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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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- Saevarsdottir, KS, et al.
(author)
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Illness severity and risk of mental morbidities among patients recovering from COVID-19: a cross-sectional study in the Icelandic population
- 2021
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In: BMJ open. - : BMJ. - 2044-6055. ; 11:7, s. e049967-
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Journal article (peer-reviewed)abstract
- To test if patients recovering from COVID-19 are at increased risk of mental morbidities and to what extent such risk is exacerbated by illness severity.DesignPopulation-based cross-sectional study.SettingIceland.ParticipantsA total of 22 861 individuals were recruited through invitations to existing nationwide cohorts and a social media campaign from 24 April to 22 July 2020, of which 373 were patients recovering from COVID-19.Main outcome measuresSymptoms of depression (Patient Health Questionnaire), anxiety (General Anxiety Disorder Scale) and posttraumatic stress disorder (PTSD; modified Primary Care PTSD Screen for DSM-5) above screening thresholds. Adjusting for multiple covariates and comorbidities, multivariable Poisson regression was used to assess the association between COVID-19 severity and mental morbidities.ResultsCompared with individuals without a diagnosis of COVID-19, patients recovering from COVID-19 had increased risk of depression (22.1% vs 16.2%; adjusted relative risk (aRR) 1.48, 95% CI 1.20 to 1.82) and PTSD (19.5% vs 15.6%; aRR 1.38, 95% CI 1.09 to 1.75) but not anxiety (13.1% vs 11.3%; aRR 1.24, 95% CI 0.93 to 1.64). Elevated relative risks were limited to patients recovering from COVID-19 that were 40 years or older and were particularly high among individuals with university education. Among patients recovering from COVID-19, symptoms of depression were particularly common among those in the highest, compared with the lowest tertile of influenza-like symptom burden (47.1% vs 5.8%; aRR 6.42, 95% CI 2.77 to 14.87), among patients confined to bed for 7 days or longer compared with those never confined to bed (33.3% vs 10.9%; aRR 3.67, 95% CI 1.97 to 6.86) and among patients hospitalised for COVID-19 compared with those never admitted to hospital (48.1% vs 19.9%; aRR 2.72, 95% CI 1.67 to 4.44).ConclusionsSevere disease course is associated with increased risk of depression and PTSD among patients recovering from COVID-19.
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- Schöll, Michael, 1980, et al.
(author)
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Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomography
- 2015
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Journal article (peer-reviewed)abstract
- Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround beta-amyloid (A beta) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar A beta, astrocytosis and cerebral glucose metabolism with the radiotracers C-11-Pittsburgh compound-B (PIB), C-11-deuterium-L-deprenyl (DED) and F-18-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar A beta or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.
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- Johansson, C., et al.
(author)
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Plasma biomarker profiles in autosomal dominant Alzheimer's disease
- 2023
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 146:3, s. 1132-1140
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Journal article (peer-reviewed)abstract
- Johansson et al. describe plasma biomarkers in a longitudinal Swedish cohort of patients with monogenic Alzheimer's disease. Plasma GFAP began to increase 10 years before symptom onset, prior to P-tau181 and NfL, suggesting that GFAP is mirroring Alzheimer's disease pathology upstream of tau phosphorylation and neurodegeneration. Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease. Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF. Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF. Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.
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| 16. |
- Li, X., et al.
(author)
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White matter changes in familial Alzheimer's disease
- 2015
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 278:2, s. 211-218
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Journal article (peer-reviewed)abstract
- BackgroundFamilial Alzheimer's disease (FAD) resulting from gene mutations in PSEN1, PSEN2 and APP is associated with changes in the brain. ObjectiveThe aim of this study was to investigate changes in grey matter (GM), white matter (WM) and the cerebrospinal fluid (CSF) in FAD. SubjectsTen mutation carriers (MCs) with three different mutations in PSEN1 and APP and 20 noncarriers (NCs) were included in the study. Three MCs were symptomatic and seven were presymptomatic (pre-MCs). MethodsWhole-brain GM volume as well as fractional anisotropy (FA) and mean diffusivity (MD) using voxel-based morphometry and tract-based spatial statistics analyses, respectively, were compared between MCs and NCs. FA and MD maps were obtained from diffusion tensor imaging. ResultsA significant increase in MD was found in the left inferior longitudinal fasciculus, cingulum and bilateral superior longitudinal fasciculus in pre-MCs compared with NCs. After inclusion of the three symptomatic MCs in the analysis, the regions became wider. The mean MD of these regions showed significant negative correlation with the CSF level of A42, and positive correlations with P-tau(181p) and T-tau. No differences were observed in GM volume and FA between the groups. ConclusionsThe results of this study suggest that FAD gene mutations affect WM diffusivity before changes in GM volume can be detected. The WM changes observed were related to changes in the CSF, with similar patterns previously observed in sporadic Alzheimer's disease.
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- Oddsson, Asmundur, et al.
(author)
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Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
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- Thorarinsdottir, Kristjana, et al.
(author)
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Using a Brief Mental Imagery Competing Task to Reduce the Number of Intrusive Memories : Exploratory Case Series With Trauma-Exposed Women
- 2022
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In: JMIR Formative Research. - : JMIR Publications. - 2561-326X. ; 6:7
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Journal article (peer-reviewed)abstract
- Background:Novel interventions should be developed for people who have undergone psychological trauma. In a previous case study, we found that the number of intrusive memories of trauma could be reduced with a novel intervention. The intervention included a brief memory reminder, a visuospatial task and mental rotation, and targeted trauma memory hotspots one at a time in separate sessions.Objective:This case series (N=3) extended the first case study with 3 new cases to determine whether a similar pattern of beneficial results is observed. We explored whether the brief intervention would result in reduced numbers of intrusive memories and whether it would impact symptoms of posttraumatic stress, depression and anxiety, and general functioning. Acceptability of the intervention was also explored.Methods:A total of 3 women completed the study: 2 with posttraumatic stress disorder and other comorbidities and 1 with subthreshold posttraumatic stress disorder. The primary outcome was the change in the number of intrusive memories from the baseline phase to the intervention phase and at the 1-month follow-up, with an assessment of the intrusion frequency at 3 months. Participants monitored the number of intrusive memories in a daily diary for 1 week at baseline, for maximum of 6 weeks during the intervention phase and for 1 week at the 1-month and 3-month follow-ups. The intervention was delivered in person or digitally, with guidance from a clinical psychologist. A repeated AB design was used (A was a preintervention baseline phase and B intervention phase). Intrusions were targeted individually, creating repetitions of an AB design.Results:The total number of intrusive memories was reduced from the baseline to the intervention phase for all participants. The total number for participant 3 (P3) reduced from 38.8 per week during the baseline phase to 18.0 per week in the intervention phase. It was 13 at the 3-month follow-up. The total number for P4 reduced from 10.8 per week at baseline to 4.7 per week in the intervention phase. It was 0 at the 3-month follow-up. The total number for P5 was reduced from 33.7 at baseline to 20.7 per week in the intervention phase. It was 8 at the 3-month follow-up. All participants reported reduction in posttraumatic stress symptoms in the postintervention phase. Depression and anxiety symptoms reduced in 2 of the 3 participants in the postintervention phase. Acceptability was favorable.Conclusions:We observed good compliance with the intervention and intrusive memory diary in all 3 cases. The number of intrusive memories was reduced for all participants during the intervention phase and at the 1-month follow-up, with some improvement in other symptoms and functioning. Further research should explore the remote delivery of the intervention and whether nonspecialists can deliver the intervention effectively.
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