Study finds little to no cortical lewy pathology in living Parkinson disease patients undergoing deep brain stimulation

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Researchers at the Icahn School of Medicine at Mount Sinai have found that patients with Parkinson disease undergoing deep brain stimulation show little to no Lewy pathology in the prefrontal cortex at the time of their DBS surgery, despite often having longstanding, clinically advanced disease.

Published in NPJ Parkinson’s Disease, the findings provide important new insight into the relationship between Parkinson disease clinical symptoms and neuropathological progression.

Lewy bodies are abnormal clumps/aggregates of the protein alpha-synuclein that build up inside nerve cells in the brain and are considered a pathological hallmark of Parkinson disease and are believed to accumulate throughout the brain as the disease progresses. The absence of this pathology, particularly among patients presumed to be in later stages of disease progression, was therefore unexpected. Previous studies—largely in postmortem tissue—have consistently found widespread Lewy pathology in patients with advanced Parkinson disease. However, little was previously known about how this hallmark of disease appears in individuals, especially at the time of deep brain
stimulation surgery.

As part of Mount Sinai’s Living Brain Project, researchers analyzed prefrontal cortex samples taken during deep brain stimulation procedures in patients with Parkinson disease and in patients undergoing deep brain
stimulation for other neurologic conditions. Researchers then compared the tissue samples to determine whether patients with Parkinson disease had a greater burden of cortical Lewy pathology than the comparison group.

Unexpectedly, nearly all biopsies from patients with Parkinson disease undergoing deep brain stimulation were negative for Lewy bodies, and the overwhelming majority also lacked Lewy neurites, the abnormal nerve-cell proteins associated with Lewy pathology. In contrast, matched postmortem samples from individuals with Parkinson disease showed, as expected, a higher burden of Lewy pathology than control samples.

“We were surprised to find that almost none of the patients living with Parkinson disease had cortical Lewy bodies, particularly because many had been living with the disease for years,” said Ariela Buxbaum Grice, a graduate student at the Icahn School of Medicine at Mount Sinai and lead author of the study. “Because this finding was so unexpected, we carefully evaluated the most likely technical explanations and found that none could explain the near-absence of Lewy bodies. That gives us confidence that this reflects a true biological characteristic within this patient population, as opposed to a laboratory artifact.”

Noam D. Beckmann, PhD, Assistant Professor of Artificial Intelligence and Human Health at the Icahn School of Medicine at Mount Sinai and senior author of the study, said the findings underscore the importance of studying molecular pathology in the context of clinical characteristics.

“This study demonstrates that clinical severity, disease progression, and neuropathological burden do not always advance together,” Dr. Beckmann said. “By studying living brain tissue alongside detailed clinical data, we can begin to identify biologically meaningful subtypes of Parkinson disease and better understand how the disease progresses, helping to guide more personalized treatment strategies in the future.”

The study also highlights the value of the Living Brain Project, a multiscale, data-driven research initiative that enables researchers to study living brain tissue collected during neurosurgical procedures. By integrating neuropathological analysis with detailed clinical information, investigators can better understand disease biology as it develops in living patients, rather than relying solely on tissue collected after death.

Brian Kopell, MD, Director of the Center for Neuromodulation, Co-Director of The Mount Sinai Hospital Movement Disorders Program, and Co-Lead of the Living Brain Project, emphasized the importance of studying living brain tissue in patients during advanced neurosurgical treatment.

“Deep brain stimulation offers a rare opportunity to study the biology of Parkinson disease directly in living patients,” Dr. Kopell said. “Many of the patients had clinically significant motor symptoms but showed very limited cortical Lewy pathology. That disconnect could change how we think about disease progression and which patients may benefit most from deep brain stimulation.”

Alexander Charney MD PhD, Director of The Charles Bronfman Institute for Personalized Medicine; Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai; Co-Lead of the Living Brain Project; and co-senior author on this manuscript, said the findings suggest that deep brain stimulation candidates may represent a biologically distinct subgroup of patients with Parkinson disease.

“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,” Dr. Charney said. “Instead, our findings suggest that many deep brain stimulationpatients may represent a motor-predominant subtype of Parkinson disease with relatively limited cortical involvement.”

The findings suggest that Parkinson disease may progress differently across biologically distinct patient groups, highlighting the complexity of the disease and the need for additional research. Rather than reflecting uniformly advanced neuropathology, patients selected for deep brain stimulation may represent a subgroup with slower or regionally distinct patterns of Lewy body accumulation.

Additional longitudinal and postmortem studies will be needed to determine whether deep brain stimulation patients experience slower cortical disease progression or represent a distinct biological subtype of Parkinson disease.

This work was supported by the National Institute on Aging and the Michael J. Fox Foundation.

Source: News Release
The Mount Sinai Hospital / Mount Sinai School of Medicine
July 1, 2026