Kaja Nordengen

• Girelli, Alberto; Solheim, Andreas; Lian, Sofie Lysholm; Storås, Tryggve Holck; Nordengen, Kaja & Mardal, Kent-Andre (2026). Multiphasic transport in the human cranial dura: how meningeal lymphatic vessels drive waste clearance from brain cerebrospinal fluid. Fluids and Barriers of the CNS. doi: 10.1186/s12987-026-00861-y. Full text in Research Archive Show summary

  Background The discovery of meningeal lymphatic vessels (mLVs) has reshaped our understanding of brain waste clearance, positioning them as a very important clearance route. However, quantifying the precise hydrodynamics and solute transport mechanisms within the human dura mater in vivo remains highly challenging due to the multiscale nature of cranial fluid dynamics and imaging resolution limits. Methods We integrated patient-specific intrathecal contrast-enhanced MRI (gMRI) data from a single healthy subject with a novel anatomical segmentation of the cranial dura mater. By employing a hierarchy of inverse mathematical and micro-mechanical models, we estimated previously inaccessible physiological transport parameters. To ensure parameter identifiability, we deliberately modeled a scenario where the meningeal lymphatic vessels act as the sole fluid efflux route, thereby establishing an upper limit for their clearance capacity. These baseline estimates subsequently informed a spatially distributed, double-porosity 3D computational model of the human dura to simulate the fluid dynamics of cranial clearance. Results Our analysis suggests that purely diffusive macroscopic models fail to replicate in vivo tracer distribution. Conversely, a dual-porosity advection-diffusion framework successfully captures the tissue kinetics. The transport within the mLV compartment is characterized by highly convective clearance (with ), with macroscopic fluid velocities and effective lymphatic diffusion coefficients yielding an upper-bound advective capacity theoretically sufficient to clear the total albumin content in the Cerebrospinal Fluid (CSF). Conclusion Based on our findings on a single subject (Gonzo) solute clearance within the human cranial dura mater emerges as multiphasic, advection-dominated process. Rather than relying on passive Fickian diffusion, molecules appear to be actively and rapidly cleared through the meningeal lymphatic network via convective mechanisms. While our assumption of exclusively mLV-driven clearance provides a theoretical upper limit for their capacity, this hierarchical modeling approach successfully bridges clinical imaging and microscopic fluid dynamics, offering quantitative insights into the primary mechanical drivers of dural fluid clearance.

• Knudtzon, Stephanie; Kirsebom, Bjørn-Eivind; Pålhaugen, Lene; Bettella, Francesco; Gisladottir, Berglind & Bahrami, Shahram [Show all 19 contributors for this article] (2026). Genotype–phenotype interaction in Alzheimer's disease immune activation. Alzheimer's & Dementia. ISSN 1552-5260. 22(1). doi: 10.1002/alz.70978. Full text in Research Archive Show summary

  Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder influenced by genetic factors, particularly related to immune activation. This study examines genotype-phenotype interactions affecting immune responses in AD as a reaction to neurodegeneration. Methods: We computed AD polygenic risk scores (PRSs) informed by shared AD-autoimmunity genetics (AD PRSINFL), AD-independent immune activation score from 10 autoimmune diseases (sum PRSIMMUNE), and standard AD PRSs for 294 individuals. Cerebrospinal fluid (CSF) immune markers (sTREM2, clusterin, fractalkine, and chitinase 3 like protein (YKL-40)) were regressed on PRSs, and their interaction with neurodegeneration markers (total tau [t-tau] or neurofilament light chain [NfL]). Results: High AD PRSINFL scores correlated with lower sTREM2 (β = −0.18, p < 0.01), clusterin (β = −0.12, p < 0.05), and fractalkine (β = −0.13, p < 0.05) levels in cases with elevated t-tau. High sum PRSIMMUNE score correlated with lower clusterin in cases with elevated NfL (β = −0.12, p < 0.05). Discussion: Genetic predisposition for immune activation might cause unfavorable immune response in early AD.

• Riseth, Jørgen Nilsen; Koch, Timo; Lian, Sofie Lysholm; Storås, Tryggve Holck; T., Zikatanov, Ludmil & Valnes, Lars Magnus [Show all 8 contributors for this article] (2026). Human brain MRI data of intrathecally injected tracer evolution over 72 hours for data-integrated simulations. Scientific Data. 13. doi: 10.1038/s41597-026-06564-1. Full text in Research Archive Show summary

  We present the Gonzo dataset: Brain MRI with processed and derivative data from one healthy male human volunteer ("Gonzo”) before and during the 72 hours after intrathecal injection of the contrast agent gadobutrol into the cerebrospinal fluid (CSF) of the spinal canal. The MRI data records include images highlighting the temporal and spatial evolution of the contrast agent in CSF, brain, and adjacent structures. In addition to raw MRI, we provide derivatives that enable numerical simulations of the transport process under study. Derivatives include T1 maps, tracer concentration maps, diffusion tensor maps, and unstructured triangulated volume meshes of the brain geometry. We also provide brain region markers obtained by image segmentation. A regional statistical analysis of the concentration data complements the image data. The presented data can be used to study the transport behavior and the underlying processes of a tracer in the brain. It is intended to contribute to and inspire new studies on the understanding of tracer transport, method development for image analysis, and simulation of brain fluid transport processes.

• Kirsebom, Bjørn-Eivind; Nilsson, Johanna; Vromen, Ellen; Arnesen, Peter Mikael; Bjørnerud, Atle & Brinkmalm, Ann [Show all 23 contributors for this article] (2025). Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer’s disease genetic pathways. Molecular Neurodegeneration. 20(1), p. 1–21. doi: 10.1186/s13024-025-00899-w. Full text in Research Archive Show summary

  Abstract Background Synapse loss is linked to cognitive symptoms in Alzheimer’s Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets. Methods We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) ( n  = 346) and Amsterdam Dementia Cohort (n =  397 ), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins. Results In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p  < 0.001) were found between 14-3-3 protein genes ( YWHAZ , YWHAE ) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway ( p  < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts. Conclusions Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.

• Richter, Grit; Kirsebom, Bjørn-Eivind; Jarholm, Jonas Alexander; Pålhaugen, Lene; Gisladottir, Berglind & Aarsland, Dag [Show all 11 contributors for this article] (2025). Comparison of CSF neurofilament light chain and total tau as neurodegeneration markers: Associations with synaptic markers and cognitive outcomes. Neurobiology of Aging. ISSN 0197-4580. 155, p. 13–23. doi: 10.1016/j.neurobiolaging.2025.07.005. Full text in Research Archive Show summary

  Clinically, Alzheimer's disease (AD) is characterized by progressive cognitive decline due to neuronal and synaptic degeneration. Neurofilament light chain (NfL) and total tau (T-tau) reflect neurodegeneration, NfL putatively more related to white and T-tau to grey matter. This study examines how cerebrospinal fluid (CSF) neurodegeneration markers (T-tau, NfL or both) are correlated with synaptic markers and clinical progression. We included 331 individuals with (n = 212) and without (n = 119) pathological CSF Aβ42/40 ratios. Associations between CSF NfL, T-tau, and the synaptic biomarkers neurogranin and BACE1 were assessed using Pearson’s correlation. Group differences in synaptic marker levels were evaluated using linear regression comparing individuals with isolated pathological T-tau, NfL, or both, versus biomarker-negative individuals. Clinical progression to MCI or dementia was assessed using a Cox proportional hazards model (n = 257; mean follow-up = 3.75 years). Linear regression and Cox proportional hazards models included age, sex, and dichotomized APOE-ε4 carriership as covariates. T-tau had a stronger correlation with neurogranin(r = 0.84) and BACE1(r = 0.73) than NfL(r = 0.51 and 0.48; p < 0.001). Group-wise comparisons confirmed this, showing that only individuals with pathological T-tau—alone or with NfL—had significantly higher synaptic marker levels (p < 0.001). Only the combination of pathological T-tau and NfL was associated with a significantly increased risk of clinical progression(HR=6.79; p < 0.001). These findings suggest that T-tau is more closely related to early synaptic dysfunction in AD than NfL. The combined elevation of both biomarkers, linked to greater clinical decline, supports a dual contribution of grey- and white matter degeneration to disease progression.

• Storås, Tryggve Holck; Lian, Sofie Lysholm; Mossige, Ingrid; Riseth, Jørgen Nilsen; Svensson, Siri Fløgstad & Løvland, Grethe [Show all 10 contributors for this article] (2025). T2-Weighted T1 Mapping and Automated Segmentation of CSF: Assessment of Solute Gradients in the Healthy Brain. Journal of Magnetic Resonance Imaging. ISSN 1053-1807. 0, p. 1–10. doi: 10.1002/jmri.70169. Full text in Research Archive Show summary

  Background Cerebrospinal fluid (CSF) serves as a medium for nutrient delivery and waste clearance. The T1 relaxation rate, R1, can be used to measure the concentration of intrinsic solutes and extrinsic contrast agents. Purpose To implement a method for R1 mapping and segmentation of CSF and to use this method to explore how R1 of CSF relates to protein content and gadobutrol after intrathecal administration. Study Type Prospective cohort study, complemented by phantom analysis. Population Ten healthy control subjects (mean age 65.5 ± 4.4 years, range 57–72 years; five males and five females) and protein‐ and gadobutrol‐gradient phantom. Field Strength/Sequence 3 T Philips Ingenia scanner; 3D T2W mixed inversion recovery spin‐echo (T2W‐mixed IRSE) sequence and 3D T1W turbo field echo (3D T1W‐TFE). Assessment R1 maps were calculated by combining IR and SE data. An automated segmentation method derived from FreeSurfer employed SE data for CSF segmentation and T1W‐TFE for anatomical reference. CSF was collected by lumbar puncture for protein measurements, and 0.25 mmol gadobutrol was injected intrathecally. Post‐contrast assessments were performed at 3, 24, 48, and 72 h. Statistical Tests One‐way ANOVA, followed by a post hoc Tukey HSD test, and simple and multiple linear regression analysis; significance level of 0.05. Results R1 of ventricular CSF 0.216 ± 0.001 s −1 was significantly lower than that surrounding the cerebellum 0.225 ± 0.001 and cerebrum 0.228 ± 0.002 and correlated with lumbar protein concentration ( R 2  = 0.56). Peak gadobutrol concentrations were 101 ± 84 μM in ventricles, 185 ± 89 μM in cerebellar SAS and 166 ± 91 μM in cerebral SAS. Corresponding concentrations were 6 ± 4, 17 ± 8, and 37 ± 18 μM at 72 h. Data Conclusion Intrinsic R1 of CSF in the subarachnoid space correlated with protein content. Intracranial CSF enrichment after intrathecal administration of gadobutrol showed a large variation among healthy volunteers. Evidence Level 2. Technical Efficacy 3.

• Sannes, Ida; Harr, Marianne Efskind; Antal, Ellen-Ann; Beyer, Mona K. & Nordengen, Kaja (2025). Acute hemorrhagic leukoencephalitis with gradual symptom onset: Case Report and literature review. Frontiers in Neuroscience. ISSN 1662-4548. 19. doi: 10.3389/fnins.2025.1557046. Full text in Research Archive Show summary

  This report highlights an atypical case of acute hemorrhagic Leukoencephalitis (AHLE) in a 73-year-old male, contributing valuable insights into the disease’s progression in older adults. AHLE, a rare and often fatal central nervous system disorder typically affecting younger individuals, with a median age of 33. Our patient experienced atypical subacute symptoms over 3 months, the longest duration reported, and ultimately achieved a functional outcome with a modified Rankin Scale (mRS) score of 2. A comprehensive review of 152 cases available through PubMed, revealing a 58% mortality rate with a median survival of just 2 days, and a mean mRS of 4.3, though survivor exhibited a more favorable mean mRS of 1.8. Only 6% of cases had a subacute onset of 3 weeks or more.

• Knudtzon, Stephanie; Nordengen, Kaja; Pålhaugen, Lene; Gisladottir, Berglind; Jarholm, Jonas Alexander & Bråthen, Geir [Show all 11 contributors for this article] (2025). Sexual dimorphisms in innate immune activation markers in predementia Alzheimer’s disease. Brain Communications. 7(3). doi: 10.1093/braincomms/fcaf161. Full text in Research Archive Show summary

  Visual impairment due to stroke is common. However, controversy exists on how best to screen for visual impairment, the timing at which to screen, and on the optimal management of the varying types of visual impairment. This European Stroke Organisation (ESO) guideline provides evidence-based recommendations to assist clinicians in decision-making on screening methods, timing of screening and assessment and management options in adult stroke survivors. The target audience for this guideline is health care providers involved in stroke care from prehospital screening, in stroke units and rehabilitation centres, ophthalmological departments and community stroke care, and for stroke survivors and care givers. The guideline was developed according to the ESO standard operating procedure and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and, where possible, meta-analyses of the literature, assessed the quality of the available evidence and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations based on the GRADE approach. We found evidence of acceptability and feasibility of early visual screening within 1 week of stroke onset. We describe the accuracy of various vision screening tools at pre-hospital and hyper/acute stages as well as specialist vision assessment. We suggest vision screening in all patients with stroke to improve detection of their visual problems We describe a range of treatment options for visual impairment post-stroke across the typical categories of impaired central vision, ocular stroke (central retinal artery occlusion), eye movements, visual fields, visual neglect and visual perception. This guideline highlights specific areas where robust evidence is lacking and where further definitive randomised controlled trials and diagnostic accuracy studies are required.

• Jaholkowski, Piotr Pawel; Bahrami, Shahram; Fominykh, Vera; Hindley, Guy; Tesfaye, Markos & Parekh, Pravesh [Show all 23 contributors for this article] (2024). Charting the shared genetic architecture of Alzheimer's disease, cognition, and educational attainment, and associations with brain development. Neurobiology of Disease. ISSN 0969-9961. 203. doi: 10.1016/j.nbd.2024.106750. Full text in Research Archive Show summary

  The observation that the risk of developing Alzheimer's disease is reduced in individuals with high premorbid cognitive functioning, higher educational attainment, and occupational status has led to the ‘cognitive reserve’ hypothesis. This hypothesis suggests that individuals with greater cognitive reserve can tolerate a more significant burden of neuropathological changes before the onset of cognitive decline. The underpinnings of cognitive reserve remain poorly understood, although a shared genetic basis between measures of cognitive reserve and Alzheimer's disease has been suggested. Using the largest samples to date and novel statistical tools, we aimed to investigate shared genetic variants between Alzheimer's disease, and measures of cognitive reserve; cognition and educational attainment to identify molecular and neurobiological foundations. We applied the causal mixture model (MiXeR) to estimate the number of trait-influencing variants shared between Alzheimer's disease, cognition, and educational attainment, and condFDR/conjFDR to identify shared loci. To provide biological insights loci were functionally characterized. Subsequently, we constructed a Structural Equation Model (SEM) to determine if the polygenic foundation of cognition has a direct impact on Alzheimer's disease risk, or if its effect is mediated through established risk factors for the disease, using a case-control sample from the UK Biobank. Univariate MiXeR analysis (after excluding chromosome 19) revealed that Alzheimer's disease was substantially less polygenic (450 trait-influencing variants) compared to cognition (11,100 trait-influencing variants), and educational attainment (12,700 trait-influencing variants). Bivariate MiXeR analysis estimated that Alzheimer's disease shared approximately 70 % of trait-influencing variants with cognition, and approximately 40 % with educational attainment, with mixed effect directions. Using condFDR analysis, we identified 18 loci jointly associated with Alzheimer's disease and cognition and 6 loci jointly associated with Alzheimer's disease and educational attainment. Genes mapped to shared loci were associated with neurodevelopment, expressed in early life, and implicated the dendritic tree and phosphatidylinositol phosphate binding mechanisms. Spatiotemporal gene expression analysis of the identified genes showed that mapped genes were highly expressed during the mid-fetal period, further suggesting early neurodevelopmental stages as critical periods for establishing cognitive reserve which affect the risk of Alzheimer's disease in old age. Furthermore, our SEM analysis showed that genetic variants influencing cognition had a direct effect on the risk of developing Alzheimer's disease, providing evidence in support of the neurodevelopmental hypothesis of the disease.

• Nordengen, Kaja & Morland, Cecilie (2024). From Synaptic Physiology to Synaptic Pathology: The Enigma of α-Synuclein. International Journal of Molecular Sciences. ISSN 1661-6596. 25(2). doi: 10.3390/ijms25020986. Full text in Research Archive
• Bahrami, Shahram; Nordengen, Kaja; Rokicki, Jaroslav; Shadrin, Alexey; Rahman, Mohammad Zillur & Smeland, Olav Bjerkehagen [Show all 17 contributors for this article] (2024). The genetic landscape of basal ganglia and implications for common brain disorders. Nature Communications. 15(1). doi: 10.1038/s41467-024-52583-0. Full text in Research Archive Show summary

  The basal ganglia are subcortical brain structures involved in motor control, cognition, and emotion regulation. We conducted univariate and multivariate genome-wide association analyses (GWAS) to explore the genetic architecture of basal ganglia volumes using brain scans obtained from 34,794 Europeans with replication in 4,808 white and generalization in 5,220 non-white Europeans. Our multivariate GWAS identified 72 genetic loci associated with basal ganglia volumes with a replication rate of 55.6% at P < 0.05 and 87.5% showed the same direction, revealing a distributed genetic architecture across basal ganglia structures. Of these, 50 loci were novel, including exonic regions of APOE, NBR1 and HLAA. We examined the genetic overlap between basal ganglia volumes and several neurological and psychiatric disorders. The strongest genetic overlap was between basal ganglia and Parkinson’s disease, as supported by robust LD-score regression-based genetic correlations. Mendelian randomization indicated genetic liability to larger striatal volume as potentially causal for Parkinson’s disease, in addition to a suggestive causal effect of greater genetic liability to Alzheimer’s disease on smaller accumbens. Functional analyses implicated neurogenesis, neuron differentiation and development in basal ganglia volumes. These results enhance our understanding of the genetic architecture and molecular associations of basal ganglia structure and their role in brain disorders.

• Knudtzon, Stephanie; Nordengen, Kaja; Grøntvedt, Gøril Rolfseng; Jarholm, Jonas Alexander; Eliassen, Ingvild Vøllo & Selnes, Per [Show all 12 contributors for this article] (2024). Age-adjusted CSF t-tau and NfL do not improve diagnostic accuracy for prodromal Alzheimer’s Disease. Neurobiology of Aging. ISSN 0197-4580. 141, p. 74–84. doi: 10.1016/j.neurobiolaging.2024.05.016. Full text in Research Archive Show summary

  Cerebrospinal fluid total-tau (t-tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer’s disease (AD). In order to adjust for age-related increases in t-tau and NfL, cross-sectional age-adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41–78 years (CN, n = 137). The age-adjusted norms for t-tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD-MCI, n = 144). Furthermore, while NfL was correlated with higher age in AD-MCI, no significant correlation was found for t-tau. The cox proportional hazard models, applied in 429 participants with baseline t-tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age-adjustments (HR = 3.39 for t-tau and HR = 3.17 for NfL), as compared to using our norms (HR = 2.29 for t-tau and HR = 1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age-related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy.

• Seferi, Gezime; Mjønes, Harald Stranger; Havik, Mona; Reiersen, Herman; Dalen, Knut Tomas & Nordengen, Kaja [Show all 7 contributors for this article] (2024). Distribution of lipid droplets in hippocampal neurons and microglia: impact of diabetes and exercise. Life Science Alliance (LSA). 7(10). doi: 10.26508/lsa.202302239. Full text in Research Archive Show summary

  Neuroinflammation, aging, and neurodegenerative disorders are associated with excessive accumulation of neutral lipids in lipid droplets (LDs) in microglia. Type 2 diabetes mellitus (T2DM) may cause neuroinflammation and is a risk factor for neurodegenerative disorders. Here, we show that hippocampal pyramidal neurons contain smaller, more abundant LDs than their neighboring microglia. The density of LDs varied between pyramidal cells in adjacent subregions, with CA3 neurons containing more LDs than CA1 neurons. Within the CA3 region, a gradual increase in the LD content along the pyramidal layer from the hilus toward CA2 was observed. Interestingly, the high neuronal LD content correlated with less ramified microglial morphotypes. Using the db/db model of T2DM, we demonstrated that diabetes increased the number of LDs per microglial cell without affecting the neuronal LD density. High-intensity interval exercise induced smaller changes in the number of LDs in microglia but was not sufficient to counteract the diabetes-induced changes in LD accumulation. The changes observed in response to T2DM may contribute to the cerebral effects of T2DM and provide a mechanistic link between T2DM and neurodegenerative disorders.

• Nordengen, Kaja; Kirsebom, Bjørn-Eivind Seljelid; Richter, Grit; Pålhaugen, Lene; Gisladottir, Berglind & Siafarikas, Nikias Ioannis [Show all 22 contributors for this article] (2023). Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer’s disease. Journal of Neuroinflammation. 20(1). doi: 10.1186/s12974-023-02973-w. Full text in Research Archive Show summary

  Background Brain innate immune activation is associated with Alzheimer’s disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles. Methods We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aβ42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A−/T−/N−, A+/T−/N−, A+/T+ or N+, or A−/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group. Results Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A−/T+ or N+, compared to A−/T−/N−). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T−/N− cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01). Conclusions Immune hypoactivation and reduced neuron–microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.

• Nordengen, Kaja; Cappelletti, Chiara; Bahrami, Shahram; Frei, Oleksandr; Pihlstrøm, Lasse & Henriksen, Sandra Pilar [Show all 11 contributors for this article] (2023). Pleiotropy with sex-specific traits reveals genetic aspects of sex differences in Parkinson’s disease. Brain. ISSN 0006-8950. 147(3), p. 858–870. doi: 10.1093/brain/awad297. Full text in Research Archive Show summary

  Parkinson’s disease is an age-related neurodegenerative disorder with a higher incidence in males than females. The causes for this sex difference are unknown. Genome-wide association studies (GWAS) have identified 90 Parkinson’s disease risk loci, but the genetic studies have not found sex-specific differences in allele frequency on autosomal chromosomes or sex chromosomes. Genetic variants, however, could exert sex-specific effects on gene function and regulation of gene expression. To identify genetic loci that might have sex-specific effects, we studied pleiotropy between Parkinson’s disease and sex-specific traits. Summary statistics from GWASs were acquired from large-scale consortia for Parkinson’s disease (n cases = 13 708; n controls = 95 282), age at menarche (n = 368 888 females) and age at menopause (n = 69 360 females). We applied the conditional/conjunctional false discovery rate (FDR) method to identify shared loci between Parkinson’s disease and these sex-specific traits. Next, we investigated sex-specific gene expression differences in the superior frontal cortex of both neuropathologically healthy individuals and Parkinson’s disease patients (n cases = 61; n controls = 23). To provide biological insights to the genetic pleiotropy, we performed sex-specific expression quantitative trait locus (eQTL) analysis and sex-specific age-related differential expression analysis for genes mapped to Parkinson’s disease risk loci. Through conditional/conjunctional FDR analysis we found 11 loci shared between Parkinson’s disease and the sex-specific traits age at menarche and age at menopause. Gene-set and pathway analysis of the genes mapped to these loci highlighted the importance of the immune response in determining an increased disease incidence in the male population. Moreover, we highlighted a total of nine genes whose expression or age-related expression in the human brain is influenced by genetic variants in a sex-specific manner. With these analyses we demonstrated that the lack of clear sex-specific differences in allele frequencies for Parkinson’s disease loci does not exclude a gen- etic contribution to differences in disease incidence. Moreover, further studies are needed to elucidate the role that the candidate genes identified here could have in determining a higher incidence of Parkinson’s disease in the male population.

• Jarholm, Jonas Alexander; Bjørnerud, Atle; Dalaker, Turi Olene; Akhavi, Mehdi Sadat; Kirsebom, Bjørn-Eivind & Pålhaugen, Lene [Show all 14 contributors for this article] (2023). Medial Temporal Lobe Atrophy in Predementia Alzheimer's Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort. Journal of Alzheimer's Disease. ISSN 1387-2877. 94(1), p. 259–279. doi: 10.3233/JAD-221274. Full text in Research Archive Show summary

  Background: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer’s disease (AD) and can be measured by segmentation of magnetic resonance images (MRI). Objective: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort. Methods: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative values of A, T, and N were determined by cerebrospinal fluid measurements of the Aβ42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N. Results: Compared to A–/T–/N– at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A– at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T–/N– and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A–, and in A+/T–/N– and A+/T+orN+ compared to A–/T–/N–. Conclusion: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts.

• Kirsebom, Bjørn-Eivind; Richter, Grit; Nordengen, Kaja; Aarsland, Dag; Bråthen, Geir & Tijms, Betty M [Show all 15 contributors for this article] (2022). Stable cerebrospinal fluid neurogranin and β-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients. Brain Communications. 4(5), p. 1–16. doi: 10.1093/braincomms/fcac244. Full text in Research Archive Show summary

  Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer’s disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T−/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer’s disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T−/N−, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer’s disease continuum and controlled with normal markers (A−/T−/N−, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T−/N− and A+/T+/N+ as compared to A−/T−/N− healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A−/T−/N− to A+/T−/N− (n = 12), from A+/T−/N− to A+/T or N+ (n = 12), remained stable A+/T−/N− (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A−/T−/N− (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A−/T−/N− healthy controls, neurogranin was unaltered in A+/T−/N− (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T−/N− (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T−/N− (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = −0.29, P = 0.0006) than neurogranin (b = −0.20, P = 0.002) and BACE1 (b = −0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T−/N− to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer’s disease subgroups, putatively with different options for treatment.

• Bahrami, Shahram; Nordengen, Kaja; Shadrin, Alexey; Frei, Oleksandr; Meer, Dennis van der & Dale, Anders [Show all 9 contributors for this article] (2022). Distributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders. Nature Communications. 13(1). doi: 10.1038/s41467-022-31086-w. Full text in Research Archive Show summary

  Abstract Despite its major role in complex human functions across the lifespan, most notably navigation, learning and memory, much of the genetic architecture of the hippocampal formation is currently unexplored. Here, through multivariate genome-wide association analysis in volumetric data from 35,411 white British individuals, we reveal 177 unique genetic loci with distributed associations across the hippocampal formation. We identify genetic overlap with eight brain disorders with typical onset at different stages of life, where common genes suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.

• Nordengen, Kaja; Pålhaugen, Lene; Bettella, Francesco; Bahrami, Shahram; Selnes, Per & Jarholm, Jonas Alexander [Show all 10 contributors for this article] (2022). Phenotype-informed polygenic risk scores are associated with worse outcome in individuals at risk of Alzheimer's disease. Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. 14(1), p. 1–13. doi: 10.1002/dad2.12350. Full text in Research Archive Show summary

  Introduction Patients with predementia Alzheimer's disease (AD) and at-risk subjects are targets for promising disease-modifying treatments, and improved polygenic risk scores (PRSs) could improve early-stage case selection. Methods Phenotype-informed PRSs were developed by selecting AD-associated variants conditional on relevant inflammatory or cardiovascular traits. The primary outcome was longitudinal changes in measures of AD pathology, namely development of pathological amyloid deposition, medial temporal lobe atrophy, and cognitive decline in a prospective cohort study including 394 adults without AD dementia. Results High-risk groups defined by phenotype-informed AD PRSs had significantly steeper volume decline in medial temporal cortices, and the high-risk group defined by the cardiovascular-informed AD PRS had significantly increased hazard ratio of pathological amyloid deposition, compared to low-risk groups. Discussion AD PRSs informed by inflammatory disorders or cardiovascular risk factors and diseases are associated with development of AD pathology markers and may improve identification of subjects at risk for progression of AD.

• Morland, Cecilie & Nordengen, Kaja (2022). N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease. International Journal of Molecular Sciences. ISSN 1661-6596. 23(3), p. 1–16. doi: 10.3390/ijms23031268. Full text in Research Archive Show summary

  N-acetyl-aspartyl-glutamate (NAAG) is the most abundant dipeptide in the brain, where it acts as a neuromodulator of glutamatergic synapses by activating presynaptic metabotropic glutamate receptor 3 (mGluR3). Recent data suggest that NAAG is selectively localized to postsynaptic dendrites in glutamatergic synapses and that it works as a retrograde neurotransmitter. NAAG is released in response to glutamate and provides the postsynaptic neuron with a feedback mechanisms to inhibit excessive glutamate signaling. A key regulator of synaptically available NAAG is rapid degradation by the extracellular enzyme glutamate carboxypeptidase II (GCPII). Increasing endogenous NAAG—for instance by inhibiting GCPII—is a promising treatment option for many brain disorders where glutamatergic excitotoxicity plays a role. The main effect of NAAG occurs through increased mGluR3 activation and thereby reduced glutamate release. In the present review, we summarize the transmitter role of NAAG and discuss the involvement of NAAG in normal brain physiology. We further present the suggested roles of NAAG in various neurological and psychiatric diseases and discuss the therapeutic potential of strategies aiming to enhance NAAG levels. Keywords: NAAG; retrograde neurotransmitter; glutamate carboxypeptidase II; Parkinson’s disease; Alzheimer’s disease; stroke; traumatic brain injury; pain; schizophrenia; epilepsy

• Sletteberg, Ruth; Nordengen, Kaja; Sorteberg, Wilhelm & Jacobsen, Eva Astrid (2021). En kvinne i 70-årene med akutt blindhet. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(13). doi: 10.4045/tidsskr.20.1034. Full text in Research Archive
• Raheel, Tayyaba Qureshi; Bjørkmo, Mona; Nordengen, Kaja; Gundersen, Vidar; Utheim, Tor Paaske & Watne, Leiv Otto [Show all 9 contributors for this article] (2020). Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis. Cells. 9(7), p. 1–12. doi: 10.3390/cells9071686. Full text in Research Archive Show summary

  GABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory is that exocytotically released GABA may be transported into perisynaptic astroglia and converted to glutamine, which is then shuttled back to the neurons for resynthesis of GABA—i.e., the glutamate/GABA-glutamine (GGG) cycle. However, an unequivocal demonstration of astroglia-to-nerve terminal transport of glutamine and the contribution of astroglia-derived glutamine to neurotransmitter GABA synthesis is lacking. By genetic inactivation of the amino acid transporter Solute carrier 38 member a1 (Slc38a1)—which is enriched on parvalbumin+ GABAergic neurons—and by intraperitoneal injection of radiolabeled acetate (which is metabolized to glutamine in astroglial cells), we show that Slc38a1 mediates import of astroglia-derived glutamine into GABAergic neurons for synthesis of GABA. In brain slices, we demonstrate the role of Slc38a1 for the uptake of glutamine specifically into GABAergic nerve terminals for the synthesis of GABA depending on demand and glutamine supply. Thus, while leaving room for other pathways, our study demonstrates a key role of Slc38a1 for newly formed GABA, in harmony with the existence of a GGG cycle.

• Nordengen, Kaja; Morland, Cecilie; Slusher, B.S. & Gundersen, Vidar (2019). Dendritic localization and exocytosis of NAAG in the rat hippocampus. Cerebral Cortex. ISSN 1047-3211. doi: 10.1093/cercor/bhz176. Full text in Research Archive Show summary

  While a lot is known about classical, anterograde neurotransmission, less is known about the mechanisms and molecules involved in retrograde neurotransmission. Our hypothesis is that N-acetylaspartylglutamate (NAAG), the most abundant dipeptide in the brain, may act as a retrograde transmitter in the brain. NAAG was predominantly localized in dendritic compartments of glutamatergic synapses in the intact hippocampus, where it was present in close proximity to synaptic-like vesicles. In acute hippocampal slices, NAAG was depleted from postsynaptic dendritic elements during neuronal stimulation induced by depolarizing concentrations of potassium or by exposure to glutamate receptor (GluR) agonists. The depletion was completely blocked by botulinum toxin B and strictly dependent on extracellular calcium, indicating exocytotic release. In contrast, there were low levels of NAAG and no effect by depolarization or GluR agonists in presynaptic glutamatergic terminals or GABAergic pre- and postsynaptic elements. Together these data suggest a possible role for NAAG as a retrograde signaling molecule at glutamatergic synapses via exocytotic release.

• Nordengen, Kaja; Kirsebom, Bjørn-Eivind; Henjum, Kristi; Selnes, Per; Gisladottir, Berglind & Wettergreen, Marianne [Show all 12 contributors for this article] (2019). Glial activation and inflammation along the Alzheimer's disease continuum. Journal of Neuroinflammation. 16:46(46), p. 1–13. doi: 10.1186/s12974-019-1399-2. Full text in Research Archive Show summary

  Background Neuronal and glial cell interaction is essential for synaptic homeostasis and may be affected in Alzheimer’s disease (AD). We measured cerebrospinal fluid (CSF) neuronal and glia markers along the AD continuum, to reveal putative protective or harmful stage-dependent patterns of activation. Methods We included healthy controls (n = 36) and Aβ-positive (Aβ+) cases (as defined by pathological CSF amyloid beta 1-42 (Aβ42)) with either subjective cognitive decline (SCD, n = 19), mild cognitive impairment (MCI, n = 39), or AD dementia (n = 27). The following CSF markers were measured: a microglial activation marker—soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of microglial inflammatory reaction—monocyte chemoattractant protein-1 (MCP-1), two astroglial activation markers—chitinase-3-like protein 1 (YKL-40) and clusterin, a neuron-microglia communication marker—fractalkine, and the CSF AD biomarkers (Aβ42, phosphorylated tau (P-tau), total tau (T-tau)). Using ANOVA with planned comparisons, or Kruskal-Wallis tests with Dunn’s pairwise comparisons, CSF levels were compared between clinical groups and between stages of biomarker severity using CSF biomarkers for classification based on amyloid pathology (A), tau pathology (T), and neurodegeneration (N) giving rise to the A/T/N score. Results Compared to healthy controls, sTREM2 was increased in SCD (p < .01), MCI (p < .05), and AD dementia cases (p < .001) and increased in AD dementia compared to MCI cases (p < .05). MCP-1 was increased in MCI (p < .05) and AD dementia compared to both healthy controls (p < .001) and SCD cases (p < .01). YKL-40 was increased in dementia compared to healthy controls (p < .01) and MCI (p < .05). All of the CSF activation markers were increased in subjects with pathological CSF T-tau (A+T−N+ and A+T+N+), compared to subjects without neurodegeneration (A−T−N− and A+T−N−). Discussion Microglial activation as indicated by increased sTREM2 is present already at the preclinical SCD stage; increased MCP-1 and astroglial activation markers (YKL-40 and clusterin) were noted only at the MCI and AD dementia stages, respectively, and in Aβ+ cases (A+) with pathological T-tau (N+). Possible different effects of early and later glial activation need to be explored.

• Kirsebom, Bjørn-Eivind; Nordengen, Kaja; Selnes, Per; Waterloo, Knut; Torsetnes, Silje Bøen & Gisladottir, Berglind [Show all 12 contributors for this article] (2018). Cerebrospinal fluid neurogranin/β-site APP-cleaving enzyme 1 predicts cognitive decline in preclinical Alzheimer's disease. Alzheimer's and Dementia: Translational Research and Clinical Interventions. 4, p. 617–627. doi: 10.1016/j.trci.2018.10.003. Full text in Research Archive Show summary

  Introduction The cerebrospinal fluid neurogranin (Ng)/β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) ratio may reflect synaptic affection resulting from reduced beta-amyloid (Aβ) clearance. We hypothesize that increased Ng/BACE1 ratio predicts the earliest cognitive decline in Alzheimer's disease. Methods We compared Ng/BACE1 levels between cases with subjective cognitive decline (n = 18) and mild cognitive impairment (n = 20) both with amyloid plaques and healthy controls (APOE-ε4+, n = 16; APOE-ε4-, n = 20). We performed regression analyses between cerebrospinal fluid levels, baseline hippocampal and amygdala volumes, and pertinent cognitive measures (memory, attention, Mini Mental State Examination [MMSE]) at baseline and after 2 years. Results Ng/BACE1 levels were elevated in both subjective cognitive decline and mild cognitive impairment compared to healthy controls. Higher Ng/BACE1 ratio was associated with lower hippocampal and amygdala volumes; lower baseline memory functions, attention, and MMSE; and significant decline in MMSE and memory function at 2-year follow-up. Discussion High Ng/BACE1 ratio predicts cognitive decline also in preclinical cases with amyloid plaques.

• Nordengen, Kaja; Heuser, Christoph; Rinholm, Johanne Egge; Matalon, Reuben & Gundersen, Vidar (2013). Localisation of N-acetylaspartate in oligodendrocytes/myelin. Brain Structure and Function. ISSN 1863-2653. doi: 10.1007/s00429-013-0691-7. Full text in Research Archive
• Morland, Cecilie; Nordengen, Kaja; Larsson, Max; Prolo, Laura M.; Farzampour, Zoya & Reimer, Richard J. [Show all 7 contributors for this article] (2013). Vesicular uptake and exocytosis of L-aspartate is independent of sialin. The FASEB Journal. ISSN 0892-6638. 27(3), p. 1264–1274. doi: 10.1096/fj.12-206300. Full text in Research Archive
• Morland, Cecilie; Nordengen, Kaja & Gundersen, Vidar (2012). Valproate causes reduction of the excitatory amino acid aspartate in nerve terminals. Neuroscience Letters. ISSN 0304-3940. 527(2), p. 100–104. doi: 10.1016/j.neulet.2012.08.042. Full text in Research Archive
• Holten, Aleksander Talgøy; Morland, Cecilie; Nordengen, Kaja & Gundersen, Vidar (2008). Vesicular Release of L- and D-Aspartate from Hippocampal Nerve Terminals: Immunogold Evidence. Open Neuroscience Journal. 2, p. 51–58. doi: 10.2174/1874082000802010051. Full text in Research Archive

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• Nordengen, Kaja (2016). Hjernen er stjernen. Ditt eneste uerstattelige organ. Kagge Forlag AS. ISBN 9788248918776. 209 p. Full text in Research Archive

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• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian; Nordengen, Kaja & Mardal, Kent-Andre (2026). Image registration as a tool for modeling and analysis of brain solute transport​. Full text in Research Archive
• Girelli, Alberto; Solheim, Andreas; Lian, Sofie Lysholm; Storås, Tryggve Holck; Nordengen, Kaja & Mardal, Kent-Andre (2026). Exploring dura hydrodynamics: The Role of the Meningeal Lymphatic Vessels in Brain Clearance. Full text in Research Archive
• Solheim, Andreas; Girelli, Alberto; Lian, Sofie Lysholm; Storås, Tryggve Holck; Nordengen, Kaja & Mardal, Kent-Andre (2026). Exploring the brain dura: Estimating meningeal lymphatic clearance through mathematical models. Full text in Research Archive
• Girelli, Alberto; Solheim, Andreas; Lian, Sofie Lysholm; Nordengen, Kaja; Storås, Tryggve Holck & Mardal, Kent-Andre (2026). Exploring the brain dura: a multiscale framework for dural lymphatic transport. Full text in Research Archive
• Girelli, Alberto; Solheim, Andreas; Lian, Sofie Lysholm; Storås, Tryggve Holck; Nordengen, Kaja & Mardal, Kent-Andre (2026). Computational Modeling of transport in the human brain dura. Full text in Research Archive
• Dietrichs, Erik Sveberg; Rogne, Tormod; Solberg, Carl Tollef & Nordengen, Kaja (2026). Norge trenger flere forskere, da må vi rekruttere tidligere. Full text in Research Archive Show summary

  KRONIKK: For første gang på 55 år er det nedgang i antall forskere. Ved norske universiteter og høyskoler var det 770 færre forskere i 2024 sammenlignet med 2023.

• Vold, Victoria; Tingvoll, Stein-Helge; Beyer, Mona K. & Nordengen, Kaja (2025). Case report: Re-evaluating reversibility of cytotoxic lesions of the corpus callosum. Frontiers in neuroimaging. 4, p. 1–8. doi: 10.3389/fnimg.2025.1436931. Full text in Research Archive Show summary

  Cytotoxic lesions of the corpus callosum (CLOCC) are a clinicoradiological diagnosis, characterized by transient neurological symptoms and magnetic resonance imaging (MRI) changes in the splenium of the corpus callosum (SCC), which in most cases is completely reversible. However, the long-term pathophysiological trajectory and ultimate neurological outcomes of CLOCC remain largely unknown due to limited long-term follow-up data. We report an 11-year follow-up of a postpartum female with CLOCC, initially presenting with transient focal neurological symptoms and extensive diffusion-restricted white matter involvement including the SCC and surrounding area with diffusion restriction and low apparent diffusion coefficient values, indicative of cytotoxic edema. The edema regressed in days; over the years, she remained asymptomatic despite persistent white matter changes on MRI in the centrum semiovale. This case challenges the view of CLOCC as completely reversible and raises questions regarding the significance of lasting white matter changes. The enduring absence of neurological symptoms and stable radiological profile throughout the decade underscores the singular nature of CLOCC and the lasting, though isolated, impact on white matter. This report contributes a crucial perspective, suggesting that CLOCC may involve just an isolated episode without recurrent events or progressive neurological decline. By offering the first longitudinal analysis of a CLOCC episode with an extended follow-up of over a decade, our case enhances current knowledge about the long-term neurological and radiological landscape of this condition. It suggests a reevaluation of the conceptual understanding of CLOCC as an entirely reversible, non-relapsing disorder, highlighting the need for further research into its long-term impacts on cerebral white matter integrity.

• Pedersen, Willy; Davanger, Svend; Mørland, Jørg; Nordengen, Kaja & Bjørnebekk, Astrid Kristine (2024). Hjernen i sentrum: Rus Forelskelse, alkohol og narkotika. De gir oss alle en rus. Hva skjer i hjernen vår da? Full text in Research Archive Show summary

  Rus kan være uskyldig spenning og rus kan være farlig. Noen er rusa på livet, sterke naturopplevelser kan gjøre at vi kjenner oss beruset. Enkelte kunstnere hevder at rusmidler gjør dem i stand til å skape større kunst, noen vil behandle lidelser med psykedelika. Mange mennesker får livet rasert som avhengige av legemidler og narkotiske stoffer. Hva skjer med hjernen når vi ruser oss? Hvorfor blir noen avhengige og andre ikke? Bli med når forskere innen naturvitenskap, psykologi og medisin diskuterer og deler av sin kunnskap om hjernen vår og rus. Innledninger og samtale er beregnet på publikum uten faglig bakgrunn i temaet. Kom og få innblikk i siste nytt fra forskningsfronten! Denne kvelden møter du Seniorforsker Astrid Kristine Bjørnebekk. Hun forsker på psykologiske årsaker til rusavhengighet og langtidseffekt på hjernen ved Oslo Universitetssykehus. Professor emeritus Jørg Mørland, har særlig arbeidet med medisinsk rusmiddelforskning, og bruk av rus og rusadferd i forbindelse med strafferett, rettstoksikologi. Han er nå tilknyttet Senter for rus- og avhengighetsforskning (SERAF) Professor emeritus Willy Pedersen, forsker på ungdom og rusmiddelbruk, mental helse og narkotikapolitikk. Det samfunnsvitenskapelige fakultet. Professor Svend Davanger, forsker på hjernens tolkning av sanseinntrykk, dens evne til å tilpasse seg og hvordan den endres av nye erfaringer. Det medisinske fakultet. Kaja Nordengen, lege og forfatter av blant annet "Hjernen er stjernen" leder oss igjennom programmet.

• Bjørnebekk, Astrid Kristine; Ystrøm, Eivind & Nordengen, Kaja (2023). Sitter personligheten din i hjernen? Full text in Research Archive
• Einevoll, Gaute & Nordengen, Kaja (2019). Podcast #2 om hjernen i podcasten Vett og vitenskap med Gaute Einevoll. [Internet]. Podcast. Full text in Research Archive
• Richter, Grit; Kirsebom, Bjørn-Eivind; Selnes, Per; Nordengen, Kaja; Waterloo, Knut & Gisladottir, Berglind [Show all 12 contributors for this article] (2019). An amyloid-coupled pre-dementia increased CSF neurogranin/BACE1 ratio may reflect early synapse affection in APOE-ɛ4 homozygotes. Full text in Research Archive
• Richter, Grit; Kirsebom, Bjørn-Eivind; Selnes, Per; Nordengen, Kaja; Waterloo, Knut & Gisladottir, Berglind [Show all 12 contributors for this article] (2019). Early increase in CSF neurogranin/BACE1 ratio in predementia APOE-ɛ4 homozygote cases with amyloid pathology. Full text in Research Archive
• Kirsebom, Bjørn-Eivind; Nordengen, Kaja; Selnes, Per; Waterloo, Knut; Brix, Britta & Vanmechelen, Eugeen [Show all 8 contributors for this article] (2018). INCREASED CSF NEUROGRANIN/BACE1 RATIO IN AMYLOID POSITIVE SUBJECTS WITH SUBJECTIVE COGNITIVE DECLINE. Full text in Research Archive
• Richter, Grit & Nordengen, Kaja (2026). CSF biomarkers as indicators of inflammation and neurodegeneration: Advancing our understanding of Alzheimer's disease pathology. Exploring biomarkers of non-specific processes involved in AD pathophysiology. UiT Norges arktiske universitet. ISSN 9788235000637. Full text in Research Archive Show summary

  Alzheimer's disease (AD) is characterized using core biomarkers associated with amyloidosis and tauopathy. While these biomarkers are pivotal for diagnosing and staging the disease, this thesis emphasizes the significance of fluid biomarkers that reflect non-specific processes in AD pathophysiology: inflammation (I) and neurodegeneration (N). This thesis investigates neurodegeneration through total tau (T-tau) and neurofilament light chain (NfL), alongside synaptic biomarkers such as BACE1 and neurogranin, as well as nine inflammatory markers covering both astroglial and microglial activation. The aim is to enhance understanding of the interaction between the core pathology and the non-specific processes in AD pathophysiology and between the N- and I-biomarkers themself. In the 2018 diagnostic criteria for AD, T-tau served as the primary N marker; however, the 2024 criteria replaced T-tau with NfL. The analysis demonstrates that T-tau shows stronger correlations with synaptic biomarkers than NfL at baseline, while individuals exhibiting elevated levels of both NfL and T-tau face an increased risk of clinical progression (Paper II). Further, the findings presented indicate that the neurogranin/BACE1 (Ng/BACE) ratio is significantly elevated in individuals with amyloidosis, with (A+T+) or without (A+T-) tauopathy. Both Ng and BACE1, when assessed individually and in combination, exhibit strong associations with memory decline (paper I). Additionally, this research highlights the interconnectedness of neurodegeneration and inflammation, as levels of CSF sTREM2, YKL-40, MCP-1, clusterin, and fractalkine—markers of immune activation—were significantly higher in groups with tau pathology, independent of amyloidosis. Notably, high levels of CSF sTREM2 are associated with preserved cognitive function among individuals exhibiting both amyloidosis and tauopathy (paper III). In conclusion, this thesis underscores the associations between neurodegeneration and inflammation in predementia stages, contributing to a deeper understanding of the various aspects of these processes and how they can be illuminated by biomarkers throughout the AD trajectory, both cross-sectionally and longitudinally, as well as in relation to cognitive function.

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