Forskningsartikler

Genotypes causing pregnancy loss and perinatalmortality 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.

Asmundur Oddsson… Geir Selbæk…Daniel F. Gudbjartsson

Background: Neuroinflammation is involved in the pathophysiology of Alzheimer’s disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system.

Methods: We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets.

Results: MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons.

Conclusions: Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.

Vera Fominykh, Alexey A Shadrin, Piotr P Jaholkowski, Shahram Bahrami, Lavinia Athanasiu, Douglas P Wightman, Emil Uffelmann, Danielle Posthuma, Geir Selbæk, Anders M Dale, Srdjan Djurovic, Oleksandr Frei, Ole A Andreassen

Late-life depression (LLD) has been linked to increased likelihood of subsequent dementia, although mechanisms responsible for this association remain largely unknown. One feature frequently observed in both LLD and dementia is elevated levels of plasma inflammatory markers. PRODE (Prognosis of Depression in the Elderly) is a prospective naturalistic study of patients with LLD (N=152; aged 60+). Patients were followed up for 3 years; follow-up data was available for 138 patients, and 36 (26.1%) developed dementia by year 3. Plasma inflammatory markers data were available for 136 patients at baseline for the following range of cytokines and chemokines: IL-1β, IL-1ra, IL-6, IL-10, IL-17a, IL-18, IL-33, TNFα, CD40L, IFN-γ, CCL-2 and CCL-4. Levels of plasma inflammatory markers were compared between 136 LLD patients and healthy controls (n=103), using first multiple linear regression (inflammatory markers as outcome) with stepwise adjustment, and then binary logistic regression with depression status (LLD vs controls) as outcome. Further, we explored whether inflammatory markers and clinical characteristics of LLD (age of onset, course) predicted progression from LLD to dementia using Cox regression. Levels of IL-1ra, IFN-γ, CCL-2, CCL-4 and IL-17a were significantly higher in LLD patients compared to controls. However, none of the inflammatory markers predicted progression from LLD to dementia. Among clinical features, only poor response to treatment significantly predicted higher risk of progression to dementia. In summary, this study replicated previous findings of an increase in inflammatory markers in LLD but did not find evidence they had increased risk of developing future dementia.

Dag Aarsland, Allan Young, Knut Engedal, John O’Brien, Geir Selbaek, Ane-Victoria Idland, Leiv-Otto Watne, Tom Borza, Mariia Bocharova

Background: Studies exploring the possible protective effect of coffee and tea consumption on dementia have shown inconsistent results so far. We aimed to investigate whether consumption of tea and different types of coffee at midlife are associated with dementia later in life and whether sex or ApoE4 influence such association.
Methods: We included 7381 participants from the Norwegian HUNT Study. Self-reported questionnaires assessed daily consumption of coffee and tea at baseline. After 22 years, individuals 70 years or older were screened for cognitive impairment.
Results: General coffee consumption and tea consumption was not associated with dementia risk. Compared to daily consumption of 0–1 cups of coffee, daily consumption of ≥8 cups of boiled coffee was associated with increased dementia risk in women (OR: 1.83, 95% CI: 1.10–3.04, p-value for trend = 0.03) and daily consumption of 4–5 cups of other types of coffee was associated with a decrease in dementia risk in men (OR: 0.48, 95% CI: 0.32–0.72, p-value for trend = 0.05). Furthermore, the association between boiled coffee and increased dementia risk was only found in ApoE4 non-carriers. Differences by sex or ApoE4 carrier status were not supported by strong statistical evidence for interaction. Tea consumption was not associated with dementia risk.
Conclusion: type of coffee may play a role in the direction of the association between coffee-drinking habits and dementia later in life.

Denise Abbel, Bjørn Olav Åsvold, Marit Kolberg, Geir Selbæk, Raymond Noordam and Håvard Kjesbu Skjellegrind

Background: The declining incidence of stroke, ischemic heart disease (IHD) and dementia (the triple threat) in Norway encourages further investigation. We analysed the risks and trends of the three conditions using data from the Global Burden of Disease study (GBD).

Methods: We used GBD 2019 estimations for age-, sex-, and risk factor-specific incidence and prevalence of “the triple threat” and their risk factor-attributed deaths and disability combined and their age-standardised rates per 100,000 population in 2019 and their changes during 1990-2019. Data are presented in means and 95% uncertainty intervals (UI).

Results: In 2019, 71.1 thousand Norwegian were living with dementia, 157.2 thousand with IHD, and 95.2 thousand with strokes. In 2019, there were 9.9 thousand (8.5 to 11.3) new cases of dementia (35.0% increase since 1990), 17.0 thousand (14.6 to 19.6) with IHD (3.6% decrease), and 8.0 thousand (7.0 to 9.1) with strokes (12.9% decrease) in Norway. During 1990-2019, their age-standardised incidence rates decreased significantly; dementia by -5.4% (-8.4 to -3.2), IHD by -30.0% (-31.4 to -28.6), and stroke by -35.3% (-38.3 to -32.2), respectively. There were significant declines in the attributable risks to both ENVIRONMENTAL and behavioural factors in Norway, but contradictory trends for metabolic risk factors during 1990-2019.

Conclusions: The risk of “the triple threat” conditions is declining in Norway, despite the increased prevalence. This offers the opportunity to find out why and how and to accelerate their joint prevention through new approaches and the promotion of the National Brain Health Strategy.

Abolfazl Avan, Anne Hege Aamodt, Geir Selbaek, Gunnar Bovim, Claudio L A Bassetti, Paul Boon, Wolfgang Grisold, Vladimir Hachinski

Sammendrag

Hensikt: Studien belyser hvilke erfaringer fysioterapeuter har med å gi fysioterapibehandling til beboere med langtidsopphold i norske sykehjem, og hvordan fysioterapeutene er involvert i behandlingen av beboere i livets sluttfase.

Design, materiale og metode: Artikkelen er basert på eksplorerende kvalitative intervjuer med seks fysioterapeuter som jobber i sykehjem. Intervjuene var semistrukturerte og datamaterialet ble analysert med systematisk tekstkondensering.

Funn: Deltakerne inntar i stor grad en tradisjonell fysioterapeutrolle med fokus på trening. De anerkjenner at fysioterapeuter har kunnskap og ferdigheter som er relevante for beboerne i livets sluttfase, men er i liten grad involvert i det tverrfaglige teamet rundt den døende.

Konklusjon: Fysioterapeutene som jobber i langtidsavdelinger i sykehjem bruker mesteparten av arbeidstiden sin på tradisjonell fysioterapi. De er ikke er involvert i lindrende behandling og omsorg i livets sluttfase, men mener at de har relevant kunnskap – og således er en ubrukt ressurs. Mangelen på fysioterapeuter i det tverrfaglige palliative teamet er et resultat av at fysioterapeutene selv ikke gir uttrykk for at de ønsker å bidra, samtidig som leger og sykepleiere ikke etterspør deres kunnskap på dette området. Organiseringen av fysioterapitjenesten i sykehjem ser også ut til å kunne påvirke det tverrfaglige samarbeidet.

Kristine Bjorheim Bøe, Tone Dahl-Michelsen & Elisabeth Wiken Telenius

Background:Behavioural and psychological symptoms of dementia (BPSD) profiles vary depending on aetiology in patients with mild-to-moderate BPSD. It is not known if similar differences exist in patients with severe BPSD.

Methods:We analysed data collected at baseline in 398 patients with severe BPSD (NPI ≥ 32) and defined diagnosis of dementia (Alzheimer’s disease (AD) 297; frontotemporal dementia (FTD) 39; Lewy body disease/Parkinsonian dementia (LBD/PD) 31; and vascular dementia (VD) 31) included in the European multicentre cohort RECAGE.

Results:Mean total NPI was 52.11 (18.55). LBD/PD patients demonstrated more hallucinations, more anxiety and more delusions than patients with other dementia. FTD patients had less delusions and more disinhibition than patients with other neurodegenerative disorders. These profiles overlapped partially with those reported in the literature in patients with less severe symptoms.

Conclusion: Patients with severe BPSD display different and specific profiles of neuropsychiatric symptoms depending on dementia aetiology.

Cognat, S. Sabia, A. Fayel, M. Lilamand, R. Handels, S. Fascendini, S. Bergh, G.B. Frisoni, A. Fabbo, M. Tsolaki, L. Frölich, O. Peters, P. Merlo, A. Ciccone, P. Mecocci, J. Dumurgier, C.A. Defanti, J. Hugon, C. Paquet

Background: Malnutrition – comprising both undernutrition and overweight – has to be addressed in the medical follow-up of older adults due to the negative consequences for the functional state and general health. Still, little is known about the nutritional state of nursing home (NH) residents, especially with respect to weight gain or weight loss after NH admission. Therefore, this study aims to evaluate changes in the body mass index (BMI) during the first year following NH admission, and to explore demographic and clinical characteristics related to BMI changes.

Methods: Data from two prospective studies that recruited participants at NH admission were combined. Demographic and clinical characteristics including the BMI were assessed at baseline and after one year. A linear regression model was estimated to explore the impact of demographic and clinical characteristics on the change in BMI.

Results: The study cohort consisted of 1,044 participants with a mean age of 84.3 years (SD7.6) at baseline; 64.2% were female. At baseline, 33% of the NH residents had severe to moderate undernutrition, while 10% were obese. During the first year of their NH stay, residents with severe to moderate undernutrition had an average increase in BMI of 1.3 kg/m2 (SD 2.2; p < 0.001), while weight changes were either very small or not significant in the other BMI groups. Characteristics related to weight gain were younger age and less agitation.

Conclusion: Malnutrition is a common health challenge at NH admission, with one third of NH residents being moderately to severely underweight and 10% being obese. However, during the first year of NH stay, there was a favourable development for underweight NH residents, as they increased their BMI, and 43.6% changed to a higher weight classification, while we observed no changes in the BMI in residents with obesity. As NH residents are in the last phase of their lives, interventions to prevent malnutrition or overweight should be initiated while still home-dwelling, and then continued in the nursing homes.

Corinna Vossius, Miguel G Borda, Bjørn Lichtwarck, Janne Myhre, May Ingvild Volungholen Sollid, Tom Borza, Ingvild Hjorth Feiring, Jūratė Šaltytė Benth, Sverre Bergh

Introduction: There is a pressing need for non-invasive, cost-effective tools for early detection of Alzheimer’s disease (AD).

Methods: Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Cox proportional models were conducted to develop a multimodal hazard score (MHS) combining age, a polygenic hazard score (PHS), brain atrophy, and memory to predict conversion from mild cognitive impairment (MCI) to dementia. Power calculations estimated required clinical trial sample sizes after hypothetical enrichment using the MHS. Cox regression determined predicted age of onset for AD pathology from the PHS.

Results: The MHS predicted conversion from MCI to dementia (hazard ratio for 80th versus 20th percentile: 27.03). Models suggest that application of the MHS could reduce clinical trial sample sizes by 67%. The PHS alone predicted age of onset of amyloid and tau.

Discussion: The MHS may improve early detection of AD for use in memory clinics or for clinical trial enrichment.

Highlights: A multimodal hazard score (MHS) combined age, genetics, brain atrophy, and memory. The MHS predicted time to conversion from mild cognitive impairment to dementia. MHS reduced hypothetical Alzheimer’s disease (AD) clinical trial sample sizes by 67%. A polygenic hazard score predicted age of onset of AD neuropathology.

Emilie T Reas, Alexey Shadrin, Oleksandr Frei, Ehsan Motazedi, Linda McEvoy, Shahram Bahrami, Dennis van der Meer, Carolina Makowski, Robert Loughnan, Xin Wang, Iris Broce, Sarah J Banks, Vera Fominykh, Weiqiu Cheng, Dominic Holland, Olav B Smeland, Tyler Seibert, Geir Selbaek, James B Brewer, Chun C Fan, Ole A Andreassen, Anders M Dale; Alzheimer’s Disease Neuroimaging Initiative