Ann Brinkmalm’s research while affiliated with University of Gothenburg and other places

Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signaling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer’s disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein (IGFBP) in the cerebrospinal fluid (CSF) – IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD biomarkers and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the QFP cohort, a unique population isolate from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and was negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 (CSF Aβ(+)/t-tau(+)). In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (HR = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049), however IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2, in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.

Background: Synaptic proteins in the cerebrospinal fluid (CSF) may reveal changes in the pre-symptomatic stages of Alzheimer’s disease (AD), thus may be candidate biomarkers for early detection of the disease. Method: The PREVENT-AD cohort includes symptom-free (upon enrolment) elderly participants who are at risk of developing AD from their family history. We used enzyme-linked immunosorbent assay kits to assess CSF samples from 129 such participants for the “classical” AD biomarkers total tau, phosphorylated (181) tau and Aβ42. We also used neuroimaging data (MRI, PET) and neuropsychological assessments (MMSE, RBANS) as potential indicators disease progression. We then used Olink Proximity Extension Assay technology in the CSF samples to measure the soluble synaptic biomarkers ADAM 22 (post-synaptic), ADAM23 (pre-synaptic). Immunoprecipitated SYT1 (pre-synaptic) from CSF were analyzed using high-resolution selected ion monitoring analyses on a quadrupole–orbitrap mass spectrometer Q Exactive. Statistical analysis of the association of these markers with evidence of disease in analyses were done included sex and APOE 4 status as covariates. Result: Among participants who remained cognitively unimpaired, we observed significant correlations between baseline CSF ADAM 22 levels and t-tau (R2 = 0.22, p < 0.0001), p-tau (R2 = 0.22, p < 0.0001), and Aβ42 (R2 = 0.06, p = 0.01488). We also found similarly suggestive correlations also between CSF ADAM 23, CSF SYT1 and the same disease markers. Covariate analyses suggested little or no variation in the associations between these synaptic proteins with t-tau and p-tau by sex, APOE 4 status, negative PET amyloid positivity (standardized uptake value ratio ≤ 1.37) and negative CSF total tau positivity (≤ 335pg/ul). PET amyloid positivity was significantly associated with ADAM22 and p-tau interactions whereas SYT1 was significantly associated with t-tau and p-tau in CSF tau-positive participants. In linear regression analyses, baseline CSF SYT1 levels correlated with the language cognitive performance trajectory slopes estimated over the course of 6 to 8 years on the RBANS (R2 = 0.03, p = 0.03425). We found no significant interaction between other CSF synaptic protein levels and other subscales of the RBANS. Conclusion: CSF synaptic protein levels show promising correlation with landmark AD proteins and emerging cognitive deficits.

Introduction La perte synaptique est un mécanisme précoce de la maladie d’Alzheimer (MA), étroitement associé aux symptômes cognitifs. La neuréguline 1 (NRG1) est un facteur de croissance impliqué dans la transmission synaptique. NRG1 est augmentée dans le liquide céphalorachidien (LCR) dans la MA et corrélée aux biomarqueurs amyloïdes, tau et synaptiques du LCR. Objectif Mesurer NRG1 plasmatique chez des patients avec une MA en comparaison à des sujets contrôles et avec d’autres pathologies neurodégénératives et étudier son association avec les marqueurs établis du LCR. Méthodes Nous avons inclus rétrospectivement 127 participants, dont des patients avec une MA au stade de trouble cognitif léger (MA-TCL, n = 27) et de trouble cognitif majeur (MA-TCM, n = 35), une démence non-MA (n = 26, Aβ-négatif), un trouble cognitif léger non-MA (n = 19) et des sujets contrôles (n = 20). Nous avons mesuré NRG1 dans le plasma et le LCR en méthode ELISA, les marqueurs MA du LCR (ratio Aβ42/Aβ40, phospho-tau et tau totale, méthode Elisa) et 3 marqueurs synaptiques du LCR : GAP-43 et neurogranine (Elisa) et SNAP-25 (spectrométrie de masse). Résultats NRG1 plasmatique était augmentée chez les patients avec une MA (TCL et TCM) par rapport aux contrôles (respectivement, p = 0,005 et p < 0,001). NRG1 plasmatique différenciait les patients MA-TCL et MA-TCM des contrôles avec des aires sous la courbe respectivement de 88,3 %, et de 87,3 %. NRG1 plasmatique corrélait à sa mesure dans le LCR (β = 0,372, p = 0,0056). NRG1 plasmatique était associée aux biomarqueurs MA du LCR dans la cohorte entière et chez les patients Aβ-positifs (β = −0,197 à 0,423) et avec GAP-43, neurogranine et SNAP-25 (β = 0,278–0,355). NRG1 plasmatique était inversement corrélée au score cognitif MMSE dans la cohorte entière et chez les patients Aβ-positifs (tous, β = −0,188, p = 0,038 ; Aβ+ : β = −0,255, p = 0,038). Conclusion NRG1 plasmatique est augmentée chez les patients avec une MA et constitue un biomarqueur non invasif prometteur pour évaluer l’atteinte synaptique de la MA.

Objective: To test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in-vivo and postmortem. Methods: Two independent observational, cross-sectional cohorts: 1) in-vivo community-dwelling, clinically normal adults from the UCSF Memory and Aging Center completed lumbar puncture and MRI (exclusion criteria, CDR>0), and 2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In-vivo measures included cerebrospinal fluid (CSF) synaptic proteins (synaptotagmin-1, SNAP-25, neurogranin, and GAP-43), Aβ42/40, ptau181, and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, VAMP, and SNARE complex), and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins*amyloid on tau, and synaptic proteins*tau on GMV). Results: 68 in-vivo older adults (age=71y, 43%F) and 633 decedents (age=90y, 68%F, 34% clinically normal) were included. Each in-vivo CSF synaptic protein moderated the relationship between Aβ42/40 and ptau181 (-0.23<𝛽s<-0.12, ps<0.05) and the relationship between ptau and GMV (-0.49<𝛽s<-0.32, ps<0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aβ-ptau and ptau-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10<𝛽s<-0.08, ps<0.05). Conclusions: Pathogenic relationships of Aβ and tau may depend on synaptic state. Synaptic markers may help identify risk and/or resilience to AD proteinopathy.

Purpose: Dysfunctional proteostasis, with decreased protein degradation and an accumulation of ubiquitin into aggregated protein inclusions, is a feature of neurodegenerative diseases. Identifying new potential biomarkers in cerebrospinal fluid (CSF) reflecting this process could contribute important information on pathophysiology. Experimental design: We developed a method combining solid-phase extraction and parallel reaction monitoring mass spectrometry and monitored the concentration of ubiquitin in CSF from subjects with Alzheimer's disease (AD), Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Four independent cross-sectional studies were conducted, Studies 1-4, including controls (n = 86) and participants with AD (n = 60), PD (n = 15) and PSP (n = 11). Results: The method showed a repeatability and intermediate precision not exceeding 6.1% and 7.9%, respectively. The determined limit of detection was 0.1nM and the limit of quantitation ranged between 0.625 and 80nM. The CSF ubiquitin concentration was found to be 1.2-1.5-fold higher in AD patients compared with controls in the three independent AD-control studies (Study 1, P<0.001; Study 2, P<0.001; and Study 3, P = 0.003). No difference was found in PD or PSP, when compared to controls. Conclusion and clinical relevance: CSF ubiquitin may reflect dysfunctional proteostasis in AD. The described method can be used for further exploration of ubiquitin as a potential biomarker in neurodegenerative diseases. This article is protected by copyright. All rights reserved.