A working-age person’s strange behaviour may be a sign of frontotemporal dementia – patient-derived cells now provide new insights into the disease
Frontotemporal dementia doesn’t usually start with memory symptoms; instead, initial symptoms may include changes in behaviour, personality or mood.
“It often takes years to reach the right diagnosis. We need new diagnostic tools and biomarkers that could help to recognise the disease earlier, for example from a blood sample,” Professor Annakaisa Haapasalo says.
The development of diagnostics and pharmacotherapy for frontotemporal dementia requires a better understanding of molecular and cellular level disease mechanisms. Haapasalo explores these using, e.g., skin cells donated by patients as well as induced pluripotent stem cells derived from them.
Annakaisa Haapasalo was appointed as Professor of Molecular Neurodegeneration at the University of Eastern Finland this summer. She has a long track record in research addressing neurodegenerative disorders. At the A. I. Virtanen Institute for Molecular Sciences, she has years of experience in leading a research group that focuses on frontotemporal dementia caused specifically by a repeat expansion in the C9orf72 gene. This gene mutation is the most common cause of hereditary frontotemporal dementia. It is particularly prevalent in Finland, where nearly 50% of patients are its carriers.
Frontotemporal dementia is a progressive memory disorder that usually starts in later working years. However, the age of onset of symptoms varies greatly, from under 30 to over 80. There may be dramatic changes in the behaviour and personality of the person affected. Symptoms vary from patient to patient, ranging from loss of inhibition, recklessness and abnormal desires to lack of initiative and apathy. Some have problems with speech, or symptoms pointing at Parkinson’s disease or ALS. “Memory symptoms may start occurring only as the disease progresses. Typically, finding the right diagnosis takes time.”
Synaptic changes may explain symptoms
Haapasalo’s interest in frontotemporal dementia was sparked by the complex nature and strong hereditariness of the disease. “Nearly all carriers of the C9orf72 repeat expansion eventually get sick. However, a large number of patients have a sporadic disease, which means that its causes are unknown.”
Patients’ skin samples allow researchers to explore how a gene mutation or a sporadic form of the disease alter cell function. Skin cells are first reprogrammed into stem cells and then used to produce different brain cells in which pathogenic changes can be investigated.
“Frontotemporal dementia seems to be associated with, e.g., abnormal function of synapses, which are responsible for passing information between neurons. We have previously shown, in a mouse neuron model, that the C9orf72 repeat expansion causes such abnormalities, and we are now studying this in patient-derived cells.”
Haapasalo leads the SynaDeg consortium funded by the EU’s JPND programme, which investigates early synaptic changes in frontotemporal dementia and Lewy body dementia. International collaboration between several universities and hospitals makes it possible to compare changes observed on the cellular level with patients’ symptoms and changes in the synaptic function in their brain, as well as with changes measured from cerebrospinal fluid and blood samples.
“We hope to discover synaptic biomarkers that are specific to frontotemporal dementia and could enable early diagnosis. Treatments targeting synaptic changes could perhaps also be developed.”
Besides neurons, Haapasalo’s group also investigates changes associated with frontotemporal dementia in microglia, that is, in immune cells regulating inflammatory responses in the brain.
“It seems that immune system function is altered in frontotemporal dementia. We are particularly interested in the interaction between neurons and microglia, and how this is linked to synaptic changes.”
Investigating disease mechanisms and testing drugs in skin cell cultures
To date, frontotemporal dementia lacks both precision diagnostics and disease-modifying therapies. However, existing diagnostic methods can exclude, e.g., Alzheimer's disease, the pharmacotherapy of which can even exacerbate symptoms of frontotemporal dementia.
Haapasalo and colleagues have also shown that frontotemporal dementia can be reliably differentiated from psychiatric disorders based on neurofilament and GFAP protein levels measured from a blood sample. These get released into the bloodstream when the central nervous system is damaged. High GFAP levels also indicate the activation of inflammatory cells and anticipate a faster progression of the disease.
Producing brain cells from patient-donated skin cells is expensive and time-consuming. However, Haapasalo’s group has also found that patient-derived skin cell cultures are usable as such in frontotemporal dementia research.
“Both carriers of the C9orf72 repeat expansion and patients with sporadic frontotemporal dementia exhibited similar changes in their skin cells to those usually found in their brain. Patients’ skin cells had impaired energy metabolism as well as protein accumulations typical of the disease.”
According to Haapasalo, in the future, patient-derived skin cell cultures could perhaps be used to test drugs developed for, e.g., frontotemporal dementia. Globally, several drugs are being developed for the hereditary forms of the disease.
Haapasalo’s research group constitutes part of the extensive Neuroscience Research Community at the University of Eastern Finland. Collaboration between researchers of frontotemporal dementia is promoted by the FinFTD research network established by Haapasalo and Anne Remes, a former Professor of Neurology at Kuopio and current Vice Rector of the University of Helsinki. Important Finnish collaborators currently include Docent Eino Solje, Director of the Brain Research Unit at the University of Eastern Finland, and Johanna Krüger, Neurologist and Docent at the University of Oulu.
“FinFTD brings together us basic researchers and clinical researchers working with patients. The exchange of ideas and information is important in both directions. My own work at the cellular and molecular levels is tremendously interesting, but being in contact with clinicians, and through them with patients for whom this research is being conducted, is really a cherry on top.”
Professor of Molecular Neurodegeneration, University of Eastern Finland, 1 June 2023–
- MSc (Biotechnology), University of Kuopio, 1996
- PhD (Neurobiology/ Biotechnology), University of Kuopio, 2003
- Title of Docent in Neurobiology, University of Eastern Finland, 2011
- Research Director, University of Eastern Finland, 2019– 2023
- Associate Professor, University of Eastern Finland, 2015–2019
- Group Leader, University of Eastern Finland, 2014–2015
- Academy Research Fellow, University of Eastern Finland, 2009–2014
- Research Specialist and Academy of Finland Postdoctoral Researcher, University of Eastern Finland, 2006–2009
- Postdoctoral Research Fellow and Academy of Finland Postdoctoral Researcher, Massachusetts General Hospital and Harvard Medical School, 2004–2006