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Anne-Brita Knapskog

Professor II - Department of Geriatric Medicine

Email a.b.knapskog@medisin.uio.no

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Visiting address Kirkeveien 166 Bygg 20 0450 Oslo

Postal address Postboks 4956 Nydalen OUS HF Ullevål sykehus 0424 Oslo

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Group leader of Oslo Clinical Dementia Research Group

The Oslo Clinical Dementia Research group has a broad approach to dementia research. Our overarching aim of research is to improve diagnostic methods for dementia disorders and ultimately provide better treatment and care for patients with dementia. To achieve this, we study:

• pathophysiological mechanisms of dementia disorders

• new and accurate clinical, digital and biological diagnostic markers of specific dementia disorders, especially Alzheimer’s disease

• artificial intelligence (AI) tools to improve diagnosis of dementia disorders in clinical practice

• the influence of comorbidities, genetic and epigenetic mechanisms, inflammatory processes, biological sex and sex-specific risk factors and stress on dementia disorders

• interventions that could prevent or slow down the dementia process, such as advanced cognitive training.

Engedal, Knut; Benth, Jurate Saltyte; Knapskog, Anne-Brita; Wagle, Jørgen Olav & Persson, Karin Ester Torun (2026). Normative Norwegian scores on the clock drawing test using the Shulman version. Journal of Alzheimer's Disease. ISSN 1387-2877. 113(2), p. 944–944. doi: 10.1177/13872877261471901. Full text in Research Archive Show summary
Background Studies have shown that the performance on the Clock Drawing Test (CDT) is influenced by age and education. Thus, normative scores are needed. Objective To develop normative Norwegian scores for Shulman's version of CDT. Methods Performance on CDT of 2572 cognitively healthy people between age 25 and 95 years were included. Ordinal regression analysis was used to derive regression-based norms with sex, age and education as covariates. Results Of all, 76.4% scored five, 12.9% scored four, 8.1% scored three and 2.5% scored zero to two. Men scored higher than women. An interaction between age and education was found. The probability of higher CDT score is highest at younger ages and among those with highest education. It progressively declines with increasing age, while higher education delays, but does not prevent this decline. Participants scoring zero to two fell below the 5 th percentile, except among women above 93 years and men above 85 years. By age 95, the probability of different scores converged. In the age range of 60 to 90 years a score of three corresponded to percentiles of 3.7–26.9 in men and 5.2–34.1 in women, while a score of four corresponded to percentiles of 9.7–50.4 in men and 13.2–59.0 in women. Conclusions Scores four and five are considered normal for any person aged 60–90 years. Whether a score of three is normal depends on the person's sex, age and educational level, whereas score zero to two should not be regarded as normal.
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
Gundrosen, Kim Frederik; Taraldsen, Kristin; Sverdrup, Karen; Knapskog, Anne-Brita; Selbæk, Geir & Tangen, Gro Gujord (2026). Changes in device-measured daily physical activity over one year in memory clinic patients. European Review of Aging and Physical Activity. ISSN 1813-7253. doi: 10.1186/s11556-026-00414-0. Full text in Research Archive Show summary
Abstract Background This longitudinal study explored the one-year change in device-measured daily physical activity in patients attending a memory clinic. Methods Physical activity was recorded in 27 memory clinic patients over four days using accelerometers (activPAL3 micro) at baseline and one-year follow-up. Daily physical activity outcomes included upright time, standing time, walking time, number of steps, number of transitions, mean upright event length, and maximum upright event length. Changes between baseline and follow-up were analysed using paired sample t-tests. Results Patients’ mean (SD) age was 69.4 (8.1) years, and 14 (51.9%) were women. The only significant change was a decrease in maximum upright event length from a mean (SD) of 84.3 (31.6) minutes at baseline to 59.2 (22.5) minutes at one-year follow-up ( p < 0.001). Conclusion Daily physical activity volume remained stable over one year, but the reduction in maximum upright event length indicates a shift in activity distribution.
Akdeniz, Bayram Cevdet; Bahrami, Shahram; Hagen, Espen; Fuhrer, Julian; Fominykh, Vera & Shadrin, Alexey [Show all 108 contributors for this article] (2026). Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer’s Disease in European Populations: Development and Validation. medRxiv. doi: 10.1101/2025.07.28.25332293. Full text in Research Archive Show summary
Abstract Objectives Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer’s disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models. Methods We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E ( APOE ) ε2 and ε4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model. Results The new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 – 85 years. Our model also improved risk stratification across ε3/3 individuals of European ancestry (OR80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset. Conclusion Our EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.
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.
Mjørud, Marit; Knapskog, Anne-Brita; Nåvik, Marit & Røsvik, Janne-Kathrin (2025). Current Best Practice for People with Frontotemporal Dementia in Norway: A Focus Group Study with Expert Healthcare Personnel. Dementia and Geriatric Cognitive Disorders Extra. 15(1), p. 152–161. doi: 10.1159/000548376. Full text in Research Archive Show summary
Introduction: Frontotemporal symptoms are usually associated with frontotemporal dementia (FTD), but people with all forms of dementia may develop these symptoms as the dementia disease progresses. Knowledge about psychosocial interventions that meet the needs of people with FTD symptoms, and literature on the subject, is hard to find. The aim of the study was to describe current practice as it is experienced by healthcare experts in the clinical field in Norway. Method: Three focus groups were conducted. Healthcare personnel with clinical experience in care and treatment to people with FTD and other dementia diseases with frontotemporal symptoms were eligible for inclusion. Qualitative directed content analysis with open coding focusing on both manifest and latent content was applied. Results: Four categories were described: (1) Dilemmas of anosognosia, (2) establishment of a diagnosis, (3) establishment of post-diagnostic support at home, and (4) establishment of care in the nursing home. Conclusion: People with FTD and other dementias with frontotemporal symptoms need rigid, easy-to-understand, predictable surroundings and healthcare personnel that are clear, friendly, and respectful in their communication. Post-diagnostic support provided in flexible systems ensuring smooth transitions between services and levels of care is required. To ensure quality of care, frontline healthcare staff should be able to recognize FTD symptoms. To achieve this, supervision and training are needed. More research about clinical care interventions and how to derive good nursing practice should be prioritized
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.
Tangen, Gro Gujord; Engedal, Knut; Persson, Karin Ester Torun; Selbæk, Geir; Dakhil, Shams & McArdle, Riona [Show all 10 contributors for this article] (2025). Validation of Spatial Orientation Screening questionnaire for use in memory clinic patients. Journal of Alzheimer's Disease. ISSN 1387-2877. 103(4), p. 1013–1022. doi: 10.1177/13872877241308877. Full text in Research Archive
Sandvig, Heidi Vihovde; Aam, Stina; Alme, Katinka Nordheim; Lydersen, Stian; Ueland, Per Magne & Ulvik, Arve [Show all 9 contributors for this article] (2024). Neopterin, kynurenine metabolites, and indexes related to vitamin B6 are associated with post-stroke cognitive impairment: The Nor-COAST study. Brain, Behavior, and Immunity. ISSN 0889-1591. 118, p. 167–177. doi: 10.1016/j.bbi.2024.02.030. 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.
Landmark, Anne Marie; Hansen, Pernille Bonnevie; Simonsen, Hanne Gram; Knapskog, Anne-Brita & Svennevig, Jan (2024). Word searching in multilingual dementia: An interdisciplinary approach. International Journal of Bilingualism. ISSN 1367-0069. 29(4), p. 1–23. doi: 10.1177/13670069241256479. Full text in Research Archive Show summary
Aims and objectives: This study investigates how multilingual speakers with dementia mobilise their multilingual and interactional resources when searching for words in a naming test setting, and how their word-search behaviour relates to lexical retrieval processes characteristic of multilinguals, as well as to aspects of cognitive decline. Methodology and approach: The study takes an interdisciplinary approach by combining conversation analysis (CA) with psycholinguistic perspectives on lexical access and neurological perspectives on cognitive decline. Data and analysis: Data for the study are video/audio-recordings of seven multilingual speakers with dementia carrying out a naming test in their two common languages, English and Norwegian. CA was used for analysing the data and developing a coding scheme for word-search strategies. These findings were explored with statistical analysis based on language background, test scores, word properties/psycholinguistic properties, and cognitive/diagnostic assessment. Findings/conclusions: Multilingual speakers with dementia mainly used six general word- search strategies in the Norwegian and English naming test sessions: turn-holding, semantic searches, phonetic searches, embodied demonstrations, code-switching to another language, and inviting help from the conversation partner. The participants used more search-strategies in English, although it was their stronger language. Code-switching appeared to be the most successful strategy in English and phonetic searches appeared to be the most successful strategy in Norwegian. In-depth analysis of two participants indicate a benefit of using multiple strategies, drawing on their full linguistic repertoire. Originality: The study adds new knowledge to the interrelated, but previously separated areas of psycholinguistic word-finding difficulties and interactional word-searching behaviour, in the context of multilingual dementia. Implications: The study has implications for our understanding of the relation between observable word-searching behaviour and mental processes of word finding in multilinguals with dementia. The study also contributes to our growing understanding of test situations as interaction, with implications for everyday interaction and clinical practice.
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.
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.
Tangen, Gro Gujord; Sverdrup, Karen; Taraldsen, Kristin; Persson, Karin Ester Torun; Engedal, Knut & Wetterberg, Peter [Show all 7 contributors for this article] (2023). Mobility and associations with levels of cerebrospinal fluid amyloid β and tau in a memory clinic cohort. Frontiers in Aging Neuroscience. 15. doi: 10.3389/fnagi.2023.1101306. Full text in Research Archive Show summary
Mobility impairments, in terms of gait and balance, are common in persons with dementia. To explore this relationship further, we examined the associations between mobility and cerebrospinal fluid (CSF) core biomarkers for Alzheimer’s disease (AD). Methods: In this cross-sectional study, we included 64 participants [two with subjective cognitive decline (SCD), 13 with mild cognitive impairment (MCI) and 49 with dementia] from a memory clinic. Mobility was examined using gait speed, Mini-Balance Evaluation Systems test (Mini-BESTest), Timed Up and Go (TUG), and TUG dual-task cost (TUG DTC). The CSF biomarkers included were amyloid-β 42 (Aβ42), total-tau (t-tau), and phospho tau (p-tau181). Associations between mobility and biomarkers were analyzed through correlations and multiple linear regression analyses adjusted for (1) age, sex, and comorbidity, and (2) SCD/MCI vs. dementia. Results: Aβ42 was significantly correlated with each of the mobility outcomes. In the adjusted multiple regression analyses, Aβ42 was significantly associated with Mini-BESTest and TUG in the fully adjusted model and with TUG DTC in step 1 of the adjusted model (adjusting for age, sex, and comorbidity). T-tau was only associated with TUG DTC in step 1 of the adjusted model. P-tau181 was not associated with any of the mobility outcomes in any of the analyses. Conclusion: Better performance on mobility outcomes were associated with higher levels of CSF Aβ42. The association was strongest between Aβ42 and Mini-BESTest, suggesting that dynamic balance might be closely related with AD-specific pathology.
Sandvig, Heidi Vihovde; Aam, Stina; Alme, Katinka Nordheim; Askim, Torunn; Beyer, Mona K. & Ellekjær, Hanne [Show all 16 contributors for this article] (2023). Plasma Inflammatory Biomarkers Are Associated With Poststroke Cognitive Impairment: The Nor-COAST Study. Stroke. ISSN 0039-2499. 54(5), p. 1303–1311. doi: 10.1161/STROKEAHA.122.041965. Full text in Research Archive Show summary
Background: Inflammation is proposed to be involved in the pathogenesis of poststroke cognitive impairment. The aim of this study was to investigate associations between concentrations of systemic inflammatory biomarkers after ischemic stroke and poststroke cognitive impairment. Methods: The Nor-COAST study (Norwegian Cognitive Impairment After Stroke) is a prospective observational multicenter cohort study, including patients hospitalized with acute stroke between 2015 and 2017. Inflammatory biomarkers, including the TCC (terminal C5b-9 complement complex) and 20 cytokines, were analyzed in plasma, collected at baseline, 3-, and 18 months poststroke, using ELISA and a multiplex assay. Global cognitive outcome was assessed with the Montreal Cognitive Assessment (MoCA) scale. We investigated the associations between plasma inflammatory biomarkers at baseline and MoCA score at 3-, 18-, and 36-month follow-ups; the associations between inflammatory biomarkers at 3 months and MoCA score at 18- and 36-month follow-ups; and the association between these biomarkers at 18 months and MoCA score at 36-month follow-up. We used mixed linear regression adjusted for age and sex. Results: We included 455 survivors of ischemic stroke. Higher concentrations of 7 baseline biomarkers were significantly associated with lower MoCA score at 36 months; TCC, IL (interleukin)-6, and MIP (macrophage inflammatory protein)-1α were associated with MoCA at 3, 18, and 36 months (P<0.01). No biomarker at 3 months was significantly associated with MoCA score at either 18 or 36 months, whereas higher concentrations of 3 biomarkers at 18 months were associated with lower MoCA score at 36 months (P<0.01). TCC at baseline and IL-6 and MIP-1α measured both at baseline and 18 months were particularly strongly associated with MoCA (P<0.01). Conclusions: Higher concentrations of plasma inflammatory biomarkers were associated with lower MoCA scores up to 36 months poststroke. This was most pronounced for inflammatory biomarkers measured in the acute phase following stroke.
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.
Jansen, Iris E.; Lee, Sven J. van der; Gomez-Fonseca, Duber; Rojas, Itziar de; Dalmasso, Maria Carolina & Grenier-Boley, Benjamin [Show all 50 contributors for this article] (2022). Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers. Acta Neuropathologica. ISSN 0001-6322. 144(5), p. 821–842. doi: 10.1007/s00401-022-02454-z. Full text in Research Archive Show summary
Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
Watne, Leiv Otto; Pollmann, Christian Thomas; Neerland, Bjørn Erik; Paulsen, Else Quist; Halaas, Nathalie Bodd & Idland, Ane-Victoria [Show all 20 contributors for this article] (2022). Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients. Journal of Clinical Investigation. ISSN 0021-9738. 133(2). doi: 10.1172/JCI163472. Full text in Research Archive Show summary
Background: The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanism underlying delirium, particularly in relation to the KP, remain elusive. Methods: We undertook a multi-center observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and one-year mortality. Results: In delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA, OR 2.26 [1.78, 2.87], p
Medbøen, Ingrid Tøndel; Persson, Karin Ester Torun; Nåvik, Marit; Totland, Torunn Holm; Bergh, Sverre & Treviño, Cathrine Selnes [Show all 20 contributors for this article] (2022). Cohort profile: the Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) - a national research and quality registry with a biomaterial collection. BMJ Open. 12(9). doi: 10.1136/bmjopen-2021-058810. Full text in Research Archive Show summary
Purpose: The Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) was established to harmonise and improve the quality of diagnostic practice across clinics assessing persons with cognitive symptoms in Norwegian specialist healthcare units and to establish a large research cohort with extensive clinical data. Participants: The registry recruits patients who are referred for assessment of cognitive symptoms and suspected dementia at outpatient clinics in Norwegian specialist healthcare units. In total, 18 120 patients have been included in NorCog during the period of 2009-2021. The average age at inclusion was 73.7 years. About half of the patients (46%) were diagnosed with dementia at the baseline assessment, 35% with mild cognitive impairment and 13% with no or subjective cognitive impairment; 7% received other specified diagnoses such as mood disorders. Findings to date: All patients have a detailed baseline characterisation involving lifestyle and demographic variables; activities of daily living; caregiver situation; medical history; medication; psychiatric, physical and neurological examinations; neurocognitive testing; blood laboratory work-up; and structural or functional brain imaging. Diagnoses are set according to standardised diagnostic criteria. The research biobank stores DNA and blood samples from 4000 patients as well as cerebrospinal fluid from 800 patients. Data from NorCog have been used in a wide range of research projects evaluating and validating dementia-related assessment tools, and identifying patient characteristics, symptoms, functioning and needs, as well as caregiver burden and requirement of available resources. Future plans: The finish date of NorCog was originally in 2029. In 2021, the registry's legal basis was reformalised and NorCog got approval to collect and keep data for as long as is necessary to achieve the purpose of the registry. In 2022, the registry underwent major changes. Paper-based data collection was replaced with digital registration, and the number of variables collected was reduced. Future plans involve expanding the registry to include patients from primary care centres. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Aksnes, Mari; Aass, Hans Christian Dalsbotten; Tiiman, Ann; Terenius, Lars; Bogdanovic, Nenad & Vukojević, Vladana [Show all 7 contributors for this article] (2022). Serum Amyloidogenic Nanoplaques and Cytokines in Alzheimer's Disease: Pilot Study in a Small Naturalistic Memory Clinic Cohort. Journal of Alzheimer's Disease. ISSN 1387-2877. 86(3), p. 1459–1470. doi: 10.3233/JAD-215504. Full text in Research Archive Show summary
Background: Neuroinflammation is a central component of Alzheimer’s disease (AD) and correlates closely with amyloid pathology. Markers of inflammation such as cytokines, and amyloidogenic aggregates, so-called nanoplaques, are both promising biomarker candidates for AD. We have previously shown that there is a relationship between the levels of nanoplaques and cytokines in cerebrospinal fluid, but it is unknown whether this association extends to serum. Objective: Investigate in a naturalistic memory clinic cohort whether the associations between nanoplaques and cytokines in the cerebrospinal fluid extends to serum. Methods: We collected serum from 49 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic (15 with clinical AD). We assessed the levels of serum nanoplaques with the novel Thioflavin-T fluorescence correlation spectroscopy (ThT-FCS) assay. Serum levels of nine cytokines (eotaxin-1, granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1 (MCP-1), gamma induced protein 10 (IP-10), macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a multiplex assay and read on a Luminex IS 200 instrument. Results: Serum nanoplaques were not increased in clinical AD patients compared to non-AD memory clinic patients and nanoplaques were not associated with any cytokines. The cytokines IL-8 and G-CSF were increased in patients with clinical AD compared to non-AD patients. Conclusion: In this small pilot study, serum nanoplaques were not associated with serum cytokines. Nanoplaque levels could not be used to separate clinical AD patients from non-AD patients in this unselected memory clinic cohort.
Soares, Jelena Zugic; Valeur, Jørgen; Benth, Jurate Saltyte; Knapskog, Anne Brita; Selbæk, Geir & Arefi, Golchin [Show all 10 contributors for this article] (2022). Vitamin D in Alzheimer's Disease: Low Levels in Cerebrospinal Fluid Despite Normal Amounts in Serum. Journal of Alzheimer's Disease. ISSN 1387-2877. 86(3), p. 1301–1314. doi: 10.3233/JAD-215536. Full text in Research Archive Show summary
Background:Vitamin D insufficiency has been suggested as a dementia risk factor. Objective:In this cross-sectional, explorative study we investigated whether levels of vitamin D in cerebrospinal fluid (CSF) are lower in patients with positive biomarkers of Alzheimer’s disease (AD) compared to cognitively healthy controls and whether polymorphisms of the vitamin D receptor (VDR) gene, FokI, BsmI, ApaI, and TaqI, are associated with levels of vitamin D in CSF and cognition. Methods:We included 100 patients≥65 years assessed for cognitive impairment and 76 cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D) in both serum and CSF, and VDR polymorphisms were analyzed. Results:The mean level of 25(OH)D in serum was 78.6 (SD 28.9) nmol/l. While serum levels of 25(OH)D were not significantly different between the groups, CSF levels of 25(OH)D were significantly lower in patients with positive AD core biomarkers (p = 0.001) compared to patients without such biomarkers. Individuals with the BsmI major homozygote genotype had significantly lower results on a 10-word delayed recall test (p = 0.044) and verbal fluency test (p = 0.013), and individuals with the TaqI major homozygote genotype had significantly lower results on a verbal fluency test (p = 0.030) compared to individuals with the corresponding minor homozygote genotype. Conclusion:Patients with positive AD core biomarkers have low CSF levels of 25(OH)D, despite sufficient serum levels. CSF levels of 25(OH)D do not seem to be affected by any of the four VDR gene polymorphisms. TaqI and BsmI major homozygote genotypes might be at increased risk for development of cognitive decline.
Soares, Jelena Zugic; Valeur, Jørgen; Benth, Jurate Saltyte; Knapskog, Anne Brita; Selbæk, Geir & Bogdanovic, Nenad [Show all 7 contributors for this article] (2022). Associations Between Intrathecal Levels of Vitamin D, Cytokines, and Core Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. Journal of Alzheimer's Disease. ISSN 1387-2877. 89(3), p. 825–834. doi: 10.3233/JAD-220407. Full text in Research Archive Show summary
Background: Several studies have examined association between vitamin D levels in serum and cognition, but little is known of vitamin D levels in cerebrospinal fluid (CSF) and association with Alzheimer’s disease (AD). Objective: In this cross-sectional, explorative study we investigated possible associations of vitamin D in CSF with biomarkers for AD, amyloid-β, tau protein/phosphorylated tau protein in CSF, and with the cytokines IL-6, IL-8, and TNF-α in CSF in patients with cognitive impairment and cognitively healthy controls. Methods: We included 100 outpatients ≥65 years referred for assessment of cognitive impairment and 76 age- and sex-matched cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D), amyloid-β, tau protein and phosphorylated tau protein, as well as IL-6, IL-8, and TNF-α, were analyzed in CSF in both groups. Results: Higher levels of 25(OH)D in CSF in all groups together were associated with lower levels of tau protein (p = 0.01) and phosphorylated tau protein (p = 0.005). We found no association between 25(OH)D levels in CSF and pathological levels of amyloid-β in CSF nor levels of IL-6 or TNF-α in CSF. Higher levels of 25(OH)D in CSF were associated with higher levels of IL-8 in CSF (p = 0.002). However, vitamin D explained only 6% of variance in IL-8. There was no significant difference between the patient groups and the control group regarding the association between 25(OH)D in CSF and any of the three cytokines in CSF. Conclusion: Participants with higher CSF levels of 25(OH)D exhibited reduced CSF levels of tau protein and phosphorylated tau protein.
Henjum, Kristi; Watne, Leiv; Godang, Kristin; Halaas, Nathalie Bodd; Eldholm, Rannveig Sakshaug & Blennow, Kaj [Show all 10 contributors for this article] (2022). Cerebrospinal fluid catecholamines in Alzheimer's disease patients with and without biological disease. Translational Psychiatry. 12. doi: 10.1038/s41398-022-01901-5. Full text in Research Archive Show summary
Noradrenergic and dopaminergic neurons are involved in cognitive functions, relate to behavioral and psychological symptoms in dementia and are affected in Alzheimer’s disease (AD). Amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N) hallmarks the AD neuropathology. Today, the AT(N) pathophysiology can be assessed through biomarkers. Previous studies report cerebrospinal fluid (CSF) catecholamine concentrations in AD patients without biomarker refinement. We explored if CSF catecholamines relate to AD clinical presentation or neuropathology as reflected by CSF biomarkers. CSF catecholamines were analyzed in AD patients at the mild cognitive impairment (MCI; n = 54) or dementia stage (n = 240) and in cognitively unimpaired (n = 113). CSF biomarkers determined AT status and indicated synaptic damage (neurogranin). The AD patients (n = 294) had higher CSF noradrenaline and adrenaline concentrations, but lower dopamine concentrations compared to the cognitively unimpaired (n = 113). AD patients in the MCI and dementia stage of the disease had similar CSF catecholamine concentrations. In the CSF neurogranin positively associated with noradrenaline and adrenaline but not with dopamine. Adjusted regression analyses including AT status, CSF neurogranin, age, gender, and APOEε4 status verified the findings. In restricted analyses comparing A+T+ patients to A−T− cognitively unimpaired, the findings for CSF adrenaline remained significant (p < 0.001) but not for CSF noradrenaline (p = 0.07) and CSF dopamine (p = 0.33). There were no differences between A+T+ and A−T− cognitively unimpaired. Thus, we find alterations in CSF catecholamines in symptomatic AD and the CSF adrenergic transmitters to increase simultaneously with synaptic damage as indexed by CSF neurogranin.
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.
Alme, Katinka Nordheim; Ulvik, Arve; Askim, Torunn; Assmus, Jörg; Mollnes, Tom Eirik & Naik, Mala [Show all 10 contributors for this article] (2021). Neopterin and kynurenic acid as predictors of stroke recurrence and mortality: a multicentre prospective cohort study on biomarkers of inflammation measured three months after ischemic stroke. BMC Neurology. 21(1), p. 1–11. doi: 10.1186/s12883-021-02498-w. Full text in Research Archive Show summary
Background Chronic low-grade inflammation is associated with both ischemic stroke and sedentary behaviour. The aim of this study was to investigate the predictive abilities of biomarkers of inflammation and immune modulation associated with sedentary behaviour for ischemic stroke recurrence and mortality in a stroke population. Methods Patients admitted to hospital for acute stroke were recruited to the prospective multicentre cohort study, the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study, from May 2015 until March 2017. Patients with ischemic stroke, blood samples available from the three-month follow-up, and no stroke recurrence before the three-month follow-up were included. Serum was analysed for C-reactive protein (CRP) with high-sensitive technique, and plasma for interleukin-6 (IL-6), neopterin, pyridoxic acid ratio index (PAr-index: 4-pyridoxic acid: [pyrioxal+pyridoxal-5′-phosphate]) and kynurenic acid (KA). Ischemic stroke recurrence and death were identified by the Norwegian Stroke Registry and the Cause of Death Registry until 31 December 2018. Results The study included 354 patients, 57% male, mean age 73 (SD 11) years, mean observation time 2.5 (SD 0.6) years, and median National Institute of Health Stroke Scale of 0 (IQR 1) at three months. CRP was associated with mortality (HR 1.40, CI 1.01, 1.96, p = 0.046), and neopterin was associated with the combined endpoint (recurrent ischemic stroke or death) (HR 1.52, CI 1.06, 2.20, p = 0.023), adjusted for age, sex, prior cerebrovascular disease, modified Rankin Scale, and creatinine. When adding neopterin and KA to the same model, KA was negatively associated (HR 0.57, CI 0.33, 0.97, p = 0.038), and neopterin was positively associated (HR 1.61, CI 1.02, 2.54, p = 0.040) with mortality. Patients with cardioembolic stroke at baseline had higher levels of inflammation at three months. Conclusion Neopterin might be a valuable prognostic biomarker in stroke patients. The use of KA as a measure of anti-inflammatory capacity should be investigated further.
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.
Halaas, Nathalie Bodd; Zetterberg, Henrik; Idland, Ane-Victoria; Knapskog, Anne Brita; Watne, Leiv Otto & Blennow, Kaj (2021). Cerebrospinal Fluid Concentration of Neurogranin in Hip Fracture Patients with Delirium. Journal of Alzheimer's Disease. ISSN 1387-2877. 81(2), p. 1–28. doi: 10.3233/jad-201341. Full text in Research Archive
Einstad, Marte Stine; Saltvedt, Ingvild; Lydersen, Stian; Ursin, Marie Helene; Munthe-Kaas, Ragnhild & Ihle-Hansen, Hege [Show all 13 contributors for this article] (2021). Associations between post-stroke motor and cognitive function: a cross-sectional study. BMC Geriatrics. 21(1), p. 1–10. doi: 10.1186/s12877-021-02055-7. Full text in Research Archive Show summary
Background: Motor and cognitive impairments are frequently observed following stroke, but are often managed as distinct entities, and there is little evidence regarding how they are related. The aim of this study was to describe the prevalence of concurrent motor and cognitive impairments 3 months after stroke and to examine how motor performance was associated with memory, executive function and global cognition. Methods: The Norwegian Cognitive Impairment After Stroke (Nor-COAST) study is a prospective multicentre cohort study including patients hospitalized with acute stroke between May 2015 and March 2017. The National Institutes of Health Stroke Scale (NIHSS) was used to measure stroke severity at admission. Level of disability was assessed by the Modified Rankin Scale (mRS). Motor and cognitive functions were assessed 3 months post-stroke using the Montreal Cognitive Assessment (MoCA), Trail Making Test Part B (TMT-B), 10-Word List Recall (10WLR), Short Physical Performance Battery (SPPB), dual-task cost (DTC) and grip strength (Jamar®). Cut-offs were set according to current recommendations. Associations were examined using linear regression with cognitive tests as dependent variables and motor domains as covariates, adjusted for age, sex, education and stroke severity. Results: Of 567 participants included, 242 (43%) were women, mean (SD) age was 72.2 (11.7) years, 416 (75%) had an NIHSS score ≤ 4 and 475 (84%) had an mRS score of ≤2. Prevalence of concurrent motor and cognitive impairment ranged from 9.5% for DTC and 10WLR to 22.9% for grip strength and TMT-B. SPPB was associated with MoCA (regression coefficient B = 0.465, 95%CI [0.352, 0.578]), TMT-B (B = -9.494, 95%CI [− 11.726, − 7.925]) and 10WLR (B = 0.132, 95%CI [0.054, 0.211]). Grip strength was associated with MoCA (B = 0.075, 95%CI [0.039, 0.112]), TMT-B (B = -1.972, 95%CI [− 2.672, − 1.272]) and 10WLR (B = 0.041, 95%CI [0.016, 0.066]). Higher DTC was associated with more time needed to complete TMT-B (B = 0.475, 95%CI [0.075, 0.875]) but not with MoCA or 10WLR.
Hernes, Susanne Miriam Sørensen; Flak, Marianne Møretrø; Løhaugen, Gro Christine Christensen; Skranes, Jon Sverre; Hol, Haakon Ramsland & Madsen, Bengt-Ove [Show all 13 contributors for this article] (2021). Working Memory Training in Amnestic and Non-amnestic Patients With Mild Cognitive Impairment: Preliminary Findings From Genotype Variants on Training Effects. Frontiers in Aging Neuroscience. 13. doi: 10.3389/fnagi.2021.624253. Full text in Research Archive Show summary
Working memory training (WMT) effects may be modulated by mild cognitive impairment (MCI) subtypes, and variations in APOE-epsilon (APOE-ε) and LMX1A genotypes. Sixty-one individuals (41 men/20 women, mean age 66 years) diagnosed with MCI (31 amnestic/30 non-amnestic) and genotyped for APOE-ε and LMX1A completed 4 weeks/20-25 sessions of WMT. Cognitive functions were assessed before, 4 weeks and 16 weeks after WMT. Except for Processing Speed, the non-amnestic MCI group (naMCI) outperformed the amnestic MCI (aMCI) group in all cognitive domains across all time-points. At 4 weeks, working memory function improved in both groups (p
Schellhorn, Till; Zucknick, Manuela; Askim, Torunn; Munthe-Kaas, Ragnhild; Ihle-Hansen, Hege & Seljeseth, Yngve Müller [Show all 13 contributors for this article] (2021). Pre-stroke cognitive impairment is associated with vascular imaging pathology: a prospective observational study. BMC Geriatrics. 21:362(362), p. 1–10. doi: 10.1186/s12877-021-02327-2. Full text in Research Archive Show summary
Background: Chronic brain pathology and pre-stroke cognitive impairment (PCI) is predictive of post-stroke dementia. The aim of the current study was to measure pre-stroke neurodegenerative and vascular disease burden found on brain MRI and to assess the association between pre-stroke imaging pathology and PCI, whilst also looking for potential sex differences. Methods: This prospective brain MRI cohort is part of the multicentre Norwegian cognitive impairment after stroke (Nor-COAST) study. Patients hospitalized with acute ischemic or hemorrhagic stroke were included from five participating stroke units. Visual rating scales were used to categorize baseline MRIs (N = 410) as vascular, neurodegenerative, mixed, or normal, based on the presence of pathological imaging findings. Pre-stroke cognition was assessed by interviews of patients or caregivers using the Global Deterioration Scale (GDS). Stroke severity was assessed with the National Institute of Health Stroke Scale (NIHSS). Univariate and multiple logistic regression analyses were performed to investigate the association between imaging markers, PCI, and sex. Results: Patients’ (N = 410) mean (SD) age was 73.6 (±11) years; 182 (44%) participants were female, the mean (SD) NIHSS at admittance was 4.1 (±5). In 68% of the participants, at least one pathological imaging marker was found. Medial temporal lobe atrophy (MTA) was present in 30% of patients, white matter hyperintensities (WMH) in 38% of patients and lacunes in 35% of patients. PCI was found in 30% of the patients. PCI was associated with cerebrovascular pathology (OR 2.5; CI = 1.4 to 4.5, p = 0.001) and mixed pathology (OR 3.4; CI = 1.9 to 6.1, p = 0.001) but was not associated with neurodegeneration (OR 1.0; CI = 0.5 to 2.2; p = 0.973). Pathological MRI markers, including MTA and lacunes, were more prevalent among men, as was a history of clinical stroke prior to the index stroke. The OR of PCI for women was not significantly increased (OR 1.2; CI = 0.8 to 1.9; p = 0.3).
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 <sup>18</sup>F-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
Alme, Katinka Nordheim; Askim, Torunn; Assmus, Jörg; Mollnes, Tom Eirik; Naik, Mala & Næss, Halvor [Show all 10 contributors for this article] (2021). Investigating novel biomarkers of immune activation and modulation in the context of sedentary behaviour: a multicentre prospective ischemic stroke cohort study. BMC Neurology. 21(1), p. 1–9. doi: 10.1186/s12883-021-02343-0. Full text in Research Archive Show summary
Background Sedentary behaviour is associated with disease, but the molecular mechanisms are not understood. Valid biomarkers with predictive and explanatory properties are required. Therefore, we have investigated traditional and novel biomarkers of inflammation and immune modulation and their association to objectively measured sedentary behaviour in an ischemic stroke population. Methods Patients admitted to hospital with acute ischemic stroke were included in the multicentre Norwegian Cognitive Impairment After Stroke (Nor-COAST) study (n = 815). For this sub-study (n = 257), sedentary behaviour was registered 3 months after stroke using position transition data from the body-worn sensor, ActivPal®. Blood samples were analysed for high sensitive C-reactive protein (hsCRP), the cytokines interleukin-6 (IL-6) and 10 (IL-10), neopterin, tryptophan (Trp), kynurenine (kyn), kynurenic acid (KA), and three B6 vitamers, pyridoxal 5′-phosphate (PLP), pyridoxal (PL), and pyridoxic acid (PA). The kynurenine/tryptophan ratio (KTR) and the pyridoxic acid ratio index (PAr = PA: PL + PLP) were calculated. Results Of the 815 patients included in the main study, 700 attended the three-month follow-up, and 257 fulfilled the inclusion criteria for this study. Sedentary time was significantly associated with levels of hsCRP, IL-6, neopterin, PAr-index, and KA adjusted for age, sex, waist circumference, and creatinine. In a fully adjusted model including all the significant biomarkers except hsCRP (because of missing values), sedentary time was independently positively associated with the PAr-index and negatively with KA. We did not find an association between sedentary behaviour, IL-10, and KTR. Conclusions The PAr-index is known to capture several modes of inflammation and has previously shown predictive abilities for future stroke. This novel result indicates that the PAr-index could be a useful biomarker in future studies on sedentary behaviour and disease progression. KA is an important modulator of inflammation, and this finding opens new and exciting pathways to understand the hazards of sedentary behaviour. Trial registration The study was registered at Clinicaltrials.gov (NCT02650531). First posted 08/01/2016.
Knapskog, Anne Brita; Engedal, Knut; Selbæk, Geir & Øksengård, Anne Rita (2021). Alzheimers sykdom – diagnostikk og behandling. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(7), p. 660–663. doi: 10.4045/tidsskr.20.0919. Full text in Research Archive
Aam, Stina; Gynnild, Mari Nordbø; Munthe-Kaas, Ragnhild; Saltvedt, Ingvild; Lydersen, Stian & Knapskog, Anne Brita [Show all 10 contributors for this article] (2021). The Impact of Vascular Risk Factors on Post-stroke Cognitive Impairment: The Nor-COAST Study. Frontiers in Neurology. 12, p. 1–11. doi: 10.3389/fneur.2021.678794. Full text in Research Archive Show summary
Introduction: Post-stroke cognitive impairment (PSCI) is common, but evidence on the impact of vascular risk factors is lacking. We explored the association between pre-stroke vascular risk factors and PSCI and studied the course of PSCI. Materials and Methods: Vascular risk factors were collected at baseline in stroke survivors (n = 635). Cognitive assessments of attention, executive function, memory, language, and the Montreal Cognitive Assessment (MoCA) were performed at 3 and/or 18 months post-stroke. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). PSCI was measured with global z; MoCA z-score; and z-score of the four assessed cognitive domains. Mixed-effect linear regression was applied with global z, MoCA z-score, and z-scores of the cognitive domains as dependent variables. Independent variables were the vascular risk factors (hypertension, hypercholesterolemia, smoking, diabetes mellitus, atrial fibrillation, coronary heart disease, previous stroke), time, and the interaction between these. The analyses were adjusted for age, education, and sex. There were between 5 and 25% missing data for the variables for PSCI. Results: Mean age was 71.6 years (SD 11.7); 42% were females; and the mean NIHSS score at admittance was 3.8 (SD 4.8). Regardless of vascular risk factors, global z, MoCA, and all the assessed cognitive domains were impaired at 3 and 18 months, with MoCA being the most severely impaired. Atrial fibrillation (AF) was associated with poorer language at 18 months and coronary heart disease (CHD) with poorer MoCA at 18 months (LR = 12.80, p = 0.002, and LR = 8.32, p = 0.004, respectively). Previous stroke was associated with poorer global z and attention at 3 and 18 months (LR = 15.46, p < 0.001, and LR = 16.20, p < 0.001). In patients without AF, attention improved from 3 to 18 months, and in patients without CHD, executive function improved from 3 to 18 months (LR = 10.42, p < 0.001, and LR = 9.33, p = 0.009, respectively). Discussion: Our findings indicate that a focal stroke lesion might be related to pathophysiological processes leading to global cognitive impairment. The poorer prognosis of PSCI in patients with vascular risk factors emphasizes the need for further research on complex vascular risk factor interventions to prevent PSCI.
Sajjad, Muhammad Umar; Blennow, Kaj; Knapskog, Anne Brita; Idland, Ane-Victoria; Chaudhry, Farrukh Abbas & Wyller, Torgeir Bruun [Show all 8 contributors for this article] (2020). Cerebrospinal Fluid Levels of Interleukin-8 in Delirium, Dementia, and Cognitively Healthy Patients. Journal of Alzheimer's Disease. ISSN 1387-2877. 73(4), p. 1363–1372. doi: 10.3233/JAD-190941. Full text in Research Archive Show summary
Background: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known. Objective: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium. Methods: In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer’s disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay. Results: Hip fracture patients had significantly higher IL-8 levels (p < 0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (p = 0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (p = 0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (p = 0.002) in delirium patients with depression. Both TNF-α and IL-1β were undetected in most patients. Conclusions: Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels.
Gynnild, Mari Nordbø; Aakerøy, Rachel; Spigset, Olav; Askim, Torunn; Beyer, Mona Kristiansen & Ihle-Hansen, Hege [Show all 15 contributors for this article] (2020). Vascular risk factor control and adherence to secondary preventive medication after ischaemic stroke. Journal of Internal Medicine. ISSN 0954-6820. 289(3), p. 1–14. doi: 10.1111/joim.13161. Full text in Research Archive Show summary
Background Studies regarding adequacy of secondary stroke prevention are limited. We report medication adherence, risk factor control and factors influencing vascular risk profile following ischaemic stroke. Methods A total of 664 home‐dwelling participants in the Norwegian Cognitive Impairment After Stroke study, a multicenter observational study, were evaluated 3 and 18 months poststroke. We assessed medication adherence by self‐reporting (4‐item Morisky Medication Adherence Scale) and medication persistence (defined as continuation of medication(s) prescribed at discharge), achievement of guideline‐defined targets of blood pressure (BP) (<140/90 mmHg), low‐density lipoprotein cholesterol (LDL‐C) (<2.0 mmol L−1) and haemoglobin A1c (HbA1c) (≤53 mmol mol−1) and determinants of risk factor control. Results At discharge, 97% were prescribed antithrombotics, 88% lipid‐lowering drugs, 68% antihypertensives and 12% antidiabetic drugs. Persistence of users declined to 99%, 88%, 93% and 95%, respectively, at 18 months. After 3 and 18 months, 80% and 73% reported high adherence. After 3 and 18 months, 40.7% and 47.0% gained BP control, 48.4% and 44.6% achieved LDL‐C control, and 69.2% and 69.5% of diabetic patients achieved HbA1c control. Advanced age was associated with increased LDL‐C control (OR 1.03, 95% CI 1.01 to 1.06) and reduced BP control (OR 0.98, 0.96 to 0.99). Women had poorer LDL‐C control (OR 0.60, 0.37 to 0.98). Polypharmacy was associated with increased LDL‐C control (OR 1.29, 1.18 to 1.41) and reduced HbA1c control (OR 0.76, 0.60 to 0.98). Conclusion Risk factor control is suboptimal despite high medication persistence and adherence. Improved understanding of this complex clinical setting is needed for optimization of secondary preventive strategies.
Munthe-Kaas, Ragnhild; Aam, Stina; Ihle-Hansen, Hege; Lydersen, Stian; Knapskog, Anne Brita & Wyller, Torgeir Bruun [Show all 15 contributors for this article] (2020). Impact of different methods defining post-stroke neurocognitive disorder: The Nor-COAST study. Alzheimer's and Dementia: Translational Research and Clinical Interventions. 6:e12000(1), p. 1–9. doi: 10.1002/trc2.12000. Full text in Research Archive Show summary
Introduction Post‐stroke neurocognitive disorder (NCD) is common; prevalence varies between studies, partially related to lack of consensus on how to identify cases. The aim was to compare the prevalence of post‐stroke NCD using only cognitive assessment (model A), DSM‐5 criteria (model B), and the Global Deterioration Scale (model C) and to determine agreement among the three models. Methods In the Norwegian Cognitive Impairment After Stroke study, 599 patients were assessed 3 months after suffering a stroke. Results The prevalence of mild NCD varied from 174 (29%) in model B to 83 (14%) in model C; prevalence of major NCD varied from 249 (42%) in model A to 68 (11%) in model C. Cohen's kappa and Cohen's quadratic weighted kappa showed fair to very good agreement among models; the poorest agreement was found for identification of mild NCD. Discussion The findings indicate a need for international harmonization to classify post‐stroke NCD.
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.
Aam, Stina; Einstad, Marte Stine; Munthe-Kaas, Ragnhild; Lydersen, Stian; Ihle-Hansen, Hege & Knapskog, Anne Brita [Show all 9 contributors for this article] (2020). Post-stroke Cognitive Impairment—Impact of Follow-Up Time and Stroke Subtype on Severity and Cognitive Profile: The Nor-COAST Study. Frontiers in Neurology. 11:699, p. 1–10. doi: 10.3389/fneur.2020.00699. Full text in Research Archive Show summary
Background: Post-stroke cognitive impairment (PSCI) is common, but evidence of cognitive symptom profiles, course over time, and pathogenesis is scarce. We investigated the significance of time and etiologic stroke subtype for the probability of PSCI, severity, and cognitive profile. Methods: Stroke survivors (n = 617) underwent cognitive assessments of attention, executive function, memory, language, perceptual-motor function, and the Montreal Cognitive Assessment (MoCA) after 3 and/or 18 months. PSCI was classified according to DSM-5 criteria. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Stroke subtype was categorized as intracerebral hemorrhage (ICH), large artery disease (LAD), cardioembolic stroke (CE), small vessel disease (SVD), or un-/other determined strokes (UD). Mixed-effects logistic or linear regression was applied with PSCI, MoCA, and z-scores of the cognitive domains as dependent variables. Independent variables were time as well as stroke subtype, time, and interaction between these. The analyses were adjusted for age, education, and sex. The effects of time and stroke subtype were analyzed by likelihood ratio tests (LR). Results: Mean age was 72 years (SD 12), 42% were females, and mean NIHSS score at admittance was 3.8 (SD 4.8). Probability (95% CI) for PSCI after 3 and 18 months was 0.59 (0.51–0.66) and 0.51 (0.52–0.60), respectively and remained constant over time. Global measures and most cognitive domains were assessed as impaired for the entire stroke population and for most stroke subtypes. Executive function and language improved for the entire stroke population (LR) = 9.05, p = 0.003, and LR = 10.38, p = 0.001, respectively). After dividing the sample according to stroke subtypes, language Aam et al. Post-stroke Cognitive Impairment improved for ICH patients (LR = 18.02, p = 0.003). No significant differences were found in the severity of impairment between stroke subtypes except for attention, which was impaired for LAD and CE in contrast to no impairment for SVD (LR = 56.58, p < 0.001). Conclusions: In this study including mainly minor strokes, PSCI is common for all subtypes, both early and long-term after stroke, while executive function and language improve over time. The findings might contribute to personalizing follow-up and offer new insights into underlying mechanisms. Further research is needed on underlying mechanisms, PSCI prevention and treatment, and relevance for rehabilitation.
Alme, Katinka Nordheim; Knapskog, Anne Brita; Næss, Halvor; Naik, Mala; Beyer, Mona K. & Ellekjær, Hanne [Show all 15 contributors for this article] (2020). Is long-bout sedentary behaviour associated with long-Term glucose levels 3 months after acute ischaemic stroke? A prospective observational cohort study. BMJ Open. 10(11), p. 1–9. doi: 10.1136/bmjopen-2020-037475. Full text in Research Archive Show summary
Background and purpose Sedentary behaviour is a risk factor for vascular disease and stroke patients are more sedentary than their age-matched peers. The association with glucose levels, as a potential mediator, is unclear, and we have investigated the association between long-bout sedentary behaviour and long-term glucose levels in stroke survivors. Methods This study uses data from the Norwegian Cognitive Impairment After Stroke study, a multicentre cohort study. The patients were recruited at hospital admission for acute stroke, and the follow-up was done at the outpatient clinic. Sedentary behaviour—being in a sitting or reclining position—was registered 3 months after stroke using position transition data from the body-worn sensor activPAL attached to the unaffected thigh. A MATLAB script was developed to extract activity data from 08:00 to 10:00 for 4 days and to categorise the data into four bout-length categories. The primary outcome was glycated haemoglobin (HbA1c), analysed at 3 months. Regression models were used to analyse the association between HbA1c and sedentary behaviour in the whole population and stratified based on a diagnosis of diabetes mellitus (DM). Age, body mass index and the use of antidiabetic drugs were added as covariates into the models. Results From a total of 815 included patients, 379 patients fulfilled the inclusion criteria for this study. We found no association between time in sedentary behaviour and HbA1c in the whole stroke population. We found time in sedentary behaviour in bouts of ≥90 min to be associated with a higher HbA1c in patients with DM. Conclusion Long-bout sedentary time is associated with a higher HbA1c in patients with DM 3 months after ischaemic stroke. Future research should investigate the benefit of breaking up sedentary time as a secondary preventive measure. Trial registration number NCT02650531, https://clinicaltrials.gov/ct2/show/NCT02650531
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.
Knapskog, Anne Brita; Henjum, Kristi; Idland, Ane-Victoria; Eldholm, Rannveig Sakshaug; Persson, Karin Ester Torun & Saltvedt, Ingvild [Show all 9 contributors for this article] (2020). Cerebrospinal fluid sTREM2 in Alzheimer’s disease: comparisons between clinical presentation and AT classification. Scientific Reports. 10, p. 1–10. doi: 10.1038/s41598-020-72878-8. Full text in Research Archive Show summary
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid β, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.
Hazen, Josje; Vistnes, Maria; Barca, Maria Lage; Eldholm, Rannveig Sakshaug; Persson, Karin Ester Torun & Brækhus, Anne [Show all 10 contributors for this article] (2019). The Association Between Circulating Inflammatory Markers and the Progression of Alzheimer Disease in Norwegian Memory Clinic Patients With Mild Cognitive Impairment or Dementia. Alzheimer Disease and Associated Disorders. ISSN 0893-0341. doi: 10.1097/WAD.0000000000000342. Full text in Research Archive Show summary
OBJECTIVE: Neuroinflammation may play an important role in the pathogenesis and progression of Alzheimer disease (AD). The aim of the present study was to detect whether increased inflammatory activity at baseline could predict cognitive and functional decline in patients with amnestic mild cognitive impairment (aMCI) or AD dementia after 2 years. METHODS: Serum samples from 242 memory clinic patients with an aMCI (n=88) or AD dementia (n=154) were analyzed for C-reactive protein and for 14 other inflammatory markers [interleukin (IL)-1β, interleukin-1 receptor antagonist, IL-6, IL-10, IL-12p40, IL-17a, IL-18, IL-22, IL-33, tumor necrosis factor, cluster of differentiation 40 ligand, interferon-γ, chemokine ligand (CCL) 2, and CCL4] by bead-based multiplex immunoassay. Disease progression was measured by the annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and annual decrease in the score on the Mini-Mental State Examination (MMSE). RESULTS: No association between increased levels of the inflammatory markers and change on the CDR-SB or MMSE score was found, but there was a significant difference in baseline IL-6 and interleukin-1 receptor antagonist levels between aMCI and AD dementia groups. CONCLUSION: Increased levels of inflammatory markers were not associated with faster progression as measured by the annual change on the CDR-SB or MMSE score.
Flak, Marianne Møretrø; Hol, Haakon Ramsland; Hernes, Susanne M S; Chang, Linda; Engvig, Andreas & Bjuland, Knut Jørgen [Show all 13 contributors for this article] (2019). Adaptive computerized working memory training in patients with mild cognitive impairment. A randomized double-blind active controlled trial. Frontiers in Psychology. 10. doi: 10.3389/fpsyg.2019.00807. Full text in Research Archive Show summary
Objective: We investigated if a 5-week computerized adaptive working memory training program (Cogmed®) of 20 to 25 sessions would be effective in improving the working memory capacity and other neuropsychological functions compared to a non-adaptive working memory training program (active-controlled) in adult patients with mild cognitive impairment (MCI). Methods: This randomized double-blinded active control trial included 68 individuals aged 43 to 88 years, 45 men and 23 women, who were diagnosed with MCI at four Memory clinics. The study sample was randomized by block randomization to either adaptive or non-adaptive computerized working memory training. All participants completed the training, and were assessed with a comprehensive neuropsychological test battery before the intervention, and at 1 and 4 months after training. Results: Compared to the non-adaptive training group, the adaptive training group did not show significantly greater improvement on the main outcome of working memory performance at 1 and 4 months after training. Conclusion: No difference were found between the two types of training on the primary outcome of working memory, or on secondary outcomes of cognitive function domains, in this sample of MCI patients. Hence, the hypothesis that the adaptive training program would lead to greater improvements compared to the non-adaptive training program was not supported. Within group analyses was not performed due to the stringent RCT design.
Soares, Jelena Zugic; Pettersen, Renate Regine; Benth, Jurate Saltyte; Knapskog, Anne Brita; Selbæk, Geir & Bogdanovic, Nenad (2019). Higher Vitamin D Levels are Associated with Better Attentional Functions: Data from the NorCog Register. The Journal of Nutrition, Health & Aging. ISSN 1279-7707. 23, p. 725–731. doi: 10.1007/s12603-019-1220-z. Full text in Research Archive
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.
Leavey, Nick; Hammond, Simon P; Shepstone, Lee; Cross, Jane; Zetterberg, Henrik & Cunningham, Colm [Show all 15 contributors for this article] (2019). Study protocol: ASCRIBED: the impact of Acute SystematiC inflammation upon cerebRospinal fluId and blood BiomarkErs of brain inflammation and injury in dementia: A study in acute hip fracture patients. BMC Neurology. 19(1). doi: 10.1186/s12883-019-1447-7. Full text in Research Archive
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.
Persson, Karin; Barca, Maria Lage; Cavallin, Lena; Brækhus, Anne; Knapskog, Anne Brita & Selbæk, Geir [Show all 7 contributors for this article] (2018). Comparison of automated volumetry of the hippocampus using NeuroQuant® and visual assessment of the medial temporal lobe in Alzheimer's disease. Acta Radiologica. ISSN 0284-1851. 59(8), p. 997–1001. doi: 10.1177/0284185117743778. Full text in Research Archive
Eldholm, Rannveig Sakshaug; Persson, Karin Ester Torun; Barca, Maria Lage; Knapskog, Anne Brita; Cavallin, Lena & Engedal, Knut [Show all 9 contributors for this article] (2018). Association between vascular comorbidity and progression of Alzheimer's disease: a two-year observational study in Norwegian memory clinics. BMC Geriatrics. 18:120(120), p. 1–8. doi: 10.1186/s12877-018-0813-4. Full text in Research Archive Show summary
Background: Vascular risk factors increase the risk of Alzheimer’s disease (AD), but there is limited evidence on whether comorbid vascular conditions and risk factors have an impact on disease progression. The aim of this study was to examine the association between vascular disease and vascular risk factors and progression of AD. Methods: In a longitudinal observational study in three Norwegian memory clinics, 282 AD patients (mean age 73. 3 years, 54% female) were followed for mean 24 (16–37) months. Vascular risk factors and vascular diseases were registered at baseline, and the vascular burden was estimated by the Framingham Stroke Risk Profile (FSRP). Cerebral medical resonance images (MRIs) were assessed for white matter hyperintensities (WMH), lacunar and cortical infarcts. The associations between vascular comorbidity and progression of dementia as measured by annual change in Clinical Dementia Rating Sum of Boxes (CDR-SB) scores were analysed by multiple regression analyses, adjusted for age and sex. Results: Hypertension occurred in 83%, hypercholesterolemia in 53%, diabetes in 9%, 41% were overweight, and 10% were smokers. One third had a history of vascular disease; 16% had heart disease and 15% had experienced a cerebrovascular event. MRI showed lacunar infarcts in 16%, WMH with Fazekas score 2 in 26%, and Fazekas score 3 in 33%. Neither the vascular risk factors and diseases, the FSRP score, nor cerebrovascular disease was associated with disease progression in AD. Conclusions: Although vascular risk factors and vascular diseases were prevalent, no impact on the progression of AD after 2 years was shown.
Flak, Marianne Møretrø; Hol, Haakon Ramsland; Hernes, Susanne M S; Chang, Linda; Ernst, Thomas & Engvig, Andreas [Show all 14 contributors for this article] (2018). Cognitive Profiles and Atrophy Ratings on MRI in Senior Patients With Mild Cognitive Impairment. Frontiers in Aging Neuroscience. 10. doi: 10.3389/fnagi.2018.00384. Full text in Research Archive Show summary
In this cross-sectional study, we sought to describe cognitive and neuroimaging profiles of Memory clinic patients with Mild Cognitive Impairment (MCI). 51 MCI patients and 51 controls, matched on age, sex, and socio-economic status (SES), were assessed with an extensive neuropsychological test battery that included a measure of intelligence (General Ability Index, “GAI,” from WAIS-IV), and structural magnetic resonance imaging (MRI). MCI subtypes were determined after inclusion, and z-scores normalized to our control group were generated for each cognitive domain in each MCI participant. MR-images were scored by visual rating scales. MCI patients performed significantly worse than controls on 23 of 31 cognitive measures (Bonferroni corrected p = 0.001), and on 8 of 31 measures after covarying for intelligence (GAI). Compared to nonamnestic MCI patients, amnestic MCI patients had lower test results in 13 of 31 measures, and 5 of 31 measures after co-varying for GAI. Compared to controls, the MCI patients had greater atrophy on Schelten's Medial temporal lobe atrophy score (MTA), especially in those with amnestic MCI. The only structure-function correlation that remained significant after correction for multiple comparisons was the MTA—long delay recall domain. Intelligence operationalized as GAI appears to be an important moderator of the neuropsychological outcomes. Atrophy of the medial temporal lobe, based on MTA scores, may be a sensitive biomarker for the functional episodic memory deficits associated with MCI.
Barca, Maria Lage; Eldholm, Rannveig Sakshaug; Persson, Karin Ester Torun; Björklöf, Guro Hanevold; Borza, Tom & Telenius, Elisabeth Wiken [Show all 11 contributors for this article] (2018). Cortisol levels among older people with and without depression and dementia. International Psychogeriatrics. ISSN 1041-6102. 31(4), p. 597–601. doi: 10.1017/S1041610218001199. Full text in Research Archive Show summary
Cortisol dysregulation has been reported in dementia and depression. Cortisol levels and its associates were investigated among older people living at home and in nursing homes, in a cross-sectional study. A sample of 650 older people, from the community (home and nursing homes) and specialized care (memory clinics and old age psychiatry wards), mean age 76.8 (SD = 10.3) (dementia n = 319, depression, n = 154, dementia plus depression n = 53, and reference group n = 124), was included. Assessment included the Mini Mental State Examination (MMSE), Cornell scale for depression in dementia, activities of daily living scales, and salivary cortisol. Number of drugs was registered. The results showed that the cortisol ratio was highest among patients with dementia and co-morbid depression in comparison to those with either depression or dementia and the reference group. Characteristics significantly associated with cortisol levels were higher MMSE score (in patients with dementia and co-morbid depression), male gender (in people with dementia), and number of medications (in the reference group). We conclude that the cortisol ratio was highest among patients with dementia and co-morbid depression in comparison to those with either depression or dementia and the reference group. The association of cortisol level with MMSE score among patients with dementia and depression could further indicate that increased stress is related to cognitive function.
Thingstad, Pernille; Askim, Torunn; Beyer, Mona K.; Bråthen, Geir; Ellekjær, Hanne & Ihle-Hansen, Hege [Show all 13 contributors for this article] (2018). The Norwegian Cognitive impairment after stroke study (Nor-COAST): study protocol of a multicentre, prospective cohort study. BMC Neurology. 18:193(193). doi: 10.1186/s12883-018-1198-x. Full text in Research Archive Show summary
Background Early and late onset post-stroke cognitive impairment (PCI) contributes substantially to disability following stroke, and is a high priority within stroke research. The aetiology for PCI is complex and related to the stroke itself, brain resilience, comorbid brain diseases, prestroke vulnerability and complications during the hospital stay. The aim of the Norwegian Cognitive Impairment After Stroke study (Nor-COAST) is to quantify and measure levels of cognitive impairments in a general Norwegian stroke population and to identify biological and clinical markers associated with prognosis for cognitive disorders following incident stroke. The study will be organised within five work packages: 1) Incidence and trajectories 2) Pathological mechanisms 3) Development of a risk score 4) Impact of physical activity and 5) Adherence to secondary prevention. Methods Nor-COAST is an ongoing multicentre (five participating hospitals), prospective, cohort study with consecutive inclusion during the acute phase and with follow-up at three and 18 months, and at three years. Inclusion criteria are stroke defined according to the WHO criteria. During the recruitment period from 18.05.2015 to 31.03.2017, 816 participants have been included. Cognitive impairment will be classified according to the DSM-5 criteria using a consensus group. Cognitive function is assessed by a standardised neuropsychological test battery, the Montreal Cognitive Assessment, Trail making A and B, ten-word immediate and delayed recall test, the Controlled Oral Word Association, Global Deterioration Scale and proxy based information by and the Ascertain Dementia 8 item informant questionnaire. Biomarkers include magnetic resonance imaging, routine blood samples and bio-banking. Clinical assessments include characteristics of the stroke, comorbidity, delirium, frailty and tests for cognitive and physical function, sensor based activity monitoring and adherence to secondary prophylaxis. Discussion Nor-COAST is the first Norwegian multicentre study to quantify burden of PCI that will provide reliable estimates in a general stroke population. A multidisciplinary approach aiming to identify biomarkers and clinical markers of overall prognosis will add new knowledge about risk profiles, including pre-stroke vulnerability and modifiable factors such as physical activity and secondary prophylaxis of relevance for clinical practice and later intervention studies.
Knapskog, Anne Brita; Brækhus, Anne & Engedal, Knut (2018). The Effect of Changing the Amyloid β42 Cut-off of Cerebrospinal Fluid Biomarkers on Alzheimer Disease Diagnosis in a Memory Clinic Population in Norway. Alzheimer Disease and Associated Disorders. ISSN 0893-0341. doi: 10.1097/WAD.0000000000000268. Full text in Research Archive
Persson, Karin; Eldholm, Rannveig Sakshaug; Barca, Maria Lage; Cavallin, Lena; Ferreira, Daniel & Knapskog, Anne Brita [Show all 11 contributors for this article] (2017). MRI-assessed atrophy subtypes in Alzheimer’s disease and the cognitive reserve hypothesis. PLOS ONE. 12(10). doi: 10.1371/journal.pone.0186595. Full text in Research Archive Show summary
Background/Aims MRI assessment of the brain has demonstrated four different patterns of atrophy in patients with Alzheimer’s disease dementia (AD): typical AD, limbic-predominant AD, hippocampal-sparing AD, and a subtype with minimal atrophy, previously referred to as no-atrophy AD. The aim of the present study was to identify and describe the differences between these four AD subtypes in a longitudinal memory-clinic study. Methods The medial temporal lobes, the frontal regions, and the posterior regions were assessed with MRI visual rating scales to categorize 123 patients with mild AD according to ICD-10 and NINCDS-ADRDA criteria and the clinical dementia rating scale (CDR) into atrophy subtypes. Demographic data, neuropsychological measures, cerebrospinal-fluid biomarkers, and progression rate of dementia at two-year follow-up were compared between the groups. Results Typical AD was found in 59 patients (48%); 29 (24%) patients had limbic-predominant AD; 19 (15%) had hippocampal-sparing AD; and 16 (13%) belonged to the group with minimal atrophy. No differences were found regarding cognitive test results or progression rates between the different subtypes. Using adjusted logistic regression analysis, we found that the patients in the minimal-atrophy group were less educated, had a lower baseline CDR sum of boxes score, and had higher levels of amyloid β in the cerebrospinal fluid. Conclusion Previous results concerning the prevalence and the similar phenotypic expressions of the four AD subtypes were confirmed. The main finding was that patients with minimal atrophy as assessed by MRI had less education than the other AD subtypes and that this could support the cognitive reserve hypothesis and, at least in part, explain the lower degree of atrophy in this group. Patients with less formal education might present with clinically typical AD symptoms before they have positive biomarkers of AD and this finding might challenge suggested biomarker-based criteria for AD.
Barca, Maria Lage; Persson, Karin; Eldholm, Rannveig Sakshaug; Benth, Jurate Saltyte; Kersten, Hege & Knapskog, Anne Brita [Show all 9 contributors for this article] (2017). Trajectories of depressive symptoms and their relationship to the progression of dementia. Journal of Affective Disorders. ISSN 0165-0327. 222, p. 146–152. doi: 10.1016/j.jad.2017.07.008. Full text in Research Archive Show summary
Background The relationship between progression of Alzheimer's disease and depression and its underlying mechanisms has scarcely been studied. Methods A sample of 282 outpatients with Alzheimer's disease (AD; 105 with amnestic AD and 177 with Alzheimer's dementia) from Norway were followed up for an average of two years. Assessment included Cornell Scale for Depression in Dementia and Clinical Dementia Rating Scale (CDR) at baseline and follow-up to examine the relationship between AD and depression. Additionally, MRI of the brain, CSF dementia biomarkers and APOE status were assessed at baseline. Progression of dementia was defined as the difference between CDR sum of boxes at follow-up and baseline (CDR-SB change). Trajectories of depressive symptoms on the Cornell Scale were identified using growth mixture modeling. Differences between the trajectories in regard to patients’ characteristics were investigated. Results Three distinct trajectories of depressive symptoms were identified: 231 (82.8%) of the patients had stable low-average scores on the Cornell Scale (Class 1); 11 (3.9%) had high and decreasing scores (Class 2); and 37 (13.3%) had moderate and increasing scores (Class 3). All classes had average probabilities over 80%, and confidence intervals were non-overlapping. The only significant characteristic associated with membership in class 3 was CDR-SB change. Limitations Not all patients screened for participation were included in the study, but the included and non-included patients did not differ significantly. Some patients with amnestic MCI might have been misdiagnosed. Conclusion A more rapid progression of dementia was found in a group of patients with increasing depressive symptoms.
Eldholm, Rannveig Sakshaug; Barca, Maria Lage; Persson, Karin; Knapskog, Anne Brita; Kersten, Hege & Engedal, Knut [Show all 10 contributors for this article] (2017). Progression of Alzheimer's disease: A longitudinal study in Norwegian memory clinics. Journal of Alzheimer's Disease. ISSN 1387-2877. 61(3), p. 1221–1232. doi: 10.3233/JAD-170436. Full text in Research Archive Show summary
Background: The course of Alzheimer’s disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression. Objective: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0–18), the cognitive test Mini-Mental State Examination (MMSE, 0–30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1). Methods: The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics. Results: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16–37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores. Conclusion: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate.
Knapskog, Anne Brita; Eldholm, Rannveig Sakshaug; Brækhus, Anne; Engedal, Knut & Saltvedt, Ingvild (2017). Factors that influence the levels of cerebrospinal fluid biomarkers in memory clinic patients. BMC Geriatrics. 17(210). doi: 10.1186/s12877-017-0611-4. Full text in Research Archive Show summary
Background The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ), phospho tau (P-tau) and total tau (T-tau) are used increasingly to support a clinical diagnosis of Alzheimer’s disease. The diagnostic power of these biomarkers has been reported to vary among different studies’ results. The results are poorer when heterogeneous groups of patients have been included compared to studies where patients with Alzheimer’s dementia (AD) and healthy controls have been studied. The aim of this study was to examine if age, APOE genotype and sex were associated with the levels of CSF biomarkers among patients referred to a memory clinic. Methods We included 257 patients from two memory clinics who had been assessed for dementia, including lumbar puncture. Results The mean age of the patients was 68.1 (SD: 8.0) years; 50.2% were women and 66.5% were APOE ε4 positive. Of these patients, 80.5% were diagnosed with AD or amnestic MCI. Both APOE ε4 and increasing age were associated with decreasing levels of Aβ, but not the levels of the tau proteins. In multiple regression analyses, disease stage, defined as a MMSE ≥25 or <25, influenced factors associated with the CSF biomarkers. Among those with MMSE score ≥ 25, age, APOE ε4 genotype, and MMSE score, in addition to a diagnosis of AD, were associated with Aβ level, with an explained variance of 0.43. When using P-tau or T-tau as a dependent variable, the presence of one or two APOE ε4 alleles, and MMSE score influenced the results, in addition to the diagnosis of AD. The explained variance was lower for P-tau (0.26) and for T-tau (0.32). Among those with MMSE <25, these variables explained very little of the variance. There were no gender differences. Conclusions We found that factors in addition to a diagnosis of AD, were associated with the levels of CSF biomarkers. Among those with MMSE ≥25, lower levels of Aβ were associated with several factors including increasing age. This is not reflected in clinical practice, where age-specific cutoffs exist only for T-tau. In this study, age was not associated with the levels of tau proteins.
Knapskog, Anne Brita; Engedal, Knut & Brækhus, Anne (2016). Performance of Cerebrospinal Fluid Biomarkers of Alzheimer Disease in a Memory Clinic in Norway. Alzheimer Disease and Associated Disorders. ISSN 0893-0341. 30(1), p. 8–14. doi: 10.1097/WAD.0000000000000126. Full text in Research Archive
Barca, Maria Lage; Engedal, Knut; Selbæk, Geir; Knapskog, Anne Brita; Laks, Jerson & Coutinho, Evandro [Show all 7 contributors for this article] (2015). Confirmatory factor analysis of the Cornell scale for depression in dementia among patient with dementia of various degrees. Journal of Affective Disorders. ISSN 0165-0327. 188, p. 173–178. doi: 10.1016/j.jad.2015.08.062. Full text in Research Archive
Knapskog, Anne Brita; Barca, Maria Lage & Engedal, Knut Arne (2014). Prevalence of depression among memory clinic patients as measured by the Cornell Scale of Depression in Dementia. Aging & Mental Health. ISSN 1360-7863. 18(5), p. 579–587. doi: 10.1080/13607863.2013.827630. Full text in Research Archive
Araujo, Narahyana Bom de; Moraes, Helena Sales; Silveira, H; Arcoverde, Cynthia; Vasques, Paulo Eduardo & Barca, Maria Lage [Show all 11 contributors for this article] (2014). Alterações cognitivas na depressão e na doença de Alzheimer: Um gradiente da depressão até a doença de Alzheimer. Arquivos de Neuro-Psiquiatria. ISSN 0004-282X. 72(9), p. 671–679. doi: 10.1590/0004-282X20140108. Full text in Research Archive
Knapskog, Anne Brita; Barca, Maria Lage & Engedal, Knut Arne (2013). A Comparison of the Cornell Scale for Depression in Dementia and the Montgomery-Aasberg Depression Rating Scale in a Memory Clinic Population. Dementia and Geriatric Cognitive Disorders. ISSN 1420-8008. 35(5-6), p. 256–265. doi: 10.1159/000348345. Full text in Research Archive
Knapskog, Anne Brita; Portugal, Maria da Glória; Barca, Maria Lage; Coutinho, Evandro Silva Freire; Laks, Jerson & Engedal, Knut Arne (2013). A cross-cultural comparison of the phenotype of depression as measured by the Cornell Scale and the MADRS in two elderly outpatient populations. Journal of Affective Disorders. ISSN 0165-0327. 144(1-2), p. 34–41. doi: 10.1016/j.jad.2012.06.003. Full text in Research Archive
Portugal, Maria da Glória; Coutinho, Evandro Silva Freire; Almeida, Cloyra; Barca, Maria Lage; Knapskog, Anne Brita & Engedal, Knut Arne [Show all 7 contributors for this article] (2012). Validation of Montgomery-Asberg Rating Scale and Cornell Scale for Depression in Dementia in Brazilian elderly patients. International Psychogeriatrics. ISSN 1041-6102. 24(8), p. 1291–1298. doi: 10.1017/S1041610211002250. Full text in Research Archive
Knapskog, Anne Brita; Barca, Maria Lage & Engedal, Knut Arne (2011). A Comparison of the Validity of the Cornell Scale and the MADRS in Detecting Depression among Memory Clinic Patients. Dementia and Geriatric Cognitive Disorders. ISSN 1420-8008. 32(4), p. 287–294. doi: 10.1159/000334983. Full text in Research Archive

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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.
Sannemann, Lena; Rhodius-Meester, Hanneke Frederica Maria; Ekelund, Mats; Flier, Wiesje M. van der; Frederiksen, Kristian Steen & Georges, Jean [Show all 18 contributors for this article] (2025). Evaluation and Validation of a Precision Medicine Platform in Neurodegenerative Disease (PROMINENT). doi: 10.1002/alz70858_105478. Full text in Research Archive
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.
Knapskog, Anne-Brita; Molfetta, Guglielmo Di; Sandvig, Heidi Vihovde; Blennow, Kaj; Zetterberg, Henrik & Aam, Stina [Show all 8 contributors for this article] (2025). Biomarkers. doi: 10.1002/alz70856_101515. Full text in Research Archive Show summary
Background Patients with vascular risk factors have a higher incidence of Alzheimer's disease (AD), and AD patients have an increased risk of experiencing stroke. About half of all stroke survivors experience post-stroke cognitive impairment (PSCI). Stroke triggers numerous inflammatory and neurodegenerative processes both in the acute and chronic phases. The aims of this study were to investigate longitudinal plasma biomarker data in a stroke population and whether high levels of neurodegenerative and acute injury biomarkers at baseline could predict PSCI. Method In this Nor-COAST substudy, we included 547 stroke patients (Age [mean = 73± 12], 56 % males, 89 % ischemic strokes, 11 % haemorrhagic strokes). Brain-derived tau (BD-tau), phosphorylated tau181 (p-tau181), total tau (t-tau), amyloid β40 (Aβ40), Aβ42, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) concentrations were measured on the Simoa platform in plasma samples collected at inclusion, and after 3, 18 and 36 months. We explored the biomarkers’ associations with cognitive decline as measured by the Montreal Cognitive Assessment (MoCA) scale up to 36 months post-stroke. Result Within the first three months BD-tau, t-tau, and GFAP concentrations declined by 43%, 20% and 76% respectively, whereas NfL levels continued to decrease up to 18 months (59%). p-tau181 increased gradually by 24 % from acute phase to 36 months. Aβ42 remained unchanged. Higher acute phase concentrations of BD-tau, NfL and p-tau181 predicted lover MoCA score up to 36 months post-stroke in patients with ischemic stroke (p value < 0.05). However, including clinical parameters attenuated the associations. These associations were not found in the patients with haemorrhagic stroke. Conclusion Concentrations of plasma BD-tau, NfL, GFAP, and t-tau were increased in the acute phase of stroke, but no significant change was seen for Aβ42. BD-tau, t-tau and GFAP concentrations decreased to stable levels within 3 months of event, NfL stabilized within 18 months, whereas p-tau181 showed an increase. Higher concentrations of BD-tau, NfL, and p-tau181 were associated with worse cognitive outcome up to 36 months post-stroke. These results indicate that stroke trigger a continuing neurodegenerative process, as demonstrated by gradually increasing concentrations of p-tau181 leading to PSCI.
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
Chwiszczuk, Luiza; Breitve, Monica Haraldseid; Kirsebom, Bjørn-Eivind; Selnes, Per; Fløvig, John Christian Jøraholmen & Knapskog, Anne Brita [Show all 10 contributors for this article] (2023). The ANeED study – ambroxol in new and early dementia with Lewy bodies (DLB): protocol for a phase IIa multicentre, randomised, double-blinded and placebo-controlled trial. Frontiers in Aging Neuroscience. 15. doi: 10.3389/fnagi.2023.1163184. Full text in Research Archive Show summary
Background: Currently, there are no disease-modifying pharmacological treatment options for dementia with Lewy bodies (DLB). The hallmark of DLB is pathological alpha-synuclein (aS) deposition. There are growing amounts of data suggesting that reduced aS clearance is caused by failure in endolysosomal and authophagic pathways, as well as and glucocerebrosidase (GCase) dysfunction and mutations in the GCase gene (GBA). The population’s studies demonstrated that the incidence of GBA mutations is higher among Parkinson’s disease (PD) patients, and carriers of such mutations have a higher risk of developing PD. The incidence of GBA mutations is even higher in DLB and a genome-wide association study (GWAS) confirmed the correlation between GBA mutations and DLB. In vivo experiments have shown that ambroxol (ABX) may increase GCase activity and GCase levels and therefore enhance aS autophagy-lysosome degradation pathways. Moreover, there is an emerging hypothesis that ABX may have an effect as a DLB modifying drug. The aims of the study “Ambroxol in new and early Dementia with Lewy Bodies (ANeED) are to investigate the tolerability, safety and effects of ABX in patients with DLB. Methods: This is a multicentre, phase IIa, double-blinded, randomised and placebo-controlled clinical trial, using a parallel arm design for 18 months’ follow-up. The allocation ratio is 1:1 (treatment:placebo). Discussion: The ANeED study is an ongoing clinical drug trial with ABX. The unique, but not fully understood mechanism of ABX on the enhancement of lysosomal aS clearance may be promising as a possible modifying treatment in DLB.
Barca, Maria Lage & Knapskog, Anne Brita (2020). Utredning av atferdsmessige og psykologiske symptomer ved demens (APSD. In Rønqvist, Thale Kinne; Wagle, Jørgen Olav & Wilson, Kjersti (Ed.), Utvidet demensutredning. En håndbok.. Aldring og helse. ISSN 9788280616517. p. 50–67. Full text in Research Archive Show summary
I henhold til Helsedirektoratets Nasjonal faglig retningslinje om demens bør pasienter med mistanke om demens tilbys utvidet demensutredning i spesialisthelsetjenesten i tilfeller der basal demensutredning ikke er tilstrekkelig for å stille en diagnose. Håndboken beskriver hvordan utvidet demensutredning bør gjennomføres i spesialisthelsetjenesten og hvordan samarbeidet mellom tjenestenivåene kan ivaretas
Aman, Yahyah; Ryan, B; Torsetnes, Silje Bøen; Knapskog, Anne Brita; Watne, Leiv & McEwan, W [Show all 7 contributors for this article] (2020). Enhancing mitophagy as a therapeutic approach for neurodegenerative diseases. International review of neurobiology. ISSN 0074-7742. 155. doi: 10.1016/bs.irn.2020.02.008. Full text in Research Archive
Flak, Marianne Møretrø; Hol, Haakon Ramsland; Hernes, Susanne M S; Chang, Linda; Ernst, Thomas & Engvig, Andreas [Show all 14 contributors for this article] (2019). Erratum: Cognitive Profiles and Atrophy Ratings on MRI in Senior Patients with Mild Cognitive Impairment (Frontiers in Aging Neuroscience (2018) 10 (384) DOI: 10.3389/fnagi.2018.00384). Frontiers in Aging Neuroscience. 10. doi: 10.3389/fnagi.2019.00037. Full text in Research Archive
Persson, Karin Ester Torun; Barca, Maria Lage; Eldholm, Rannveig Sakshaug; Knapskog, Anne Brita; Vistnes, Maria & Cavallin, Lena [Show all 12 contributors for this article] (2018). MRI assessed atrophy subtypes in Alzheimer’s disease with mild degree of dementia. Full text in Research Archive
Tangen, Gro Gujord; Selbæk, Geir; Knapskog, Anne Brita & Taraldsen, Kristin (2018). Spatial navigation in persons with cognitive impairment – an explorative study of assessment methods and the relationship to physical activity and physical function. Full text in Research Archive
Eldholm, Rannveig Sakshaug; Barca, Maria Lage; Persson, Karin Ester Torun; Knapskog, Anne Brita; Kersten, Hege & Skovlund, Eva [Show all 9 contributors for this article] (2018). Do vascular risk factors and vascular diseases influence disease progression in Alzheimer's disease? Foredrag som ledd i felles symposium med tittelen "Biomarkers and clinical factors in mild cognitive impairment and dementia - a multicenter study" holdt av forskningsgruppen bak studien Progression of Alzheimer's Disease and Resource use (PADR). 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
Aam, Stina; Munthe-Kaas, Ragnhild; Ihle-Hansen, Hege; Knapskog, Anne Brita & Saltvedt, Ingvild (2018). Classifying cognitive impairment after stroke - The Nor-COAST study. Full text in Research Archive
Tangen, Gro Gujord; Knapskog, Anne Brita; Mengshoel, Anne Marit & Selbæk, Geir (2018). Romlig orienteringsevne hos personer med kognitiv svikt - betydning for fysisk funksjon og aktivitet. 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
Nåvik, Marit; Medbøen, Ingrid Tøndel; Totland, Torunn Holm; Jensen, Else Kristin; Knapskog, Anne Brita & Selbæk, Geir [Show all 7 contributors for this article] (2018). Norsk register for personer som utredes for kognitive symptomer i spesialisthelsetjenesten. PROM når pasienten glemmer. Full text in Research Archive
Eldholm, Rannveig Sakshaug; Barca, Maria Lage; Persson, Karin Ester Torun; Knapskog, Anne Brita; Selbæk, Geir & Engedal, Knut [Show all 8 contributors for this article] (2018). Symptom profiles in Alzheimer's disease patients with and without cerebrovascular disease. Full text in Research Archive
Knapskog, Anne Brita & Bogdanovic, Nenad (2017). Re: Glemsk og glemt. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 137(10), p. 685–685. doi: 10.4045/tidsskr.17.0388. Full text in Research Archive
Barca, Maria Lage; Persson, Karin; Eldholm, Rannveig Sakshaug; Knapskog, Anne Brita; Kersten, Hege & Saltvedt, Ingvild [Show all 9 contributors for this article] (2016). Prognostic factors in mild cognitive impairment and Alzheimer's disease (symposium). Full text in Research Archive
Eldholm, Rannveig Sakshaug; Persson, Karin; Barca, Maria Lage; Brækhus, Anne; Knapskog, Anne Brita & Selbæk, Geir [Show all 9 contributors for this article] (2016). Prognostic factors for Progression of Alzheimer's disease and use of Resources (PADR) study. Full text in Research Archive
Eldholm, Rannveig Sakshaug; Persson, Karin; Barca, Maria Lage; Brækhus, Anne; Knapskog, Anne Brita & Selbæk, Geir [Show all 9 contributors for this article] (2016). Progression of Alzheimer's disease: the influence of vascular risk factors and diseases. A longitudinal study in Norwegian memory clinics. Full text in Research Archive
Knapskog, Anne Brita (2011). Assessment of depression in dementia using proxy versus self reported information. International Psychogeriatrics. ISSN 1041-6102. 23, p. S88–S88. Full text in Research Archive
Knapskog, Anne Brita; Barca, Maria Lage & Engedal, Knut Arne (2011). A comparison of the validity of the Cornell Scale and the MADRS in detecting depression among memory clinic patients. International Psychogeriatrics. ISSN 1041-6102. 23, p. S155–S156. Full text in Research Archive
Alme, Katinka Nordheim; Knapskog, Anne-Brita; Askim, Torunn; Naik, Mala & Næss, Halvor (2022). Sedentary behaviour and cerebrovascular disease: molecular mechanisms and the impact of bout duration. : A multicentre cohort study. Universitetet i Bergen. ISSN 9788230866276. Full text in Research Archive Show summary
Abstract Background: Sedentary behaviour is associated with vascular disease, and being sedentary for long periods at a time is believed to be associated with the highest risk. The molecular mechanisms are presumed to follow metabolic and inflammatory pathways. Details about these pathways or the length of a clinical significant sedentary bout is not known. Aims: The primary aim of this study was to investigate the association between sedentary behaviour and novel blood biomarkers with potential predictive and explanatory properties. The secondary aim was to investigate the impact of sedentary behaviour bout length on these biomarkers. Materials and methods: Patients admitted to hospital for acute stroke were included in the multicentre cohort study entitled the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study (n=815). At the three-month assessment (n=700), sedentary behaviour was measured using the body-worn sensor ActivPAL. Blood samples were drawn for analyses at the local laboratory directly, and biobank samples were stored and later analysed for inflammatory biomarkers at two research laboratories. The long-term outcomes, ischemic stroke recurrence and mortality was identified using national registries. Results: Glycated haemoglobin A (HbA1c) was positively associated with sedentary behaviour accumulated through bouts of 90 minutes or more. Total sedentary time was associated with higher levels of the inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL-6), the pyridoxic acid ratio-index (PAr-index), and neopterin, and lower levels of kynurenic acid (KA). The study did not have enough power for investigating the impact of bout length on these biomarkers. There were no associations between the biomarkers and ischemic stroke recurrence. Mortality was associated with higher levels of CRP. When added to the same model, neopterin and KA showed positive and negative associations to mortality, respectively. Conclusion and implications: The results support that the impact of sedentary behaviour on disease progression is mediated through known vascular risk factors and novel biomarkers can be useful for future intervention studies.

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Published Feb. 18, 2026 1:11 PM - Last modified May 27, 2026 3:52 PM

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