| 1. |
- Brugulat-Serrat, Anna, et al.
(författare)
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Enhancing the Sensitivity of Memory Tests: Reference Data for the Free and Cued Selective Reminding Test and the Logical Memory Task from Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels.
- 2021
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 84:1, s. 119-128
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer's disease pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment.The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory Scale-IV in a sample of individuals aged 50-70 years with normal levels of amyloid-β and tau cerebrospinal fluid (CSF) biomarkers.The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable.We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected.The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment.
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| 2. |
- Erickson, Pontus, et al.
(författare)
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Prevalence and Clinical Implications of a β-Amyloid-Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease.
- 2023
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Ingår i: JAMA neurology. - 2168-6157. ; 80:9, s. 969-979
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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.
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| 3. |
- Hale, Madeline R, et al.
(författare)
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Associations between recall of proper names in story recall and CSF amyloid and tau in adults without cognitive impairment.
- 2024
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Ingår i: Neurobiology of aging. - 1558-1497. ; 133, s. 87-98
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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.
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| 4. |
- Mattsson-Carlgren, Niklas, et al.
(författare)
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Cerebrospinal fluid biomarkers in autopsy-confirmed Alzheimer disease and frontotemporal lobar degeneration
- 2022
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Ingår i: Neurology. - 0028-3878. ; 98:11, s. 1137-1150
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives To determine how fully automated Elecsys CSF immunoassays for β-amyloid (Aβ) and tau biomarkers and an ultrasensitive Simoa assay for neurofilament light chain (NFL) correlate with neuropathologic changes of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). Methods We studied 101 patients with antemortem CSF and neuropathology data. CSF samples were collected a mean of 2.9 years before death (range 0.2–7.5 years). CSF was analyzed for Aβ40, Aβ42, total tau (T-tau), tau phosphorylated at amino acid residue 181 (P-tau), P-tau/Aβ42 and Aβ42/Aβ40 ratios, and NFL. Neuropathology measures included Thal phases, Braak stages, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) scores, AD neuropathologic change (ADNC), and primary and contributory pathologic diagnoses. Associations between CSF biomarkers and neuropathologic features were tested in regression models adjusted for age, sex, and time from sampling to death. Results CSF biomarkers were associated with neuropathologic measures of Aβ (Thal, CERAD score), tau (Braak stage), and overall ADNC. The CSF P-tau/Aβ42 and Aβ42/Aβ40 ratios had high sensitivity, specificity, and overall diagnostic performance for intermediate-high ADNC (area under the curve range 0.95–0.96). Distinct biomarker patterns were seen in different FTLD subtypes, with increased NFL and reduced P-tau/T-tau in FTLD–TAR DNA-binding protein 43 and reduced T-tau in progressive supranuclear palsy compared to other FTLD variants. Discussion CSF biomarkers, including P-tau, T-tau, Aβ42, Aβ40, and NFL, support in vivo identification of AD neuropathology and correlate with FTLD neuropathology.
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| 5. |
- Milà-Alomà, Marta, et al.
(författare)
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CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.
- 2021
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Ingår i: Neurology. - 1526-632X. ; 97:21
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Tidskriftsartikel (refereegranskat)abstract
- To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers.This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions.CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration.ClinicalTrials.gov Identifier NCT02485730.
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| 6. |
- Moody, Jason F, et al.
(författare)
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Associations between diffusion MRI microstructure and cerebrospinal fluid markers of Alzheimer's disease pathology and neurodegeneration along the Alzheimer's disease continuum.
- 2022
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- White matter (WM) degeneration is a critical component of early Alzheimer's disease (AD) pathophysiology. Diffusion-weighted imaging (DWI) models, including diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and mean apparent propagator MRI (MAP-MRI), have the potential to identify early neurodegenerative WM changes associated with AD.We imaged 213 (198 cognitively unimpaired) aging adults with DWI and used tract-based spatial statistics to compare 15 DWI metrics of WM microstructure to 9 cerebrospinal fluid (CSF) markers of AD pathology and neurodegeneration treated as continuous variables.We found widespread WM injury in AD, as indexed by robust associations between DWI metrics and CSF biomarkers. MAP-MRI had more spatially diffuse relationships with Aβ42/40 and pTau, compared with NODDI and DTI.Our results suggest that WM degeneration may be more pervasive in AD than is commonly appreciated and that innovative DWI models such as MAP-MRI may provide clinically viable biomarkers of AD-related neurodegeneration in the earliest stages of AD progression.
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| 7. |
- Nair, Ajay Kumar, et al.
(författare)
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Asthma amplifies dementia risk: Evidence from CSF biomarkers and cognitive decline.
- 2022
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Ingår i: Alzheimer's & dementia (New York, N. Y.). - : Wiley. - 2352-8737. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Evidence from epidemiology, neuroimaging, and animal models indicates that asthma adversely affects the brain, but the nature and extent of neuropathophysiological impact remain unclear.We tested the hypothesis that asthma is a risk factor for dementia by comparing cognitive performance and cerebrospinal fluid biomarkers of glial activation/neuroinflammation, neurodegeneration, and Alzheimer's disease (AD) pathology in 60 participants with asthma to 315 non-asthma age-matched control participants (45-93 years), in a sample enriched for AD risk.Participants with severe asthma had higher neurogranin concentrations compared to controls and those with mild asthma. Positive relationships between cardiovascular risk and concentrations of neurogranin and α-synuclein were amplified in severe asthma. Severe asthma also amplified the deleterious associations that apolipoprotein E ε4 carrier status, cardiovascular risk, and phosphorylated tau181/amyloid beta42 have with rate of cognitive decline.Our data suggest that severe asthma is associated with synaptic degeneration and may compound risk for dementia posed by cardiovascular disease and genetic predisposition.Those with severe asthma showed evidence of higher dementia risk than controls evidenced by: higher levels of the synaptic degeneration biomarker neurogranin regardless of cognitive status, cardiovascular or genetic risk, and controlling for demographics.steeper increase in levels of synaptic degeneration biomarkers neurogranin and α-synuclein with increasing cardiovascular risk.accelerated cognitive decline with higher cardiovascular risk, genetic predisposition, or pathological tau.
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| 8. |
- Palpatzis, Eleni, et al.
(författare)
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Lifetime Stressful Events Associated with Alzheimer's Pathologies, Neuroinflammation and Brain Structure in a Risk Enriched Cohort
- 2024
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Ingår i: ANNALS OF NEUROLOGY. - 0364-5134 .- 1531-8249.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD.MethodsThis cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau181 and A beta 1-42/1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods.ResultsWithin the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau181 and IL-6. Participants with history of psychiatric disease and men, showed lower A beta 1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively.InterpretationWe did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024
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| 9. |
- Pelkmans, Wiesje, et al.
(författare)
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Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression.
- 2023
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 20:1, s. 483-93
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Tidskriftsartikel (refereegranskat)abstract
- We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages.We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade.Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p-tau181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ42/40 and Aβ-PET, and CSF YKL-40 partly explained the association between Aβ-PET, p-tau181 , and NfL.Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL-40 mediates the latter association between Aβ and downstream Aβ-induced tau pathology and tau-induced neuronal injury.Lower CSF Aβ42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ. CSF YKL-40 mediated Aβ-induced tau phosphorylation and tau-induced neuronal injury.
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| 10. |
- Salvadó, Gemma, et al.
(författare)
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Cerebral amyloid-β load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:5, s. 788-800
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Tidskriftsartikel (refereegranskat)abstract
- The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages.In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated.Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent.Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau.
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