‘Unexpected’ study results find no toxic protein clumps in Parkinson’s patients

Many people with advanced Parkinson’s disease may actually not have widespread accumulation of toxic protein clumps known as Lewy bodies, which have long been thought to accompany the neurological condition in its later stages, according to a new study from U.S. researchers.

The scientists found that most patients undergoing surgical treatment lacked Lewy bodies – alpha-synuclein protein clumps considered a Parkinson’s hallmark – despite having lived with the disease for years. Specifically, these clumps, or aggregates, were not seen among nearly 98% of patients whose brain tissue was collected during deep brain stimulation (DBS), a treatment that aims to ease the disease’s symptoms.

Lewy bodies, however, were present in matched samples of Parkinson’s patients obtained after death, per the study.

“By studying living brain tissue alongside detailed clinical data, we can begin to identify biologically meaningful subtypes of Parkinson’s disease and better understand how the disease progresses, helping to guide more personalized treatment strategies in the future,” Noam D. Beckmann, PhD, a professor at the Icahn School of Medicine at Mount Sinai and senior author of the study, said in a university news story detailing the research findings.

“This study demonstrates that clinical severity, disease progression, and neuropathological burden do not always advance together,” Beckmann added.

The results were described in a brief communication titled “Lewy pathology largely absent in prefrontal cortices of Parkinson’s disease patients undergoing deep brain stimulation,” published in the journal npj parkinson’s disease. The study was supported by the National Institute on Aging and The Michael J. Fox Foundation for Parkinson’s Research.

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Parkinson’s is caused by a gradual loss of dopaminergic neurons, the nerve cells that produce dopamine, a chemical involved in motor control. The ensuing reduction of dopamine signaling leads to the disease’s motor symptoms.

Toxic clumps of alpha-synuclein protein are a hallmark of Parkinson’s

A hallmark of Parkinson’s is the accumulation of abnormal clumps of alpha-synuclein protein, known as Lewy bodies, which are toxic to nerve cells and may spread throughout the brain. These protein aggregates are believed to contribute to disease progression.

Previous studies have found widespread Lewy bodies, including in the cortex, the outermost layer of the brain, in  people with advanced Parkinson’s.

DBS is a surgical procedure that involves implanting electrodes into specific brain areas to modulate neural activity. It is most commonly used to treat people with advanced Parkinson’s symptoms, for whom motor symptoms are not well controlled with medication, or who experience side effects of medications.

In this study, the researchers analyzed whether Parkinson’s patients undergoing DBS had more advanced disease at the time of the surgery by evaluating the presence of Lewy bodies in the cortex.

The team specifically analyzed biopsies from the prefrontal cortex, a part of the cortex that regulates complex cognitive functions, obtained during DBS surgery in people with Parkinson’s. These samples were then compared with those obtained from people who underwent the procedure for other neurological conditions. The researchers noted that the samples were obtained as part of the Living Brain Project at Mount Sinai, from 167 participants, of whom 77.2% had Parkinson’s. Overall, the samples came from slightly more men (60.5%) than women. The average age of these patients was 62.1 years.

Nearly all samples from Parkinson’s patients (97.6%) did not show Lewy bodies in the prefrontal cortex, and 88% lacked both Lewy bodies and Lewy neurites – alpha-synuclein clumps in nerve fibers, which are precursors to Lewy bodies. This was similar to the findings for patients who received DBS for other conditions.

“These findings challenge the assumption that patients undergoing deep brain stimulation necessarily have widespread cortical Lewy pathology based solely on disease duration or symptom severity,” said Alexander Charney, MD, PhD, professor at Mount Sinai and colead of the Living Brain Project. “Instead, our findings suggest that many DBS patients may represent a motor-predominant subtype of Parkinson’s disease with relatively limited cortical involvement.”

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No clear explanation for these findings

In comparison with these data, the researchers noted that in postmortem tissue from people with Parkinson’s, more than 70% of samples showed the presence of Lewy bodies. That compared with fewer than 10% of samples with no signs of these toxic protein clumps. Lewy neurites were also observed more frequently in Parkinson’s patients, the data showed.

These results persisted after adjusting for patients’ age, in both living patients and postmortem samples, the researchers noted.

The findings suggest that people with Parkinson’s undergoing DBS “may be less neuropathologically advanced in progression than previously thought,” the researchers wrote.

Ariela Buxbaum Grice, a graduate student and lead author of the study, called this finding “so unexpected.”

“We were surprised to find that almost none of the patients living with Parkinson’s disease had cortical Lewy bodies, particularly because many had been living with the disease for years,” Grice said, adding that the team “carefully evaluated the most likely technical explanations and found that none could explain the near absence of Lewy bodies.”

According to Grice, “that gives us confidence that this reflects a true biological characteristic within this patient population, as opposed to a laboratory artifact.”

Overall, per the team, the results suggest that patients undergoing DBS for motor fluctuations or other complications of medical therapy do not exhibit Lewy bodies in cortical brain regions at the time of the surgery.

“This may be explained by the DBS selection process, which may enrich for patients belonging to a [Parkinson’s disease] subgroup defined by motor-predominant [Parkinson’s] and minimal cognitive involvement,” the researchers wrote.