Caroline Graff Group

Translational Genetics of Neurodegenerative disease

Research focus

We study the genetics and neuropathology of neurodegenerative diseases in particular Alzheimer disease (AD), Frontotemporal lobar degeneration (FTLD) and FTLD associated with amyotrophic lateral sclerosis (ALS). Our research is translational from patients and families to the laboratory and back. If you are interested to participate in research please contact us via NVS Kliniskforskning Graff (kliniskforskning-graff@nvs.ki.se) or contact one of the group members directly.

Activities

Our activities include:

  • Clinical follow-up studies of families with inherited neurodegenerative diseases to describe the pathological staging of disease in particular
    • the GENFI study (genfi.org) and
    • a study on dominantly inherited Alzheimer disease
  • Recruit clinical treatment trials for genetic forms of FTD within the framework of (thefpi.org)
  • Whole genome sequencing to identify known and unknown genetic factors in early onset cognitive diseases
  • We host a webpage for and organize the activites in the Swedish FTD Initiative (frontallobsdemens.se)
  • We participate in global association studies in case-control cohorts in AD and
  • Neuropathological studies of human brain tissue
  • We imnplement our research in close collaboration with the out-patient clinic at the Unit for hereditary dementia, (Mottagning för ärftliga demenssjukdomar) Clinical Genetics, Karolinska University Hospital, Solna.
  • We have large sample collections of DNA, fibroblasts, RNA, plasma, serum and CSF.
  • FTD such as IGAP (International Genomics of Alzheimer’s Project), ECEOD (European Consortium on Early Onset Dementia, EADC (European Alzheimer Disease Consortium) and FTD-GWAS, ICFGC and whole genome sequencing projects such as the FTLD-TDP WGS Consortium, FTDGSC

Research projects

Below follows a description of two of our research projects:

Experimental and clinical studies of inherited forms of dementia

Of particular interest is to develop biomarkers for early diagnosis in AD and FTLD which we do by studying family members with 50% risk of inheriting a dominant disease causing mutation. During the course of the study the study subjects perform an extensive battery of clinical examinations as well as tissue sampling. Our hope is to better understand the natural history of AD and FTLD respectively, develop specific and sensitive biomarkers for early diagnosis and identify new drug targets. We also hope that our research will facilitate recruiting clinical trials for this group of families with early onset autosomal dominant disease. Currently we have two ongoing clinical trials in collaboration with the Clinical Trials Unit, Karolinska University Hospital Huddinge, for progranulin and C9orf72 mutation carriers diagnosed with FTD or ALS.

Our studies on genetic FTD are part of a European Canadian  FTD studies We are partners of the international Genetic FTD intitiative (genfi.org) and we lead a national network on FTD called Swedish FTD Initiative. SweFTDI is engaged in experimental and clinical research and organize all interest groups in FTD i.e. clinicians, researchers, care givers, patients and families. On our webpage you can find  current activities and publications such as “Clinical guidelines for FTD” available via the website (Frontallobsdemens.se).

Frontotemporal dementia (FTD)

FTD is a group of neurodegenerative diseases characterized by neuronal dysfunction in the anterior temporal lobes and frontal lobes. The clinical symptoms are characterized by behavioural changes and or language dysfunctions. There is a clinical, genetic and neuropathological overlap with ALS (amyotrophic lateral sclerosis). We investigate the genetics and neuropathology of FTD in both clinical studies of at-risk subjects as well as experimental studies of patient derived cells and fluids. Please visit our homepage at Swedish FTD Inititative (frontallobsdemens.se) for more information about FTD, details on diagnostic criteria and ongoing activities.

The Brain Bank at Karolinska Institutet

The Brain Bank at Karolinska Institutet was a core-facility between 2013-2018. Due to a temporary termination of funding the activities and webpage was temporarily shut-down July-December 2018. Again in 2019 the Brain Bank was granted infrastructure funding from CIMED (2019-2021). However, as of 2022 we have limited services but are happy to provide access to available tissue if possible, upon request.  Please see the webpage for more information (http://www.ki.se/brainbank).
The continued goal is to manage human brain and spinal cord tissue for research.
We are currently discussing possible solutions for future biobanking in collaboration with the Karolinska University Hospital.

Research group leader

Caroline Graff

Professor/specialist physician

Group members

Abbe Ullgren

PhD student

Catharina Roman

Research nurse

Emma Ehn

PhD Student

Jessica Pege

Research coordinator

Jose Laffita

Laboratory manager

Selected publications

Fluid biomarkers in frontotemporal dementia: past, present and future
Swift I J, Sogorb-Esteve A, Heller C, Synofzik M, Graff C, et al
J Neurol Neurosurg Psychiatry . 2021 Feb;92(2):204-215

Cerebrospinal Fluid YKL-40 and Neurogranin in Familial Alzheimer's Disease: A Pilot Study
Thordardottir S, Almkvist O, Johansson C, Zetterberg H, Blennow K, Graff C
J Alzheimers Dis . 2020;76(3):941-953

Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers
Remnestål J, Öijerstedt L, Ullgren A, Olofsson J, Bergström S, Kultima K, et al 
Transl Neurodegener. 2020 Jun 23;9(1):27

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study
Moore K, Nicholas J, Grossman M, McMillan C, Irwin J, Massimo L, et al
Lancet Neurol. 2020 Feb;19(2):145-156

Confirmation of high frequency of C9orf72 mutations in patients with frontotemporal dementia from Sweden
Öijerstedt L, Chiang H, Björkström J, Forsell C, Lilius L, Lindström A-K, et al
Neurobiol Aging. 2019 Dec;84:241.e21-241.e25

Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease.
Almkvist O, Rodriguez-Vieitez E, Thordardottir S, Amberla K, Axelman K, Basun H, et al
J Int Neuropsychol Soc 2017 03;23(3):195-203

TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
van der Zee J, Gijselinck I, Van Mossevelde S, Perrone F, Dillen L, Heeman B, et al
Hum. Mutat. 2017 03;38(3):297-309

Defeating Alzheimer's disease and other dementias: a priority for European science and society.
Winblad B, Amouyel P, Andrieu S, Ballard C, Brayne C, Brodaty H, et al
Lancet Neurol 2016 Apr;15(5):455-532

Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy.
Piras A, Collin L, Grüninger F, Graff C, Rönnbäck A
Acta Neuropathol Commun 2016 Mar;4():22

Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.
Rodriguez-Vieitez E, Saint-Aubert L, Carter S, Almkvist O, Farid K, Schöll M, et al
Brain 2016 Mar;139(Pt 3):922-36

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.
Rohrer J, Nicholas J, Cash D, van Swieten J, Dopper E, Jiskoot L, et al
Lancet Neurol 2015 Mar;14(3):253-62

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.
Rohrer J, Nicholas J, Cash D, van Swieten J, Dopper E, Jiskoot L, et al
Lancet Neurol 2015 Mar;14(3):253-62

Preclinical cerebrospinal fluid and volumetric magnetic resonance imaging biomarkers in Swedish familial Alzheimer's disease.
Thordardottir S, Ståhlbom A, Ferreira D, Almkvist O, Westman E, Zetterberg H, et al
J. Alzheimers Dis. 2015 ;43(4):1393-402

Frontotemporal dementia and its subtypes: a genome-wide association study.
Ferrari R, Hernandez D, Nalls M, Rohrer J, Ramasamy A, Kwok J, et al
Lancet Neurol 2014 Jul;13(7):686-99