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Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer's disease.

ABSTRACT: Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic work-up of dementia in clinical practice and the design of clinical trials. Here, we created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm by evaluating cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau biomarkers in 426 participants from BioFINDER-2, that represent the entire spectrum of AD. The model composition and main analyses were replicated in 222 participants from the Knight ADRC cohort. SuStaIn revealed in the two cohorts that the data was best explained by a single biomarker sequence (one subtype), and that five CSF biomarkers (ordered: Aβ42/40, tau phosphorylation occupancies at the residues 217 and 205 [pT217/T217 and pT205/T205], microtubule-binding region of tau containing the residue 243 [MTBR-tau243], and total tau) were sufficient to create an accurate disease staging model. Increasing CSF stages (0-5) were associated with increased abnormality in other AD-related biomarkers, such as Aβ- and tau-PET, and aligned with different phases of longitudinal biomarker changes consistent with current models of AD progression. Higher CSF stages at baseline were associated with higher hazard ratio of clinical decline. Our findings indicate that a common pathophysiologic molecular pathway develops across all AD patients, and that a single CSF collection is sufficient to reliably indicate the presence of both AD pathologies and the degree and stage of disease progression.

SUBMITTER: Salvado G

PROVIDER: S-EPMC10370223 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer's disease.

Salvadó Gemma G Horie Kanta K Barthélemy Nicolas R NR Vogel Jacob W JW Binette Alexa Pichet AP Chen Charles D CD Aschenbrenner Andrew J AJ Gordon Brian A BA Benzinger Tammie L S TLS Holtzman David M DM Morris John C JC Palmqvist Sebastian S Stomrud Erik E Janelidze Shorena S Ossenkoppele Rik R Schindler Suzanne E SE Bateman Randall J RJ Hansson Oskar O

medRxiv : the preprint server for health sciences 20230716

Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic work-up of dementia in clinical practice and the design of clinical trials. Here, we created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm by evaluating cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau biomarkers in 426 participants from BioFINDER-2, that represent the entire spectrum of AD. The model composition and main analyses were replicated in 222 participants f ...[more]

PMID: 37503281

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Project description:BackgroundDelirium and dementia share symptoms of cognitive dysfunctions, and mechanisms of neuroinflammation appear involved in both conditions. Triggering receptor expressed on myeloid cells 2 (TREM2) is linked to dementia and neurodegenerative disease. It encodes expression of an innate immune receptor in the brain expressed by microglia. The level of the soluble fragment of TREM2 (sTREM2) is reported to increase in the cerebrospinal fluid (CSF) already in prodromal and asymptomatic Alzheimer's disease.MethodsWe analyzed the level of CSF sTREM2 in relation to delirium and dementia. The study included patients with or without pre-existing dementia who underwent acute hip fracture surgery (n = 120), and some of the patients developed delirium (n = 65). A medical delirium cohort (n = 26) was also examined. ELISA was used to determine the level of sTREM2 in CSF.ResultsDelirium was associated with a higher level of CSF sTREM2 only among those without pre-existing dementia (p = 0.046, n = 15, n = 44), particularly among patients developing delirium after CSF sampling (p = 0.02, n = 7, n = 44). Between patients with dementia, there was no group difference, but the CSF sTREM2 level increased with waiting time for surgery (rS = 0.39, p = 0.002, n = 60) and correlated well with the CSF Alzheimer's disease biomarkers, Aβ42, and t-tau/p-tau (rS = 0.40, p = 0.002, rS = 0.46, p < 0.001/ rS = 0.49, p < 0.001, n = 60). Among patients with dementia, the level of Aβ38 and Aβ40 also correlated positively with sTREM2 in CSF (Aβ38MSDrS = 0.44, p = 0.001; Aβ40MSDrS = 0.48, p < 0.001; Aβ42MSDrS = 0.43, p < 0.001, n = 60).ConclusionThe findings reinforce the involvement of neuroinflammation in delirium, yet with separate responses in patients with or without pre-existing dementia. Our findings support the concept of primed microglia in neurodegenerative disease and central immune activation after a peripheral trauma in such patients. A CSF biomarker panel of neuroinflammation might be valuable to prevent delirium by identifying patients at risk.

Project description:BackgroundDown syndrome (DS), caused by chromosome 21 trisomy, is associated with an ultra-high risk of dementia due to Alzheimer's disease (AD), driven by amyloid precursor protein (APP) gene triplication. Understanding relevant molecular differences between those with DS, those with sporadic AD (sAD) without DS, and controls will aid in understanding AD development in DS. We explored group differences in plasma concentrations of amyloid-β peptides and tau (as their accumulation is a characteristic feature of AD) and cytokines (as the inflammatory response has been implicated in AD development, and immune dysfunction is common in DS).MethodsWe used ultrasensitive assays to compare plasma concentrations of the amyloid-β peptides Aβ40 and Aβ42, total tau (t-tau), and the cytokines IL1β, IL10, IL6, and TNFα between adults with DS (n = 31), adults with sAD (n = 27), and controls age-matched to the group with DS (n = 27), and explored relationships between molecular concentrations and with age within each group. In the group with DS, we also explored relationships with neurofilament light (NfL) concentration, due to its potential use as a biomarker for AD in DS.ResultsAβ40, Aβ42, and IL1β concentrations were higher in DS, with a higher Aβ42/Aβ40 ratio in controls. The group with DS showed moderate positive associations between concentrations of t-tau and both Aβ42 and IL1β. Only NfL concentration in the group with DS showed a significant positive association with age.ConclusionsConcentrations of Aβ40 and Aβ42 were much higher in adults with DS than in other groups, reflecting APP gene triplication, while no difference in the Aβ42/Aβ40 ratio between those with DS and sAD may indicate similar processing and deposition of Aβ40 and Aβ42 in these groups. Higher concentrations of IL1β in DS may reflect an increased vulnerability to infections and/or an increased prevalence of autoimmune disorders, while the positive association between IL1β and t-tau in DS may indicate IL1β is associated with neurodegeneration. Finally, NfL concentration may be the most suitable biomarker for dementia progression in DS. The identification of such a biomarker is important to improve the detection of dementia and monitor its progression, and for designing clinical intervention studies.

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Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer's disease.

Publications

Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer's disease.

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