CSF, Blood, and MRI Biomarkers in Skogholt's Disease-A Rare Neurodegenerative Disease in a Norwegian Kindred

Klaus Thanke Aspli; Jan O Aaseth; Trygve Holmøy; Kaj Blennow; Henrik Zetterberg; Bjørn-Eivind Kirsebom; Tormod Fladby; Per Selnes

doi:10.3390/brainsci13111511

CSF, Blood, and MRI Biomarkers in Skogholt's Disease-A Rare Neurodegenerative Disease in a Norwegian Kindred

Brain Sci. 2023 Oct 26;13(11):1511. doi: 10.3390/brainsci13111511.

Authors

Klaus Thanke Aspli^{1

2}, Jan O Aaseth³, Trygve Holmøy^{2

4}, Kaj Blennow^{5

6

7

8}, Henrik Zetterberg^{5

6

9

10

11

12}, Bjørn-Eivind Kirsebom^{2

13

14}, Tormod Fladby^{2

4}, Per Selnes^{2

15}

Affiliations

¹ Department of Neurology, Innlandet Hospital Trust, 2381 Lillehammer, Norway.
² Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway.
³ Research Department, Innlandet Hospital Trust, 2381 Brumunddal, Norway.
⁴ Department of Neurology, Akershus University Hospital, 1478 Nordbyhagen, Norway.
⁵ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, 43153 Mölndal, Sweden.
⁶ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 43153 Mölndal, Sweden.
⁷ Institut du Cerveau et de la Moelle Épinière (ICM), Pitié-Salpêtrière Hospital, Sorbonne Université, 75651 Paris, France.
⁸ First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China.
⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
¹⁰ UK Dementia Research Institute, University College London, London WC1N 3AR, UK.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹³ Department of Neurology, University Hospital of North Norway, 9019 Tromsø, Norway.
¹⁴ Department of Psychology, Faculty of Health Sciences, UiT, the Arctic University of Norway, 9019 Tromsø, Norway.
¹⁵ Department of Research, Akershus University Hospital, 1478 Nordbyhagen, Norway.

Abstract

Skogholt's disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and peripheral myelin pathology is unclear. Increased cerebrospinal fluid (CSF) concentrations of protein have been confirmed, and recently, very high concentrations of CSF total and phosphorylated tau have been detected in Skogholt patients. The symptoms and observed biomarker changes in Skogholt's disease are largely nonspecific, and further studies are necessary to elucidate the disease mechanisms. Here, we report the results of neurochemical analyses of plasma and CSF, as well as results from the morphometric segmentation of cerebral magnetic resonance imaging. We analyzed the biomarkers Aβ_1--42, Aβ_1-40, Aβ_x-38, Aβ_x-40, Aβ_x-42, total and phosphorylated tau, glial fibrillary acidic protein, neurofilament light chain, platelet-derived growth factor receptor beta, and beta-trace protein. All analyzed CSF biomarkers, except neurofilament light chain and Aβ_1/x-42, were increased several-fold. In blood, none of these biomarkers were significantly different between the Skogholt and control groups. MRI volumetric segmentation revealed decreases in the ventricular, white matter, and choroid plexus volumes in the Skogholt group, with an accompanying increase in white matter lesions. The cortical thickness and subcortical gray matter volumes were increased in the Skogholt group. Pathophysiological changes resulting from choroidal dysfunction and/or abnormal CSF turnover, which may cause the increases in CSF protein and brain biomarker levels, are discussed.

Keywords: GFAP; MRI; NFL; PDGFRβ; Skogholt’s disease; amyloid beta; blood–brain barrier; tau protein; β-trace protein.

Grants and funding

This research was funded by the Innlandet Hospital Trust, Norway. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018); the European Union’s Horizon Europe research and innovation programme under grant agreement No. 101053962; Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862); the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C); the Bluefield Project; the Olav Thon Foundation; the Erling-Persson Family Foundation; Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270); the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No. 860197 (MIRIADE); the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). The sponsors had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results. BEK was supported by a grant from Helse-Nord (HNF1540-20). The DDI project was funded by the Norwegian Research Council and JPND/PMI-AD (NRC 311993).