| 1. |
- Giannisis, Andreas, 1993-
(författare)
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Peripheral apolipoprotein E and its emerging role in neurodegenerative disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human apolipoprotein E gene (APOE) is polymorphic and coding for three common alleles; ε2, ε3, and ε4. Carriers of the ε4 allele are at a higher risk of developing sporadic late-onset Alzheimer’s Disease (AD). This association appears to be influenced by inherited traits, race, and sex. The connection between APOE genotype and AD-related pathological processes has been studied excessively, however, less attention has been devoted to the apolipoprotein E (apoE) protein levels per se, most possibly due to the inconsistent results presented in studies assessing potential links between cerebrospinal fluid (CSF) apoE levels and AD, and because systemic apoE cannot cross the blood-brain barrier (BBB). Nevertheless, low plasma apoE levels were found to enhance AD and dementia risk, with the APOE ε4 genotype influencing this risk by promoting a reduction of the plasma apoE levels in some populations. In this thesis, we speculate that peripheral apoE-dependent mechanisms are linked to neurodegeneration. To address this hypothesis, we performed a set of clinical and experimental studies. In the first three studies, we aimed to determine whether hepatic APOE ε4 genotype, plasma apoE levels, and diet are linked to brain function and cognition by utilizing a mouse model with humanized-livers that are characterized by the presence of human apoE only in the plasma. A comparison between the brains of APOE ε4/ε4 and APOE ε2/ε3 humanized-liver mice revealed altered endogenous murine apoe levels as well as altered levels of synaptic, neuroinflammatory, and insulin signaling-related markers in the cortex and hippocampus. Higher plasma apoE4 levels were also linked to these associations, mainly in the hippocampus of the humanized APOE ε4/ε4 liver mice. A similar, though less pronounced, effect was observed in the brains of APOE ε3/ε3 humanized-liver mice that were fed a high-fat, versus a normal diet. Utilizing the plasma from APOE ε3/ε3 humanized-liver mice, we further observed that the distribution of apoE3 in plasma lipoparticles differed between sexes. In addition, higher total plasma apoE3 levels were beneficial to the activity levels but appeared to have a negative impact on cognition in these mice. In the remaining studies, we aimed to determine how plasma apoE levels, apoE isoform distribution, and the formation of monomers and disulfide-linked homodimers and heterodimers with apolipoprotein A-II (apoA-II) are influenced by APOE genotype and AD. For that purpose, we studied two cohorts of Norwegian, Black/African-American (B/AA), and non-Hispanic white (NHW) cognitively healthy subjects and patients with AD or mild cognitive impairment (MCI). Only in Norwegian individuals, we observed lower levels of plasma apoE due to AD and APOE ε4 genotype. In addition, in these subjects, the apoE monomer/dimer profile seemed to be influenced by AD status. In the cohort of B/AAs and NHWs, these associations were absent. In both cohorts, we observed associations between plasma apoE levels and CSF AD biomarker levels. Lastly, B/AA subjects presented the highest plasma apoE levels with APOE ε4/ε4-carrying subjects exhibiting significantly higher plasma apoE levels than NHW APOE ε4/ε4 subjects.Overall, our studies suggest that hepatic APOE genotype and plasma apoE levels are associated with AD-related neuropathological changes which seem to be influenced by other factors like race and diet. Whether this influence is due to differences in apoE levels or apoE function (i.e. different distribution between lipoparticles) remains to be investigated in future studies.
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| 2. |
- Keshavan, Ashvini, et al.
(författare)
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Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: A comparison of Lumipulse and established immunoassays.
- 2020
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with pre-symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET).In 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays, and inter-platform Pearson correlations were derived. Logistic regressions and receiver-operating characteristic analysis generated CSF cut-points optimizing concordance with 18F-florbetapir amyloid PET status (n=63).Measurements of CSF Aβ, p-tau181, and their ratios correlated well across platforms (r 0.84-.94, P<.0001); those of t-tau and t-tau/Aβ42 correlated moderately (r 0.57-0.79, P<.0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.110 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40, and 25.3 for Lumipulse Aβ42/p-tau181.The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology.
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| 3. |
- Wagen, Aaron Z, et al.
(författare)
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Life course, genetic, and neuropathological associations with brain age in the 1946 British Birth Cohort: a population-based study.
- 2022
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Ingår i: The Lancet. Healthy longevity. - 2666-7568. ; 3:9
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Tidskriftsartikel (refereegranskat)abstract
- A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age.Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy.Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD.Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility.Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.
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| 4. |
- Wellington, Henrietta, et al.
(författare)
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Increased CSF neurogranin concentration is specific to Alzheimer disease.
- 2016
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Ingår i: Neurology. - 1526-632X. ; 86:9, s. 829-35
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Tidskriftsartikel (refereegranskat)abstract
- To assess the specificity of the dendritic protein neurogranin (Ng) in CSF from patients with a broad range of neurodegenerative diseases including a variety of dementias, tauopathies, and synucleinopathies.
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| 5. |
- Williams, Thomas E, et al.
(författare)
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Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial.
- 2022
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Ingår i: Neurology(R) neuroimmunology & neuroinflammation. - 2332-7812. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Improved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.The MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.A total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.We found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.MS-STAT: NCT00647348.This study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.
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