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 since team members are working both with genetic counselling as well as with research.

Activities

Our activities include:

  • studies of families with inherited dementia
  • association studies in case-control cohorts
  • neuropathological studies of human brain tissue
  • studies of mechanisms of neurodegeneration, spread of Aβ pathology and effect on intracellular functions such as mitochondria and autophagy
  • genetic counselling for families with inherited forms of dementia in the Memory clinic at Karolinska University hospital, Huddinge
  • screening patient samples from the clinic for mutations in known disease causing genes and apply our result in a clinical genetics setting

Research projects

Below follows a description of two of our research projects:

The Brain Bank at Karolinska Institutet

The Brain Bank at Karolinska Institutet is a core-facility since 2013, with the overall goal to build up and maintain the infrastructure of a brain bank for research on human brain and spinal cord tissue. We have established a brain donation program for informed consent and standardized collection of high quality nervous tissue which is available to anyone who wants to be a donor or wish to include brain/spinal cord donation in their research studies. Interested researchers are welcome to apply for brain tissue from the Brain Bank at KI. Tissue request forms are available on our homepage.  All procedures will conform to the highest ethical, legal and scientific standards to meet the needs of tissue donors, the general community and researchers.  For more information see ki.se/brainbank or contact us at Brainbank@nvs.ki.se

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 future clinical trials in this group of patients with early onset autosomal dominant disease.  Naturally being brought up in families with inherited forms of neurodegenerative disease has an effect on the family members on an existential and emotional level. Thus, we conduct quantitative (questionnaires) and qualitative (interviews) studies to get a better understanding of what it is like to live with the risk to develop early onset AD.

We are partners in several national and international collaborations such as: GENFI (Genetic FTD initiative), Swedish Brain Power, Strat Neuro, Brain Net Europe, IGAP (International Genomics of Alzheimer’s Project), ECEOD (European Consortium on Early Onset Dementia, EADC (European Alzheimer Disease Consortium) and FTD-GWAS. 

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 characterzed by behavioural changes and or language dysfunction. 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. We are partners of the international Genetic FTD intitiative (genfi.org.uk) and we have recently initiated a National consortia called Swedish FTD Inititative (FTDemens.se).

Group members

Research group leader, professor, MD, PhD

Caroline Graff

Phone: +46-(0)73-383 93 99
E-mail: Caroline.Graff@ki.se

PhD student

Linn Öijerstedt

Organizational unit: Graff
E-mail: linn.oijerstedt@ki.se

Graduate Student

Charlotte Johansson

Organizational unit: Graff
E-mail: charlotte.johansson@ki.se

Postdoc

Karthick Natarajan

Organizational unit: Graff
E-mail: karthick.natarajan@ki.se

Associated

Håkan Thonberg

Organizational unit: Graff
E-mail: Hakan.Thonberg@ki.se

Associated

Mikaela Cruz-Delgado

Organizational unit: Division of Neurogeriatrics
E-mail: mikaela.cruz-delgado@ki.se

Biomedical scientist

Marianne Petro

Organizational unit: Graff
E-mail: marianne.petro@ki.se

Associated

Steinunn Thordardottir

Organizational unit: Division of Neurogeriatrics
E-mail: steinunn.thordardottir@ki.se

Selected publications

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 Mar;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 Mar;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

Neuropathological characterization of two siblings carrying the MAPT S305S mutation demonstrates features resembling argyrophilic grain disease.
Rönnbäck A, Nennesmo I, Tuominen H, Grueninger F, Viitanen M, Graff C
Acta Neuropathol. 2014 Feb;127(2):297-8

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration.
Chiang H, Forsell C, Lilius L, Öijerstedt L, Thordardottir S, Shanmugarajan K, et al
Eur. J. Hum. Genet. 2013 Nov;21(11):1260-5

Dissertations

2012 Huei-Hsin Chiang

Thesis title: Genetic characterization of patients with frontotemporal dementia and amyotrophic lateral sclerosis in the Nordic countries

2010 Lina Keller

Thesis title: Genetics in Dementia: Impact of sequence variations for families and populations

2008 Behnosh Fakhri Björk

Thesis title:  Association studies on susceptibility genes in Alzheimer disease

 

 

GeneticsNeurobiologyPathology