Ketamine can help address dyskinesia in Parkinson’s, reveals study

A new study has uncovered findings about the nature of levodopa-induced dyskinesia in Parkinson’s disease, and how the anaesthetic ketamine can help address the condition.

Levodopa is administered to Parkinson’s patients to help counter the loss of dopamine that contributes to the condition. However, after years of this treatment, many patients experience involuntary and uncontrollable movements known as levodopa-induced dyskinesia.

In a new study, researchers have now discovered that the brain’s motor cortex, responsible for controlling movement, becomes disconnected during dyskinetic episodes.

They found that the firing patterns of brain neurons showed little correlation with the dyskinetic movements, suggesting a fundamental disconnection rather than direct causation, challenging the currently prevailing view that the motor cortex actively generates these uncontrollable movements.

According to lead researcher Abhilasha Vishwanath at the University of Arizona, because of the disconnect between motor cortical activity and these uncontrollable movements, there’s probably not a direct link, but rather an indirect way in which these movements are being generated.

“There are about 80 billion neurons in the brain, and they hardly shut up at any point. So, there are a lot of interactions between these cells that are ongoing all the time,” Vishwanath said.

“It’s like an orchestra where the conductor goes on vacation,” said Stephen Cowen, senior author of the study.

“Without the motor cortex properly coordinating movement, downstream neural circuits are left to spontaneously generate these problematic movements on their own.”

Ketamine as a treatment

Previous work from the team has shown the potential of the common anaesthetic ketamine as a therapy for the problem.

In the work, the team showed that ketamine could help disrupt abnormal repetitive electrical patterns in the brain that occur during dyskinesia – potentially helping the motor cortex to regain some control over movement.

This works as ketamine initially disrupts abnormal electrical patterns occurring during dyskinesia, then later triggers much slower processes that allow for changes in the connectivity and activity of brain cells over time, known as ‘neuroplasticity’.

The team said their work shows that beneficial effects can be seen even after a few months with just one dose of ketamine.

A Phase 2 clinical trial is now being conducted, testing low doses of ketamine infusions as a treatment for the condition which the researchers say has shown promising early results.

According to Cowen, ketamine doses could be tweaked in a way such that the therapeutic benefits are maintained with minimised side effects, and entirely new therapeutic approaches could be developed based on the study’s findings about motor cortex involvement in dyskinesia.

“By understanding the basic neurobiology underlying how ketamine helps these dyskinetic individuals, we might be able to better treat levodopa-induced dyskinesia in the future,” Cowen said.

Dancing lowers depression associated with Parkinson’s disease

A new study has revealed that dancing lowers the depression associated with Parkinson’s disease, and the benefits can be seen in multiple ways.

The study followed 23 participants in the Sharing Dance Parkinson’s programme at Canada’s National Ballet School who had a diagnosis of Parkinson’s disease, as well as 11 healthy controls, who were mostly family members or caretakers.

The participants took weekly dance classes for eight months, which progressed from simple leg and foot work and pliés to interpretive movements, waltzes, and more complicated, choreographed dances.

“It was very cool to see that dance had a positive effect on the mood circuits in the brain, which we could see in the imaging,” said Faculty of Health associate professor Joseph DeSouza, an author of the study.

“These improvements that we could see on MRI brain scans were also reported by the participants via survey. Our study is the first to demonstrate these benefits across these two detection methods.”

The researchers found that after each dance class, reported depression rates dropped, and the effect was cumulative from class to class, with significant improvements after eight months.

They also found that the MRI scans showed reduced signals in a frontal-cortex brain region associated with emotional regulation and that in a smaller subset of the participants, a significant decrease in depression scores was correlated with changes in the SCG node.

“We essentially showed that SCG BOLD [blood oxygen level–dependent] signal decreases while dancing over time. Which means that the SCG was not functioning as fast as it would if you had depression,” said Bearss.

Parkinson disease is a progressive neurodegenerative disease. Before diagnosis, there is a prodromal phase that can last two to 10 years and is characterised by low mood, even before other symptoms appear, such as tremors and other issues with motor control.

“People with Parkinson’s disease tend to have multiple symptoms that are not just motor related, there are a lot of symptoms that include mental and social well-being impairments, one of those being depression,” said Bearss.

This research builds on a three-year-long study that found that dance training helps people with Parkinson disease with motor control, mood, and other functions of daily living.

Dance is thought to have a double benefit, with music activating the brain’s reward centres, and the movement acting on sensory and motor circuits. DeSouza, who has been dancing with participants in the programme for 14 years, says that while dancing is not a treatment for Parkinson disease per se, the benefits are clear.

“We’re not trying to cure Parkinson’s with dance,” says DeSouza, also with the Centre for Vision Research and Connected Minds at York.

“What we’re trying to do is to have people live a better quality of life. This goes for both those with the disease, and their families that take care of them — they also get benefits of feeling better.”

Evidence links dementia to brain waste clearing problems

A new study has tested a biomarker linked to vascular dementia and proposed an explanation for how cognitive impairment arises. 

Vascular dementia is usually caused by cerebral small vessel disease (cSVD), which damages the brain’s small blood vessels, but researchers don’t yet know the exact mechanism linking cSVD to dementia. One theory involves problems with the glymphatic system, which helps clear waste from the brain.

A team of researchers have now found new evidence in support of that theory.

The group analysed brain scans and cognitive tests from a total of 3750 people, then used technique known Diffusion Tensor Image Analysis along the Perivascular Space – or DTI-ALPS – to determine how well the glymphatic system was functioning in each person based on their brain scans.

The researchers compared the DTI-ALPS results with the cognitive test results and found that people with lower DTI-ALPS scores also performed lower on cognitive tests. The study confirmed that a low DTI-ALPS score is a biomarker for cSVD and suggests that glymphatic damage may be driving cognitive decline.

“The most significant finding is that we found a clear link between DTI-ALPS and cognitive function in all four cohorts, with ages ranging from middle-age through older adulthood,” said Danny Wang, PhD, the study’s senior author at the Keck School of Medicine’s Stevens INI.

Wang and his team also analysed the progression of symptoms across study participants, finding a possible pathway to explain how glymphatic problems lead to cognitive impairment.

The results provide a target for clinical researchers seeking to develop treatments for vascular dementia, Wang said, and may also prove useful for treating symptoms of Alzheimer’s disease.

The DTI-ALPS biomarker relies on magnetic resonance imaging (MRI) to measure water movement along perivascular spaces, fluid-filled regions around the brain’s blood vessels that are a key part of the glymphatic system. If researchers detect changes in DTI-ALPS score, that can indicate damage and suggest that the waste clearance system is not functioning as it should.

In the present study, the team analysed MRI scans to collect a measure of DTI-ALPS for each participant. They compared those measurements to each person’s level of executive function, a composite score of cognition that includes memory, attention, planning, emotion regulation and other abilities that tend to suffer as dementia progresses.

The researchers found that lower DTI-ALPS scores, which indicated damage to the glymphatic system, were associated with worse executive function. That link was verified independently in four separate participant groups—from the MarkVCID consortium; the University of California, Davis; the University of California, San Francisco; and the Framingham Heart Study.

Independently validating the DTI-ALPS biomarker in each of the four cohorts provides strong evidence for the glymphatic system’s role in cSVD and vascular dementia, Wang said.

The researchers also conducted a mediation analysis, which studies the process or mechanism connecting two or more variables.

In this case, they found that another biomarker – “free water” or excess water in the brain’s white matter – helped explain the link between glymphatic problems and cognitive decline.

In this potential pathway, “first waste clearance is impaired, which causes accumulation of free water in the brain’s white matter. That leads to tissue damage and eventually to cognitive impairment,” said the paper’s first author, Xiaodan Liu, assistant researcher in radiology at the University of California, San Francisco.

More research, including longitudinal work, is needed to confirm whether each step in that pathway is causal. But the team’s findings indicate that the DTI-ALPS score biomarker for vascular dementia is robust and ready to be used in clinical trials, Wang said.

Those studies could explore enhancing glymphatic function as a way to treat vascular dementia. Lifestyle changes such as exercising more and improving sleep quality are one way to do that, Wang said, and future studies may also reveal medications that can help.

The findings could also provide clues for how to treat Alzheimer’s disease, which has been linked to low DTI-ALPS scores in other studies.