Forskningsartikler

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

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

Purpose: To synthesize qualitative empirical research that expands the knowledge of what people with dementia consider to be essential for daily living in a dementia-friendly society.

Methods: The authors searched phrases in the databases AgeLine, CINAHL, EMBASE, MedLine, PsycINFO, PubMed, ORIA, SveMed+, and Cochrane Library. Research articles that involved people with dementia and were conducted in Western countries, written in English, published in peer-reviewed academic journals using qualitative methods, and published within the past decade were included. The research included was critically and systematically appraised using the critical appraisal skills program checklist for qualitative research, and the findings were analyzed according to Graneheim and Lundman’s method of qualitative content analysis.

Results: Overall, 1122 records-561 from 2019 and 561 from 2021-were identified through the search, and nine studies were included in the final synthesis. The studies included were from the United Kingdom (five studies), Australia (three studies), and New Zealand (one study). Through the analysis process, the following main theme emerged: giving voice to people with dementia, which summarizes the essence of what people with dementia believe is essential for daily living in a dementia-friendly society. The main theme covered two themes: a sense of being valued and a sense of being safeguarded, each of which contained subthemes.

Conclusion: To meet the WHO’s and the governments worldwide intention to develop dementia-friendly societies, further research should focus on the voices of people with dementia. By including those concerned, the political goals of a dementia-friendly society can be achieved.

Johanne Alteren, Aud Johannessen, Anne Marit Lyberg, Inger-Lise Magnussen

Background: The Mini-Mental State Examination (MMSE), a simple test for measuring global cognitive function, is frequently used to evaluate cognition in older adults. To decide whether a score on the test indicates a significant deviation from the mean score, normative scores should be defined. Moreover, because the test may vary depending on its translation and cultural differences, normative scores should be established for national versions of the MMSE.

Objective: We aimed to examine normative scores for the third Norwegian version of the MMSE.

Methods: We used data from two sources: the Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) and the Trøndelag Health Study (HUNT). After persons with dementia, mild cognitive impairment, and disorders that may cause cognitive impairment were excluded, the sample contained 1,050 cognitively healthy persons, 860 from NorCog, and 190 from HUNT, whose data we subjected to regression analyses.

Results: The normative MMSE score varied from 25 to 29, depending on years of education and age. More years of education and younger age were associated with higher MMSE scores, and years of education was the strongest predictor.

Conclusion: Mean normative MMSE scores depend on test takers’ years of education and age, with level of education being the strongest predictor.

Knut Engedal, Jūratė Šaltytė Benth, Linda Gjøra, Håvard Kjesbu Skjellegrind, Marit Nåvik, Geir Selbæk

Background: Mobility impairments, in terms of gait and balance, are common in persons with dementia. To explore this relationship further, we examined the associations between mobility and cerebrospinal fluid (CSF) core biomarkers for Alzheimer’s disease (AD).
Methods: In this cross-sectional study, we included 64 participants [two with subjective cognitive decline (SCD), 13 with mild cognitive impairment (MCI) and 49 with dementia] from a memory clinic. Mobility was examined using gait speed, Mini-Balance Evaluation Systems test (Mini-BESTest), Timed Up and Go (TUG), and TUG dual-task cost (TUG DTC). The CSF biomarkers included were amyloid-β 42 (Aβ42), total-tau (t-tau), and phospho tau (p-tau181). Associations between mobility and biomarkers were analyzed through correlations and multiple linear regression analyses adjusted for (1) age, sex, and comorbidity, and (2) SCD/MCI vs. dementia.
Results: Aβ42 was significantly correlated with each of the mobility outcomes. In the adjusted multiple regression analyses, Aβ42 was significantly associated with Mini- BESTest and TUG in the fully adjusted model and with TUG DTC in step 1 of the adjusted model (adjusting for age, sex, and comorbidity). T-tau was only associated with TUG DTC in step 1 of the adjusted model. P-tau181 was not associated with any of the mobility outcomes in any of the analyses.
Conclusion: Better performance on mobility outcomes were associated with higher levels of CSF Aβ42. The association was strongest between Aβ42 and Mini-BESTest, suggesting that dynamic balance might be closely related with AD-specific pathology.

Gro Gujord Tangen, Karen Sverdrup, Kristin Taraldsen, Karin Persson, Knut Engedal, Peter Bekkhus-Wetterberg and Anne-Brita Knapskog

Summary

Despite evidence suggesting that insomnia is associated with the risk of dementia and cognitive dysfunction, studies have shown mixed results. Dementia has a long prodromal phase, and studies with long follow-up are required to avoid reverse causality. In our 11-year follow-up study, we assessed whether probable insomnia disorder (PID) based on diagnostic criteria, and insomnia symptoms were associated with risk of all-cause dementia, Alzheimer’s disease (AD) and cognition, measured with the Montreal Cognitive Assessment scale. We also examined if Apolipoprotein E genotype modified any associations with dementia through interaction. We analysed data from 7492 participants in the Norwegian Trøndelag Health Study. PID was not associated with all-cause dementia (odds ratio = 1.03, 95% confidence interval = 0.74–1.43), AD (odds ratio = 1.07, 95% confidence interval = 0.71–1.60) or Montreal Cognitive Assessment score (regression coefficient = 0.37, 95% confidence interval = −0.06 to 0.80). The insomnia symptom “difficulties maintaining sleep” was associated with a lower risk of all-cause dementia (odds ratio = 0.81, 95% confidence interval = 0.67–0.98), AD (odds ratio = 0.73, 95% confidence interval = 0.57–0.93), and better Montreal Cognitive Assessment score, mean 0.40 units (95% confidence interval = 0.15–0.64). No interaction with Apolipoprotein E genotype was found. PID and insomnia symptoms did not increase the risk of dementia in our study. More research with longer follow-up is needed, and future studies should explore if the associations to dementia risk vary across insomnia subtypes.

Selma Selbæk-Tungevåg, Geir Selbæk, Bjørn Heine Strand, Christian Myrstad, Gill Livingston, Stian Lydersen, Sverre Bergh, Linda Ernstsen

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