Specific brain regions found more vulnerable to dementia with Lewy bodies

Dementia with Lewy bodies is one of the most common forms of dementia in older adults, after Alzheimer's disease. It takes its name from "Lewy bodies," abnormal clumps of a protein called alpha-synuclein, first identified by neurologist Friedrich Lewy, that accumulate inside neurons and contribute to damaging them. The disease manifests through visual hallucinations, fluctuating cognition, agitated and often violent movements during dreams, and motor symptoms similar to those of Parkinson's disease.

But contrary to what has long been assumed, the brain tissue loss it causes may not be random: it appears to preferentially affect certain regions of the brain that share specific biological characteristics.

That's what a study published in the Journal of Biomedical Science demonstrates. The research was led by an international team headed by Shady Rahayel, a professor at Université de Montréal's Faculty of Medicine and a researcher at the Center for Advanced Research in Sleep Medicine at Hôpital du Sacré-Cœur de Montréal, in collaboration with teams from McGill, Newcastle, Cambridge and Toronto, along with the Canadian Consortium on Neurodegeneration in Aging (CCNA).

Atrophy that predominates at the back of the brain

By comparing MRI brain scans of 83 people diagnosed with dementia with Lewy bodies to those of 86 healthy individuals, the researchers observed marked cortical thinning, particularly in the parietal, temporal and occipital regions, corresponding to the posterior portion of the brain, as had already been reported in previous studies.

Genes linked to mitochondria and synapses

The original contribution of our study lies in its second stage. By comparing our findings to a map of gene activity in healthy human brains, we showed that the regions most affected by cortical thinning in dementia with Lewy bodies are also those where certain genes are more transcribed, notably genes linked to mitochondrial function (the cell's "powerhouses") and to synapses (communication between neurons). In other words, these regions appear to be inherently more fragile, which could make them more prone to degeneration."

Shady Rahayel, Professor, Université de Montréal's Faculty of Medicine

At the crossroads of Parkinson's and Alzheimer's, yet distinct

Many of these genes are also found in the biological mechanisms associated with Parkinson's disease and Alzheimer's disease, supporting the idea that dementia with Lewy bodies sits biologically at the intersection of the two.

But the team also isolated a group of 90 genes unique to dementia with Lewy bodies, not associated with either Parkinson's or Alzheimer's diseases. These genes are instead linked to GABA (gamma-aminobutyric acid), the brain's main chemical messenger for slowing neuronal activity, somewhat like a brake pedal that keeps the nervous system from running out of control. This finding could help explain some of the disease's distinctive symptoms, such as visual hallucinations, as well as patients' marked sensitivity to benzodiazepine-type medications, which act on this very braking system.

The role of neurotransmitters and brain connections

The most atrophied brain regions in people living with dementia with Lewy bodies also show distinctive patterns of serotonin, dopamine, and GABA receptors. The comparison was made by cross-referencing the brain atrophy map with maps showing, region by region, the normal density of receptors for these chemical messengers. These maps come from an imaging technique called positron emission tomography (PET), which shows where, and in what quantity, these receptors are found in the brain.

Finally, Professor Rahayel and his colleagues showed that cortical thinning follows the brain's major structural connectivity pathways: the affected regions are more strongly interconnected through nerve fiber networks. This finding supports the idea that the disease may spread from one brain region to another along these connections, much like a trail of gunpowder spreading along a network rather than appearing at random.

Toward new therapeutic targets

"These results show that the vulnerability of certain brain regions to dementia with Leyw bodies is not random, but reflects a combination of molecular factors and neural networks that could one day be targeted by new treatments aimed specifically at the GABAergic inhibitory circuits affected in this disease," concludes Shady Rahayel.