Forskningsartikler

Abstract:
Introduction: The presence of psychosis in Alzheimer’s disease (AD) is suggested to be associated with distinct molecular and neuropathological profiles in the brain.

Methods: We assessed brain DNA methylation in AD donors with psychosis (AD+P) and without psychosis (AD-P) using the EPIC array. Weighted gene correlation network analysis identified modules of co-methylated genes in a discovery cohort (PITT-ADRC: N = 113 AD+P, N = 40 AD-P), with validation in an independent cohort (BDR: N = 79 AD+P, N = 117 AD-P), with Gene Ontology and cell-type enrichment analysis. Genetic data were integrated to identify methylation quantitative trait loci (mQTLs), which were co-localized with GWAS for related traits.

Results: We replicated one AD+P associated module, which was enriched for synaptic pathways and in excitatory and inhibitory neurons. mQTLs in this module co-localized with variants associated with schizophrenia and educational attainment.

Discussion: This represents the largest epigenetic study of AD+P to date, identifying pleiotropic relationships between AD+P and related traits.

Highlights: DNA methylation was assessed in the prefrontal cortex in subjects with AD+P and AD-P. WGCNA identified six modules of co-methylated loci associated with AD+P in a discovery cohort. One of the modules was replicated in an independent cohort. This module was enriched for synaptic genes and in excitatory and inhibitory neurons. mQTLs mapping to genes in the module co-localized with GWAS loci for schizophrenia and educational attainment.

Morteza Kouhsar, Luke Weymouth, Adam R Smith, Jennifer Imm, Claudia Bredemeyer, Yehani Wedatilake, Ali Torkamani, Sverre Bergh, Geir Selbæk, Jonathan Mill, Clive Ballard, Robert A Sweet, Julia Kofler, Byron Creese, Ehsan Pishva, Katie Lunnon

Abstract

Late-life depression (LLD) has been linked to increased likelihood of 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. The present study aimed to compare the levels of 12 plasma inflammatory markers between older people with LLD and controls, and to explore whether these markers, along with clinical characteristics, can predict dementia in patients with LLD within 3 years of follow-up. Using multiple linear regression with stepwise adjustment, we compared levels of plasma inflammatory markers (IL-1β, IL-1ra, IL-6, IL-10, IL-17a, IL-18, IL-33, TNFα, CD40L, IFN-γ, CCL-2 and CCL-4) between 136 inpatients with LLD (PRODE cohort) and 103 cognitively healthy non-depressed controls (COGNORM cohort). In the PRODE cohort, follow-up data was available for 139 patients (of them 123 had data on baseline plasma inflammatory markers); 36 (25.9%) developed dementia by Year 3 (n = 31 for those with cytokine data). Using Cox proportional hazards regression, we explored whether inflammatory markers and clinical characteristics of LLD (age of onset, treatment response, number of episodes) predicted progression to dementia during follow-up. Levels of IL-1ra, CCL-2, CCL-4, IFN-γ and IL-17a were significantly higher in LLD patients compared to controls in the majority of models. However, none of the inflammatory markers predicted progression from LLD to dementia in the PRODE cohort. Among clinical features, only poor response to treatment significantly predicted higher risk of progression to dementia.

M Bocharova, T Borza, L O Watne, K Engedal, J T O’Brien, G Selbæk, A V Idland, J Hodsoll, A H Young & D Aarsland

Abstract

Background:
Childlessness, as well as having a high number of children, has been reported to be associated with an elevated risk of dementia compared to having 2–3 children. The mechanisms underlying these relationships are not well understood and may be mediated by different midlife risk factors. We examined the mediating role of various factors on the relationship between the number of children and dementia risk. These factors include socioeconomic factors (e.g., occupational complexity), psychosocial (e.g.., social activities, loneliness, life satisfaction), lifestyle (e.g., smoking, physical inactivity, alcohol intake), and chronic diseases (e.g., obesity, diabetes, depression, hearing impairment and hypertension).

Methods:
Using a historic cohort design, we included 9,745 participants born between 1931–48, with a mean age of 78.2 (SD = 6.4) years at the time of cognitive testing in the HUNT4 70 + sub-study (2017–2019). Further measures were obtained through data linkage between information from Statistics Norway and the HUNT1(1984–86), and HUNT2 (1995–97) Surveys. Causal mediation analyses using an inverse odd weighting approach were conducted to decompose the total effect of the number of children (0, 1, or 4 + children vs. 2–3) on the risk of dementia at age 70 + years into direct and indirect effects with mediators assessed at a mean age of 50.7 (SD = 6.4) years. The analyses were adjusted for age, sex, marital status at age 25 years, educational status, and religion assessed during HUNT3 (2006–2008).

Results:
Overall, 15.7% were diagnosed with dementia. The proportions with dementia by the number of children were 22.3% among those with no children, 21.4% for those with one child, 13% for those with 2–3 children (specifically, 12.6% for those with 2 children and 13.4% for those with 3 children), and 19.9% for those with 4 + children. Compared to the reference group of individuals with 2–3 children, the dementia risk was higher among the groups with no children (relative risk (RR): 1.30, 95% confidence interval (CI) (1.12, 1.51)), those with one child (RR: 1.30, 95% CI (1.14, 1.47)) and those with 4 + children (RR: 1.12, 95% CI (1.01, 1.24)). The elevated risks of dementia were not mediated by the socioeconomic, psychosocial, lifestyle, or chronic diseases related factors that we tested. Sex-stratified analysis showed higher dementia risk for men without children and women with one or 4 + children compared to those with 2–3 children, with similar patterns across sexes. None of the mediators contributed to mediation in either group. None of the mediators appeared to contribute through mediation in either group.

Conclusions:
Our findings suggest that the number of children—specifically being childless, having one child, or having four or more children—may influence the risk of dementia. These relationships were not mediated by psychosocial, lifestyle, and socioeconomic factors, or markers of chronic diseases in adulthood considered in this study.

Teferi Mekonnen, Vegard Skirbekk, Ekaterina Zotcheva, Bo Engdahl, Bernt Bratsberg, Astanand Jugessur, Catherine Bowen, Geir Selbæk, Hans-Peter Kohler, Jennifer R. Harris, Sarah E. Tom, Steinar Krokstad, Trine Holt Edwin, Yehani Wedatilake, Katrin Wolfova, Dana Kristjansson, Yaakov Stern, Asta Kristine Håberg & Bjørn Heine Strand

Introduction
Informal care estimates for use in health-economic models are lacking. We aimed to estimate the association between informal care time and dementia symptoms across Europe.
Methods
A secondary analysis was performed on 13,529 observations in 5,369 persons from 9 European pooled cohort or trial studies in community-dwelling persons with dementia. A mixed regression model was fitted to time spent on instrumental or basic activities of daily living using disease severity and demographic characteristics.
Results
Daily informal care time was 0.5 hours higher in moderate compared to mild and 1.3h higher in severe compared to mild cognitive impairment. Likewise, this was 1.2h and 2.7h for functional disability and 0.3h and 0.6h for behavioral symptoms in the same directions.
Discussion
Estimates can be used in both single- and multi-domain health-economic models for dementia in European settings.

Ron Handels, Somboon Hataiyusuk, Anders Wimo, Anders Sköldunger, Christian Bakker, Anja Bieber, Alfonso Ciccone, Carlo Alberto Defanti, Andrea Fabbo, Sara Fascendini, Lutz Frölich, Chloé Gervès-Pinquié, Manuel Gonçalves-Pereira, Kate Irving, Raymond Koopmans, Patrizia Mecocci, Paola Merlo, Bernhard Michalowsky, Oliver Peters, Yolande Pijnenburg, Óscar Ribeiro, Geir Salbaek, Larissa Schwarzkopf, Hilde Verbeek, Marjolein de Vugt, Bob Woods, Orazio Zanetti, Bengt Winblad, Linus Jönsson; Actifcare consortium, ICTUS/DSA group, PLASA/DSA group, RECAGE consortium, RightTimePlaceCare consortium

Abstract:

Purpose: Being a young carer of a parent with dementia can be challenging, with many carers undertaking various practical and caring tasks. The weekend course Time to be young? gathers young carers, aiming to support them to cope with their challenges in everyday life. The aim of this study was to explore their role as a caregiver and the experienced impact of the course on their strategies of coping in their everyday life.

Participants and Methods: The study had a qualitative descriptive design inspired by Lindseth and Norberg’s phenomenological hermeneutical method, using individual semi-structured interviews for data collection. The participants were recruited from former participants of the course Time to be young?, and the final sample included eight participants.
Results: Through the analysis, four main themes were identified: 1) Help to accept the situation, 2) A sense of community, 3) The need for information and 4) The need to live one’s own life. The study found that attendance at Time to be young? for young adults having a parent with dementia affected their coping strategies in their situation as a young care.
Conclusion: The study demonstrated the importance of courses like Time to be young?, and need for a meeting place, tailored information about dementia, and an opportunity to share and reflect upon their experiences as a young carer.

Celine Haaland-Johansen, Ingebjørg Haugen & Anne Marie Mork Rokstad

Online ahead of print.

Background: Sense of coherence (SOC) is a disposition to perceive things as comprehensible, manageable and meaningful. Lower SOC is associated with subjective burden and psychological morbidity in family caregivers, including in dementia. However, the evidence-base mainly comprises small-scale or cross-sectional studies. More should be known about SOC stability, causal relationships, and international contexts. We aimed to study longitudinal links between dementia caregivers’ SOC, subjective burden, and anxiety and depression symptoms in a multinational sample.

Methods: We analyzed the EU-Actifcare cohort (451 dyads of community-dwelling people with mild-moderate dementia and their caregivers). Caregivers’ assessments included: SOC scale, Relatives’ Stress Scale, Hospital Anxiety and Depression Scale. A cross-lagged panel model was used to investigate associations between these measures at baseline, 6 and 12-month follow-ups, controlling for covariates.

Results: Caregivers’ subjective burden, anxiety and depression symptoms increased over time, SOC remaining overall stable. Considering the first six-month follow-up, we found bidirectional relationships between SOC and subjective burden, and SOC and anxiety symptoms, while lower SOC predicted depression symptoms but not vice versa. For the remaining follow-up period, both anxiety and depression symptoms predicted lower SOC but not vice versa.

Limitations: Convenience sampling precludes full generalizability.

Conclusions: This large longitudinal study shed more light on interplays between SOC, subjective burden and mental health outcomes in dementia caregivers. Findings were consistent with SOC potential protective role against burden and psychological morbidity. However, they also supported reverse causality regarding part of the associations. Caregivers’ SOC levels may be directly influenced by subjective burden and psychological morbidity.

Manuel Gonçalves-Pereira, Maria J Marques, Regina F Alves, Hannah Jelley, Claire Wolfs, Gabriele Meyer, Anja Bieber, Kate Irving, Louise Hopper, Orazio Zanetti, Daniel M Portolani, Geir Selbaek, Janne Røsvik, Anders Sköldunger, Britt-Marie Sjölund, Marjolein de Vugt, Frans Verhey, Bob Woods

Abstract

Objectives: Dementia significantly impacts quality of life, health care costs, and caregiver burden, being a leading cause of death among older adults. We investigated predictors of mortality in people with severe behavioral and psychological symptoms of dementia (BPSD).

Design: A multicentric longitudinal observational study was conducted, comprising clinical assessments at baseline and every 6 months for 3 years.

Setting and participants: People with severe BPSD (Neuropsychiatric Inventory, NPI ≥32) living at home.

Methods: Data on demographics and clinical characteristics were collected at baseline and during 6-monthly follow-ups over 3 years. The main outcome was mortality, documented over a total period of 4 years and analyzed using the Cox proportional hazards model.

Results: Of the 508 patients with dementia with severe BPSD, 165 (32.5%) died during the 4-year follow-up. Non-survivors were older (79.8 ± 7.7 vs 77.3 ± 8.0; P < .001), more likely to be male (58.8% vs 38.5%; P < .001), and had higher BPSD severity (NPI: 57.2 ± 20.2 vs 50.3 ± 17.9; P < .001), lower cognitive function according to the Mini-Mental State Examination (MMSE) (13.5 ± 6.6 vs 16.4 ± 5.9; P < .001), and worse functional status according to the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Scale (ADCS) (28.8 ± 16.4 vs 36.3 ± 17.2; P < .001) at baseline. Significant predictors of mortality included male sex (hazard ratio [HR], 2.03; 95% confidence interval [95% CI], 1.46-2.82; P < .001), older age at diagnosis (HR, 1.05; 95% CI, 1.03-1.07; P < .001), higher NPI scores (HR, 1.01; 95% CI, 1.01-1.02; P = .002), lower MMSE (HR, 0.95; 95% CI, 0.93-0.98; P = .001), lower ADCS (HR, 0.98; 95% CI, 0.98-0.99; P = .015), and lower quality of life rated by proxy (HR, 0.97; 95% CI, 0.95-0.99; P = .021). The use of antidepressants (HR, 0.69; 95% CI, 0.48-0.98; P = .038) was associated with increased survival. Delusions (HR, 1.0; 95% CI, 1.03-1.12; P < .001), hallucinations (HR, 1.07; 95% CI, 1.02-1.11; P = .002), and agitation/aggression (HR, 1.05; 95% CI, 1.01-1.09; P = .021) were significantly linked to increased mortality.

Conclusions and implications: Older age, male sex, severe BPSD, and lower cognitive and quality of life scores significantly predict increased mortality in patients with severe BPSD.

Aline Mendes, François R Herrmann, Sverre Bergh, Bruno Mario Cesana, Ron Handels, Alfonso Ciccone, Emmanuel Cognat, Andrea Fabbo, Sara Fascendini, Giovanni B Frisoni, Lutz Froelich, Maria Cristina Jori, Patrizia Mecocci, Paola Merlo, Oliver Peters, Magdalini Tsolaki, Carlo Alberto Defanti

Abstract:
Introduction: It is unclear how midlife depression and anxiety affect dementia risk. We examined this in a Norwegian cohort followed for 30 years.

Methods: Dementia status at age 70+ in the fourth wave of the Trøndelag Health Study (HUNT4, 2017-2019, N = 9745) was linked with anxiety and depression from HUNT1 (1984-1985), HUNT2 (1995-1997), HUNT3 (2006-2008), and HUNT4. Longitudinal anxiety and depression score, and prevalence trajectories during 1984-2019 by dementia status at HUNT4 were fitted using mixed effects regression adjusting for age, sex, education, and lifestyle and health factors.

Results: Dementia at HUNT4 was associated with higher case prevalence at all waves, from 1.9 percentage points (pp) (95% CI: 0.1-3.7) higher at HUNT1 to 7.6 pp (95% CI: 5.7-9.6) higher at HUNT4.

Discussion: Our findings show that depression and anxiety was more common more than 30 years before dementia onset in those who later developed dementia.

Highlights: Older individuals with dementia had a higher prevalence of mixed anxiety- and depressive symptoms (A + D), both concurrently with and more than three decades prior to their dementia diagnosis. Older individuals with dementia had higher levels of anxiety, both concurrently and up to two decades prior to their dementia diagnosis. Depressive symptoms increased by time among those who developed dementia, but not among others. Results were similar for all cause dementia, Alzheimer’s disease, and other types of dementia; however, for vascular dementia, the difference was not significant until dementia was present.

Ragnhild Holmberg Aunsmo, Bjørn Heine Strand, Kaarin J. Anstey, Sverre Bergh, Mika Kivimäki, Sebastian Köhler, Steinar Krokstad, Gill Livingston, Fiona E. Matthews, Geir Selbæk

Abstract:

Objective: What are the core capabilities physiotherapists need to deliver quality care when working with people with dementia and their families/caregivers?

Design: A three-round modified e-Delphi study.

Participants: Panel members were physiotherapists experienced in working with people with dementia and/or educating and/or researching in the dementia field.

Methods: A steering group (16 international physiotherapists and a consumer) developed a draft framework including 129 core capabilities across 5 domains for panel members to rate their appropriateness for inclusion as a core capability to provide high quality care to people with dementia and their caregivers/families. The RAND/UCLA method was used to assess consensus.

Results: Thirty-five physiotherapists from 11 countries participated in Round 1, 31 (89%) in Round 2 and 28 (80% of Round 1) in Round 3. All core capabilities were rated appropriate for inclusion in each round. Panel members recommended wording refinements across the rounds and suggested 51 core capabilities for consideration. Three rounds were needed to reach consensus, resulting in 137 core capabilities rated appropriate for inclusion across 5 domains: 1) Knowledge and understanding, n = 36; 2) Assessment, n = 39; 3) Management, interventions and prevention n = 40; 4) Communication, therapeutic relationship and person-centred care, n = 17; and 5) Physiotherapists self-management and improvement, n = 5.

Conclusions: This e-Delphi study outlines the core capabilities physiotherapists need to provide high quality care to people with dementia and their families/caregivers. These core capabilities can be used by physiotherapists to help identify knowledge/skill gaps, as well as by educators to improve their training of undergraduate and postgraduate students, and clinicians.

Morag E Taylor, Karen Sverdrup, Julie Ries, Erik Rosendahl, Gro Gujord Tangen, Elisabeth Telenius, Katherine Lawler, Keith Hill, Annika Toots, Hans Hobbelen, Vanina Dal Bello-Haas, Abi Hall, Susan W Hunter, Victoria A Goodwin, Julie Whitney, Michele L Callisaya