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Parkinson鈥檚 disease patients suffering from postural instability and gait difficulty have significantly lower levels of a brain protein called alpha-synuclein (伪-syn) than normally found in cerebrospinal fluid. The discovery has implications for drug development and was made during a聽study at in the US,聽published online in the journal .

Alpha-synuclein鈥檚 function in the brain is currently unknown but of great interest to Parkinson鈥檚 researchers because it is a major constituent of Lewy bodies 鈥� the protein clumps that are the pathological hallmark of Parkinson鈥檚 disease.

The illness gradually destroys neurons that produce the chemical dopamine, which conveys nerve signals, in turn causing the tremors and difficulty moving that are a common symptom of Parkinson鈥檚 disease. The prevailing wisdom has been that these neurons may die from a toxic reaction to alpha-synuclein deposits.

However, Parkinson鈥檚 disease has been linked to some gene variants that affect how the immune system works, leading to an alternative theory that alpha-synuclein causes Parkinson鈥檚 disease by triggering the immune system to attack the brain.

In addition to its presence in the brain, alpha-synuclein can be found in peripheral tissues and body fluids. The Movement Disorders study, called , is the first to try to differentiate the biomarkers of neurodegeneration in Parkinson鈥檚 disease patients based on fluids collected from spinal fluid, blood and saliva.

The cross-sectional, observational study collected data and body fluid samples from 120 people with moderately advanced Parkinson鈥檚 disease and 100 control volunteers across eight academic sites in the US聽at two points over two weeks.

Dr Jennifer Goldman, a movement disorders neurologist at Rush University Medical Center and the study lead author, has profiled the Parkinson鈥檚-associated protein levels in these biofluids and their relationships to clinical features of the disease. The study found that levels of alpha-synuclein were lower in cerebrospinal fluid from Parkinson鈥檚 patients with certain motor function impairments 鈥� specifically in those who had more problems with balance and walking compared to those with more tremor.

In addition, levels of beta-amyloid, known for its association with Alzheimer鈥檚 disease, were lower in those with Parkinson鈥檚 and related to worse scores on a memory recall in Parkinson鈥檚 as measured on a test of thinking and memory given to study participants.

The study also showed that alpha-synuclein levels in plasma and saliva did not differ between people with Parkinson鈥檚 and control volunteers, and alpha-synuclein did not significantly correlate among other biological fluids.

Findings can help guide selection for clinical trials

鈥淭hese are important insights for the ongoing pursuit of accessible biomarker tests to diagnose and track the disease,鈥� said Goldman. 鈥淔or example, people with Parkinson鈥檚 and lower beta-amyloid may be more likely to develop memory problems and therefore would benefit more from a cognitive therapy,鈥� said Goldman. 鈥淓nrolling this population in trials can help us see a treatment effect more clearly than testing the therapy on people who will not have this symptom.鈥�

Next steps include validation of these findings in the Parkinson鈥檚 Progression Markers Initiative, a biomarkers study sponsored by the that is following more than 1500 people with Parkinson鈥檚 or risk factors and control volunteers over at least five years. Additionally, trials ongoing or launching in the near future could use alpha-synuclein or beta-amyloid levels as exploratory biomarkers in motor symptom or cognition drug trials, respectively.

Parkinson鈥檚 disease is the second most common age-related neurodegenerative disorder after Alzheimer鈥檚 disease, affecting an estimated 7 million to 10 million people worldwide.

Many of the affected neurons signal via the neurotransmitter dopamine; therefore, traditional therapy continues to rely on dopamine replacement therapy. This approach alleviates symptoms, but does not halt disease progression. Currently, there is no cure for Parkinson鈥檚 disease.

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