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| 2. |
- Mila-Aloma, M., et al.
(författare)
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Cognitively unimpaired individuals with a low burden of A beta pathology have a distinct CSF biomarker profile
- 2021
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-beta (A beta) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of A beta pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile. Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF A beta 42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and alpha-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F-18]-FDG, and [F-18]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of A beta pathology: (1) positive CSF A beta 42/40 and < 30 Centiloids in A beta PET, (2) positive CSF A beta 42/40 and negative A beta PET visual read, and (3) 20-40 Centiloid range in A beta PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding A beta-negative group, adjusted by age and sex. Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the A beta-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2. Conclusions: There are biologically meaningful A beta-downstream effects in individuals with a low burden of A beta pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of A beta pathology for clinical trials.
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| 3. |
- Salvado, G., et al.
(författare)
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Brain alterations in the early Alzheimer's continuum with amyloid-beta, tau, glial and neurodegeneration CSF markers
- 2022
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer's disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer's pathology. Here, we evaluated, in the earliest stages of the Alzheimer's continuum, associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer's disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-beta and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and alpha-synuclein using the Roche NeuroToolKit. We first used the amyloid-beta/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer's disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-beta-positive tau-negative participants with respect to the reference amyloid-beta-negative tau-negative group. Both amyloid-beta and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-beta in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components' expression had different behaviours across amyloid-beta/tau stages. Taken together, our results show that CSF amyloid-beta and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer's continuum, which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes. Salvado et al. show that amyloid-beta and tau pathologies, in combination with different aspects of glial response, have distinctive associations with brain's structure and function in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and glucose metabolism at the earliest stages of the Alzheimer's continuum.
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| 4. |
- Akinci, M., et al.
(författare)
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Prepandemic Alzheimer Disease Biomarkers and Anxious-Depressive Symptoms During the COVID-19 Confinement in Cognitively Unimpaired Adults
- 2022
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Ingår i: NEUROLOGY. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:14
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Increased anxious-depressive symptomatology is observed in the preclinical stage of Alzheimer disease (AD), which may accelerate disease progression. We investigated whether beta-amyloid, cortical thickness in medial temporal lobe structures, neuroinflammation, and sociodemographic factors were associated with greater anxious-depressive symptoms during the COVID-19 confinement. Methods This retrospective observational study included cognitively unimpaired older adults from the Alzheimer's and Families cohort, the majority with a family history of sporadic AD. Participants performed the Hospital Anxiety and Depression Scale (HADS) during the COVID-19 confinement. A subset had available retrospective (on average: 2.4 years before) HADS assessment, amyloid [F-18] flutemetamol PET and structural MRI scans, and CSF markers of neuroinflammation (interleukin-6 [IL-6], triggering receptor expressed on myeloid cells 2, and glial fibrillary acidic protein levels). We performed multivariable linear regression models to investigate the associations of prepandemic AD-related biomarkers and sociodemographic factors with HADS scores during the confinement. We further performed an analysis of covariance to adjust by participants' prepandemic anxiety-depression levels. Finally, we explored the role of stress and lifestyle changes (sleep patterns, eating, drinking, smoking habits, and medication use) on the tested associations and performed sex-stratified analyses. Results We included 921 (254 with AD biomarkers) participants. beta-amyloid positivity (B = 3.73; 95% CI = 1.1 to 6.36; p = 0.006), caregiving (B = 1.37; 95% CI 0.24-2.5; p = 0.018), sex (women: B = 1.95; 95% CI 1.1-2.79; p < 0.001), younger age (B = -0.12; 95% CI -0.18 to -0.052; p < 0.001), and lower education (B = -0.16; 95% CI -0.28 to -0.042; p = 0.008) were associated with greater anxious-depressive symptoms during the confinement. Considering prepandemic anxiety-depression levels, we further observed an association between lower levels of CSF IL-6 (B = -5.11; 95% CI -10.1 to -0.13; p = 0.044) and greater HADS scores. The results were independent of stress-related variables and lifestyle changes. Stratified analysis revealed that the associations were mainly driven by women. Discussion Our results link AD-related pathophysiology and neuroinflammation with greater anxious-depressive symptomatology during the COVID-19-related confinement, notably in women. AD pathophysiology may increase neuropsychiatric symptomatology in response to stressors. This association may imply a worse clinical prognosis in people at risk for AD after the pandemic and thus deserves to be considered by clinicians.
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| 5. |
- Alemany, S., et al.
(författare)
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Associations between air pollution and biomarkers of Alzheimer's disease in cognitively unimpaired individuals
- 2021
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120. ; 157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-beta (A beta) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of A beta 42, A beta 40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO2,) and particulate matter (PM2.5, PM2.5 abs, PM10). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF A beta status and APOE-epsilon 4 carriership was also assessed. Results: A consistent pattern of results indicated that greater exposure to NO2 and PM2.5 absorbance was associated with higher levels of brain A beta deposition, while greater exposure to PM10 and PM(2.5)was associated with higher levels of CSF NfL. Most associations were driven by individuals that were A beta-positive. Although APOE-epsilon 4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-epsilon 4 carriers. Conclusion: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD.
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| 6. |
- Cacciaglia, R., et al.
(författare)
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Age, sex and APOE-epsilon 4 modify the balance between soluble and fibrillar beta-amyloid in non-demented individuals: topographical patterns across two independent cohorts
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27, s. 2010-2018
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid (A beta) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct A beta pools, reflecting the clearance of soluble A beta as opposed to the presence of A beta fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited A beta. Unveiling such interactions shall aid our understanding of the biological pathways underlying A beta deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-epsilon 4 and female sex, on the association between CSF and PET A beta, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher A beta deposition for any given level of CSF A beta 42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-epsilon 4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-epsilon 4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral A beta aggregation, with APOE-epsilon 4 possibly facilitating a co-localization between A beta and tau along the disease continuum.
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| 7. |
- Cacciaglia, R, et al.
(författare)
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Age, sex and APOE-ε4 modify the balance between soluble and fibrillar β-amyloid in non-demented individuals: topographical patterns across two independent cohorts
- 2022
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 27:4, s. 2010-2018
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid (Aβ) pathology is the earliest detectable pathophysiological event along the Alzheimer’s continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aβ pools, reflecting the clearance of soluble Aβ as opposed to the presence of Aβ fibrils in the brain. An open question is whether risk factors known to increase Alzheimer’s’ disease (AD) prevalence may promote an imbalance between soluble and deposited Aβ. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aβ deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aβ, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aβ deposition for any given level of CSF Aβ42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aβ aggregation, with APOE-ε4 possibly facilitating a co-localization between Aβ and tau along the disease continuum.
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| 8. |
- Cumplido-Mayoral, I., et al.
(författare)
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Biological brain age prediction using machine learning on structural neuroimaging data: Multi-cohort validation against biomarkers of Alzheimer's disease and neurodegeneration stratified by sex
- 2023
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Ingår i: Elife. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Brain--age can be inferred from structural neuroimaging and compared to chronological age (brain--age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging--derived measures from the UK Biobank dataset (N=22,661) were used to predict brain--age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD, and OASIS. Brain-age delta was associated with abnormal amyloid-ss, more advanced stages (AT) of AD pathology and APOE-e4 status. Brain--age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain--age delta as a non-invasive marker of biological brain aging in non--demented individuals with abnormal levels of biomarkers of AD and axonal injury.
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| 9. |
- Grau-Rivera, O., et al.
(författare)
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Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease
- 2021
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRecognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.MethodsThis prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n=2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [F-18]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.ResultsWeight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p=0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p=0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p=0.001) and was greater among participants with an A+T+ profile (p<0.01) at follow-up. Weight change was positively associated with CSF A42/40 ratio (beta =0.099, p=0.032) and negatively associated with CSF p-tau (beta=-0.141, p=0.005), t-tau (beta=-0.147 p=0.004) and neurogranin levels (beta=-0.158, p=0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.ConclusionsWeight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-beta accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.Trial registrationNCT01835717, NCT02485730, NCT02685969.
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| 10. |
- Lessa Benedet, Andréa, et al.
(författare)
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Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum
- 2021
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:12, s. 1471-1483
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Tidskriftsartikel (refereegranskat)abstract
- Question What are the levels of plasma glial fibrillary acidic protein (GFAP) throughout the Alzheimer disease (AD) continuum, and how do they compare with the levels of cerebrospinal fluid (CSF) GFAP? Findings In this cross-sectional study, plasma GFAP levels were elevated in the preclinical and symptomatic stages of AD, with levels higher than those of CSF GFAP. Plasma GFAP had a higher accuracy than CSF GFAP to discriminate between amyloid-beta (A beta)-positive and A beta-negative individuals, also at the preclinical stage. Meaning This study suggests that plasma GFAP is a sensitive biomarker that significantly outperforms CSF GFAP in indicating A beta pathology in the early stages of AD. Importance Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. Objective To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. Design, Setting, and Participants This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisiere cohort (Paris, France), which included individuals with symptomatic AD. Main Outcomes and Measures Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-beta 42/40 (A beta 42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. Results A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisiere participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) A beta-negative individuals (TRIAD: A beta-negative mean [SD], 185.1 [93.5] pg/mL, A beta-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: A beta-negative mean [SD], 121.9 [42.4] pg/mL, A beta-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU A beta-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] A beta-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU A beta-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI A beta-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU A beta-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated A beta-positive from A beta-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant A beta pathology. Conclusions and Relevance This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and A beta pathology even among individuals in the early stages of AD. This cross-sectional cohort study evaluates plasma glial fibrillary acidic protein levels throughout the entire Alzheimer disease continuum, from preclinical Alzheimer disease to Alzheimer disease dementia, compared with cerebrospinal fluid glial fibrillary acidic protein.
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