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Cerebral Microcirculation and Biomarkers in Subarachnoid Haemorrhage: Laser Doppler flowmetry and proteomics in patients during neurocritical care
Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.ORCID iD: 0000-0002-9969-6284
2026 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Aneurysmal subarachnoid haemorrhage is a severe form of stroke with high mortality and many patients left with debilitating sequelae. The first 10-14 days after bled is a period of specific risk for secondary injuries and more research is needed to understand their mechanisms.

We found laser-Doppler flowmetry to be a feasible method for long time recordings of cerebral microcirculatory flow with a low rate of artifacts. Vasomotion of the cerebral vessels could be registered and vasomotion frequencies varied over time and between hemispheres. Correlation between microcirculatory flow and clinically monitored parameters was calculated and trended over time.

In cerebral microdialysate we found the novel biomarkers Transthyretin in nine proteoforms, and Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) in four proteoforms. Both Transthyretin and GAPDH proteoforms vary in different pattern over time after subarachnoid haemorrhage.

We also found Erythropoietin (EPO) and Tumor Necrosis Alpha-Related Apoptosis Inducing Ligand (TRAIL) in increasing values among patients who developed vasospasm, while Neurofilament Light chain (NFL), Glial Fibrillary Acidic Protein (GFAP) and Interleukin-6 (IL-6) showed decreasing values. The trend of these biomarkers may reflect metabolic changes and varying protein expression after subarachnoid bled.

The studies forming this thesis are small and hypothesis generating but show that cerebral microcirculation can be studied in a neurocritical care setting and that data can be correlated to routinely monitored parameters. We have also shown that novel biomarkers can shed new light on cerebral metabolism and protein expression during development of secondary brain injuries. Further studies in larger patient cohorts, combining these methods over time and relating them to outcome measures, will have to be performed before they can be introduced into clinical decision making.

Abstract [sv]

Aneurysmal subaraknoidalblödning (hjärnhinneblödning) är en allvarlig form av stroke med hög risk för allvarliga komplikationer. De första 10-14 dagarna efter blödningen är extra känsliga och olika mekanismer kan bidra till sekundära hjärnskador.

Vi har utvecklat laser-Doppler metodik för användning i långtidsbruk under neurointensivvård och funnit låg risk för störningar. Undersökningarna har visat att hjärnans blodkärl varierar sin storlek på ett periodiskt vid (vasomotion) och att vasomotionen varierade över tid och mellan hjärnhalvorna och detta kunde jämföras med andra övervakningsmetoder som används vid neurointensivvård.

Via mikrodialysteknik hittade vi bärarproteinet Transthyretin i 9 olika former liksom enzymet Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) vilka varierade över tid efter subaraknoidalblödningen. Vi kunde även hitta 5 andra proteiner och såg att de varierade över tid och med olika mönster hos de patienter som drabbades av komplikationen kärlkramp i hjärnans blodkärl. Proteinerna Erythropoietin (EPO) och Tumor Necrosis Alpha-related Apoptosis Inducing Ligand (TRAIL) ökade i samband med kärlkramp och Neurofilament Light chain (NFL), Glial Fibrillary Acidic Protein (GFAP) och Interleukin-6 (IL-6) minskade i samband med kärlkramp.

De studier som underbygger avhandlingen är små och hypotes-genererande men visar att det går att mäta den kritiska mikrocirkulationen och att detta kan jämföras med andra rutinmätvärden under neurointensivvård. Vi har också sett att nya biomarkörer kan tillföra kunskap och beskriva de förlopp som sker efter subaraknoidalblödning.

Det behövs större och jämförande studier där vi testar dessa metoder och kombinerar dem med andra mätvärden och utfallsmått för patienterna innan det går att börja använda dessa tekniker för kliniskt beslutsfattande.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2026. , p. 77
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 2030
National Category
Neurology
Identifiers
URN: urn:nbn:se:liu:diva-222742DOI: 10.3384/9789181184495ISBN: 9789181184488 (print)ISBN: 9789181184495 (electronic)OAI: oai:DiVA.org:liu-222742DiVA, id: diva2:2052336
Public defence
2026-05-08, Hugo Theorellsalen, building 440, Campus US, Linköping, 09:00
Opponent
Supervisors
Available from: 2026-04-13 Created: 2026-04-13 Last updated: 2026-04-14Bibliographically approved
List of papers
1. Analysis of laser Doppler flowmetry long-term recordings for investigation of cerebral microcirculation during neurointensive care
Open this publication in new window or tab >>Analysis of laser Doppler flowmetry long-term recordings for investigation of cerebral microcirculation during neurointensive care
2022 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 16, article id 1030805Article in journal (Refereed) Published
Abstract [en]

Cerebral blood flow is monitored in the neurointensive care unit (NICU) to avoid further brain damage caused by secondary insults following subarachnoid hemorrhage and brain trauma. Current techniques are mainly snap-shot based and focus on larger vessels. However, continuous monitoring of the smaller vessels may help detect the onset of secondary insults at an earlier stage. In this study, long-term measurements of brain microcirculation with laser Doppler flowmetry (LDF) were performed and evaluated. The aim was to identify and describe physiological signal variations and separate these from movement artifacts. Fiberoptic probes for subcortical LDF recordings of perfusion and total light intensity (TLI) were implanted in three patients with subarachnoid hemorrhage. Data were successfully collected and visualized in real-time over 4 days, resulting in 34, 12, and 8.5 h per patient. Visual observation, wavelet transforms, moving medians, and peak envelopes were used to identify and describe movement artifacts and physiological changes. Artifacts occurred in <5% of the total recording time and could be identified through signal processing. Identified physiological signal patterns included a slowly increasing perfusion trend over hours, vasomotion mainly at 2 cycles/min both in the perfusion and the TLI, and rapid, synchronized changes in the TLI and the perfusion on 38 occasions. Continuous LDF recordings indicating changes in the microvascular blood flow can increase the understanding of the microcirculation in the injured brain. In the long run, this may become a complement for the detection of secondary insults at an earlier stage than possible with todays techniques.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2022
Keywords
human brain; laser Doppler flowmetry (LDF); neurointensive care unit (NICU); microcirculation; vasomotion; cortical spreading depolarizations (CSD); signal analysis
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-190346 (URN)10.3389/fnins.2022.1030805 (DOI)000886258100001 ()36408392 (PubMedID)2-s2.0-85142145314 (Scopus ID)
Available from: 2022-12-06 Created: 2022-12-06 Last updated: 2026-05-13
2. Cerebral microcirculation in neurointensive care patients: An observational and comparative analysis of laser Doppler flowmetry signals and clinical monitoring data
Open this publication in new window or tab >>Cerebral microcirculation in neurointensive care patients: An observational and comparative analysis of laser Doppler flowmetry signals and clinical monitoring data
Show others...
2026 (English)In: Biomedical Signal Processing and Control, ISSN 1746-8094, E-ISSN 1746-8108, Vol. 114, article id 109217Article in journal (Refereed) Published
Abstract [en]

Purpose: Multimodal monitoring is used in the neurointensive care unit (NICU) to avoid further brain injury in patients with subarachnoid haemorrhage (SAH). The aims were to investigate cerebral microcirculation in patients with SAH using laser Doppler flowmetry (LDF), and to compare LDF data with intracranial pressure (ICP) and mean arterial pressure (MAP). Methods: An LDF system with an in-house developed two-channel fibre optical probe and software was used for bedside monitoring of microvascular CBF (Perf) in seven patients. Analyses of mean, peak-to-peak amplitude and frequency variations were performed on selected data based on protocol information. Analysis of frequency variations focused on vasomotion. Data comparisons were evaluated on longer timescales using Pearson correlation and on shorter timescales using a moving correlation index. Results: Microvascular data were successfully recorded for up to 10 days, resulting in 274 h of artefact-free data. The average perfusion ranged from 91 +/- 29 a.u. to 424 +/- 242 a.u. across patients and channels. Vasomotion was observed in 7-37 % and 4-44 % in the Perf and ICP data, respectively, with spatial, temporal, and interpersonal variations. Occasional positive and negative correlations between Perf and clinically monitored data were found on shorter timescales. Conclusion: Correlations varied daily among all individuals, confirming the need for moving indices to track correlation over time. Combining vasomotion analysis and correlations with clinical data can increase the knowledge about the underlying mechanisms of blood flow regulation in the injured brain in SAH patients.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2026
Keywords
Neurocritical care; Subarachnoid haemorrhage (SAH); Laser Doppler flowmetry (LDF); Vasomotion; Human brain; Intracranial pressure (ICP)
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:liu:diva-220349 (URN)10.1016/j.bspc.2025.109217 (DOI)001633379300001 ()2-s2.0-105023699594 (Scopus ID)
Note

Funding Agencies|Swedish Foundation for Strategic Research (SSF) [RMX18-0056]; Swedish Research Council [2020-03131]

Available from: 2026-01-14 Created: 2026-01-14 Last updated: 2026-04-13
3. Altered levels of transthyretin in human cerebral microdialysate after subarachnoid haemorrhage using proteomics; a descriptive pilot study
Open this publication in new window or tab >>Altered levels of transthyretin in human cerebral microdialysate after subarachnoid haemorrhage using proteomics; a descriptive pilot study
2023 (English)In: Proteome Science, E-ISSN 1477-5956, Vol. 21, no 1, article id 10Article in journal (Refereed) Published
Abstract [en]

BackgroundSubarachnoid haemorrhage (SAH) is one of the most severe forms of stroke in which delayed cerebral ischemia is one of the major complications. Neurointensive care aims at preventing and treating such complications and identification of biomarkers of early signs of ischemia might therefore be helpful.MethodsWe aimed at describing proteome profile in cerebral microdialysate in four patients with aneurysmal SAH using two dimensional gel electrophoresis in combination with mass spectrometry in search for new biomarkers for delayed cerebral ischemia and to investigate if there were temporal fluctuations in those biomarkers over time after aneurysmal bleed.ResultsThe results showed transthyretin in nine different proteoforms (1001, 1102, 2101, 3101, 4101, 4102, 5001, 5101, 6101) in cerebral microdialysate samples from four patients having sustained SAH. Several proteoforms show highly differing levels and pooled analysis of all samples showed varying optical density related to time from aneurysmal bleed, indicating a temporal evolution.ConclusionsTransthyretin proteoforms have not earlier been shown in cerebral microdialysate after SAH and we describe differing levels based on proteoform as well as time from subarachnoid bleed. Transthyretin is well known to be synthetized in choroid plexus, whilst intraparenchymal synthesis remains controversial. The results need to be confirmed in larger studies in order to further describe transthyretin.

Place, publisher, year, edition, pages
BMC, 2023
Keywords
Proteomics; subarachnoid hemorrhage; microdialysis; transthyretin; prealbumin; biomarkers; brain ischemia
National Category
Biochemistry Molecular Biology
Identifiers
urn:nbn:se:liu:diva-196700 (URN)10.1186/s12953-023-00210-z (DOI)001022446800001 ()37420193 (PubMedID)2-s2.0-85164180623 (Scopus ID)
Available from: 2023-08-21 Created: 2023-08-21 Last updated: 2026-05-13

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Ginstman, Fredrik

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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesDepartment of Neurosurgery
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