NfL (AUC >= 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively.Discussion: P-tau/A beta 42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.
|
|
