New Finding Challenges Dementia Age-Associated Beliefs

Dr Rob Hicks

January 10, 2022

Researchers from Newcastle University have, for the first time, identified changes in the brains of deceased infants with Krabbe disease that are similar to those changes seen in dementia with Lewy bodies and Parkinson’s Disease.

Dr Daniel Erskine, Alzheimer’s Research UK Research Fellow at Newcastle University, who is an expert in Lewy bodies and led the study, said: "These findings challenge the view that changes to the brain that underlie these forms of dementia are merely age-associated."

Krabbe disease is a rare autosomal recessive neurodegenerative childhood disorder arising in 1 in every 100,000 births, caused by a mutation in the GALC gene. This results in the loss of the protective myelin nerve coating with the disease typically resulting in death by the age of 2 years.

In both dementia with Lewy bodies and Parkinson's disease, a protein called alpha-synuclein builds up creating Lewy bodies, resulting in nerve cell damage.

The research, published in the journal Brain, involved studying the post-mortem brain tissue of four infants who died of Krabbe disease, comparing the brain tissue with four infant controls. The researchers found widespread accumulations of alpha-synuclein, a small protein abundant in the brain and found mainly in neuron presynaptic terminals, where it’s believed to play a role in maintaining an adequate supply of synaptic vesicles.

Prion-like Capacity

To determine whether alpha-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties the researchers evaluated its seeding capacity using the real-time quaking-induced conversion assay. 

The researchers said they did not identify Lewy bodies in the brain tissue of those infants with Krabbe disease, however, changes to the protein alpha-synuclein that are normally associated with dementia with Lewy bodies and Parkinson’s disease were identified.

In particular, the researchers say they found "aggregation into fibrils" similar to those observed in Lewy body disease, "confirming the prion-like capacity of Krabbe disease-derived alpha-synuclein." They highlighted that the alpha-synuclein protein in Krabbe disease was able to stick together and spread through the brain, a key change associated with dementia with Lewy bodies and Parkinson’s disease and that is thought to drive the progression of both diseases.

Dr Rosa Sancho, head of research at the charity Alzheimer’s Research UK, said: "In dementia with Lewy bodies, the protein alpha-synuclein forms clumps called Lewy bodies inside brain nerve cells. While Lewy bodies were not found in the brains of infants in this study, researchers have shown for the first time that alpha-synuclein had a similar capacity to spread through the brain in Krabbe disease."

Dysfunction of Specific Biological Pathways

The finding that alpha-synuclein in Krabbe disease shared key qualities that are normally only associated with age-associated neurodegenerative disease like dementia with Lewy bodies was "highly remarkable", said Dr Erskine. "This phenomenon has only been reported previously in the brains of older people with neurodegenerative diseases, so these findings challenge the view that changes to the brain that underlie these forms of dementia are merely age-associated, but are instead the result of dysfunction of specific biological pathways."

"We know dementia is caused by brain diseases, and this research offers more evidence that the disease that cause dementia are caused by biological processes going awry rather than as a by-product of old age," added Dr Rosa Sancho.

Cannot Stop Ageing, Can Potentially Fix Something

The authors said, "We report, for the first time to our knowledge, the presence of alpha-synuclein with prion-like characteristics in the brain tissue of infants." The study findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease. Dr Erskine commented, "This is an important message, as while we cannot stop ageing, we can potentially fix something that is not working properly."

"Building on these findings to help develop new drugs that target this common biological pathway could change the lives of people with both conditions," said Dr Sancho.

Both Dr Erskine and Dr Sancho paid tribute to the parents for making this research possible.

"These research findings have only been made possible from the support of the families donating their loved ones’ brains for research and I would like to pay tribute to them for their generosity in helping others in a time of unparalleled grief," said Dr Erskine.

Dr Sancho echoed these sentiments, saying: "We’re incredibly grateful to the families of those whose brains were studied in this research, and who made this important discovery possible."

The research was funded by Alzheimer’s Research UK.

Christopher Hatton et al. Prion-like α-synuclein pathology in the brain of children with Krabbe disease, Brain (2022). DOI: 10.1093 / brain / awac002

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