Up to four in five people with Parkinson’s disease (PD) will develop dementia during the course of their illness. As many as three-quarters of PD patients will lose weight as a complication of PD. Those who lose weight are more likely to develop problems with their memory (cognitive impairment) and have symptoms such as hallucinations than those who do not. Previous studies have linked the potential of the hormone ghrelin playing a role in Parkinson’s disease dementia (PDD).

Ghrelin is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a “hunger hormone” because it increases food intake. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Now ghrelin may have insights into neurological disorders such as dementia in PD. A Swansea-led research team says they have discovered that the gut hormone is a key regulator of new nerve cells in the adult brain.

Their findings, “Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and is Altered in Parkinson’s Dementia in Humans,” is published in Cell Reports Medicine and led by Jeff Davies, PhD, associate professor of molecular neurobiology at Swansea University Medical School.

The researchers focused on the gut hormone acyl-ghrelin (AG), which is known to promote brain cell formation. A structural change to the hormone results in two distinct forms: AG and unacylated-ghrelin (UAG).

“Circulating factors are known to both enhance and impair neuronal plasticity and learning in adult mammals. However, the mechanisms underlying these effects are not completely understood,” noted the researchers.

The team sought to determine whether UAG modulated hippocampal plasticity and memory function and whether plasma levels of acyl-ghrelin and UAG were associated with dementia in humans. Using a mouse model, the researchers observed the effect of UAG administered peripherally for seven days.

The researchers collaborated with researchers from Newcastle University in the U.K. and Monash University in Australia. They examined the role of AG and UAG in the brain, and also compared blood collected from Parkinson’s disease patients diagnosed with dementia with cognitively intact PD patients and a control group.

The teams found higher levels of UAG, reduced hippocampal neurogenesis and brain plasticity, and acyl-ghrelin reversed spatial memory impairments.

“These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice.”

To determine relevance in humans, the researchers analyzed circulating AG:UAG in PD patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. The researchers observed plasma AG:UAG was only reduced in PDD patients.

“Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT+ cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia.”

Their work highlights the role ghrelin plays as a regulator of new nerve cells in the adult brain and represents a new target that may one day lead to more effective therapies for people with Parkinson’s disease.

Their findings also highlight that the AG:UAG ratio could serve as a biomarker, which would allow earlier detection of dementia in people with Parkinson’s disease.

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