First Sign of Dementia Observed to be Abnormal Synaptic Connections

Brain tissue death may not be the first symptom of dementia.

The authors of a new study found that the earliest symptoms of dementia may be caused by altered stability in brain cell connections, as opposed to tissue death. These findings suggest that treating dementia in the early stages of the disease may be critical for the success of future treatments, according to a study in Cell Reports.

In a collaborative effort between the University of Bristol and Eli Lilly, researchers studied the behavior of synapses in rodent models of human frontotemporal dementia.

The academic-pharma team used cutting-edge microscopy techniques to image the insides of the animal models. The authors discovered that prior to the death of synapses and neurons, the synaptic connections are abnormal, according to the study.

In healthy brains, relatively few synapses are added and lost as the brain makes memories or learns a new skill, but in patients with dementia, synaptic behavior was found to be altered. The authors reported that while some synapses were unstable, others appeared to be frozen.

Unbalanced synaptic activity was found to be linked to neuronal activation, while the brain was working, according to the study.

Although dementia is linked to the death of neurons in the brain, these new findings suggest that the connections between neurons and synapses are involved in the very early stages of dementia.

Additionally, the study results suggest early symptoms of dementia may be related to synapse stability as opposed to the death of brain tissue, which is now thought to come later, according to the authors.

"The need for new treatments for dementia has never been greater, but our ability to make effective new drugs has been hampered by the fact that we don't yet fully understand the causes of this debilitating group of diseases,” said lead author Michael Ashby, PhD, researcher at the University of Bristol. "Because neurons are so closely dependent on their synaptic partners, it is possible that the changes in synapse stability could be actually part of the reason that neurons begin to die. If this is true, then it points towards new therapeutic strategies based on treating these very early abnormalities in synaptic behaviour [sic]."

Due to increased understanding of the mechanisms behind dementia, researchers can now focus on targeting the synaptic connections to stabilize them and potentially prevent disease progression. However, the results must be confirmed through further studies.

“The data were one of the most comprehensive longitudinal assessments of the detailed mechanisms of synapse dysfunction in a model of tauopathy in vivo,” said Michael O'Neill, PhD, Head of Molecular Pathology at Lilly Research Laboratories. “The in vivo 2-photon technique is very powerful, but is slow and labour [sic] intensive to carry out and the collaboration with Bristol has allowed us achieve this dataset in a rapid and effective way."

If confirmed, these findings have the potential to revolutionize the way dementia is treated in the early stages, which could improve the lives of millions around the world.

"This new study adds weight to the growing body of evidence suggesting that synapses become disconnected before nerve cells themselves die. By using sophisticated microscopes, the Bristol team has gained valuable new insight into the stability of synapses and how this affects communication between nerve cells,” said Rosa Sancho, PhD, head of research at Alzheimer’s Research UK. "There are 850,000 people in the UK living with dementia including over 4,600 in Bristol alone. Researchers the world over are hunting for ways to tackle the diseases that cause dementia and protect nerve cells from damaging disease processes. As well as improving our understanding of how synapses are affected in dementia, these interesting findings will help inform future research into drugs that could help keep nerve cells healthy for longer."