Forskningsartikler

Abstract

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer’s disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+–SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.

Jun-Ping Pan  (潘君平), Ping-Jie Wang  (王平洁), Jianying Zhang  (张剑英), Anne-Brita Knapskog, Leiv Otto Watne, He-Ling Wang  (王鹤龄), Maria Jose Lagartos-Donate, Sofie Lautrup, Li-Peng Mao  (茅立鹏), Qian Wang  (王倩), Zhi-Peng Ling  (凌志鹏), Shi-qi Zhang  (张诗琦), Tomás Schmauck-Medina, Ruixue Ai  (艾瑞雪), Trine Holt Edwin, Tianjiao Zhang  (张天娇), Ingvild Saltvedt, Rannveig Sakshaug Eldholm, Annabel Smith, Kateřina Veverová, Domenica Caponio, Asgeir Kobro-Flatmoen, Huanhuan Pang  (庞欢欢), Zijian Wang  (王子健), Haoyun Wang  (王昊云), Li-juan Gao  (高利娟), Nathalie Bodd Halaas, Garry Wong, Martin Vyhnalek, Oscar Junhong Luo  (罗钧洪), William A. McEwan, Jon Storm-Mathisen, Li Gan, Zeping Hu  (胡泽平), Henrik Zetterberg, Menno P. Witter, Dag Aarsland, Geir Selbæk, Guobing Chen  (陈国兵) & Evandro Fei Fang  (方飛)

Sammendrag
Bakgrunn: Nærmere 90 % av norske kommuner har et hukommelsesteam eller en ressursperson for demens, men det er lite kunnskap om innholdet i tjenestene og hvordan teamene ivaretar sine oppgaver.

Metode: Hensikten med studien var å undersøke og beskrive ansatte i hukommelsesteams erfaringer med organisering, rammefaktorer og ivaretagelse av oppgaver. Vi gjennomførte fire fokusgruppeintervjuer med 18 ansatte i hukommelsesteam fra ulike deler av landet. Intervjuene ble analysert i tråd med prinsipper for innholdsanalyse.

Hovedresultater: Deltagerne beskrev ingen sammenheng mellom kommunestørrelse og hukommelsesteametsstørrelse. De opplevde et stort sprik mellom behov og ressurser. Hukommelsesteamene trakk frem at samarbeidetmed fastlegen er svært viktig, men samarbeidet er sårbart, og mange kommuner mangler arenaer og systematikk for samarbeid. Mangel på kommunale planer og prioriteringer gjør at det er opp til teamene selv å prioritere de knappe ressursene de har.

Konklusjon: Resultatene fra studien indikerer et behov for at kommunene gir hukommelsesteamene en tydelig posisjon i organiseringen av tilbudet til personer med demens og deres familier. Det synes å være behov for økte ressurser, tydeligere retning for prioritering og kvalitet, samt tilrettelegging av arenaer for samarbeid internt i kommunene, spesielt med fastleger.

Siren Eriksen, Mona Michelet, Klaus Amundsen, Hege Askestad, Thea Cathrine Bredholt, Torunn Edøy, Knut Engedal, Marianne Lingner, Kjersti Løkken Aakerholm, Trude Irene Solberg & Anne Marie Mork Rokstad

Abstract

Clarissa Giebel, Rabih Chattat, Iva Holmerova, Louise Hopper, Jurate
Macijauskiene, Megan Rose Readman, Oscar Ribeiro, Anne Marie Rokstad,
Anthony Scerri, Dorota Szczesniak, Catherine Talbot, Jochen Rene Thyrian,
Lindsay Groenvynck, Marco Brigiano, Gill Windle & on behalf of the
INTERDEM Taskforce on Inequalities in Dementia

Sara E. Stinson, Alexey A. Shadrin, Zillur Rahman, Linn Rødevand, Iris J. Broce, Geir Selbæk, Hreinn Stefansson, Jan Haavik, Nadine Parker, Elise Koch, Oleksandr Frei, Kevin S. O’Connell, Olav B. Smeland, Srdjan Djurovic, Anders M. Dale, Dennis van der Meer, Ole A. Andreassen

Abstract

Objective: Accurate cognitive screening tests for culturally, linguistically, and educationally diverse populations remain scarce, contributing to diagnostic inequities. To address this, we examined the cross-cultural properties and diagnostic accuracy of the Multicultural Cognitive Examination (MCE) in classifying mild cognitive impairment (MCI), dementia, Alzheimer’s disease (AD) dementia, and non-AD dementia in participants with diverse backgrounds.

Method: In this retrospective cross-sectional study, we aggregated data from 1,449 participants across 11 countries. Multiple linear regression models were used to determine the influence of demographic variables on MCE scores, which informed the creation of regression-based normative data. Diagnostic accuracies were examined using Receiver Operating Characteristics (ROC) curves.

Results: The cohort consisted of 1001 cognitively intact participants, 140 patients with MCI, and 308 patients with dementia. 54.2% had immigrant backgrounds and originated from 63 different countries. MCE scores were significantly influenced by education and age, but not by sex or immigrant status. The MCE demonstrated high accuracy in differentiating cognitively intact participants from patients with dementia (AUC: .95) and MCI (AUC: .84). The MCE was both accurate for classifying AD dementia (AUC: .97) and non-AD dementia (AUC: .94).

Conclusions: This study supports the clinical utility of the MCE as a culturally robust and highly accurate cognitive screening test. Future studies should examine the ability of the MCE to monitor cognitive decline.

Daniel Kjaergaard, Alfonso Delgado-Álvarez, Gunhild Waldemar, Ulrike Beinhoff, Peter Bekkhus-Wetterberg, Sanne Franzen, Caitlin H Illingworth, Jerson Laks, Alvaro Lozano-Ruiz, Andreas Lueschow, Jordi A Matias-Guiu, Simone Pomati, Kurt Segers, Rozita Torkpoor, Jørgen Wagle, T Rune Nielsen

Abstract

Objectives: This study explores how healthcare professionals in Norwegian municipal memory teams experience working as case managers for people with dementia and their informal caregivers, and the approaches they employ to fulfil this role.

Method: A qualitative descriptive design was employed, using focus groups with 18 case managers from a range of municipalities. Data were analysed using thematic content analysis.

Results: Three overarching themes emerged: (1) tailoring support, (2) being committed and available, and (3) contributing to cooperation and competence development. Participants described how they adapted services to individual needs throughout the dementia trajectory, drawing on both professional expertise and personal resources. While the role was experienced as meaningful, it was also described as demanding, involving high levels of personal involvement and vulnerability due to limited resources. Case managers also played a key role in competence development and multidisciplinary collaboration.

Conclusion: The case manager role facilitates flexible, person-centred support, and continuity of care. However, its effectiveness is highly dependent on individual commitment and is vulnerable to resource constraints. Strengthening structural and professional conditions is essential to ensure the delivery of high-quality dementia care.

Mona Michelet, Siren Eriksen, Kariann Krohne, Thea C Bredholt, Knut Engedal, Hege Askestad, Trude Solberg, Anne Marie Mork Rokstad

Abstract:

Background: Neuropsychiatric symptoms (NPS) are highly prevalent in nursing home residents. The main aims of this study were to examine whether music-based care (MBC) had sustained effects on NPS in nursing home residents with dementia and chronic pain and to describe the distribution of NPS.

Methods: A secondary analysis of a cluster-randomised controlled trial with intervention and control groups was performed. The 8-week MBC intervention included daily individualised prerecorded music integration. A large sample of nursing home residents with dementia and chronic pain in 12 nursing homes in Norway were screened for pain and dementia by experts and included in the study. The Neuropsychiatric Inventory Nursing Home Edition (NPI-NH) was completed for the residents at pre-test and after the 8-week MBC intervention. Descriptive statistics were used to characterise the sample, and multilevel mixed model analysis assessed the difference in change in NPI-NH scores before and after the intervention between the groups.

Results: The sample (n = 232) had a mean age of 86 years (SD 8.8), with 71% being female. Overall, 41%, 38% and 21% had severe, moderate or mild dementia, respectively, while 77% had moderate pain and 23% severe pain. Over two-thirds (68%) of the sample had at least one clinically important (≥ 4) NPI-NH symptom at pre-test, with mean NPI-NH total score of 19 (range 0–89). The most commonly identified NPI-NH subcategories were agitation (44%), affective symptoms (34%) and psychosis (25%) at pre-test. There was no significant difference in changes either comparing the NPI-NH total score (p = 0.396) (confidence interval: CI [–2.6 to 6.6]) between the intervention group (n = 108) and the control group (n = 124) or comparing any of the three NPI subcategories: psychosis (p = 0.203) (CI [–0.5 to 2.3]), agitation (p = 0.830) (CI [–2.3 to 1.8]) or affective symptoms (p = 0.447) (CI [–0.9 to 2.1]).

Conclusions: No statistically significant sustained effect of the MBC intervention on NPI symptoms was found among residents with dementia and chronic pain. Future studies should include measurement points closer to the intervention to evaluate short-term effects of MBC.

Martin Elstad Myrenget, Reidun Sandvik, Petter Borchgrevink, Geir Selbæk, Milada Småstuen, Vegar Rangul, Odd Håpnes, Audun Myskja, Bettina Husebø, Tone Rustøen

ABSTRACT
Background Subjective memory impairment (SMI) is used as a proxy for objective memory, although their relationship remains unclear. Moreover, SMI is suggested to be a risk factor for dementia. This study investigated associations between SMI and (1) concurrent objective memory performance, (2) early‐life general cognitive abilities (GCA), and (3) if SMI and objective memory scores were associated with distinct or overlapping sociodemographic, health, and lifestyle risk factors for dementia. Material and Methods 2690 participants between 30 and 90 years from the general, geographical population study HUNT4 were included. SMI scores were from the Meta‐Memory‐Questionnaire. Verbal, spatial, and ability to differentiate between similar representations (pattern separation) were tested concurrently. GCA was from conscription at age 18. We implemented multiple imputation and inverse probability weighting from the entire population to account for selection bias. Results Higher SMI scores were associated with verbal memory and GCA, but not spatial or pattern separation memory. There was an interaction between sex and verbal memory on SMI, with men reporting higher SMI than women at similar lower verbal memory performance. Higher SMI scores were associated with higher age, blood pressure, depression, sleep, fatigue, and chronic pain, but not APOE4 or lifestyle variables. All memory tests were positively associated with each other and negatively with age. Diabetes was associated with verbal memory. Conclusion In the general population, SMI was weakly linked to concurrent verbal memory and GCA in adolescence. Health, in particular mental health, was highly associated with SMI but not objective memory performance. Thus, SMI is a complement to memory testing, not a proxy.

Simon Holmvik, Daniel Radosław Sokołowski, Ragnhild Bergene Skråstad, Olav Spigset, Bjørn Heine Strand, Asta Kristine Håberg

Abstarct

Objective: To evaluate and compare the predictive value of eight dementia risk scores for late-life cognitive function and cognitive decline; ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS(-APOE), and a Lancet commission-based risk score.

Methods: Using Norwegian Trøndelag Health Study (HUNT) data, we calculated risk scores from lifestyle and health data of 7221 dementia-free participants (mean age: 76.8 years, 54.1% female) collected in HUNT3 (2006–2008). Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA) 11 years later in HUNT4 70+, and reassessed in 4716 participants 4 years thereafter. Associations between continuous risk scores or risk score tertiles, cognition and cognitive decline were examined using linear mixed-effects models. Logistic regression models were used to test associations between risk scores and a ≥ 3-point decline in MoCA scores.

Results: All risk scores were significantly associated with cognitive function and cognitive decline. Associations with cognitive function ranged from UKBDRS β per 1SD=-1.61(95%CI:-1.72,-1.51) to CAIDE (β=-0.74;95%CI:-0.82,-0.67), and with yearly cognitive decline from Lancet (β=-0.23;95%CI:-0.27,-0.18) to CAIDE (β=-0.04;95%CI:-0.07,-0.02). High-low risk group differences in cognitive function were largest for CogDrisk (β=-3.04;95%CI:-3.27,-2.81), LIBRA (β=-3.04;95%CI:-3.27,-2.80) and lowest for CAIDE (β=-1.65;95%CI:-1.86,-1.44). High-risk groups showed the steepest decline for UKBDRS-APOE (β=-0.43;95%CI:-0.52,-0.34), Lancet (β=-0.39;95%CI:-0.48,-0.30), and LIBRA (β=-0.38;95%CI:-0.47,-0.28). All scores predicted ≥3-point decline modestly: AUCs were highest for UKBDRS (AUC=0.61;95%CI:0.60,0.63), UKBDRS-APOE (0.61;95%CI:0.60,0.63), CogDrisk (0.60;95%CI:0.58,0.62), and Lancet (0.60;95%CI:0.58,0.61), but none outperformed a model including age and education alone (0.61;95%CI:0.60,0.63).

Conclusion: Risk scores captured meaningful gradients in cognition and decline but offered limited discriminatory accuracy beyond demographics, supporting their use for prevention-oriented risk profiling rather than prediction.

Josephine Stuebs, Geir Selbæk, Bjørn Heine Strand, Gill Livingston, Kaarin J. Anstey, Kay Deckers, Mika Kivimäki, Steinar Krokstad, Fiona E. Mathews & Ellen Melbye Langballe