Nikias Ioannis Siafarikas

• 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.

• Hemminghyth, Mathilde Suhr; Breitve, Monica Haraldseid; Chwiszczuk, Luiza; Gisladottir, Berglind; Hessen, Erik & Siafarikas, Nikias Ioannis [Show all 12 contributors for this article] (2025). Demographically unadjusted cognitive test scores may enhance the validity of mild cognitive impairment as a dementia prodrome. Applied neuropsychology: Adult. ISSN 2327-9095. doi: 10.1080/23279095.2025.2518576. Full text in Research Archive
• Eriksson, Cecilia Magdalena; Kirsebom, Bjørn-Eivind Seljelid; Espenes, Ragna; Siafarikas, Nikias Ioannis; Waterloo, Knut & Rongve, Arvid [Show all 10 contributors for this article] (2024). Depressive Symptoms Are Not Associated with Predementia Cerebrospinal Fluid Amyloid Pathology. Dementia and Geriatric Cognitive Disorders Extra. 14(1), p. 40–48. doi: 10.1159/000539284. Full text in Research Archive Show summary

  Introduction: Depressive symptoms are associated with Alzheimer’s disease (AD), but their neurobiological and neuropsychological correlates remain poorly understood. We investigate if depressive symptoms are associated with amyloid (Aβ) pathology and cognition in predementia AD. Methods: We included subjective cognitive decline (SCD, n = 160) and mild cognitive impairment (MCI, n = 192) from the dementia disease initiation cohort. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS-15). Aβ pathology was determined using cerebrospinal fluid (CSF) Aβ42/40 ratio. Associations between depressive symptoms and cognition were assessed with logistic regression. Results: Only the Aβ negative MCI group (MCI-Aβ−) was associated with depressive symptoms (odds ratio [OR] = 2.65, p = 0.005). Depressive symptoms were associated with worse memory in MCI-Aβ− (OR = 0.94, p = 0.039), but with better performance in MCI-Aβ+ (OR = 1.103, p = 0.001). Conclusion: Our results suggest that depressive symptoms in MCI are neither associated with Aβ pathology, nor AD-associated memory impairment. However, memory impairment in non-AD MCI may relate to depressive symptoms.

• 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.

• Pereira, Catherine; Hosar, Agnes Magdalena & Siafarikas, Nikias Ioannis (2022). Grunnleggende undersøkelsesverktøy mangler i norsk psykiatri. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(7), p. 584–584. doi: 10.4045/tidsskr.22.0191. Full text in Research Archive
• Barca, Maria Lage; Alnæs, Dag; Engedal, Knut; Persson, Karin Ester Torun; Eldholm, Rannveig Sakshaug & Siafarikas, Nikias Ioannis [Show all 11 contributors for this article] (2022). Brain Morphometric Correlates of Depressive Symptoms among Patients with and without Dementia. Dementia and Geriatric Cognitive Disorders Extra. 12(2), p. 107–114. doi: 10.1159/000521114. Full text in Research Archive Show summary

  Introduction: Findings regarding brain morphometry among patients with dementia and concomitant depressive symptoms have been inconsistent. Thus, the aim of the present study was to test the hypothesis that dementia and concomitant depressive symptoms are associated with structural brain changes in the temporal lobe measured with structural magnetic resonance imaging (MRI). Methods: A sample of 492 patients from Norwegian memory clinics (n = 363) and Old Age Psychiatry services (n = 129) was studied. The assessment included the Cornell Scale for Depression in Dementia (CSDD), Instrumental Activities of Daily Living Scale, Mini Mental State Examination, and MRI of the brain, processed with FreeSurfer to derive ROI measures of cortical thickness, volume, and area using the Desikan-Killiany parcellation, as well as subcortical volumes. Dementia was diagnosed according to ICD-10 research criteria. Correlates of brain morphometry using multiple linear regression were examined. Results: Higher scores on the CSDD were associated with larger cortical volume (β = 0.125; p value = 0.003) and area of the left isthmus of the cingulate gyrus (β = 0.151; p value = <0.001) across all patients. Inclusion of an interaction term (dementia × CSDD) revealed a smaller area in the left temporal pole (β = −0.345; p value = 0.001) and right-transverse temporal cortex (β = −0.321; p value = 0.001) in patients with dementia and depressive symptoms. Discussion/Conclusion: We confirm the previous findings of structural brain changes in temporal regions among patients with dementia and concomitant depressive symptoms. This may contribute to a better understanding of the mechanisms underlying depression in dementia. To the best of our knowledge, this is the largest study conducted on this topic to date.

• Siafarikas, Nikias Ioannis; Alnæs, Dag; Sanchez, Jennifer Monereo; Lund, Martina J.; Selbæk, Geir & Korsnes, Maria Stylianou [Show all 13 contributors for this article] (2021). Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment and Alzheimer's disease with dementia. International Psychogeriatrics. ISSN 1041-6102. 33(11), p. 1217–1228. doi: 10.1017/S1041610221000934. Full text in Research Archive Show summary

  We present associations between neuropsychiatric symptoms (NPS) and brain morphology in a large sample of patients with mild cognitive impairment (MCI) and Alzheimer’s disease with dementia (AD dementia). Several studies assessed NPS factor structure in MCI and AD dementia, but we know of no study that tested for associations between NPS factors and brain morphology. The use of factor scores increases parsimony and power. For transparency, we performed an additional analysis with selected Neuropsychiatric Inventory – Questionnaire (NPI-Q) items. Including regional cortical thickness, cortical and subcortical volumes, we examined associations between NPS and brain morphology across the whole brain in an unbiased fashion. We reported both statistical significance and effect sizes, using linear models adjusted for multiple comparisons by false discovery rate (FDR). Moreover, we included an interaction term for diagnosis and could thereby compare associations of NPS and brain morphology between MCI and AD dementia. We found an association between the factor elation and thicker right anterior cingulate cortex across MCI and AD dementia. Associations between the factors depression to thickness of the banks of the left superior temporal sulcus and psychosis to the left post-central volume depended on diagnosis: in MCI these associations were positive, in AD dementia negative. Our findings indicate that NPS in MCI and AD dementia are not exclusively associated with atrophy and support previous findings of associations between NPS and mainly frontotemporal brain structures.

• Siafarikas, Nikias Ioannis; Kirsebom, Bjørn-Eivind; Srivastava, Deepak P; Eriksson, Cecilia Magdalena; Auning, Eirik & Hessen, Erik [Show all 10 contributors for this article] (2021). Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression. Scientific Reports. 11. doi: 10.1038/s41598-021-99794-9. Full text in Research Archive Show summary

  To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as “predementia AD with depression”.

• Siafarikas, Nikias; Selbæk, Geir; Fladby, Tormod; Benth, Jurate Saltyte; Auning, Eirik & Aarsland, Dag (2018). Frequency and subgroups of neuropsychiatric symptoms in mild cognitive impairment and different stages of dementia in Alzheimer's disease. International Psychogeriatrics. ISSN 1041-6102. 30(1), p. 103–113. doi: 10.1017/S1041610217001879. Full text in Research Archive
• Fladby, Tormod; Pålhaugen, Lene; Selnes, Per; Waterloo, Knut; Bråthen, Geir & Hessen, Erik [Show all 27 contributors for this article] (2017). Detecting at-risk Alzheimer's disease cases. Journal of Alzheimer's Disease. ISSN 1387-2877. 60(1), p. 97–105. doi: 10.3233/JAD-170231. Full text in Research Archive
• Siafarikas, Nikias & Preuss, Ulrich (2014). Delir bei Demenz. Fortschritte der Neurologie Psychiatrie. ISSN 0720-4299. 82(9), p. 492–501. doi: 10.1055/s-0034-1366626. Full text in Research Archive

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• Siafarikas, Nikias Ioannis (2024). Neuropsychiatric and Cognitive Symptoms: Two Sides of the Same Coin? Journal of Alzheimer's Disease. ISSN 1387-2877. 98(1), p. 75–78. doi: 10.3233/JAD-231418. Full text in Research Archive
• Siafarikas, Nikias Ioannis; Kirsebom, Bjørn-Eivind; Srivastava, Deepak P.; Eriksson, Cecilia Magdalena; Auning, Eirik & Hessen, Erik [Show all 10 contributors for this article] (2022). Author Correction: Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression (Scientific Reports, (2021), 11, 1, (20375), 10.1038/s41598-021-99794-9). Scientific Reports. 12(1). doi: 10.1038/s41598-022-22274-1. Full text in Research Archive
• Bergem, Astrid Liv Mina; Siafarikas, Nikias; Nilsen, Thomas Severin; Magnus, Per; Rosness, Tor Atle & Strand, Bjørn Heine [Show all 10 contributors for this article] (2016). A Norwegian twin study of heritability and environmental factors in Alzheimer’s disease and other dementias. Full text in Research Archive

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