Researchers propose new definition of Parkinson’s disease based on biomarkers

Lewy body diseases (Parkinson’s disease and Lewy body dementia) should be defined as alpha-synuclein diseases of neurons rather than as clinical syndromes, a new position paper proposes.

“Parkinson’s disease and Lewy body dementia are now defined by their clinical features, and alpha-synuclein pathology is the gold standard for establishing a definitive diagnosis,” said Tanya Simni of Northwestern University in Chicago. Written by medical doctors. lancet neurology.

Until recently, alpha-synuclein, a neuropathological hallmark of Parkinson’s disease and Lewy body dementia, could only be reliably measured post-mortem. Seed amplification assays, first developed in 2016, have shown high sensitivity and specificity in differentiating Parkinson’s disease from healthy controls in cerebrospinal fluid (CSF).

“Given that this seed amplification assay can be used to detect alpha-synuclein in neurons, we believe it is time to redefine Parkinson’s disease and Lewy body dementia based on biology rather than clinical features. “We propose,” write Simuni et al. “While we recognize that the biological definitions of Parkinson’s disease and Lewy body dementia are undergoing significant change, we believe this reflects the availability of tools to establish gold standard diagnoses across the lifespan. I am.”

The proposed definition establishes a staging system known as the Neural Alpha-Synuclein Disease Integrated Staging System (NSD-ISS) that is rooted in the level of functional impairment caused by biological anchors and clinical signs or symptoms. .

The staging system begins with abnormalities in alpha-synuclein biomarkers, then dopaminergic neuron dysfunction is assessed by imaging, and then by the appearance and progression of downstream clinical signs or symptoms and dysfunction. . Incorporates genetic risk factors.

Clifford Jack Jr., MD, of the Mayo Clinic in Rochester, Minnesota, said the conceptual steps behind this framework parallel efforts that have led to a new way of looking at Alzheimer’s disease. Attached commentary.

“The core principles of the criteria proposed by Simuni et al. are that (1) disease is biologically defined based on objective in vivo biomarkers, and (2) disease is diagnostic even in the absence of clinical symptoms. and (3) clinical. Symptoms in the absence of biomarkers are not sufficient to diagnose disease” — a principle that also underlies the 2018 policy. National Institute on Aging-Alzheimer’s Association Jack pointed out the research framework.

Both frameworks recognize that the disease process begins before the onset of symptoms and can be diagnosed during the preclinical period, Jacques noted. “By separating the syndrome from the biology, the criteria for neuronal alpha-synuclein disease also recognize that syndrome manifestations are not necessarily specific to neuronal alpha-synuclein pathology.” he wrote.

Simuni et al. pointed out that a biological definition and NSD-ISS research framework are essential to enable intervention trials at early stages of the disease. “The NSD-ISS will evolve to incorporate data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated,” the researchers wrote. .

“At present, the NSD-ISS is intended for research use only, and its application in clinical practice is premature and inappropriate,” they stressed.

in personal opinion A paper was also published in lancet neurologyDr. Anthony Lang of Toronto Western Hospital in Canada and his colleagues have proposed a different way to classify Parkinson’s disease. Its biological framework, known as SynNeurGe, includes the presence or absence of pathological alpha-synuclein (S) in tissue or CSF, evidence of underlying neurodegeneration (N) as defined by neuroimaging, and , or a record of a strong pathogenic gene variant (G). It makes people more susceptible to Parkinson’s disease.

Although both NSD-ISS and SynNeurGe were developed for research purposes, there is a risk that these standards may be applied prematurely in clinical practice, says Bastian Bloom, MD, of Radboud University Medical Center in Nijmegen, the Netherlands. and his co-authors point out.another Explanation.

“Although still preliminary and in need of robust validation, these frameworks could pave the way for new studies of disease modification in Parkinson’s disease and perhaps other alpha-synucleinopathies,” Bloom and colleagues wrote. There is.

“These frameworks also highlight substantial knowledge gaps that merit further research,” they added. “As we move toward validating the biological definition of Parkinson’s disease, the field will benefit if both frameworks are updated and integrated into a unified standard.”