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| 2. |
- van Doorn, Ljcv, et al.
(författare)
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Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes
- 2017
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 56:2, s. 543-555
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., A beta(42), total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF A beta(42) levels inversely correlated to VV/TIV in the whole study population (A beta(42): r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF A beta(42) alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF A beta(42) levels.
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| 4. |
- Bader, I., et al.
(författare)
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Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study
- 2023
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Ingår i: Alzheimer's Research & Therapy. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies.Methods Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests.Results 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (beta = - 0.22, OR = 0.80, p < .05), more prior study visits (beta = - 0.93, OR = 0.40, p < .001), and positive family history of dementia (beta = 2.08, OR = 8.02, p < .01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PCresearch = 27.4%, PCclinical = 9.0%, X-2 = 10.56, p = .001), and loss of research interest (PCclinical = 46.3%, PCresearch = 16.5%, X-2 = 32.34, p < .001).Conclusions The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018-002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site.
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| 5. |
- Collij, L. E., et al.
(författare)
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The amyloid imaging for the prevention of Alzheimer's disease consortium: A European collaboration with global impact
- 2023
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAmyloid-beta (A beta) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and 'Small and Medium-sized enterprises' (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population. The AMYPAD studiesIn the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [F-18]flutemetamol or [F-18]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method. ResultsAMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BPND), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging A beta burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine. Future stepsThe AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.
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| 6. |
- 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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| 7. |
- Maxwell, Tania L., et al.
(författare)
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Global dataset of soil organic carbon in tidal marshes
- 2023
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Ingår i: Scientific Data. - : Springer Nature. - 2052-4463. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Tidal marshes store large amounts of organic carbon in their soils. Field data quantifying soil organic carbon (SOC) stocks provide an important resource for researchers, natural resource managers, and policy-makers working towards the protection, restoration, and valuation of these ecosystems. We collated a global dataset of tidal marsh soil organic carbon (MarSOC) from 99 studies that includes location, soil depth, site name, dry bulk density, SOC, and/or soil organic matter (SOM). The MarSOC dataset includes 17,454 data points from 2,329 unique locations, and 29 countries. We generated a general transfer function for the conversion of SOM to SOC. Using this data we estimated a median (± median absolute deviation) value of 79.2 ± 38.1 Mg SOC ha−1 in the top 30 cm and 231 ± 134 Mg SOC ha−1 in the top 1 m of tidal marsh soils globally. This data can serve as a basis for future work, and may contribute to incorporation of tidal marsh ecosystems into climate change mitigation and adaptation strategies and policies.
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| 8. |
- Salvado, G., et al.
(författare)
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Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers
- 2019
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.MethodsA total of 516 participants of the ALFA+ Study (N=205) and ADNI (N=311) underwent amyloid PET imaging ([F-18]flutemetamol and [F-18]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys (R) tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of A(42), tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded.ResultsAll Centiloid cut-offs fell within the range of 25-35, except for CSF A(42) that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/A(42) ratios was higher than that of CSF A(42). Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs.ConclusionsA cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.Trial registrationALFA+ Study, NCT02485730ALFA PET Sub-study, NCT02685969
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| 9. |
- Salvado, G., et al.
(författare)
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The protective gene dose effect of the APOE epsilon 2 allele on gray matter volume in cognitively unimpaired individuals
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:7, s. 1383-1395
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Harboring two copies of the apolipoprotein E (APOE) epsilon 2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. Methods: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired epsilon 2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of epsilon 2 genotypic groups were compared to each other and to the reference group (APOE epsilon 3/epsilon 3). Results: Carrying at least one epsilon 2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE epsilon 2 homozygotes, but not APOE epsilon 2 heterozygotes, showed larger GM volumes in areas related to successful aging. Discussion: In addition to the known resistance against amyloid-beta deposition, the larger GM volumes in key brain regions may confer APOE epsilon 2 homozygotes additional protection against AD-related cognitive decline.
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| 10. |
- 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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