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Neurology

Parkinson's Disease
New Parkinson's Definition Proposed Based on Biomarkers
— Framework focuses on the biology of Lewy body diseases
by Judy George, Deputy Managing Editor, MedPage Today January 26, 2024


A computer rendering of neurons containing Lewy bodies


Lewy body diseases -- Parkinson's disease and dementia with Lewy bodies -- should be defined as neuronal alpha-synuclein disease, not as clinical syndromes, a new position paper proposed.

"Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with alpha-synuclein pathology as the gold standard to establish the definitive diagnosis," wrote Tanya Simuni, MD, of Northwestern University in Chicago, and colleagues in Lancet Neurologyopens in a new tab or window.

Until recently, alpha-synuclein -- the neuropathological hallmark of Parkinson's disease and dementia with Lewy bodies -- could be reliably measured only postmortem. A seed amplification assayopens in a new tab or window first developed in 2016 now shows high sensitivity and specificity in distinguishing Parkinson's from healthy controls in cerebrospinal fluid (CSF).

"We propose that, given our ability to detect neuronal alpha-synuclein using this seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies on the basis of biology rather than clinical features," Simuni and colleagues wrote. "We recognize that a biological definition for Parkinson's disease and dementia with Lewy bodies is a major shift, but we believe that reflects the availability of tools to establish the gold standard diagnosis during life."

The proposed definition establishes a staging system, known as the neuronal alpha-synuclein disease integrated staging system (NSD-ISS), rooted in biological anchors and the level of functional impairment caused by clinical signs or symptoms.

The staging system starts with an abnormality in an alpha-synuclein biomarker, followed by dopaminergic neuronal dysfunction assessed by imaging, and then by the downstream appearance and progression of clinical signs or symptoms and functional impairment. Genetic risk factors are incorporated.

The conceptual steps behind this framework parallel the efforts that led to new ways of looking at Alzheimer's disease, observed Clifford Jack Jr., MD, of the Mayo Clinic in Rochester, Minnesota, in an accompanying commentaryopens in a new tab or window.

"Central tenets of the criteria proposed by Simuni and colleagues are: (1) the disease is defined biologically on the basis of objective in vivo biomarkers; (2) the disease can be diagnosed in the absence of clinical manifestations; and (3) clinical manifestations in the absence of biomarkers are not sufficient to diagnose the disease" -- principles that also underlie the 2018 National Institute on Aging-Alzheimer's Associationopens in a new tab or window research framework, Jack noted.

Both frameworks recognize that the disease process begins before symptom onset and can be diagnosed in the preclinical period, Jack pointed out. "By separating the syndrome from the biology, the neuronal alpha-synuclein disease criteria also recognize that syndromic presentation is not always specific for neuronal alpha-synuclein pathology," he wrote.

A biological definition and the NSD-ISS research framework are essential to enable interventional trials at early disease stages, Simuni and colleagues noted. "The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated," they wrote.

"Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate," they emphasized.

In a personal viewopens in a new tab or window paper also published in Lancet Neurology, Anthony Lang, MD, of Toronto Western Hospital in Canada, and colleagues proposed another way of classifying Parkinson's disease. Their biological framework, known as SynNeurGe, includes the presence or absence of pathological alpha-synuclein (S) in tissues or CSF, evidence of underlying neurodegeneration (N) defined by neuroimaging, and documentation of pathogenic gene variants (G) that cause or strongly predispose people to Parkinson's disease.

Both NSD-ISS and SynNeurGe were developed for research use, but there's a risk these criteria will be applied prematurely in clinical settings, noted Bastiaan Bloem, MD, PhD, of Radboud University Medical Centre in Nijmegen, the Netherlands, and co-authors in another commentaryopens in a new tab or window.

"Although still tentative and in need of robust validation, these frameworks will pave the way for new research into disease modification in Parkinson's disease and possibly other alpha-synucleinopathies," Bloem and colleagues wrote.

"The frameworks also underscore substantial knowledge gaps that deserve further study," they added. "As we move towards a validated biological definition of Parkinson's disease, it would benefit the field if both frameworks, once updated, are unified into integrated criteria."

https://www.medpagetoday.com/neurology/parkinsonsdisease/108446?xid=nl_mpt_Neurology_update_2024-01-26&eun=g1294347d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Automated%20Specialty%20Update%20Neurology%20BiWeekly%20FRIDAY%202024-01-26&utm_term=NL_Spec_Neurology_Update_Active