Vascular defects appear to underlie the development of Parkinson’s disease

Parkinson's disease

Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy body in Substantia nigra in Parkinson’s disease. Credit: Wikipedia

In an unexpected discovery, researchers from Georgetown University Medical Center have identified what appears to be a significant vascular defect in patients with moderately severe Parkinson’s disease. The finding could help explain an earlier result of the same study in which the drug nilotinib was able to stop motor and non-motor (cognition and quality of life) decline in the long term.

The researchers say that their findings, detailed in a study published November 12, 2021, in Neurological genetics, suggests that the blood vessel walls called the blood-brain barrier, which normally act as a crucial filter to protect the brain from toxins as well as allow the passage of nutrients to nourish it, do not work properly in some Parkinson’s patients: It bans toxins from leaving the brain and inhibits nutrients such as glucose in penetrating. Perhaps even more damaging, the dysfunctional barrier allows inflammatory cells and molecules from the body to enter and damage the brain.

The research, the first longitudinal study to use such advanced genomics, now gives investigators a new target for therapeutic intervention in Parkinson’s disease, says the study’s senior author, Charbel Moussa, MBBS, Ph.D., director of the Medical Center’s Translational Neurotherapeutics Program.

The new discovery comes from the second part of a Phase II clinical trial that included the next generation of whole genome sequencing of cerebrospinal fluid from 75 Parkinson’s patients, before and after treatment with a recycled leukemia drug, nilotinib or a placebo.

This study lasted 27 months; the initial trial was double-blind and patients were randomized to either placebo or 150 mg or 300 mg nilotinib for 12 months. Patients had severe Parkinson’s disease; all treated with optimal care, and many (30%) had also used the most sophisticated treatments possible, such as deep brain stimulation. The second part of the study used an adaptive design, and all participants had a 3-month washout period before re-randomization to either 150 mg or 300 mg for an additional 12 months. After 27 months, nilotinib was shown to be safe and patients receiving nilotinib showed a dose-dependent increase in dopamine, the chemical lost due to neuronal destruction.

“It seemed that nilotinib stopped motor and non-motor decline in patients taking the 300 mg higher dose,” says Moussa. The clinical results of this study were published in Movement disorders in March 2021.

The current part of the study, just published, examined the cerebrospinal fluid in patients via epigenomics, which is a systematic analysis of the global state of gene expression, in the context of continuing clinical findings. The new analysis helps explain the clinical findings.

Nilotinib inactivated a protein (DDR1) that destroyed the ability of the blood-brain barrier to function properly. When DDR1 was inhibited, normal transport of molecules in and out of the brain filter resumed, and the inflammation dropped to the point that dopamine, the neurotransmitter depleted by the disease process, was produced again.

Moussa and his team have been working for a long time on the effects that nilotinib (Tasigna) can have on neurodegeneration, including Alzheimer’s and Parkinson’s diseases. The drug was approved in 2007 for chronic myelogenous leukemia (CML), but Moussa reasoned that its mechanism of action can help the brain destroy toxins that develop in the brain of patients with neurodegenerative disorders.

“Nilotinib not only overturns the brain’s waste disposal system to eliminate bad toxic proteins, but it also appears to repair the blood-brain barrier to allow this toxic waste to leave the brain and allow nutrients in,” explains Moussa. “Parkinson’s disease is generally thought to involve mitochondrial or energy deficits that may be caused by environmental toxins or by toxic protein accumulation; it has never been identified as a vascular disease.”

“As far as we know, this is the first study to show that the body’s blood-brain barrier potentially offers a target for the treatment of Parkinson’s disease,” says Moussa. “A lot of work needs to be done, but just knowing that a patient’s cerebral vascular system plays a significant role in the development of the disease is a very promising discovery.”

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More information:
CSF microRNAs reveal attenuation of angiogenesis and autophagy in Parkinson’s disease, Neurological genetics (2021). DOI: 10.1212 / NXG.00000000000000633

Provided by Georgetown University Medical Center

Citation: Vascular defects appear to underlie the development of Parkinson’s disease (2021, November 12) Retrieved November 13, 2021 from parkinson-disease.html

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