Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study

Montoliu‐Gaya, Laia; Alcolea, Daniel; Ashton, Nicholas J.; Pegueroles, Jordi Malé i; Levin, Johannes; Bosch, Beatríz; Lantero‐Rodriguez, Juan; Carmona‐Iragui, María; Wagemann, Olivia; Balasa, Mircea; Kac, Przemysław R; Barroeta, Isabel; Lladó, Albert; Brum, Wagner S.; Videla, Laura; González‐Ortiz, Fernándo; Benejam, Bessy; Martínez, Javier José Arranz; Karikari, Thomas K.; Nübling, Georg; Bejanin, Alexandre; Benedet, Andréa Lessa; Blesa, Rafael; Lleó, Alberto; Blennow, Kaj; Castilla, Joaquı́n; Zetterberg, Henrik; Fortea, Juan

doi:10.1016/j.ebiom.2023.104547

Cited by 20 publications

(15 citation statements)

References 32 publications

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“…In our study, we found that GFAP was the only blood biomarker associated with the level of Aβ pathology estimated by PET. This is in line with previous findings where higher plasma GFAP concentrations have been associated with higher Aβ load determined using PET imaging [ 37 , 38 , 76 , 77 ] and in genetic forms of AD [ 78 , 79 ]. Astrocytes are activated and express GFAP in the context of neurodegeneration [ 33 ] and in the presence of Aβ [ 34 ].…”

Section: Discussionsupporting

confidence: 93%

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly

Koivumäki,

Ekblad,

Lantero-Rodriguez

et al. 2024

Alz Res Therapy

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Background Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aβ deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample. Methods Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aβ-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aβ accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex). Results Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aβ pathology. Plasma t-tau concentration did not associate with any of the measured pathologies. Conclusions Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.

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Section: Discussionsupporting

confidence: 93%

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly

Koivumäki,

Ekblad,

Lantero-Rodriguez

et al. 2024

Alz Res Therapy

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“…Questions remain, however, regarding whether astrocytes are key drivers of pathological inflammatory mechanisms of disease in LBD and also whether the currently utilized markers GFAP and YKL-40 accurately detect pro-inflammatory activation states of astrocytes when measured in CSF or blood [55]. GFAP levels track with neurodegenerative biomarkers in AD, predict conversion from MCI to AD, and increase longitudinally [17,[123][124][125]. Therefore, GFAP may not distinguish CNS inflammation from neurodegeneration in dementia.…”

Section: Contribution Of Inflammatory and Related Immune System Compo...mentioning

confidence: 99%

Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

Loveland,

Yu,

Churilov

et al. 2023

IJMS

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Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson’s disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development.

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“…[9][10][11][12] Moreover, plasma amyloid-beta (Aβ42/40) has been suggested as an enrichment aid for AD trials investigating preclinical and prodromal disease stages. 13,14 Glial fibrillary acidic protein (GFAP), a marker of astrogliosis, has been associated with the onset of Aβ deposition, [15][16][17] and has been shown to decrease with the administration of anti-amyloid therapies. 2 Therefore, the aim of the present study was to develop and validate a method to measure a broad panel of AD-related biomarkers, including p-tau, GFAP, NfL, Aβ40, and Aβ42, from venous dried plasma spot (DPS venous ) collection.…”

Section: Introductionmentioning

confidence: 99%

Biomarkers of Alzheimer's disease and neurodegeneration in dried blood spots—A new collection method for remote settings

Huber,

Blennow,

Zetterberg

et al. 2024

Alzheimer's & Dementia

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BACKGROUNDWe aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPSvenous) for the diagnosis and monitoring of neurodegenerative diseases in remote settings.METHODSIn a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aβ) 40, Aβ42; and phosphorylated tau (p‐tau181 and p‐tau217) were measured in paired DPSvenous and ethylenediaminetetraacetic acid plasma samples with single‐molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers.RESULTSAll DPSvenous and plasma analytes correlated significantly, except for Aβ42. In the validation cohort, DPSvenous GFAP, NfL, p‐tau181, and p‐tau217 differed between CSF Aβ‐positive and ‐negative individuals and were associated with worsening cognition.DISCUSSIONOur data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPSvenous extends the utility of blood‐based biomarkers to remote settings with simplified sampling conditions, storage, and logistics.Highlights A wide array of biomarkers related to Alzheimer's disease (AD) and neurodegeneration were detectable in dried plasma spots (DPSvenous). DPSvenous biomarkers correlated with standard procedures and cognitive status. DPSvenous biomarkers had a good diagnostic accuracy discriminating amyloid status. Our findings show the potential interchangeability of DPSvenous and plasma sampling. DPSvenous may facilitate remote and temperature‐independent sampling for AD biomarker measurement. Innovative tools for blood biomarker sampling may help recognizing the earliest changes of AD.

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Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study

Cited by 20 publications

References 32 publications

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly

Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

Biomarkers of Alzheimer's disease and neurodegeneration in dried blood spots—A new collection method for remote settings

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