Nathalie Bodd Halaas

• Titlestad, Irit; Watne, Leiv Otto; Blennow, Kaj; Zetterberg, Henrik; Myrstad, Marius & Dunjic, Emilija [Show all 15 contributors for this article] (2026). CSF neurofilament light chain concentration in patients with delirium following hip fracture: a multicenter prospective study. BMC Geriatrics. 26(1). doi: 10.1186/s12877-026-07630-4. Full text in Research Archive Show summary

  Background Studies suggest delirium is associated with neuronal injury, which may further raise mortality risk. Neuronal injury can be assessed by measuring neurofilament light chain (NFL) concentrations in cerebrospinal fluid (CSF). This study aimed to investigate the association of CSF-NfL with delirium and mortality in patients with hip fracture. Methods The study comprised two prospective cohorts of 548 hip fracture patients with per-operative CSF samples. CSF-NfL concentrations were measured using a commercial ELISA. Delirium was assessed daily from admission until the fifth postoperative day and survival censored at one year. The multivariable analyses (Logistic and Cox regression) were adjusted for age, sex, glomerular filtration rate, dementia status, comorbidity, and Activities of Daily Living. Additionally, Cox regression was adjusted for delirium. Results In total, 259 (52%) patients developed delirium. In univariate analysis, CSF-NfL was higher among patients with delirium (2116 pg/ml versus 1366 pg/ml, odds ratio (OR) 2.21, (95% confidence interval (CI) [1.75,2,78], P < 0.001). In adjusted analysis, CSF-NfL was not significant (OR 1.29, [0.92,1.81], P = 0.128) and only remained significantly associated with delirium in the subgroup of patients without dementia (OR 1.84, [1.17, 2.89], P = 0.007). In unadjusted analysis of mortality, CSF-NfL was significantly associated with death at one year (hazard ratio (HR) 1.60, [1.37, 1.87], P < 0.001) but not in adjusted analysis (HR 1.03 [0.84, 1.26], P = 0.736). Conclusions Our findings show that CSF-NfL concentrations were associated with delirium in patients without pre-existing dementia, suggesting possible undiagnosed dementia or, less likely, delirium-related neuronal injury. The CSF-NfL-associated mortality hazard was non-significant after adjustment, mainly for delirium. Thus, the clinical context must be considered when studying CSF-NfL and delirium.

• 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
• Hella, Mathias Nikolai Petersen; Halaas, Nathalie Bodd; Sønnesyn, Hogne; Bergland, Anne Katrine; Hetland, Hanne Brit & Blennow, Kaj [Show all 14 contributors for this article] (2025). Neurogranin in cerebrospinal fluid as a marker of synaptic dysfunction in hip fracture patients with delirium: a multicentre cross-sectional study. BMJ Open. 15(11). doi: 10.1136/bmjopen-2024-097579. Full text in Research Archive Show summary

  Objectives: Neurogranin (Ng) has a role in synaptic plasticity and is considered a biomarker of synaptic dysfunction, a process hypothesised to be important in delirium. Few studies examining Ng in delirium exist, with mixed findings. This study aimed to investigate associations between cerebrospinal fluid (CSF) Ng concentrations and delirium in acutely admitted hip fracture patients. Design: Cross-sectional study. Setting: Acutely admitted orthopaedic patients with hip fracture recruited from four participating hospitals in eastern Norway, representing secondary and tertiary care settings. Participants: This study included 392 hip fracture patients. All admitted hip fracture patients operated in spinal anaesthesia were, regardless of age, considered for inclusion. Methods: An in-house ELISA was used to measure CSF Ng concentration in patients acutely admitted with a hip fracture (n=392). Delirium status was evaluated daily according to The Diagnostic and Statistical Manual of Mental Disorders, Fifth Editions criteria independently by two experienced geriatricians. A value > 3.44 on The Informant Questionnaire on Cognitive Decline in the Elderly was used as a surrogate marker of probable dementia. Results: 180 patients (46 %) developed delirium and 70% of these had dementia. CSF Ng concentration did not differ significantly between those with and without delirium (176 pg/mL vs 164 pg/mL), with an estimated difference in medians of 12 (95% CI −5.8 to 29.8), p=0.185. Analyses adjusted for age, gender and dementia status did not show a statistically significant difference in Ng concentrations between the patients. Conclusions: We did not find an association between delirium and CSF concentrations of Ng. This could imply that synaptic dysfunction and degeneration, involving Ng, are not key processes in the development of delirium. Further studies on other synaptic proteins are warranted to better explore synaptic dysfunction’s potential role in the pathophysiology of delirium.

• Capogna, Elettra; Sørensen, Øystein; Watne, Leiv; Roe, James Michael; Strømstad, Marie Lorentsen & Idland, Ane-Victoria [Show all 12 contributors for this article] (2025). Subtypes of brain change in aging and their associations with cognition and Alzheimer’s disease biomarkers. Neurobiology of Aging. ISSN 0197-4580. 147, p. 124–140. doi: 10.1016/j.neurobiolaging.2024.12.009. Full text in Research Archive Show summary

  Structural brain changes underlie cognitive changes and interindividual variability in cognition in older age. By using structural MRI data-driven clustering, we aimed to identify subgroups of cognitively unimpaired older adults based on brain change patterns and assess how changes in cortical thickness, surface area, and subcortical volume relate to cognitive change. We tested (1) which brain structural changes predict cognitive change (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimer’s disease biomarkers, and (3) the degree of overlap between clusters derived from different structural modalities in 1899 cognitively healthy older adults followed up to 16 years. We identified four groups for each brain feature, based on the degree of a main longitudinal component of decline. The minimal overlap between features suggested that each contributed uniquely and independently to structural brain changes in aging. Cognitive change and baseline cognition were associated with cortical area change, whereas higher baseline levels of phosphorylated tau and amyloid-β related to changes in subcortical volume. These results may contribute to a better understanding of different aging trajectories.

• 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.

• Bratseth, Vibeke; Watne, Leiv Otto; Neerland, Bjørn Erik; Halaas, Nathalie Bodd; Pollmann, Christian Thomas & Karabeg, Adi [Show all 11 contributors for this article] (2024). Increased cell-free DNA in CSF and serum of hip fracture patients with delirium. Brain Communications. 7(1). doi: 10.1093/braincomms/fcae452. Full text in Research Archive Show summary

  Delirium is a neuropsychiatric syndrome commonly presenting during acute illness. The pathophysiology of delirium is unknown, but neuroinflammation is suggested to play a role. In this cross-sectional study, we aimed to investigate whether cell-free DNA and markers of neutrophil extracellular traps in serum and CSF were associated with delirium and neuronal damage, assessed by neurofilament light chain. Hip fracture patients (n = 491) with a median (25, 75 percentiles) age of 83 (74, 88) years and 69% females were enrolled at Oslo University Hospital, Diakonhjemmet Hospital, Akershus University Hospital and Bærum Hospital. Delirium was assessed daily, pre- and postoperatively. Cognitively healthy adults (n = 32) with a median (25, 75 percentiles) age of 75 (70, 77) years and 53% females were included as controls. Cell-free DNA was measured by using the fluorescent nucleic acid stain Quant-iT PicoGreen® in serum and CSF. Myeloperoxidase-DNA and citrullinated histone H3 were analysed by enzyme-linked immunosorbent assay in serum. Hip fracture patients have significantly higher levels of cell-free DNA and neutrophil extracellular traps in blood than cognitively healthy controls. In hip fracture patients without dementia, cell-free DNA in CSF and serum was significantly higher in patients with (n = 68) versus without (n = 221) delirium after adjusting for age and sex (70 (59, 84) versus 62 (53, 77) ng/ml, P = 0.037) and 601 (504, 684) versus 508 (458, 572) ng/ml, P = 0.007, respectively). In the total hip fracture cohort, CSF levels of cell-free DNA and neurofilament light chain were significantly correlated after adjusting for age and sex (r = 0.441, P < 0.001). The correlation was stronger in those with delirium (r = 0.468, P < 0.001) and strongest in delirious patients without dementia (r = 0.765, P = 0.045). In delirious patients without dementia, significantly higher levels of cell-free DNA in CSF and serum were shown. The association between cell-free DNA and neurofilament light chain suggest simultaneous release of cell-free DNA and neuronal damage during delirium.

• 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.

• Titlestad, Irit; Watne, Leiv; Caplan, Gideon A.; McCann, Adrian; Ueland, Per Magne & Neerland, Bjørn Erik [Show all 15 contributors for this article] (2023). Impaired glucose utilization in the brain of patients with delirium following hip fracture. Brain. ISSN 0006-8950. 147(1), p. 215–223. doi: 10.1093/brain/awad296. Full text in Research Archive Show summary

  Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and β-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, β-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.

• 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.

• Aksnes, Mari; Capogna, Elettra; Vidal-Piñeiro, Didac; Chaudhry, Farrukh Abbas; Myrstad, Marius & Idland, Ane-Victoria [Show all 13 contributors for this article] (2023). Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals. Neurobiology of Aging. ISSN 0197-4580. 131, p. 11–23. doi: 10.1016/j.neurobiolaging.2023.05.012. Full text in Research Archive Show summary

  Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer’s disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β42 and phosphorylated tau181. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging.

• Capogna, Elettra; Watne, Leiv; Sørensen, Øystein; Guichelaar, Carlijn Jamila; Idland, Ane-Victoria & Halaas, Nathalie Bodd [Show all 11 contributors for this article] (2023). Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers – in cognitively unimpaired older adults. Brain, Behavior, and Immunity. ISSN 0889-1591. 113, p. 56–65. doi: 10.1016/j.bbi.2023.06.027. Full text in Research Archive Show summary

  Concentrations of pro-inflammatory cytokines –interleukin-6 (IL-6) and interleukin-8 (IL-8) – are increased with age and in Alzheimer’s disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62–91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time – up to 9 years – with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.

• Solvang, Stein-Erik Hafstad; Hodge, Allison; Watne, Leiv; Cabral-Marques, Otavio; Nordrehaug, Jan Erik & Giles, Graham G. [Show all 16 contributors for this article] (2022). Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging. Oxidative Medicine and Cellular Longevity. ISSN 1942-0900. 2022, p. 1–15. doi: 10.1155/2022/5019752. Full text in Research Archive Show summary

  The kynurenine pathway is implicated in aging, longevity, and immune regulation, but longitudinal studies and assessment of the cerebrospinal fluid (CSF) are lacking. We investigated tryptophan (Trp) and downstream kynurenine metabolites and their associations with age and change over time in four cohorts using comprehensive, targeted metabolomics. The study included 1574 participants in two cohorts with repeated metabolite measurements (mean age at baseline and ), 3161 community-dwelling older adults (age range 71-74 years), and 109 CSF donors (mean age ). In the first two cohorts, age was associated with kynurenine (Kyn), quinolinic acid (QA), and the kynurenine to tryptophan ratio (KTR), and inversely with Trp. Consistent with these findings, Kyn, QA, and KTR increased over time, whereas Trp decreased. Similarly, QA and KTR were higher in community-dwelling older adults of age 74 compared to 71, whereas Trp was lower. Kyn and QA were more strongly correlated with age in the CSF compared to serum and increased in a subset of participants with repeated CSF sampling () over four years. We assessed associations with frailty and mortality in two cohorts. QA and KTR were most strongly associated with mortality and frailty. Our study provides robust evidence of changes in tryptophan and kynurenine metabolism with human aging and supports links with adverse health outcomes. Our results suggest that aging activates the inflammation and stress-driven kynurenine pathway systemically and in the brain, but we cannot determine whether this activation is harmful or adaptive. We identified a relatively stronger age-related increase of the potentially neurotoxic end-product QA in brain.

• 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

• Vidal-Piñeiro, Didac; Sørensen, Øystein; Blennow, Kaj; Capogna, Elettra; Halaas, Nathalie Bodd & Idland, Ane-Victoria [Show all 12 contributors for this article] (2022). Relationship between cerebrospinal fluid neurodegeneration biomarkers and temporal brain atrophy in cognitively healthy older adults. Neurobiology of Aging. ISSN 0197-4580. 116, p. 80–91. doi: 10.1016/j.neurobiolaging.2022.04.010. Full text in Research Archive Show summary

  It is unclear whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration predict brain atrophy in cognitively healthy older adults, whether these associations can be explained by phosphorylated tau181 (p-tau) and the 42 amino acid form of amyloid-β (Aβ42) biomarkers, and which neural substrates may drive these associations. We addressed these questions in 2 samples of cognitively healthy older adults who underwent longitudinal structural MRI up to 7 years and had baseline CSF levels of heart-type fatty-acid binding protein (FABP3)=, total-tau, neurogranin, and neurofilament light (NFL) (n = 189, scans = 721). The results showed that NFL, total-tau, and FABP3 predicted entorhinal thinning and hippocampal atrophy. Brain atrophy was not moderated by Aβ42 and the associations between NFL and FABP3 with brain atrophy were independent of p-tau. The spatial pattern of cortical atrophy associated with the biomarkers overlapped with neurogenetic profiles associated with expression in the axonal (total-tau, NFL) and dendritic (neurogranin) components. CSF biomarkers of neurodegeneration are useful for predicting specific features of brain atrophy in older adults, independently of amyloid and tau pathology biomarkers.

• 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.

• 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
• 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.

• Neerland, Bjørn Erik; Halaas, Nathalie Bodd; Idland, Ane-Victoria; Henjum, Kristi; Blennow, Kaj & Zetterberg, Henrik [Show all 7 contributors for this article] (2020). Fatty Acid-Binding Protein 3 in Cerebrospinal Fluid of Hip Fracture Patients with Delirium. Journal of Alzheimer's Disease. ISSN 1387-2877. 77(1), p. 183–190. doi: 10.3233/JAD-200364. Full text in Research Archive Show summary

  Background: Delirium is associated with dementia and thus biomarkers reflecting neurodegeneration are of interest. Fatty acid-binding protein 3 (FABP3) is a cytoplasmic neuronal protein that has been isolated from the brain. It is released following brain injury and concentrations in cerebrospinal fluid (CSF) are also higher in neurodegenerative disorders such as Alzheimer’s disease (AD). Objective: To examine the relationship between CSF FABP3 concentration and delirium in hip fracture patients compared to a group of cognitively normal controls. Methods: CFS FABP3 concentration was measured in 128 hip fracture patients with (n = 71) and without (n = 57) delirium, and in cognitively unimpaired adults ≥64 years (n = 124) undergoing elective surgery. Results: CSF FABP3 (pg/ml) concentration (median (IQR)) was higher in hip-fracture patients compared to cognitively normal controls (5.7 (4.2–7.7) versus 4.5 (3.4–6.1), p &lt; 0.001). There was a significant weak correlation between age and CSF FABP3 (ρ= 0.3, p &lt; 0.001). After adjustment for age, the association between CSF FABP3 and hip-fracture was no longer statistically significant (β= 0.05, p = 0.5). There were no significant differences in CSF FABP3 concentration between hip fracture patients with (5.4 (4.1–8.2)) and without (5.8 (4.2–7.2)) delirium. CSF FABP3 concentration correlated positively with CSF AD biomarkers p-tau (ρ= 0.7, p &lt; 0.01) and t-tau (ρ= 0.7, p &lt; 0.01). Conclusion: CSF FABP3 concentrations were higher in hip fracture patients compared with cognitively normal older adults, indicating ongoing age-related neurodegeneration in these patients. There were no differences of CSF FABP3 concentrations across delirium groups, suggesting that neuronal damage or degeneration reflected by FABP3 may not be directly linked to delirium pathophysiology.

• Halaas, Nathalie Bodd; Henjum, Kristi; Blennow, Kaj; Dakhil, Shams; Idland, Ane-Victoria & Nilsson, Lars [Show all 13 contributors for this article] (2019). CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults. Cerebral Cortex. ISSN 1047-3211. 00, p. 1–12. doi: 10.1093/cercor/bhz240. Full text in Research Archive Show summary

  Neuroinflammation may be a key factor in brain atrophy in aging and age-related neurodegenerative disease. The objective of this study was to test the association between microglial expression of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2), as a measure of neuroinflammation, and brain atrophy in cognitively unimpaired older adults. Brain magnetic resonance imagings (MRIs) and cerebrospinal fluid (CSF) sTREM2, total tau (t-tau), phosphorylated181 tau (p-tau), and Aβ42 were analyzed in 115 cognitively unimpaired older adults, classified according to the A/T/(N)-framework. MRIs were repeated after 2 (n = 95) and 4 (n = 62) years. High baseline sTREM2 was associated with accelerated cortical thinning in the temporal cortex of the left hemisphere, as well as bilateral hippocampal atrophy, independently of age, Aβ42, and tau. sTREM2-related atrophy only marginally increased with biomarker positivity across the AD continuum (A−T− #x2292; A+T− #x2292; A+T+) but was significantly stronger in participants with a high level of p-tau (T+). sTREM2-related cortical thinning correlated significantly with areas of high microglial-specific gene expression in the Allen Human Brain Atlas. In conclusion, increased CSF sTREM2 was associated with accelerated cortical and hippocampal atrophy in cognitively unimpaired older participants, particularly in individuals with tau pathology. This suggests a link between neuroinflammation, neurodegeneration, and amyloid-independent tauopathy.

• Halaas, Nathalie Bodd; Blennow, Kaj; Idland, Ane-Victoria; Wyller, Torgeir Bruun; Ræder, Johan & Frihagen, Frede Jon [Show all 9 contributors for this article] (2018). Neurofilament light in serum and cerebrospinal fluid of hip fracture patients with delirium. Dementia and Geriatric Cognitive Disorders. ISSN 1420-8008. 46(5-6), p. 346–357. doi: 10.1159/000494754. Full text in Research Archive Show summary

  Background: Delirium is associated with new-onset dementia, suggesting that delirium pathophysiology involves neuronal injury. Neurofilament light (NFL) is a sensitive biomarker for neuroaxonal injury. Methods: NFL was measured in cerebrospinal fluid (CSF) (n = 130), preoperative serum (n = 192), and postoperative serum (n = 280) in hip fracture patients, and in CSF (n = 123) and preoperative serum (n = 134) in cognitively normal older adults under-going elective surgery. Delirium was diagnosed with the Confusion Assessment Method. Re-sults: Median serum NFL (pg/mL) was elevated in delirium in hip fracture patients (94 vs. 54 pre- and 135 vs. 92 postoperatively, both p < 0.001). Median CSF NFL tended to be higher in hip fracture patients with delirium (1,804 vs. 1,636, p = 0.074). Serum and CSF NFL were posi-tively correlated (ρ = 0.56, p < 0.001). Conclusion: Our findings support an association be-tween neuroaxonal injury and delirium. The correlation between serum and CSF NFL supports the use of NFL as a blood biomarker in future delirium studies.

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• Hella, Mathias Nikolai Petersen; Bergland, Anne Katrine; Soennesyn, Hogne; Halaas, Nathalie Bodd; Watne, Leiv & Bonanni, Laura [Show all 7 contributors for this article] (2023). What we know about the possible link between delirium and dementia with Lewy bodies, and why we need to learn more. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 147(5), p. 401–402. doi: 10.1111/acps.13526. Full text in Research Archive

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