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| 2. |
- Hong, S. J., et al.
(författare)
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TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
- 2021
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:10, s. 1628-1640
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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| 3. |
- Abildgaard, Amanda B., et al.
(författare)
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HSP70-binding motifs function as protein quality control degrons
- 2023
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 80:1
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Tidskriftsartikel (refereegranskat)abstract
- Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding.
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| 4. |
- Einarsdottir, Sigrun, et al.
(författare)
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Vaccination against tick-borne encephalitis (TBE) after autologous and allogeneic stem cell transplantation
- 2021
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 39:7, s. 1035-1038
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Our aim was to assess response and side effects of 4 doses of TBE vaccine to patients (pts) after allo- and autologous stem cell transplantation (SCT). PATIENTS: Included were 104 pts with leukaemia, myeloma and lymphoma, median age 61 yrs. METHODS: Vaccine (FSME-Immun (R)) was given at 9, 10, 12, and 21 months post-transplant. Serum samples were obtained before and after vaccinations. Healthy controls (n = 27) received 3 vaccinations. Assessments of TBE specific IgG antibodies were performed by Enzygnost anti-TBE ELISA test (Siemens, Sweden). Results: Antibody levels (>12 U/mL; "seropositivity") were seen in 77% and 80% of pts after allo- and autoSCT; IgG levels; 89 vs 94 U/mL. Ongoing chronic GvHD and immunosuppression (n = 29) was associated with sero-negativity in the last sample (p = 0.007). All controls (n = 27) developed protective antibody levels. Conclusions: TBE vaccination was safe, and 4 doses starting 9 months post-SCT, induced seropositivity in a vast majority of pts. (C) 2021 Elsevier Ltd. All rights reserved.
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| 5. |
- Hong, Shengjun, et al.
(författare)
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Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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| 6. |
- Ma, Y., et al.
(författare)
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Measurement batch differences and between-batch conversion of Alzheimer's disease cerebrospinal fluid biomarker values
- 2021
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Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Batch differences in cerebrospinal fluid (CSF) biomarker measurement can introduce bias into analyses for Alzheimer's disease studies. We evaluated and adjusted for batch differences using statistical methods. Methods A total of 792 CSF samples from 528 participants were assayed in three batches for 12 biomarkers and 3 biomarker ratios. Batch differences were assessed using Bland-Altman plot, paired t test, Pitman-Morgan test, and linear regression. Generalized linear models were applied to convert CSF values between batches. Results We found statistically significant batch differences for all biomarkers and ratios, except that neurofilament light was comparable between batches 1 and 2. The conversion models generally had high R-2 except for converting P-tau between batches 1 and 3. Discussion Between-batch conversion allows harmonized CSF values to be used in the same analysis. Such method may be applied to adjust for other sources of variability in measuring CSF or other types of biomarkers.
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| 7. |
- Neumann, Alexander, et al.
(författare)
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Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.
- 2023
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Ingår i: Genome medicine. - 1756-994X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n=205 controls, n=546 mild cognitive impairment, n=222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analysesof the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
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| 8. |
- Shi, Liu, et al.
(författare)
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Replication study of plasma proteins relating to Alzheimer's pathology.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 17:9, s. 1452-1464
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Tidskriftsartikel (refereegranskat)abstract
- This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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| 9. |
- Alifier, Marek, et al.
(författare)
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Cardiac Surgery is Associated with Biomarker Evidence of Neuronal Damage.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1211-1220
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Tidskriftsartikel (refereegranskat)abstract
- Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures.Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma.Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aβ40, and Aβ42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery.Tau increased during surgery (1752%, p=0.0001) and NFL rose seven days post-surgery (1090%, p<0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aβ40 and Aβ42.Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia.
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| 10. |
- Alme, Tomas Nordheim, et al.
(författare)
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Chronic fatigue syndromes: real illnesses that people can recover from
- 2023
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Ingår i: Scandinavian Journal of Primary Health Care. - : TAYLOR & FRANCIS LTD. - 0281-3432 .- 1502-7724. ; 41:4, s. 372-376
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Tidskriftsartikel (refereegranskat)abstract
- The Oslo Chronic Fatigue Consortium consists of researchers and clinicians who question the current narrative that chronic fatigue syndromes, including post-covid conditions, are incurable diseases. Instead, we propose an alternative view, based on research, which offers more hope to patients. Whilst we regard the symptoms of these conditions as real, we propose that they are more likely to reflect the brains response to a range of biological, psychological, and social factors, rather than a specific disease process. Possible causes include persistent activation of the neurobiological stress response, accompanied by associated changes in immunological, hormonal, cognitive and behavioural domains. We further propose that the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation.Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities. Finally, we call for a much more open and constructive dialogue about these conditions. This dialogue should include a wider range of views, including those of patients who have recovered from them.
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