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Low Thalamic NAA-Concentration Corresponds to Strong Neural Activation in Working Memory in Kleine-Levin Syndrome
Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery.
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-2167-2450
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2Article in journal (Refereed) Published
Abstract [en]

Background

Kleine Levin Syndrome (KLS) is a rare disorder of periodic hypersomnia and behavioural disturbances in young individuals. It has previously been shown to be associated with disturbances of working memory (WM), which, in turn, was associated with higher activation of the thalamus with increasing WM load, demonstrated with functional magnetic resonance imaging (fMRI). In this study we aimed to further elucidate how these findings are related to the metabolism of the thalamus.

Methods

fMRI and magnetic resonance spectroscopy were applied while performing a WM task. Standard metabolites were examined: n-acetylaspartate (NAA), myo-inositol, choline, creatine and glutamate-glutamine. Fourteen KLS-patients and 15 healthy controls participated in the study. The patients with active disease were examined in asymptomatic periods.

Results

There was a statistically significant negative correlation between thalamic fMRI-activation and thalamic NAA, i.e., high fMRI-activation corresponded to low NAA-levels. This correlation was not seen in healthy controls. Thalamic levels of NAA in patients and controls showed no significant differences between the groups. None of the other metabolites showed any co-variation with fMRI-activiation.

Conclusion

This study shows negative correlation between NAA-levels and fMRI-activity in the left thalamus of KLS-patients while performing a WM task. This correlation could not be found in healthy control subjects, primarily interpreted as an effect of increased effort in the patient group upon performing the task. It might indicate a disturbance in the neuronal networks responsible for WM in KLS patients, resulting in higher effort at lower WM load, compared with healthy subjects. The general relationship between NAA and BOLD-signal is also discussed in the article.

Place, publisher, year, edition, pages
2013. Vol. 8, no 2
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-85927DOI: 10.1371/journal.pone.0056279ISI: 000316849500009OAI: oai:DiVA.org:liu-85927DiVA: diva2:573819
Available from: 2012-12-03 Created: 2012-12-03 Last updated: 2017-12-07Bibliographically approved
In thesis
1. The Non-Invasive Brain Biopsy: Implementation and Application of Quantitative Magnetic Resonance Spectroscopy on Healthy and Diseased Human Brain
Open this publication in new window or tab >>The Non-Invasive Brain Biopsy: Implementation and Application of Quantitative Magnetic Resonance Spectroscopy on Healthy and Diseased Human Brain
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: In this thesis, one of the major objectives was to implement a method for (absolute) quantitative magnetic resonance spectroscopy (qMRS) of the human brain, intended for clinical use. The implemented method was based on standard spatially selective MRS sequences. The tissue water was used as an internal reference, which was calibrated using whole brain quantitative magnetic resonance imaging (qMRI). The second objective was to apply the method in clinical neuroimaging investigation, of different disease processes in the human brain.

Materials and Methods: In total, 158 subjects were included and 507 MRS measurements (330 in white matter and 177 in the thalamus) were acquired.

In a cross-sectional study of multiple sclerosis (MS), 35 ‘clinically definite MS’ (CDMS) patients were included, of which 15 were atypical CDMS patients with a very low number of white matter lesions (two or fewer), and 20 were typical CDMS patients with white matter lesions (three or more) were included. The metabolite concentrations in normal appearing white matter (NAWM) and the thalamus were assessed using the qMRS method developed in this thesis, and the brain parenchymal fraction (BPF) was calculated from the qMRI data. A cohort of 27 CDMS patients were then treated with Natalizumab and examined both at baseline, and after one year of treatment. Both qMRS and CSF samples for the purpose of assessing intrathecal inflammation were obtained. In addition, the frontal deep white matter (FDWM) and the thalamus were investigated in 20 idiopathic normal pressure hydrocephalus (iNPH) patients using qMRS. Finally, the left thalamus of 14 Kleine-Levin Syndrome (KLS) patients were examined using both qMRS and functional MRI (fMRI) of neurological activation of the left thalamus during a working memory test. Moreover, 63 healthy subjects were included as controls for this work.

Results: A quantitative MRS method based on water referencing was successfully developed, implemented, and evaluated at 1.5 T. Both healthy subjects and MS patients showed a positive correlation between the concentrations of total Creatine (tCr) and myo Inositol (mIns) and age, and also a negative correlation with BPF were observed. Glutamate and Glutamine (Glx) levels were elevated for all MS patient groups compared to healthy controls. In contrast, lower concentrations of total N-acetyl aspartate and N-acetyl aspartate glutamate (tNA) and higher mIns concentrations in NAWM were only observed in MS patients that had developed white matter lesions. Moreover, the change in concentrations of tCr and total Choline (tCho) in MS patients during Natalizumab-treatment were positively correlated with markers of intrathecal inflammation. The iNPH patients had lower tNA and N-acetyl aspartate (NAA) concentrations in the thalamus compared to the controls. In addition, the NAA concentrations in the left thalamus were inversely correlated to the fMRI activation in the left thalamus during the working memory test in KLS patients.

Discussion: The calculated calibration factors were in good agreement with the results found in the literature, indicating that the calibration factors were accurate.

The observed elevated Glx concentration in MS could be due to increased concentrations of glutamate (Glu), which is neurotoxic at high concentrations, thus the elevated Glx could be linked to the clinically observed neurodegeneration in MS both in patients that have developed lesions and in atypical patients that do not develop any (or extremely few) lesions.

Both tCr and mIns can be used as glia markers, thus the correlations of tCr and mIns concentrations with both age and BPF indicates that the local glia cell density, or tissue fraction, increases with age and atrophy. Moreover, the higher mIns concentrations in the NAWM of MS patients with a substantial white matter lesion load indicate that the glia tissue amount in NAWM is increased in MS patients that develop lesions. NAA is neuronal-specific, thus the lower tNA concentrations indicate that the neurone concentration is lower in the NAWM of MS patients that develop MS lesions. The lack of correlation between tNA with age and BPF in combination with the presence of correlation between tCr and mIns with both age and BPF, might be explained using a model for neurodegeneration. In which, there is a higher neurone loss compared to the glia loss. However, the lost tissue is compensated by compression of the tissue, which keeps the density of neurones more or less constant and the density of glia increased.

The low concentration levels of the neuronal marker NAA in the thalamus of the iNPH patients indicates that the basal ganglia-thalamic-subcortical frontal circuits are damage or at least strongly modulated in the thalamus.

The correlation between strong activation in left thalamus during a working memory test with the neuronal marker NAA indicate that the KLS patients that have low neuronal concentration also needed to utilise the working memory circuitry more heavily in order to perform the task as healthy subjects.

Conclusion: It is possible to use qMRI for accurate and robust determination of qMRS in clinical practice, even at 1.5 T field strength. The tGlx concentration may be an important marker for pathology in the nonlesional white matter of MS-patients. The increased glia and loss of neurones in the NAWM are associated with the formation of white matter lesions.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1328
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85929 (URN)978-91-7519-795-1 (ISBN)
Public defence
2012-12-21, Elsa Brändströmsalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-12-03 Created: 2012-12-03 Last updated: 2014-10-02Bibliographically approved
2. On the Kleine-Levin Syndrome
Open this publication in new window or tab >>On the Kleine-Levin Syndrome
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Populärvetenskaplig sammanfattning på svenska

Kleine-Levins syndrom är en sömnsjukdom som beskrevs av Willi Kleine 1925 och därefter utvecklades i fallbeskrivningar av Max Levin och McDonald Chritchley. De symptom som beskrevs var återkommande sömnperioder (periodisk hypersomnia), en tendens att äta mycket i samband med dessa perioder (hyperfagi) och ökad sexdrift i samband med perioderna (hypersexualitet) och, i senare beskrivningar, kognitiva och beteendemässiga störningar. Enligt tidigare beskrivningar var patienterna återställda mellan sömnperioderna. Dessa varade i dagar-veckor och återkom flera gånger årligen. Sjukdomen debuterade vanligtvis i tonåren och beskrevs gå över efter åtta år.

d avhandling beskriver diagnosens utveckling över tid och sätter forskningen i sitt teoretiska sammanhang. Med det senare menas att det diskuteras hur forskningen förhåller sig till en diagnos som förändras över tid och där olika läkare kan ha olika kunskap kring och förhållningssätt till diagnosen.

De studier som ingår i avhandlingen har undersökt flera olika aspekter av Kleine-Levins syndrom. Den första studien undersökte arbetsminnet hos patienterna och kunde påvisa att det var nedsatt jämfört med friska försökspersoner, även mellan sömnperioderna, något som inte var visat systematiskt tidigare. Dessutom sågsandra aktiveringsmönster i hjärnan när patienterna försökte klara arbetsminnesuppgiften, jämfört med aktiveringsmönstren hos friska försökspersoner. Hos hälften av patienterna sågs dessutom avvikande blodflöde i delar av hjärnan även när ingen särskild arbetsuppgift utfördes. Detta sågs även hos patienter som tillfrisknat.

Då det funnits hypoteser i annan forsking att sjukdomen kan ha ett genetiskt/ärftligt inslag undersöktes huruvida patienterna hade en gen som tidigare har kopplats till sjukdomen. I den grupp av patienter som undersöktes i avhandlingens sista artikel kunde dock ingen sådan koppling ses.

Slutsatsen av forskningsresultaten är att (1) patienter med Kleine-Levins syndrom har en störning av arbetsminnet som verkar konstant. (2) De uppvisar andra hjärnaktiveringsmönster än friska personer som gör samma arbetsminnesuppgift. (3) Hälften av patienterna har ett avvikande blodflödesmönster även i vila och efter tillfrisknande. (4) En eventuell ärftlig komponent kan inte påvisas avseende de undersökta generna.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 52 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1588
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-141282 (URN)9789176854464 (ISBN)
Public defence
2017-09-30, Digitalissalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2017-09-28 Created: 2017-09-28 Last updated: 2017-10-04Bibliographically approved

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Tisell, AndersEngström, MariaKarlsson, ThomasDahlqvist Leinhard, OlofLundberg, PeterLandtblom, Anne-Marie

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