Trine Holt Edwin

• Pan, Junping; Wang, Ping-Jie; Zhang, Jianying; Knapskog, Anne-Brita; Watne, Leiv Otto & Wang, He-Ling [Show all 40 contributors for this article] (2026). Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer’s disease pathology. Nature Aging. 6(5), p. 1079–1102. doi: 10.1038/s43587-026-01108-z. Full text in Research Archive
• Sandvig, Heidi Vihovde; Saltvedt, Ingvild Tina; Edwin, Trine Holt; Aam, Stina; Alme, Katinka Nordheim & Eldholm, Rannveig Sakshaug [Show all 13 contributors for this article] (2025). Associations between systemic inflammation and cognitive trajectories post-stroke. Scientific Reports. 15(1), p. 1–13. doi: 10.1038/s41598-025-27119-1. Full text in Research Archive Show summary

  Our objective was to explore whether plasma inflammatory biomarkers and related metabolites in acute phase and 3 months after stroke were associated with different cognitive trajectories and with changes in cognition post-stroke. The Norwegian Cognitive Impairment After Stroke (Nor-COAST) study was a prospective, multicentre cohort study of patients with acute stroke, followed up at 3, 18, and 36 months post-stroke. First, we modelled cognitive trajectory groups based on Montreal Cognitive Assessment (MoCA) scores and used multinominal logistic regression to study the associations between systemic inflammatory biomarkers/metabolites and group membership. Second, using mixed linear regression, we investigated whether the same biomarkers/metabolites were associated with changes in MoCA scores over time, stratified by pre-stroke cognitive status. The 466 participants had mean (SD) age 72 (12) years, 59% were males, and mean (SD) NIHSS score at admittance was 4 (4.8). Higher acute-phase values of the terminal complement complex, interleukin 6, macrophage inflammatory protein 1α, neopterin, quinolinic acid, and PA ratio = 4-pyridoxic acid / (pyridoxal + pyridoxal 5’-phosphate) and higher 3-month values of neopterin were associated with increased risk of being in the group characterized by low and declining MoCA score compared to the group of best MoCA score (p < 0.01). Higher acute-phase values of tumour necrosis factor and interleukin 8, were associated with progressive decline in the MoCA score (p < 0.01). Premorbid factors, and in particular pre-stroke frailty, had more impact on the models than stroke-related factors, and partly confounded several of these associations. Higher degrees of systemic inflammation in the acute phase were associated with worse cognitive trajectories and may reflect the response to the acute stroke, stroke-related complications and/or premorbid conditions. Trial registration: ClinicalTrials.gov: NCT02650531. Retrospectively registered January 8, 2016. First participant included May 18, 2015.

• Nordnes, Per Raymond; Edwin, Trine Holt; Flak, Marianne Møretrø; Løhaugen, Gro; Skranes, Jon Sverre & Chang, Linda [Show all 9 contributors for this article] (2025). The effect of working memory training on patient and informant reported executive function in mild cognitive impairment: an interventional study. BMC Neurology. 25(404). doi: 10.1186/s12883-025-04381-4. Full text in Research Archive Show summary

  Background Self-reported outcome measures are rarely described in individuals with mild cognitive impairment (MCI). In this study, we investigated the effect of computerized working memory training on self- and relatives reported executive function measures. Methods A total of 50 individuals with MCI were recruited from five memory clinics in Southern Norway and underwent a 5-week/20–25 sessions computerized working memory training program. Both individuals and relatives scored the “Behavior Rating Inventory of Executive Function for Adults” (BRIEF-A) before, and at least four months after finalizing training. Statistical analyses included paired t-tests and mixed ANOVA with rater type (participant/informant) and time (baseline/4-months). Results Mixed ANOVA revealed significant (adjusted p  ≤ 0.025) participant-informant x time interactions for Working Memory, Metacognition Index and Global Executive Composite, suggesting that the changes in ratings over time differed between participants and informants. Post hoc tests revealed that at baseline participants rated themselves as significantly more impaired (adjusted p  ≤ 0.036) than informants on the Working Memory scale, the Metacognitive Index and the Global Executive Composite. After training, no significant differences were found between participant and informant reports. After training participants reported significant improvements on Working Memory (adjusted p  = 0.038), Metacognition Index (adjusted p  = 0.038), with working memory improving from above the established clinically significant impairment threshold to the normal range. The change in Global Executive Composite was not significant after correction for multiple comparisons (adjusted p  = 0.057). No significant changes were found for relatives’ reported scores between the two time points. Excluding participants developing dementia during the study enhanced the difference in mean values before and after the intervention for these outcomes. Conclusion Computerized working memory training significantly improved self-reported executive function in individuals with MCI. While informant reports remained stable, the prior significant discrepancy between self- and informant ratings converged after training due to this improvement. These findings suggest that training can enhance subjective cognitive experience and awareness, offering potential clinical benefits for individuals with MCI. Our study highlights self-report measures as valuable and sensitive outcomes in MCI interventions, capturing the personal experiences of cognitive change. Trial registration ClinicalTrials.gov, NCT01991405. Registered on 18.11.2013.

• Persson, Karin Ester Torun; Rhodius-Meester, Hanneke Frederica Maria; Edwin, Trine Holt; Knapskog, Anne-Brita; Wetterberg, Peter & Selbæk, Geir [Show all 8 contributors for this article] (2025). Automatic MRI Volumetry Assisted Visual Assessment of the Medial Temporal Lobe in Clinical Dementia Work‐Up. Brain and Behavior. 15(10), p. 1–9. doi: 10.1002/brb3.70948. Full text in Research Archive Show summary

  ABSTRACT Introduction: Efficient and cost‐effective diagnostic tools for supporting dementia assessment are increasingly important. We aimed to evaluate whether providing neuroradiologists with volumetric data from an automatic MRI software, NeuroQuant, enhanced the diagnostic accuracy of their visual MRI assessment. Methods: Two neuroradiologists assessed brain MRIs from 366 patients (mean age 67.5 years, SD 9.2, and 52% females) with subjective cognitive decline (SCD, n 79), mild cognitive impairment (MCI, n 86), or dementia ( n 201). The MCI and dementia patients were further diagnosed according to an etiology of Alzheimer's disease (AD, n 217) versus non‐AD ( n 70). In random order the neuroradiologists visually evaluated medial temporal lobe atrophy (MTA, scale 0–4) with and without having access to the NeuroQuant report of age and sex adjusted volumetric percentiles of the hippocampus. Receiver operating characteristics (ROCs) analyses were conducted to calculate the area under the curves (AUCs) for the visual MTA, the automated NeuroQuant percentile, and the combined NeuroQuant‐assisted MTA in discriminating dementia from SCD and AD from non‐AD. Results: The AUC of the visual MTA for dementia versus SCD discrimination increased slightly but not significantly when the neuroradiologists were provided with NeuroQuant results (AUC 0.76–0.79, p 0.28). Yet, the isolated NeuroQuant evaluation reached the highest accuracy (AUC 0.85, p  < 0.001), significantly better than the MTA assessment ( p 0.002) and the NeuroQuant‐assisted MTA ( p 0.04). Only the isolated NeuroQuant assessment discriminated AD from non‐AD (AUC 0.60, p 0.006). Conclusion: On the basis of our findings, we suggest an increased use of clinically approved automatic volumetry methods in radiological departments.

• Bratsberg, Bernt Magne; Harris, Jennifer Ruth; Skirbekk, Vegard Fykse; Stern, Yaakov; Håberg, Asta & Selbæk, Geir [Show all 8 contributors for this article] (2025). Occupational social interaction is associated with reduced dementia risk: The Trøndelag Health Study (HUNT). Psychology and Aging. ISSN 0882-7974. 41(1), p. 12–24. doi: 10.1037/pag0000940. Full text in Research Archive Show summary

  Lifetime social engagement could build cognitive reserve and lower the risk of dementia through compensatory effects on brain health. We aimed to investigate whether social interaction at work is protective of later-life cognitive impairment. Data from 9,248 participants of the population-based Norwegian HUNT4 70+ Study (2017-2019), with cognitive assessments at or after age 70, were linked retrospectively to longitudinal registry-based employment information spanning ages 30-65 years. An occupational social interaction score was computed using occupational characteristics from the O*NET database. Multinomial logistic regression was used to estimate the associations between occupational social interaction and dementia and mild cognitive impairment (MCI), while linear regression was used to model the association with cognition using the Montreal Cognitive Assessment (MoCA). The models were subsequently adjusted for confounding variables age, sex, education, and apolipoprotein E-ε4 genotype, as well as for midlife family, health, and lifestyle-related variables collected from national registries and earlier Trøndelag Health Study waves. Higher occupational social interaction was associated with reduced risks of dementia and MCI, and better MoCA performance. Adjusted for confounding from age, sex, education, and apolipoprotein E-ε4, each standard deviation higher occupational social interaction score was associated with a relative risk ratio of 0.89 for dementia (p = .003), 0.88 for MCI (p < .001), and a 0.31-point higher MoCA score (p < .001). Our findings highlight the importance of occupational social interaction in preserving and promoting cognitive health in later life

• Ustad, Astrid; Edwin, Trine Holt; Melsæter, Kjerstin Næss; Sverdrup, Karen; Tangen, Gro Gujord & Døhl, Øystein [Show all 9 contributors for this article] (2025). Daily physical activity and trajectories of care service use among older adults: the HUNT4 Trondheim 70+ study. Frontiers in Public Health. 13. doi: 10.3389/fpubh.2025.1539179. Full text in Research Archive
• Yitayew, Teferi Mekonnen; Skirbekk, Vegard Fykse; Håberg, Asta; Engdahl, Bo Lars; Zotcheva, Ekaterina & Jugessur, Astanand [Show all 18 contributors for this article] (2025). Mediators of educational differences in dementia risk later in life: evidence from the HUNT study. BMC Public Health. 25, p. 1–12. doi: 10.1186/s12889-025-22592-9. Full text in Research Archive Show summary

  Despite a well-known inverse association between education and dementia risk, the mediating mechanisms are not well understood. We explored how lifestyle and health risk factors across the life-course mediate the relationship between education and dementia among adults aged 70 + years. We included 7,655 participants with dementia diagnoses and education information, using a historical cohort design linking prospective exposure data across the life course from the HUNT4 70 + Study with registry data from Statistics Norway and earlier HUNT surveys. We conducted causal mediation analysis to assess the mediating roles of occupational characteristics, lifestyle factors (smoking, physical inactivity), and health risk factors (obesity, hypertension, diabetes, hearing impairment, cardiovascular diseases, LDL cholesterol, depression, anxiety) assessed during early, middle, and late adulthood in the relationship between education and dementia in later life. Participants with lower education were more likely to have dementia with odds ratios of 1.99, 1.88, 1.83 for the model’s accounting exposure to mediators during early, middle, and late adulthood, respectively. These associations were partially mediated by the joint effect of health and lifestyle risk factors from early through late adulthood (mediated 11.55–19.50%). Health risk factors from early to late adulthood jointly mediated 6.85–13.06% of the effect of low education on dementia risk later in life. Additionally, lifestyle factors during middle and late adulthood jointly mediated 4.11–4.96% of the total effect of low education on dementia risk later in life. Educational differences in dementia risk can partly mediated by lifestyle and health factors across the life course. These findings suggest potential targets to address varying dementia risks linked to education levels.

• Mekonnen, Teferi; Skirbekk, Vegard; Zotcheva, Ekaterina; Engdahl, Bo; Bratsberg, Bernt & Jugessur, Astanand [Show all 19 contributors for this article] (2025). Number of children and dementia risk: a causal mediation analysis using data from the HUNT study linked with national registries in Norway. BMC Neurology. 25(1). doi: 10.1186/s12883-025-04044-4. Full text in Research Archive Show summary

  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.

• Edwin, Trine Holt; Håberg, Asta; Zotcheva, Ekaterina; Bratsberg, Bernt Magne; Jugessur, Astanand & Engdahl, Bo Lars [Show all 16 contributors for this article] (2024). Trajectories of Occupational Cognitive Demands and Risk of Mild Cognitive Impairment and Dementia in Later Life The HUNT4 70+ Study. Neurology. ISSN 0028-3878. 102(9). doi: 10.1212/WNL.0000000000209353. Full text in Research Archive
• Amland, Rachel; Selbæk, Geir; Brækhus, Anne; Edwin, Trine Holt; Engedal, Knut & Knapskog, Anne-Brita [Show all 8 contributors for this article] (2024). Clinically feasible automated MRI volumetry of the brain as a prognostic marker in subjective and mild cognitive impairment. Frontiers in Neurology. 15. doi: 10.3389/fneur.2024.1425502. Full text in Research Archive Show summary

  Background/aims: The number of patients suffering from cognitive decline and dementia increases, and new possible treatments are being developed. Thus, the need for time efficient and cost-effective methods to facilitate an early diagnosis and prediction of future cognitive decline in patients with early cognitive symptoms is becoming increasingly important. The aim of this study was to evaluate whether an MRI based software, NeuroQuant® (NQ), producing volumetry of the hippocampus and whole brain volume (WBV) could predict: (1) conversion from subjective cognitive decline (SCD) at baseline to mild cognitive impairment (MCI) or dementia at follow-up, and from MCI at baseline to dementia at follow-up and (2) progression of cognitive and functional decline defined as an annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. Methods: MRI was performed in 156 patients with SCD or MCI from the memory clinic at Oslo University Hospital (OUH) that had been assessed with NQ and had a clinical follow-up examination. Logistic and linear regression analyses were performed with hippocampus volume and WBV as independent variables, and conversion or progression as dependent variables, adjusting for demographic and other relevant covariates including Mini-Mental State Examination-Norwegian Revised Version score (MMSE-NR) and Apolipoprotein E ɛ4 (APOE ɛ4) carrier status. Results: Hippocampus volume, but not WBV, was associated with conversion to MCI or dementia, but neither were associated with conversion when adjusting for MMSE-NR. Both hippocampus volume and WBV were associated with progression as measured by the annual change in CDR-SB score in both unadjusted and adjusted analyses. Conclusion: The results indicate that automated regional MRI volumetry of the hippocampus and WBV can be useful in predicting further cognitive decline in patients with early cognitive symptoms.

• Knapskog, Anne-Brita; Edwin, Trine Holt; Ueland, Per Magne; Ulvik, Arve; Fang, Fei & Eldholm, Rannveig Sakshaug [Show all 11 contributors for this article] (2024). Sex-specific associations of kynurenic acid with neopterin in Alzheimer’s disease. Alzheimer's Research & Therapy. 16(1). doi: 10.1186/s13195-024-01531-7. Full text in Research Archive Show summary

  Background: Sex differences in neuroinflammation could contribute to women’s increased risk of Alzheimer’s disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further. Methods: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years. Results: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression. Discussion: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women.

• Aksnes, Mari; Schibstad, Mari Haavig; Chaudhry, Farrukh Abbas; Neerland, Bjørn Erik; Caplan, Gideon A. & Saltvedt, Ingvild Tina [Show all 17 contributors for this article] (2024). Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium. Communications Medicine. 4(1). doi: 10.1038/s43856-024-00558-z. Full text in Research Archive Show summary

  Background The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. Methods Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer’s disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. Results Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. Conclusions Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

• Persson, Karin Ester Torun; Barca, Maria Lage; Edwin, Trine Holt; Cavallin-Eklund, Lena; Tangen, Gro Gujord & Rhodius-Meester, Hanneke Frederica Maria [Show all 9 contributors for this article] (2024). Regional MRI volumetry using NeuroQuant versus visual rating scales in patients with cognitive impairment and dementia. Brain and Behavior. 14(2). doi: 10.1002/brb3.3397. Full text in Research Archive Show summary

  Background and purpose: The aims were to compare the novel regional brain volumetric measures derived by the automatic software NeuroQuant (NQ) with clinically used visual rating scales of medial temporal lobe atrophy (MTA), global cortical atrophy-frontal (GCA-f), and posterior atrophy (PA) brain regions, assessing their diagnostic validity, and to explore if combining automatic and visual methods would increase diagnostic prediction accuracy. Methods: Brain magnetic resonance imaging (MRI) examinations from 86 patients with subjective and mild cognitive impairment (i.e., non-dementia, n = 41) and dementia (n = 45) from the Memory Clinic at Oslo University Hospital were assessed using NQ volumetry and with visual rating scales. Correlations, receiver operating characteristic analyses calculating area under the curves (AUCs) for diagnostic accuracy, and logistic regression analyses were performed. Results: The correlations between NQ volumetrics and visual ratings of corresponding regions were generally high between NQ hippocampi/temporal volumes and MTA (r = -0.72/-0.65) and between NQ frontal volume and GCA-f (r = -0.62) but lower between NQ parietal/occipital volumes and PA (r = -0.49/-0.37). AUCs of each region, separating non-dementia from dementia, were generally comparable between the two methods, except that NQ hippocampi volume did substantially better than visual MTA (AUC = 0.80 vs. 0.69). Combining both MRI methods increased only the explained variance of the diagnostic prediction substantially regarding the posterior brain region. Conclusions: The findings of this study encourage the use of regional automatic volumetry in locations lacking neuroradiologists with experience in the rating of atrophy typical of neurodegenerative diseases, and in primary care settings.

• Aksnes, Mari; Edwin, Trine Holt; Saltvedt, Ingvild Tina; Eldholm, Rannveig Sakshaug; Chaudhry, Farrukh Abbas & Halaas, Nathalie Bodd [Show all 9 contributors for this article] (2023). Sex-specific associations of matrix metalloproteinases in Alzheimer’s disease. Biology of Sex Differences. 14(1). doi: 10.1186/s13293-023-00514-x. Full text in Research Archive Show summary

  Introduction Alzheimer’s disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-β (Aβ) and tau pathology. However, there is a need for biomarkers reflecting additional pathological pathways. Matrix metalloproteinases (MMPs) have recently been highlighted as candidate biomarkers for sex-specific mechanisms and progression in AD. Methods In this cross-sectional study, we investigated nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in the cerebrospinal fluid of 256 memory clinic patients with mild cognitive impairment or dementia due to AD and 100 cognitively unimpaired age-matched controls. We studied group differences in MMP/TIMP levels and examined the associations with established markers of Aβ and tau pathology as well as disease progression. Further, we studied sex-specific interactions. Results MMP-10 and TIMP-2 levels differed significantly between the memory clinic patients and the cognitively unimpaired controls. Furthermore, MMP- and TIMP-levels were generally strongly associated with tau biomarkers, whereas only MMP-3 and TIMP-4 were associated with Aβ biomarkers; these associations were sex-specific. In terms of progression, we found a trend towards higher MMP-10 at baseline predicting more cognitive and functional decline over time exclusively in women. Conclusion Our results support the use of MMPs/TIMPs as markers of sex differences and progression in AD. Our findings show sex-specific effects of MMP-3 and TIMP-4 on amyloid pathology. Further, this study highlights that the sex-specific effects of MMP-10 on cognitive and functional decline should be studied further if MMP-10 is to be used as a prognostic biomarker for AD.

• Knapskog, Anne Brita; Aksnes, Mari; Edwin, Trine Holt; Ueland, Per Magne; Ulvik, Arve & Fang, Fei [Show all 11 contributors for this article] (2023). Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 19(12), p. 5573–5582. doi: 10.1002/alz.13162. Full text in Research Archive Show summary

  INTRODUCTION The kynurenine pathway's (KP) malfunction is closely related to Alzheimer's disease (AD), for antagonistic kynurenic acid (KA) and agonistic quinolinic acid act on the N-methyl-D-aspartate receptor, a possible therapeutic target in treating AD. METHODS In our longitudinal case–control study, KP metabolites in the cerebrospinal fluid were analyzed in 311 patients with AD and 105 cognitively unimpaired controls. RESULTS Patients with AD exhibited higher concentrations of KA (β = 0.18, P < 0.01) and picolinic acid (β = 0.20, P < 0.01) than the controls. KA was positively associated with tau pathology (β = 0.29, P < 0.01), and a higher concentration of KA was associated with the slower progression of dementia. DISCUSSION The higher concentrations of neuroprotective metabolites KA and picolinic acid suggest that the activation of the KP's neuroprotective branch is an adaptive response in AD and may be a promising target for intervention and treatment. Highlights Patients with Alzheimer's disease (AD) exhibited higher concentrations of kynurenic acid and picolinic acid than controls. Higher concentrations of kynurenic acid were associated with slower progression of AD. Potential neurotoxic kynurenines were not increased among patients with AD. Activation of the kynurenine pathway's neuroprotective branch may be an adaptive response in AD.

• Zotcheva, Ekaterina; Bratsberg, Bernt Magne; Strand, Bjørn Heine; Jugessur, Astanand; Engdahl, Bo Lars & Bowen, Catherine [Show all 17 contributors for this article] (2023). Trajectories of occupational physical activity and risk of later-life mild cognitive impairment and dementia: the HUNT4 70+ study. The Lancet Regional Health - Europe. 34. doi: 10.1016/j.lanepe.2023.100721. Full text in Research Archive Show summary

  High levels of occupational physical activity (PA) have been linked to an increased risk of dementia. We assessed the association of trajectories of occupational PA at ages 33–65 with risk of dementia and mild cognitive impairment (MCI) at ages 70+. Methods We included 7005 participants (49.8% were women, 3488/7005) from the HUNT4 70+ Study. Group-based trajectory modelling was used to identify four trajectories of occupational PA based on national registry data from 1960 to 2014: stable low (30.9%, 2162/7005), increasing then decreasing (8.9%, 625/7005), stable intermediate (25.1%, 1755/7005), and stable high (35.2%, 2463/7005). Dementia and MCI were clinically assessed in 2017–2019. We performed adjusted multinomial regression to estimate relative risk ratios (RRR) with 95% confidence intervals (CI) for dementia and MCI. Findings 902 participants were diagnosed with dementia and 2407 were diagnosed with MCI. Absolute unadjusted risks for dementia and MCI were 8.8% (95% CI: 7.6–10.0) and 27.4% (25.5–29.3), respectively, for those with a stable low PA trajectory, 8.2% (6.0–10.4) and 33.3% (29.6–37.0) for those with increasing, then decreasing PA; while they were 16.0% (14.3–17.7) and 35% (32.8–37.2) for those with stable intermediate, and 15.4% (14.0–16.8) and 40.2% (38.3–42.1) for those with stable high PA trajectories. In the adjusted model, participants with a stable high trajectory had a higher risk of dementia (RRR 1.34, 1.04–1.73) and MCI (1.80, 1.54–2.11), whereas participants with a stable intermediate trajectory had a higher risk of MCI (1.36, 1.15–1.61) compared to the stable low trajectory. While not statistically significant, participants with increasing then decreasing occupational PA had a 24% lower risk of dementia and 18% higher risk of MCI than the stable low PA group. Interpretation Consistently working in an occupation with intermediate or high occupational PA was linked to an increased risk of cognitive impairment, indicating the importance of developing strategies for individuals in physically demanding occupations to prevent cognitive impairment.

• Persson, Karin Ester Torun; Leonardsen, Esten Høyland; Edwin, Trine Holt; Knapskog, Anne-Brita; Tangen, Gro Gujord & Selbæk, Geir [Show all 9 contributors for this article] (2023). Diagnostic accuracy of brain age prediction in a memory clinic population and comparison with clinically available volumetric measures. Scientific Reports. 13. doi: 10.1038/s41598-023-42354-0. Full text in Research Archive Show summary

  The aim of this study was to assess the diagnostic validity of a deep learning-based method estimating brain age based on magnetic resonance imaging (MRI) and to compare it with volumetrics obtained using NeuroQuant (NQ) in a clinical cohort. Brain age prediction was performed on minimally processed MRI data using deep convolutional neural networks and an independent training set. The brain age gap (difference between chronological and biological age) was calculated, and volumetrics were performed in 110 patients with dementia (Alzheimer’s disease, frontotemporal dementia (FTD), and dementia with Lewy bodies), and 122 with non-dementia (subjective and mild cognitive impairment). Area-under-the-curve (AUC) based on receiver operating characteristics and logistic regression analyses were performed. The mean age was 67.1 (9.5) years and 48.7% (113) were females. The dementia versus non-dementia sensitivity and specificity of the volumetric measures exceeded 80% and yielded higher AUCs compared to BAG. The explained variance of the prediction of diagnostic stage increased when BAG was added to the volumetrics. Further, BAG separated patients with FTD from other dementia etiologies with > 80% sensitivity and specificity. NQ volumetrics outperformed BAG in terms of diagnostic discriminatory power but the two methods provided complementary information, and BAG discriminated FTD from other dementia etiologies.

• Persson, Karin Ester Torun; Edwin, Trine Holt; Knapskog, Anne Brita; Tangen, Gro Gujord; Selbæk, Geir & Engedal, Knut (2022). Hippocampal Atrophy Subtypes of Alzheimer's Disease Using Automatic MRI in a Memory Clinic Cohort: Clinical Implications. Dementia and Geriatric Cognitive Disorders. ISSN 1420-8008. 51(1), p. 80–89. doi: 10.1159/000522382. Full text in Research Archive Show summary

  Introduction: One pathological hallmark of Alzheimer’s disease (AD) is atrophy of medial temporal brain regions that can be visualized on magnetic resonance imaging (MRI), but not all patients will have atrophy. The aim was to use MRI to categorize patients according to their hippocampal atrophy status and to present prevalence of the subtypes, difference in clinical symptomatology and progression, and factors associated with hippocampal subtypes. Methods: We included 215 patients with AD who had been assessed with the clinically available MRI software NeuroQuant (NQ; CorTechs labs/University of California, San Diego, CA, USA). NQ measures the hippocampus volume and calculates a normative percentile. Atrophy was regarded to be present if the percentile was ≤5. Demographics, cognitive measurements, AD phenotypes, apolipoprotein E status, and results from cerebrospinal fluid and amyloid positron emission tomography analyses were included as explanatory variables of the hippocampal subtypes. Results: Of all, 60% had no hippocampal atrophy. These patients were younger and less cognitively impaired concerning global measures, memory function, and abstraction but impaired concerning executive, visuospatial, and semantic fluency, and more of them had nonamnestic AD, compared to those with hippocampal atrophy. No difference in progression rate was observed between the two groups. In mild cognitive impairment patients, amyloid pathology was associated with the no hippocampal atrophy group. Conclusion: The results have clinical implications. Clinicians should be aware of the large proportion of AD patients presenting without atrophy of the hippocampus as measured with this clinical MRI method in the diagnostic set up and that nonamnestic phenotypes are more common in this group as compared to those with atrophy. Furthermore, the findings are relevant in clinical trials.

• Aksnes, Mari; Tiiman, Ann; Edwin, Trine Holt; Terenius, Lars; Bogdanovic, Nenad & Vukojevic, Vladana [Show all 7 contributors for this article] (2021). Comparison of cerebrospinal fluid amyloidogenic nanoplaques with core biomarkers of Alzheimer's disease. Frontiers in Aging Neuroscience. 12:608628, p. 1–11. doi: 10.3389/fnagi.2020.608628. Full text in Research Archive Show summary

  Accurate biomarkers of Alzheimer’s disease (AD) are essential for early diagnosis and intervention. Available biomarkers are not sufficient to permit the monitoring of AD progression over time, and additional biomarkers are required. Measures of aggregated amyloid-β (Aβ) could be useful biomarkers for AD. Here, we investigate whether levels of Thioflavin-T (ThT) positive amyloid aggregates, i.e., nanoplaques, in cerebrospinal fluid (CSF) could serve as useful biomarkers for AD. One-hundred and eighteen memory clinic patients were AT(N) classified, and CSF nanoplaque concentrations were compared between patients on the “Alzheimer’s continuum” (A+ patients) and patients with “Normal AD biomarkers” or “Non-AD pathologic change” (A− patients). CSF nanoplaque concentrations and sizes were quantified using the novel ThT-Fluorescence Correlation Spectroscopy (ThT-FCS) assay, and core biomarkers (Aβ42, total tau and phosphorylated tau) were determined by enzyme-linked immunosorbent assays. We investigated the association between nanoplaque concentrations and core biomarkers, and the diagnostic value of nanoplaque levels. Nanoplaque levels were increased in A+ patients compared to A− patients. Nanoplaque concentrations were negatively associated with Aβ42, but not related to total tau or phosphorylated tau measures. Quantification of nanoplaques did not improve the classification of patients on the Alzheimer’s continuum compared to the core biomarkers alone. Dynamic changes in nanoplaques concentration and size throughout AD stages should be explored in longitudinal studies.

• Müller, Ebba Gløersen; Stokke, Caroline; Stokmo, Henning Langen; Edwin, Trine Holt; Knapskog, Anne Brita & Rootwelt-Revheim, Mona Elisabeth (2021). Evaluation of semi-quantitative measures of 18F-Flutemetamol PET for the clinical diagnosis of Alzheimer’s disease. Quantitative Imaging in Medicine and Surgery (QIMS). ISSN 2223-4292. 12(1). doi: 10.21037/qims-21-188. Full text in Research Archive Show summary

  Background: 18F-flutemetamol positron emission tomography (PET) is used to assess cortical amyloid-β burden in patients with cognitive impairment to support a clinical diagnosis. Visual classification is the most widely used method in clinical practice although semi-quantification is beneficial to obtain an objective and continuous measure of the Aβ burden. The aims were: first to evaluate the correspondence between standardized uptake value ratios (SUVRs) from three different software, Centiloids and visual classification, second to estimate thresholds for supporting visual classification and last to assess differences in semi-quantitative measures between clinical diagnoses. Methods: This observational study included 195 patients with cognitive impairment who underwent 18F-flutemetamol PET. PET images were semi-quantified with SyngoVia, CortexID suite, and PMOD. Receiver operating characteristics curves were used to compare visual classification with composite SUVR normalized to pons (SUVRpons) and cerebellar cortex (SUVRcer), and Centiloids. We explored correlations and differences between semi-quantitative measures as well as differences in SUVR between two clinical diagnosis groups: Alzheimer’s disease-group and non-Alzheimer’s disease-group. Results: PET images from 191 patients were semi-quantified with SyngoVia and CortexID and 86 PET-magnetic resonance imaging pairs with PMOD. All receiver operating characteristics curves showed a high area under the curve (>0.98). Thresholds for a visually positive PET was for SUVRcer: 1.87 (SyngoVia) and 1.64 (CortexID) and for SUVRpons: 0.54 (SyngoVia) and 0.55 (CortexID). The threshold on the Centiloid scale was 39.6 Centiloids. All semi-quantitative measures showed a very high correlation between different software and normalization methods. Composite SUVRcer was significantly different between SyngoVia and PMOD, SyngoVia and CortexID but not between PMOD and CortexID. Composite SUVRpons were significantly different between all three software. There were significant differences in the mean rank of SUVRpons, SUVRcer, and Centiloid between Alzheimer’s disease-group and non-Alzheimer’s disease-group. Conclusions: SUVR from different software performed equally well in discriminating visually positive and negative 18F-Flutemetamol PET images. Thresholds should be considered software-specific and cautiously be applied across software without preceding validation to categorize scans as positive or negative. SUVR and Centiloid may be used alongside a thorough clinical evaluation to support a clinical diagnosis.

• Aksnes, Mari; Aass, Hans Christian Dalsbotten; Tiiman, Ann; Edwin, Trine Holt; Terenius, Lars & Bogdanovic, Nenad [Show all 8 contributors for this article] (2021). Associations of cerebrospinal fluid amyloidogenic nanoplaques with cytokines in Alzheimer's disease. Translational Neurodegeneration. ISSN 2096-6466. 10(1). doi: 10.1186/s40035-021-00244-3. Full text in Research Archive Show summary

  Background: The aggregation of amyloid β (Aβ) is central in the pathogenesis of Alzheimer's disease (AD). Recently it has been shown that specifically, larger, Thioflavin T-binding Aβ aggregates are associated with increased neuroinflammation and cytokine release. This study was aimed to quantify fibrillary amyloid aggregates, so-called nanoplaques, and investigate their relationship with cytokines in the cerebrospinal fluid (CSF). Methods: CSF was collected from 111 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic. The patients were grouped based on their amyloid status. The CSF nanoplaque concentration was quantified with the Thioflavin T-fluorescence correlation spectroscopy (ThT-FCS) assay. The levels of nine cytokines (eotaxin-1, granulocyte stimulating factor, interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1, gamma-induced protein 10, macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a magnetic bead-based multiplex assay and read on a Luminex IS 200 instrument. Results: There were 49 amyloid-negative and 62 amyloid-positive patients in the cohort; none of the cytokines differed significantly between the amyloid groups. The increased nanoplaque levels were associated with levels of MIP-1β below the lower limit of quantification, and with decreased levels of MIP-1α and IL-8. The associations remained significant when adjusted for age, sex, cognitive function, apolipoprotein ε4 status and CSF core biomarker levels. Conclusion: The cytokine levels were not associated with amyloid status in this cohort. The nanoplaque levels were negatively associated with MIP-1β, MIP-1α and IL-8, which is in line with recent findings suggesting that the upregulation of some cytokine markers has a protective role and is negatively associated with AD progression.

• Edwin, Trine Holt; Strand, Bjørn Heine; Persson, Karin Ester Torun; Engedal, Knut; Selbæk, Geir & Knapskog, Anne Brita (2021). Neuropsychiatric symptoms and comorbidity: Associations with dementia progression rate in a memory clinic cohort. International Journal of Geriatric Psychiatry. ISSN 0885-6230. 36(6), p. 960–969. doi: 10.1002/gps.5500. Full text in Research Archive Show summary

  Objectives Neuropsychiatric symptoms (NPS) are associated with dementia severity and progression rate. NPS clusters have different neurobiological underpinnings; therefore, their effect on dementia progression may differ. Further, little is known about whether individual comorbidities affect progression rate. We investigated the effect of NPS clusters and individual comorbidities on dementia progression. Methods A memory clinic cohort with all‐cause dementia (N = 442), was followed for up to three years from diagnosis. Previously, we found trajectory groups of dementia progression in this cohort: one with slow progression and two with rapid progression. In the present study, using principal component analysis, three symptom clusters of NPS were on the Neuropsychiatric Inventory Questionnaire (NPI‐Q): agitation, affective, and psychosis symptom clusters. Data regarding comorbidity were collected by linkage to the Norwegian patient registry. Multinomial logistic regression was applied to explore the association between NPS clusters and comorbidity with trajectory‐group membership. Results Adjusted for demographics, dementia aetiology, comorbidity, and cognition, we found that, at the time of dementia diagnosis, for every point within the psychosis symptom cluster of the NPI‐Q, the risk of rapid progression increased by 53%; for every point within the affective symptom cluster, the risk of rapid progression increased by 29%. A previous diagnosis of mental and behavioural disorders (excluding dementia) decreased the risk of rapid dementia progression by 65%. Conclusions Psychosis and affective symptom clusters at the time of diagnosis were associated with rapid progression of dementia. Previous diagnoses of mental and behavioural disorders (excluding dementia) were associated with slow progression.

• Müller, Ebba Gløersen; Edwin, Trine Holt; Strand, Bjørn Heine; Stokke, Caroline; Rootwelt-Revheim, Mona Elisabeth & Knapskog, Anne Brita (2021). Is Amyloid Burden Measured by ¹⁸F-Flutemetamol PET Associated with Progression in Clinical Alzheimer's Disease? Journal of Alzheimer's Disease. ISSN 1387-2877. 85(1), p. 197–205. doi: 10.3233/jad-215046. Full text in Research Archive
• Aksnes, Mari; Müller, Ebba Gløersen; Tiiman, Ann; Edwin, Trine Holt; Terenius, Lars & Rootwelt-Revheim, Mona-Elisabeth [Show all 9 contributors for this article] (2020). Amyloidogenic nanoplaques in cerebrospinal fluid: Relationship to amyloid brain uptake and clinical Alzheimer's disease in a memory clinic cohort. Journal of Alzheimer's Disease. ISSN 1387-2877. 77(2), p. 831–842. doi: 10.3233/JAD-200237. Full text in Research Archive Show summary

  Background: Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer’s disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). Objective: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. Methods: Nanoplaque levels in the CSF from 54 memory clinic patients were compared between sub-groups classified by 18F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. Results: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. Conclusion: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients.

• Edwin, Trine Holt; Henjum, Kristi; Nilsson, Lars; Watne, Leiv; Persson, Karin Ester Torun & Eldholm, Rannveig Sakshaug [Show all 12 contributors for this article] (2020). A high cerebrospinal fluid soluble TREM2 level is associated with slow clinical progression of Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 12(1). doi: 10.1002/dad2.12128. Full text in Research Archive Show summary

  Introduction: The progression rate of Alzheimer's disease (AD) varies and might be affected by the triggering receptor expressed on myeloid cells (TREM2) activity. We explored if cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), a proxy of microglial activity, is associated with clinical progression rate. Methods: Patients with clinical AD (N = 231) were followed for up to 3 years after diagnosis. Cognitively healthy controls (N = 42) were followed for 5 years. CSF sTREM2 was analyzed by enzyme-linked immunosorbent assay. Group-based trajectory modeling revealed distinct clinical progression groups. Results: Higher CSF sTREM2 was associated with slow clinical progression. The slow- and medium-progressing groups had higher CSF sTREM2 than the cognitively healthy, who had a similar level to patients with rapid clinical progression. Discussion: CSF sTREM2 levels were associated with clinical progression in AD, regardless of core biomarkers. This could be useful in assessing disease development in relation to patient care and clinical trial recruitment. Keywords: Alzheimer's disease; Clinical Dementia Rating scale; disease progression; soluble triggering receptor expressed on myeloid cells 2 (sTREM2); trajectories.

• Mjørud, Marit; Selbæk, Geir; Bjertness, Espen; Edwin, Trine Holt; Engedal, Knut & Knapskog, Anne Brita [Show all 7 contributors for this article] (2020). Time from dementia diagnosis to nursing-home admission and death among persons with dementia: A multistate survival analysis. PLOS ONE. 15(12). doi: 10.1371/journal.pone.0243513. Full text in Research Archive Show summary

  Objectives: To estimate transition times from dementia diagnosis to nursing-home (NH) admission or death and to examine whether sex, education, marital status, level of cognitive impairment and dementia aetiology are associated with transition times. Design: Markov multistate survival analysis and flexible parametric models. Setting: Participants were recruited from the Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) in specialist healthcare between 2008 and 2017 and followed until August 2019, a maximum of 10.6 years follow-up time (mean 4.4 years, SD 2.2). Participants’ address histories, emigration and vital status were retrieved from the National Population Registry from time of diagnosis and linked to NorCog clinical data. Participants 2,938 home-dwelling persons with dementia, ages 40–97 years at time of diagnosis (mean 76.1, SD 8.5). Results: During follow-up, 992 persons (34%) were admitted to nursing-homes (NHs) and 1,556 (53%) died. Approximately four years after diagnosis, the probability of living in a NH peaked at 19%; thereafter, the probability decreased due to mortality. Median elapsed time from dementia diagnosis to NH admission among those admitted to NHs was 2.28 years (IQR 2.32). The probability of NH admission was greater for women than men due to women´s lower mortality rate. Persons living alone, particularly men, had a higher probability of NH admission than cohabitants. Age, dementia aetiology and severity of cognitive impairment at time of diagnosis did not influence the probability of NH admission. Those with fewer than 10 years of education had a lower probability of NH admission than those with 10 years or more, and this was independent of the excess mortality in the less-educated group. Conclusion: Four years after diagnosis, half of the participants still lived at home, while NH residency peaked at 19%. Those with fewer than 10 years of education were less often admitted to NH.

• Edwin, Trine Holt; Strand, Bjørn Heine; Persson, Karin Ester Torun; Engedal, Knut; Selbæk, Geir & Knapskog, Anne Brita (2020). Trajectories and risk factors of dementia progression: a memory clinic cohort followed up to 3 years from diagnosis. International Psychogeriatrics. ISSN 1041-6102. 33(8), p. 779–789. doi: 10.1017/S1041610220003270. Full text in Research Archive Show summary

  Objectives: Patients with dementia follow different trajectories of progression. We aimed to investigate which factors at the time of diagnosis could predict trajectory group membership. Design: Longitudinal observational study. Setting: Specialized memory clinic, Oslo University Hospital in Norway. Participants: Patients assessed at the memory clinic, between 12 January 2009 and 31 July 2016, who were registered in the Norwegian Registry of persons assessed for cognitive symptoms (NorCog) and diagnosed with dementia after the baseline examination period (n = 442). The patients were followed up to 3 years, with an average of 3.5 examinations. Measurements: Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), the Consortium to Establish a Registry of Alzheimer’s disease (CERAD) 10-item word list delayed recall, the Clock Drawing Test, (CDT) Trail Making Test A (TMT-A), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Based on changes in scores on the CDR-SB, we used group-based trajectory modeling (GBTM) to explore the presence of trajectory groups. Multinomial logistic regression was used to explore whether a set of baseline variables could predict trajectory group membership. Results: Three trajectory groups were identified, one with a slow progression rate and two with more-rapid progression. Rapid progression was associated with older age, lower cognitive function (MMSE and TMT-A), and more-pronounced neuropsychiatric symptoms (NPI-Q) at the time of diagnosis. Conclusions: Our findings demonstrate the heterogeneity of dementia progression and describe risk factors for rapid progression, emphasizing the need for individual follow-up regimes. For future intervention studies, our results may guide the selection of patients.

• Strand, Bjørn Heine; Knapskog, Anne Brita; Persson, Karin Ester Torun; Edwin, Trine Holt; Bjertness, Espen & Engedal, Knut [Show all 7 contributors for this article] (2019). The Loss in Expectation of Life due to Early-Onset Mild Cognitive Impairment and Early-Onset Dementia in Norway. Dementia and Geriatric Cognitive Disorders. ISSN 1420-8008. 47, p. 355–365. doi: 10.1159/000501269. Full text in Research Archive
• Müller, Ebba Gløersen; Edwin, Trine Holt; Stokke, Caroline; Navelsaker, Sigrid Stensby; Babovic, Almira & Bogdanovic, Nenad [Show all 8 contributors for this article] (2019). Amyloid-β PET—Correlation with cerebrospinal fluid biomarkers and prediction of Alzheimer´s disease diagnosis in a memory clinic. PLOS ONE. 14(8), p. 1–15. doi: 10.1371/journal.pone.0221365. Full text in Research Archive Show summary

  Background: Alzheimer’s disease (AD) remains a clinical diagnosis but biomarkers from cerebrospinal fluid (CSF) and more lately amyloid imaging with positron emission tomography (PET), are important to support a diagnosis of AD. Objective: To compare amyloid-β (Aβ) PET imaging with biomarkers in CSF and evaluate the prediction of Aβ PET on diagnosis in a memory clinic setting. Methods: We included 64 patients who had lumbar puncture and Aβ PET with 18F-Flutemetamol performed within 190 days. PET was binary classified (Flut+ or Flut-) and logistic regression analyses for correlation to each CSF biomarker; Aβ 42 (Aβ42), total tau (T-tau) and phosphorylated tau (P-tau), were performed. Cut-off values were assessed by receiver operating characteristic (ROC) curves. Logistic regression was performed for prediction of clinical AD diagnosis. We assessed the interrater agreement of PET classification as well as for diagnoses, which were made both with and without knowledge of PET results. Results: Thirty-two of the 34 patients (94%) in the Flut+ group and nine of the 30 patients (30%) in the Flut- group had a clinical AD diagnosis. There were significant differences in all CSF biomarkers in the Flut+ and Flut- groups. Aβ42 showed the highest correlation with 18F-Flutemetamol PET with a cut-off value of 706.5 pg/mL, corresponding to sensitivity of 88% and specificity of 87%. 18F-Flutemetamol PET was the best predictor of a clinical AD diagnosis. We found a very high interrater agreement for both PET classification and diagnosis. Conclusions: The present study showed an excellent correlation of Aβ42 in CSF and 18F-Flutemetamol PET and the presented cut-off value for Aβ42 yields high sensitivity and specificity for 18F-Flutemetamol PET. 18F-Flutemetamol PET was the best predictor of clinical AD diagnosis.

• Strand, Bjørn Heine; Knapskog, Anne Brita; Persson, Karin Ester Torun; Edwin, Trine Holt; Amland, Rachel & Mjørud, Marit [Show all 9 contributors for this article] (2018). Survival and years of life lost in various aetiologies of dementia, mild cognitive impairment (MCI) and subjective cognitive decline (SCD) in Norway. PLOS ONE. 13(9). doi: 10.1371/journal.pone.0204436. Full text in Research Archive Show summary

  Abstract INTRODUCTION: Alzheimer's disease patients are reported to have higher survival rate compared to patients with vascular dementia or dementia with Lewy bodies. There is a paucity of studies investigating survival including persons with cognitive decline and dementia of various aetiologies. OBJECTIVES: We aimed to compare survival for patients with subjective cognitive decline, mild cognitive impairment, Alzheimer's disease, vascular dementia, mixed Alzheimer's/vascular dementia, dementia with Lewy bodies/Parkinson's disease, and other dementias compared to the general Norwegian population, taking into account the role of gender, cognitive function, function in everyday activities, comorbidity and education. METHODS: Patients (N = 4682), ≥65 years, in the The Norwegian register of persons assessed for cognitive symptoms (NorCog) during 2009-2017 were followed for mortality in the National Registry until January 2018. Flexible parametric survival models were applied to estimate relative survival, life expectancy and years of life lost for diagnostic groups compared with the general population. RESULTS: Patients with vascular dementia or dementia with Lewy bodies/Parkinson's had the shortest survival, followed by mixed dementia, Alzheimer's disease, unspecified dementia, mild cognitive impairment and subjective cognitive decline. At age 70 years, men with vascular dementia or dementia with Lewy bodies/Parkinson's had life expectancy of 4.7 years, which corresponded to 10.3 years of life lost compared to the general population. Years of life lost for other diagnoses were 10.0 years for mixed dementia, 9.2 years for Alzheimer's disease, 9.3 years for other dementias, 5.2 years for mild cognitive impairment and 2.2 years for subjective cognitive decline. Corresponding years of life lost in women were: 12.7 years, 10.5 years, 9.8 years, 10.6 years, 7.8 years, and 2.6 years. Poor relative survival among dementia patients was associated with male gender, comorbidity, low cognitive function, and low function in activities of daily living. CONCLUSIONS: Compared with the general population, patients with subjective cognitive decline had no significant loss in life expectancy, while patients with mild cognitive impairment and all dementia subtypes had large losses, especially those with a diagnosis of vascular dementia or dementia with Lewy bodies/Parkinson's.

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• Hernes, Susanne Miriam Sørensen; Nordnes, Per Raymond; Hol, Haakon Ramsland; Ringstad, Geir Andre; Knapskog, Anne-Brita & Emhjellen, Petter Espeseth [Show all 9 contributors for this article] (2026). The REACT MCI study: a randomized controlled clinical trial on the effect of repeated advanced cognitive training in mild cognitive impairment. doi: 10.1186/s13063-026-09711-6. Full text in Research Archive Show summary

  Background Mild cognitive impairment (MCI) and its course have multiple determining factors with both detrimental and compensatory processes in the brain. Computerized working memory training can improve cognitive function and individuals with MCI are potential targets. Since more than 1/3 of these individuals develop dementia within 5 years, any intervention postponing the progression will be immensely important. We aim to investigate the efficiency and cost-effectiveness of working memory training in MCI. Methods In this blinded randomized controlled trial, 213 participants will be allocated to three groups: (1) one 5-week period of working memory training, (2) two 5-week periods of working memory training, or (3) the active control group. The participants are followed for a period of 48 months (3, 6, 12, 24, and 48 months). Furthermore, we investigate microstructural effects of working memory training on magnetic resonance imaging and seek to identify high responders to training by assessing the association with function in the glymphatic system and genetic variations. Finally, the impact of working memory training on quality of life and relatives’ stress, and whether it is a cost-effective approach in MCI, will be assessed. Discussion Effective therapy for MCI is lacking. Finding an intervention postponing the progression of MCI is of great importance for patients as well as for the global economy and health care.

• Edwin, Trine Holt; Nordnes, Per Raymond; Knapskog, Anne-Brita; Løhaugen, Gro; Ringstad, Geir Andre & Hol, Haakon Ramsland [Show all 8 contributors for this article] (2025). Computerized Working Memory Training vs Active Control in Mild Cognitive Impairment. Alzheimer's & Dementia. ISSN 1552-5260. 21(S4). doi: 10.1002/alz70858_100914. Full text in Research Archive Show summary

  Background: Working memory training may enhance cognitive function in Mild Cognitive Impairment (MCI). Given that one-third of individuals with MCI progress to dementia within five years, interventions that delay progression are critical. This study investigates the effect of home-based computerized working memory training on cognitive function in MCI. Method: In this multi-center randomized controlled trial, participants with MCI were assigned to either a five-week home-based computerized working memory training program (n = 94) or an active control group playing web-based solitaire (n = 53). All participants received weekly coaching by telephone. We analyzed the change in working memory, measured by the Spatial Span Backwards subtest (higher score indicates better working memory), from baseline to 3 months post-intervention. A mixed-effects model with robust standard errors was employed to account for both fixed and random effects. Fixed effects included treatment group, age, sex, and General Ability Index (GAI), while the random effect accounted for variability between centers. Result: Among 147 participants (mean age 68 years; standard deviation 7.5; 43% women), the Spatial Span Backwards score improved significantly in the working memory training group compared to the active control group at 3 months (least squares mean difference, 0.60; 95% confidence interval, 0.44 to 0.75 p <0.001). Conclusion: In individuals with MCI, home-based computerized working memory training significantly improved working memory after 3 months compared to active controls.

• Ustad, Astrid; Melsæter, Kjerstin Næss; Edwin, Trine Holt; Sverdrup, Karen; Tangen, Gro Gujord & Døhl, Øystein [Show all 9 contributors for this article] (2024). Daily physical activity and trajectories of care services use among older adults: The HUNT4 Trondheim 70+ Study. Full text in Research Archive
• Sandvig, Heidi Vihovde; Edwin, Trine Holt; Aam, Stina; Alme, Katinka Nordheim; Lydersen, Stian & Mollnes, Tom Eirik [Show all 12 contributors for this article] (2024). Abstract ID: 0066 Trajectories of post-stroke cognitive function related to systemic inflammatory biomarkers and metabolites: The Nor-COAST study. Cerebral Circulation - Cognition and Behavior. ISSN 2666-2450. 6, p. 50–51. doi: 10.1016/j.cccb.2024.100315. Full text in Research Archive
• Strand, Bjørn Heine; Knapskog, Anne Brita; Edwin, Trine Holt; Persson, Karin Ester Torun; Amland, Rachel & Mjørud, Marit [Show all 9 contributors for this article] (2018). Survival in dementia and milder cognitive diagnoses. Results from the TRAIL-DEM Project. Full text in Research Archive
• Edwin, Trine Holt; Strand, Bjørn Heine; Knapskog, Anne Brita; Amland, Rachel; Persson, Karin Ester Torun & Mjørud, Marit [Show all 9 contributors for this article] (2018). TRAILDEM- Trajectories of cognitive impairment and dementia, and risk factors for progression. Full text in Research Archive

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