Markers of inflammation and neurodegeneration in muliple sclerosis

The main line of my thesis projects is searching for biomarkers and evidence of optimal correlation with clinical and para-clinical outcome measurements in multiple sclerosis (MS): investigating the biochemical biomarker in blood/plasma (cerebrosterol) and in cerebrospinal fluid (CSF) (oligoclonal bands (OCB)) and the correlation with MRI lesion load (paper 1 and paper IV); investigating the genetic biomarker (CYP46A1) for susceptibility and disability progression in MS (Paper III); comparison of the well-known positron emission tomography (PET) ligand and peripheral benzodiazepine receptor (PBR) antagonist, [11C]PK11195, and a new PET ligand [11C]vinpocetine (tissue receptor biomarker). Both ligands denote areas of active ongoing inflammation in MS (paper II).

Paper I: How levels of cerebrosterol – a brain specific cholesterol metabolite - correlate with inflammatory and neurodegenerative markers on brain MRI; Paper II: PET ligand and PBR agonist, [11C]vinpocetine, facilitates cholesterol delivery to the mitochondrial membrane, a pilot study to investigate whether the new [11C]vinpocetine is a better marker of MS inflammatory lesion areas compared to the old PET-PBR marker [11C]PK11195; Paper III: A study of how a single nucleotide polymorphism in the gene CYP46A1, coding for cholesterol hydroxylating enzyme 24S-hydroxylase, influences susceptibility and prognosis in MS singly and in synergism with another gene variant implicated in cholesterol turnover, APOE ε4; and Paper IV: Investigation of a CSF inflammation biomarker–OCB, and carriership of specific HLA gene alleles and the correlation with MRI outcome measures: total T1 and T2 lesion load, as well as T2 lesion load extension in MS specific compartments.

The most important findings are: Paper I. Results in this paper support the possibility that cerebrosterol in plasma is a potential marker of neurodegeneration in the relapsing remitting MS group; Paper II. PET ligand [11C]vinpocetine is a marker of activated glia in MS lesions and binds in different ways compared to [11C]PK11195; Paper III. CYP46A1 alone or in combination with APOE ε4 does not affect susceptibility for MS; men, as carriers of both the CYP46A1 SNP rs754203–AA variant and APOE ε4 need walking assistance 17 years earlier compared with noncarrier men. However, results are lacking statistical significance, due to small sample size; and Paper IV. OCB in CSF, HLA-DRB1*15, and HLA-DRB1*04 affect neither T1 lesion load on brain MRI at MS specific localizations nor total T2 lesion load. This paper supports the possibility that infratentorial T2 lesion load is associated with OCB in CSF.

List of scientific papers

I. Plasma cerebrosterol and magnetic resonance imaging measures in multiple sclerosis. Karrenbauer VD, Leoni V, Lim ET, Giovannoni G, Ingle GT, Sastre-Garriga J, Thompson AJ, Rashid W, Davies G, Miller DH, Björkhem I, Masterman T. Clin Neurol Neurosurg. 2006 Jul; 108(5):456-60.
https://doi.org/10.1016/j.clineuro.2005.07.010

II. Functional neuroimaging in multiple sclerosis with radiolabelled glia markers: Preliminary comparative PET studies with [11C]vinpocetine and [11C]PK11195 in MS patients. Vas A, Shchukin Y, Karrenbauer VD, Cselényi Z, Kostulas K, Hillert J, Savic I, Takano A, Halldin C, Gulyás B. J Neurol Sci. 2008 Jan 15;264(1-2):9-17.
https://doi.org/10.1016/j.jns.2007.07.018

III. Effect of CYP46A1 genotypes on susceptibility and prognosis in multiple sclerosis. Virginija Danylaitė Karrenbauer, Lisa Barcellos, Thomas Masterman, Kerstin, Imrell. [Manuscript]

IV. Impact of cerebrospinal-fluid oligoclonal immunoglobulin bands and HLADRB1 risk alleles on brain magnetic-resonance imaging lesion load in Swedish multiple sclerosis patients at age 40. Virginija Danylaitė Karrenbauer, Robert Prejs, Thomas Masterman, Jan Hillert, Anna Glaser, Kerstin Imrell. [Submitted]