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- Wightman, D. P., et al.
(author)
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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
- 2021
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:9, s. 1276-1282
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Journal article (peer-reviewed)abstract
- Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.
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- Kirsebom, B. E., et al.
(author)
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Stable cerebrospinal fluid neurogranin and beta-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients
- 2022
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In: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:5
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Journal article (peer-reviewed)abstract
- Kirsebom & Richter et al. report that levels of the CSF synapse markers neurogranin and BACE1 remain stable in Alzheimer's disease A/T/N subgroups, even when progressing to dementia. Their results suggest that CSF levels may differentiate pathomechanistic Alzheimer's disease subtypes, putatively with different options for treatment. Cerebrospinal fluid (CSF) beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer's disease continuum and controlled with normal markers (A-/T-/N-, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n = 12), from A+/T-/N- to A+/T or N+ (n = 12), remained stable A+/T-/N- (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A-/T-/N- (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T-/N- (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = -0.29, P = 0.0006) than neurogranin (b = -0.20, P = 0.002) and BACE1 (b = -0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer's disease subgroups, putatively with different options for treatment.
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- Timotijevic, L., et al.
(author)
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Designing a research infrastructure (RI) on food behaviour and health : Balancing user needs, business model, governance mechanisms and technology
- 2021
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In: Trends in Food Science & Technology. - : Elsevier Ltd. - 0924-2244 .- 1879-3053. ; 116, s. 405-414
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Journal article (peer-reviewed)abstract
- Background: A better understanding of food-related behaviour and its determinants can be achieved through harmonisation and linking of the various data-sources and knowledge platforms. Scope: We describe the key decision-making in the development of a prototype of the Determinants and Intake Platform (DI Platform), a data platform that aims to harmonise and link data on consumer food behaviour. It will be part of the Food Nutrition Health Research Infrastructure (FNH-RI) that will facilitate health, social and food sciences. Approach: The decision-making was based on the evidence of user needs and data characteristics that guided the specification of the key building blocks of the DI Platform. Eight studies were carried out, including consumer online survey; interview studies of key DI Platform stakeholders; desk research and workshops. Key findings: Consumers were most willing to share data with universities, then industry and government. Trust, risk perception and altruism predicted willingness to share. For most other stakeholders non-proprietary data was most likely to be shared. Lack of data standards, and incentives for sharing were the main barriers for sharing data among the key stakeholders. The value of various data types would hugely increase if linked with other sources. Finding the right balance between optimizing data sharing and minimizing ethical and legal risks was considered a key challenge. Conclusions: The development of DI Platform is based on careful balancing of the user, technical, business, legal and ethical requirements, following the FAIR principles and the need for financial sustainability, technical flexibility, transparency and multi-layered organisational governance.
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- Borda, MG, et al.
(author)
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Timed Up and Go in People with Subjective Cognitive Decline Is Associated with Faster Cognitive Deterioration and Cortical Thickness
- 2022
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In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 51:1, s. 63-72
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Journal article (peer-reviewed)abstract
- <b><i>Introduction:</i></b> Early markers of neurodegeneration provide an opportunity to detect, monitor, and initiate interventions in individuals who have an increased risk of developing dementia. Here, we investigated whether the Timed Up and Go (TUG) test is associated with early brain neurodegeneration and whether the TUG test could be a marker of cognitive decline in people with subjective cognitive decline (SCD). <b><i>Methods:</i></b> This is a longitudinal analysis of the Dementia Disease Initiation Study, a prospective, community-based, cohort study from Norway, designed to investigate early markers of cognitive impairment and dementia. Participants were classified as SCD and healthy controls (HC). The main studied variables were the TUG test and cognition as measured by the Mini-Mental State Examination and the Consortium to Establish a Registry for Alzheimer’s Disease memory composite score. Additionally, we investigated the cross-sectional association of brain morphology with the TUG using 1.5T-MRI. <b><i>Results:</i></b> The sample included 45 participants (SCD = 21, HC = 24) followed during a mean time of 1.50 ± 0.70 years. At baseline, the cognitive performance did not differ between the groups, but TUG was longer in SCD. Slower baseline TUG was associated with a faster cognitive decline in both groups and it was also associated with reduced cortical thickness especially in motor, executive, associative, and somatosensory cortical regions in people with SCD. <b><i>Discussion/Conclusion:</i></b> TUG predicted cognitive change in individuals with SCD, and there was a negative association between TUG and cortical thickness. TUG is a promising cheap and noninvasive marker of early cognitive decline and may help initiate interventions in individuals who have an increased risk of dementia.
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- Christiansen, O., et al.
(author)
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Predictors of upgrading from low-grade cancer at prostatectomy in men with biparametric magnetic resonance imaging
- 2022
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In: Central European Journal of Urology. - : Polish Urological Association. - 2080-4806 .- 2080-4873. ; 75:1, s. 35-40
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Journal article (peer-reviewed)abstract
- Introduction Prostate-specific antigen (PSA) density has previously been identified as a predictor of histological upgrading at radical prostatectomy, but how information from pre-treatment biparametric magnetic resonance imaging (bpMRI) contributes needs further clarification. The objective of this register-based study was to identify predictors of upgrading at prostatectomy in men with Grade group (GG) 1 and pre-treatment bpMRI. Material and methods This single-center study included men with GG 1 cancer on prediagnostic biopsy, who underwent bpMRI and robotic-assisted radical prostatectomy (RARP) between March 2014 and September 2019. We estimated logistic regression models to explore predictors for upgrading. The explored potential predictors were age, PSA density, tumor stage and Prostate Imaging Reporting and Data System (PI-RADS) score (dichotomised 1-3 versus 4-5). Results Upgrading was observed in 56% (73/130) of the men. PSA density was the only significant predictor for upgrading (unadjusted OR = 1.7, 95% CI 1.2; 2.4 adjusted OR = 1.7, 95% CI 1.2; 2.5). The probability of upgrading was lower for men with a PIRADS 1-3 than for PIRADS 4-5, but the difference was not statistically significant (adjusted OR 0.4, 95% CI 0.2; 1.1, p = 0.082). Among men with PI-RADS 1-3, the probability increased with increasing PSA density (p = 0.036). With PI-RADS 4-5 the probability of upgrading was high over the entire PSA density range. Conclusions PSA density is a clinically important factor to predict upgrading from GG1 when bpMRI shows PI-RADS 1-3. In men with PI-RADS 4-5 on bpMRI, the probability of an undetected GG 2-5 cancer is high regardless of the PSA density.
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| 10. |
- Jansen, Iris E, et al.
(author)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Journal article (peer-reviewed)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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