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New Parkinson's Definition Proposed Based on Biomarkers

— Framework focuses on the biology of Lewy body diseases

MedpageToday
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 .

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 assay 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 .

"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 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 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 .

"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."

  • Judy George covers neurology and neuroscience news for ֱ, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more.

Disclosures

The position paper was supported by Cure Parkinson's, Lewy Body Dementia Association, the Michael J. Fox Foundation for Parkinson's Research, Parkinson Canada, Parkinson's U.K., and Shake It Up Foundation Australia. Research officers at the Michael J. Fox Foundation for Parkinson's Research were involved in designing NSD-ISS and writing the position paper.

Simuni reported consulting work for 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway, Critical Path for Parkinson's Consortium, Denali, the Michael J. Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Sunovion, Takeda, UCB, Vanqua Bio, and Voyager. Co-authors reported relationships with pharmaceutical companies and other organizations.

Jack declared no competing interests.

Lang reported relationships with AbbVie, AFFiRis, Alector, Amylyx, Aprinoia, Biogen, BioAdvance, Blue Rock, BioVie, Bristol Myers Squibb, CoA Therapeutics, Denali, Janssen, Jazz, Lilly, Novartis, Paladin, Pharma 2B, PsychoGenetics, Retrophin, Roche, Sun Pharma, UCB, and Sunovion; he also co-shares a patent for diagnostic assays that includes alpha-synuclein seeding testing. Co-authors reported relationships with industry and other groups.

Bloem and colleagues declared no competing interests.

Primary Source

Lancet Neurology

Simuni T, et al "A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research" Lancet Neurol 2024; DOI: 10.1016/S1474-4422(23)00405-2.

Secondary Source

Lancet Neurology

Jack CR "Criteria for a biological definition of neuronal α-synuclein disease -- a major conceptual step forward" Lancet Neurol 2024; DOI: 10.1016/S1474-4422(23)00456-8.

Additional Source

Lancet Neurology

Höglinger GU, et al "A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria" Lancet Neurol 2024; DOI: 10.1016/S1474-4422(23)00404-0.

Additional Source

Lancet Neurology

Darweesh SKL, et al “Has the time come to redefine Parkinson’s disease?” Lancet Neurol 2024; DOI: 10.1016/S1474-4422(23)00503-3.