Biomarkers in frontotemporal dementia : findings from the GENFI study

Frontotemporal dementia (FTD) is a group of neurodegenerative diseases including a wide range of clinical phenotypes, neuropathological hallmarks, and genetic causes. People with FTD typically present with deficits in behaviour and/or language which largely overlap with symptoms of other types of dementia and primary psychiatric disorders. FTD is associated with considerable suffering for both patients and their next of kin, and there is unfortunately no effective treatment for FTD yet. In genetic FTD, the disease is inherited in an autosomal dominant pattern where several causative mutations have been identified. The Genetic frontotemporal Initiative study (GENFI) is a prospective study enrolling individuals with a 50% risk of genetic FTD. Research visits are performed annually including medical and neuropsychological assessments, magnetic resonance imaging of the brain, and collection of biofluids. The purpose of this thesis was to investigate FTD at different stages with the aim to find biomarkers for FTD. Currently, no biomarkers specific for FTD are being used in clinical practice, and finding reliable biomarkers is essential for diagnostic and prognostic purposes as well as for the development of therapeutic interventions.

In study I, we performed a genetic screen in an FTD cohort from Sweden and found that mutations were particularly frequent in the C9orf72 gene. Interestingly, mutations were found in patients with apparent sporadic FTD suggesting that there are additional factors contributing to the development of disease.

In study II, practice effects of repeated neuropsychological testing were investigated in the GENFI cohort. Presymptomatic individuals carrying either a C9orf72 or a GRN mutation had lower practice effects than controls. This study warrants for caution when interpreting potential treatment effects unless practice effects have been considered.

In studies III-V, different biomarkers in cerebrospinal fluid (CSF) and plasma were explored using a multiplexed suspension bead array technique. Several proteins in CSF, and some in plasma, were found at altered levels in patients with FTD compared to unaffected individuals. In addition, we present indications that a couple of CSF proteins may be altered already in a presymptomatic stage.

In summary, genetic and potential cognitive and fluid biomarkers were identified in this thesis. Additional studies are required to determine each biomarker’s respective relevance in FTD, including their future value in a clinical setting.

List of scientific papers

I. Öijerstedt L, Chiang HH, Björkström J, Forsell C, Lilius L, Lindström AK, Thonberg H, Graff C. Confirmation of high frequency of C9orf72 mutations in patients with frontotemporal dementia from Sweden. Neurobiology of Aging. 2019 Dec;84:241.
https://doi.org/10.1016/j.neurobiolaging.2019.03.009

II. Öijerstedt L, Andersson C, Jelic V, van Swieten JC, Jiskoot LC, Seelaar H, Borroni B, Sanchez-Valle R, Moreno F, Laforce R Jr, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonca A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Frisoni G, Ghidoni R, Sorbi S, Rohrer JD, Graff C; Genetic Frontotemporal Dementia Initiative (GENFI). Practice effects in genetic frontotemporal dementia and at-risk individuals: a GENFI study. Journal of Neurology, Neurosurgery and Psychiatry. 2021 Aug 18:jnnp-2021-327005.
https://doi.org/10.1136/jnnp-2021-327005

III. Remnestål J*, Öijerstedt L*, Ullgren A, Olofsson J, Bergström S, Kultima K, Ingelsson M, Kilander L, Uhlén M, Månberg A, Graff C, Nilsson P. Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers. Translational Neurodegeneration. 2020 Jun 23;9(1):27. *Shared first authors.
https://doi.org/10.1186/s40035-020-00198-y

IV. Bergström S*, Öijerstedt L*, Remnestål J, Olofsson J, Ullgren A, Swieten, Synofzik, Sanchez-Valle, Moreno, Finger, Masellis, Tartaglia, Vandenberghe, Laforce, Galimberti, Borroni, R Butler, Gerhard, Ducharme, Rohrer, Månberg, Graff G, Nilsson P, on behalf of the Genetic Frontotemporal Dementia Initiative (GENFI). A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study. Molecular Neurodegeneration. 2021 Nov 27;16(1):79. *Shared first authors.
https://doi.org/10.1186/s13024-021-00499-4

V. Öijerstedt L*, Ullgren A*, Olofsson J, Bergström S, Remnestål J, Månberg A, van Swieten J, Jiskoot L, Seelaar H, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Synofzik M, Galimberti D, Rowe J, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Frisoni G, Ghidoni R, Sorbi S, Rohrer JD, Nilsson P, Graff C, on behalf of the Genetic Frontotemporal Dementia Initiative (GENFI). A large-scale proteomic profiling of plasma in genetic FTD: a GENFI study. *Shared first authors. [Manuscript]