Forskningsartikler

BACKGROUND: The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.
METHODS: We undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality.
RESULTS: In delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 [1.78, 2.87], P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (β 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.
CONCLUSION: Our data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.

Leiv Otto Watne, Christian Thomas Pollmann, Bjørn Erik Neerland, Else Quist-Paulsen, Nathalie Bodd Halaas, Ane-Victoria Idland, Bjørnar Hassel, Kristi Henjum, Anne-Brita Knapskog, Frede Frihagen, Johan Raeder, Aasmund Godø, Per Magne Ueland, Adrian McCann, Wender Figved, Geir Selbæk, Henrik Zetterberg, Evandro F Fang, Marius Myrstad, Lasse M Giil

Background: Psychosis is a debilitating syndrome occurring in 40-60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving etiology. In this study we performed an epigenome-wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of 192 post-mortem brain samples.
Method: Brain samples with corresponding in life neuropsychiatric assessments were obtained from the University of Pittsburgh Alzheimer’s disease Research Center (PITT-ADRC). AD pathology was assessed and classified using CERAD neuritic plaque density score, Braak neurofibrillary tangle stages and NIA-RI criteria. The presence or absence of delusions and hallucinations was scored on the CERAD Behavioral Rating Scale. DNA was extracted, bisulfite treated and then profiled on the Illumina Methylation EPIC Array.
Result: After data processing and quality control we used linear regression models to compare 152 AD+P samples to 40 AD samples without psychosis (AD-P). A regional analysis of spatially correlated p-values highlighted four differentially methylated regions (DMRs) associated with psychosis, which are being replicated in other data sets and validated for cell specificity using fluorescence activated nuclei sorting (FANS).
Conclusion: The development of effective therapies for AD+P is an urgent priority. To address this we have collated a well powered study cohort to interrogate the epigenetic basis of AD+P, finding significant methylomic variation. This variation provides an insight into potential mechanisms and biomarkers which will help to identify drug targets and enable better treatment with existing medications.

Luke Stephen Weymouth, Morteza P Kouhsar, Byron Creese, Sverre Bergh, Yehani Wedatilake, Ali Torkamani, Adam R. Smith, Geir Selbaek, Robert Sweet, Clive G Ballard, Jonathan Mill, Julia Kofler, Ehsan Pishva, Katie Lunnon

The overall aim was to explore the prevalence and persistent regular prescription of opioids and paracetamol among nursing home (NH) residents with dementia at admission and over time. A total of 996 residents with dementia, mean (SD) age 84.5 (7.6) years and (36.1% men), were included at admission (A1). Yearly assessments were performed for two years (A2 and A3) or until death. Pain was assessed using the Mobilization-Observation-Behavior-Intensity-Dementia-2 (MOBID-2) Pain Scale. Information regarding prescription of analgesics, general physical health, personal activities of daily living, severity of dementia, neuropsychiatric symptoms, and prescription of psychotropic drugs was collected. A generalized linear mixed model was used to explore whether pain severity was associated with persistent and persistent prescription of opioids and/or paracetamol across timepoints. At A1, 495 of 996 (49.7%) NH residents were prescribed analgesics and prevalence increased at the follow-ups (A2: n = 630, 65.1%; A3: n = 382, 71.2%). Paracetamol was the most frequently prescribed analgesic at all assessments (A1: 45.5%; A2: 59.5%; A3: 67.1%). Opioid prescriptions were quite prevalent (A1: 18.1%; A2: 25.1%; A3: 28.3%), with odds approximately 13 times (OR = 13.3, 95% CI 6.8–26.0) and 9 times (OR = 8.6, 95% CI 3.7–20.3) higher for prescription at follow-up A2 and A3, respectively, relative to prescription at A1. In adjusted analyses, higher pain intensity and poor physical health were associated with prescription and persistent prescription of opioids and paracetamol. In conclusion, prevalence and persistent prescription of analgesics were high in NH residents with dementia. The odds for the prescription of opioids at follow-up were high if prescribed at baseline. Interdisciplinary collaboration, routine assessment of pain at admission and regularly thereafter, and systematic drug reviews are essential to adequately assess and treat pain in NH residents with dementia.

Anne-Sofie Helvik, Sverre Bergh, Kamile Kabukcuoğlu, Jūratė Šaltytė Benth, Bjørn Lichtwarck, Bettina Husebø, Kjerstin Tevik

Sammendrag

Seksuelle relasjoner mellom personer med demens som bor på sykehjem, kan skape utfordringer. Demenssykdommer kjennetegnes av kognitiv svikt og kan påvirke personers evne til å ta beslutninger og forstå konsekvenser. Mye tyder på at helselovgivningen ikke gir helse- og omsorgspersonell god nok veiledning når utfordringer oppstår.

I artikkelen drøftes ulike helserettslige utfordringer med utgangspunkt i et empirisk eksempel. Utfordringene omhandler de sykehjemansattes vurdering av plikt og anledning til å gripe inn i en seksuell relasjon, vurdering av frivillighet, vurdering av samtykkekompetanse og involvering av pårørende. Disse komplekse problemstillingene der ulike verdier, faglig kompetanse, menneskerettigheter, helselovgivning og straffebestemmelser må veies opp mot hverandre og ses i sammenheng, ofte av ansatte uten juridisk kompetanse, krever tiltak for å sikre en mer enhetlig tilnærming og likebehandling av personer med demenssykdom på sykehjem. Det økende antallet personer med demens i Norge krever at disse utfordringene får større juridisk oppmerksomhet, og dagens regelsett må ses i sammenheng og lovforståelsen tydeliggjøres i for eksempel faglige veiledere.

Kjersti Wilson, Anne-Lene Egeland Arnesen, Kariann Krohne and Siren Eriksen

Objectives: This meta-aggregation aims to interpret and synthesize present knowledge on the lifeworld perspectives of people with dementia and develop a model for guidance in clinical practice.

Method: The data consist of four meta-syntheses describing different lifeworld perspectives in accordance with van Manen’s existentials: lived relations, lived space, lived time and lived body. The meta-aggregation summarizes a range of views expressed by people with dementia in qualitative, interview-based studies, with the aim of generating a reliable model based on the studies’ findings.

Results: In total, 88 studies among 1,191 persons with dementia were included. Sixteen areas of focus were found, representing four perspectives: (a) lived relations, consisting of connectedness, independence, equality and competence; (b) lived space, consisting of belonging, meaningfulness, safety and security, and autonomy; (c) lived time, consisting of being rooted in the past, being in the present, viewing the future and being in process; and (d) lived body, consisting of being functional, trustworthy, adaptable and presentable. A model shaped as a tree trunk captures the lifeworld perspectives of people with dementia.

Conclusion: Sixteen areas were revealed from this meta-aggregation and form the basis of a model. This model may be used as a guide for health care personnel to ensure the overall lifeworld-perspectives of people with dementia in care for the target group and conduct lifeworld-preserving care with a person-centred approach.

Siren Eriksen, Knut Engedal and Ellen Karine Grov

Background: Genome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology. Methods: Here, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB. Findings: Between November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported at GBA, SNCA, STX1B, and APOE. However, the sex-stratified analysis revealed that the GBA and SNCA signals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far. Interpretation: These data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials’ design in DLB.

Elizabeth Gibbons, Arvid Rongve, Itziar de Rojas, Alexey Shadrin, Kaitlyn Westra, Allison Baumgartner, Levi Rosendall, Zachary Madaj, Dena G. Hernandez, Owen A. Ross, Valentina Escott-Price, Claire Shepherd, Laura Parkkinen, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge,…Geir Selbæk…Jose Bras

Background:
Nursing home (NH) residents are in their last phase of life, and two aims of the NH’s medical care in Norway is to prevent unnecessary hospital admissions that would not benefit the resident and to facilitate a peaceful death in familiar surroundings when the time comes. However, little is known about the share of residents dying in NHs and the causes of death. We therefore evaluated the cause and place of death in a cohort of NH residents followed from the time of NH admission until death.

Methods:
NH residents were followed from admission to the NH and over the entire course of their NH stay. Demographic and clinical data were collected. Cause and place of death were retrieved from the Norwegian Cause of Death Registry.

Results:
Of 1283 residents, 6.2% died in hospital and 91.2% in a NH. Those who died in hospitals were more often male, died sooner after NH admission, had a less severe degree of dementia and had poorer general health. Dementia was the most common underlying cause of death, followed by cardiovascular disease.

Conclusions:
Dementia is one of the main causes of death in NH residents. In addition, our findings indicate a low number of inappropriate referrals to hospital during the last stage of life. However, further research should explore whether the terminal phase of NH residents is formed in accordance with their preferences and whether appropriate palliative care is offered.

Corinna Vossius, Sverre Bergh, Geir Selbæk, Bjørn Lichtwarck and Janne Myhre

Background:
The CERAD Word List Memory Test (WLMT) is widely used in the assessment of older adults with suspected dementia. Although normative data of the WLMT exist in many different regions of the world, normative data based on large population-based cohorts from the Scandinavian countries are lacking.
Objective: To develop normative data for the WLMT based on a large population-based Norwegian sample of healthy older adults aged 70 years and above, stratified by age, gender, and education.
Methods: A total of 6,356 older adults from two population-based studies in Norway, HUNT4 70 + and HUNT4 Trondheim 70+, were administered the WLMT. Only persons with normal cognitive function were included. We excluded persons with a diagnosis of mild cognitive impairment (MCI) and dementia, and persons with a history of stroke and/or depression. This resulted in 3,951 persons aged between 70 and 90 years, of whom 56.2% were females. Regression-based normative data were developed for this sample.
Results: Age, gender, and education were significant predictors of performance on the WLMT list-learning subtests and the delayed recall subtest, i.e., participants of younger age, female sex, and higher education level attained higher scores compared to participants of older age, male sex, and lower level of education.
Conclusion: Regression-based normative data from the WMLT, stratified by age, gender, and education from a large population-based Norwegian sample of cognitively healthy older adults aged 70 to 90 years are presented. An online norm calculator is available to facilitate scoring of the subtests (in percentiles and z-scores).

Jørgen Wagle, Geir Selbæk, Jratėaltytė Benth, Linda Gjøra, Thale Kinne Rønqvist, Peter Bekkhus-Wetterberg, Karin Persson, Knut Engedal

Background: Several modifiable lifestyle risk factors for dementia have been identified, but it is unclear how much the Norwegian public knows about the relationship between lifestyle and brain health. Therefore, this study aimed to investigate knowledge about modifiable dementia risk and protective factors and beliefs and attitudes towards dementia and dementia risk reduction in a randomly selected subsample of the Norwegian population.
Methods: The total sample (n = 1435) included individuals aged 40-70 years from four counties (Oslo, Innlandet, Nordland and Trøndelag) in Norway. Two online questionnaires were used to measure (1) awareness about dementia risk reduction and (2) an individual`s motivation to change behaviour for dementia risk reduction (MOCHAD-10).
Results: Of the participants, 70% were aware of the potential of dementia risk reduction in general. Physical inactivity (86%), cognitive inactivity (84%) and social isolation (80%) were the most frequently recognised dementia risk factors. On the other hand, diabetes (26%), coronary heart disease (19%), hearing loss (18%) and chronic kidney disease (7%) were less often recognised as dementia risk factors. Comparing men and women, the only significant difference was that women were more likely to report parents with dementia as a risk factor compared to men. Gender, age and educational differences were seen in beliefs and attitudes towards dementia prevention:women reported more negative feelings and attitudes towards dementia than men;those aged 40-49 years – more likely than older age groups – reported that ‘knowing family members with dementia’ or ‘having risk factors’ made them believe they had to change their lifestyle and behaviour.
Conclusions: The results indicate that 70% of the Norwegian public are aware of the potential for dementia risk reduction in general. However, there are major gaps in existing knowledge, particularly for cardiovascular risk factors such as hypertension, coronary heart disease, hypercholesterolemia and metabolic factors (diabetes, obesity). These findings underline the importance of further informing the Norwegian public about lifestyle-related risk and protective factors of dementia. Differences in beliefs and attitudes towards dementia risk prevention by age, gender and education require tailored public risk reduction interventions.

Grete Kjelvik, Anne Marie Mork Rokstad, Josephine Stuebs, Pernille Thingstad, Kay Deckers, Sebastian Köhler, Geir Selbæk