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Parkinson’s disease (PD) and dementia with Lewy bodies are currently defined by clinical features, which can be heterogeneous and do not capture the presymptomatic phase of neurodegeneration.
Recent advances have enabled the detection of misfolded and aggregated alpha-synuclein protein (synucleinopathy) — a key pathologic feature of these diseases — allowing for earlier and more accurate diagnosis. This has led two international research groups to propose a major shift from a clinical to a biological definition of the disease.
Both groups emphasized the detection of alpha-synuclein through recently developed seed amplification assays as a key diagnostic and staging tool, although they differ in their approaches and criteria.
NSD-ISS
NSD is defined by the presence during life of pathologic neuronal alpha-synuclein (S, the first biological anchor) in cerebrospinal fluid (CSF), regardless of the presence of any specific clinical syndrome. Individuals with pathologic neuronal alpha-synuclein aggregates are at a high risk for dopaminergic neuronal dysfunction (D, the second key biological anchor).
Dr. Simuni and colleagues also proposed the NSD integrated staging system (NSD-ISS) rooted in the S and D biological anchors coupled with the degree of functional impairment caused by clinical signs or symptoms.
Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B).
The presence of clinical manifestations marks the transition to stage 2 and beyond, with stage 2 characterized by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment.
“An advantage of the NSD-ISS will be to reduce heterogeneity in clinical trials by requiring biological consistency within the study cohort rather than identifying study participants on the basis of clinical criteria for Parkinson’s disease and dementia with Lewy bodies,” Dr. Simuni and colleagues pointed out in a position paper describing the NSD-ISS published online earlier this year in The Lancet Neurology.
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.”
For now, the NSD-ISS is intended for research use only and not in the clinic.
The SynNeurGe Research Diagnostic Criteria
Separately, a team led by Anthony Lang, MD, with the Krembil Brain Institute at Toronto Western Hospital, Toronto, Ontario, Canada, proposed the SynNeurGe biological classification of PD.
Described in a companion paper published online in The Lancet Neurology, their “S-N-G” classification emphasizes the important interactions between three biological factors that contribute to disease: The presence or absence of pathologic alpha-synuclein (S) in tissues or CSF, an evidence of underlying neurodegeneration (N) defined by neuroimaging procedures, and the documentation of pathogenic gene variants (G) that cause or strongly predispose to PD.
These three components link to a clinical component, defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features.
As with the NSD-ISS, the SynNeurGe model is intended for research purposes only and is not ready for immediate application in the clinic.
Both groups acknowledged the need for studies to test and validate the proposed classification systems.
Caveats, Cautionary Notes
Adopting a biological definition of PD would represent a shift as the field has prompted considerable discussion and healthy debate.
Commenting for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, said the principle behind the proposed classifications is where “the field needs to go.”
“Right now, people with Parkinson’s take too long to get a confirmed diagnosis of their disease, and despite best efforts, clinicians can get it wrong, not diagnosing people or maybe misdiagnosing people,” Dr. Beck said. “Moving to a biological basis, where we have better certainty, is going to be really important.”
Beck noted that the NSD-ISS “goes all in on alpha-synuclein,” which does play a big role in PD, but added, “I don’t know if I want to declare a winner after the first heat. There are other biomarkers that are coming to fruition but still need validation, and alpha-synuclein may be just one of many to help determine whether someone has Parkinson’s disease or not.”
Un Kang, MD, director of translational research at the Fresco Institute for Parkinson’s & Movement Disorders at NYU Langone Health, New York City, told this news organization that alpha-synuclein has “very high diagnostic accuracy” but cautioned that the adoption of a biological definition for PD would not usurp a clinical diagnosis.
“We need both,” Dr. Kang said. “But knowing the underlying pathology is important for earlier diagnosis and testing of potential therapies to treat the molecular pathology. If a patient doesn’t have abnormal synuclein, you may be treating the wrong disease.”
The coauthors of recent JAMA Neurology perspective said the biological definitions are “exciting, but there is “wisdom” in tapping the brakes when attempting to establish a biological definition and classification system for PD.
“Although these two proposals represent significant steps forward, a sprint toward the finish line may not be wise,” wrote Njideka U. Okubadejo, MD, with University of Lagos, Nigeria; Joseph Jankovic, MD, with Baylor College of Medicine, Houston; and Michael S. Okun, MD, with University of Florida Health, Gainesville, Florida.
“A process that embraces inclusivity and weaves in evolving technological advancements will be important. Who benefits if implementation of a biologically based staging system for PD is hurried?” they continued.
The proposals rely heavily on alpha-synuclein assays, they noted, which currently require subjective interpretation and lack extensive validation. They also worry that the need for expensive and, in some regions, unattainable biological fluids (CSF) or imaging studies (dopamine transporter scan) may limit global access to both PD trials and future therapeutics.
They also worry about retiring the name Parkinson’s disease.
“Beyond the historical importance of the term Parkinson disease, any classification that proposes abandoning the two words in either clinical or research descriptions could have unintended global repercussions,” Dr. Okubadejo, Dr. Jankovic, and Dr. Okun cautioned.
Dr. Beck told this news organization he’s spoken to clinicians at meetings about this and “no one really likes the idea” of retiring the term Parkinson’s disease.
Frederick Ketchum, MD, and Nathaniel Chin, MD, with University of Wisconsin–Madison, worry about the “lived” experience of the asymptomatic patient after receiving a biological diagnosis.
“Biological diagnosis might enable effective prognostication and treatment in the future but will substantially change the experience of illness for patients now as new frameworks are slowly adopted and knowledge is gained,” they said in a correspondence in The Lancet Neurology.
“Understanding and addressing this lived experience remains a core task for health professionals and must be made central as we begin an era in which neurological diseases are redefined on a biological basis,” Dr. Ketchum and Dr. Chin advised.
A complete list of agencies that supported this work and author disclosures are available with the original articles. Dr. Beck and Dr. Kang had no relevant disclosures.
A version of this article first appeared on Medscape.com.
Parkinson’s disease (PD) and dementia with Lewy bodies are currently defined by clinical features, which can be heterogeneous and do not capture the presymptomatic phase of neurodegeneration.
Recent advances have enabled the detection of misfolded and aggregated alpha-synuclein protein (synucleinopathy) — a key pathologic feature of these diseases — allowing for earlier and more accurate diagnosis. This has led two international research groups to propose a major shift from a clinical to a biological definition of the disease.
Both groups emphasized the detection of alpha-synuclein through recently developed seed amplification assays as a key diagnostic and staging tool, although they differ in their approaches and criteria.
NSD-ISS
NSD is defined by the presence during life of pathologic neuronal alpha-synuclein (S, the first biological anchor) in cerebrospinal fluid (CSF), regardless of the presence of any specific clinical syndrome. Individuals with pathologic neuronal alpha-synuclein aggregates are at a high risk for dopaminergic neuronal dysfunction (D, the second key biological anchor).
Dr. Simuni and colleagues also proposed the NSD integrated staging system (NSD-ISS) rooted in the S and D biological anchors coupled with the degree of functional impairment caused by clinical signs or symptoms.
Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B).
The presence of clinical manifestations marks the transition to stage 2 and beyond, with stage 2 characterized by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment.
“An advantage of the NSD-ISS will be to reduce heterogeneity in clinical trials by requiring biological consistency within the study cohort rather than identifying study participants on the basis of clinical criteria for Parkinson’s disease and dementia with Lewy bodies,” Dr. Simuni and colleagues pointed out in a position paper describing the NSD-ISS published online earlier this year in The Lancet Neurology.
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.”
For now, the NSD-ISS is intended for research use only and not in the clinic.
The SynNeurGe Research Diagnostic Criteria
Separately, a team led by Anthony Lang, MD, with the Krembil Brain Institute at Toronto Western Hospital, Toronto, Ontario, Canada, proposed the SynNeurGe biological classification of PD.
Described in a companion paper published online in The Lancet Neurology, their “S-N-G” classification emphasizes the important interactions between three biological factors that contribute to disease: The presence or absence of pathologic alpha-synuclein (S) in tissues or CSF, an evidence of underlying neurodegeneration (N) defined by neuroimaging procedures, and the documentation of pathogenic gene variants (G) that cause or strongly predispose to PD.
These three components link to a clinical component, defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features.
As with the NSD-ISS, the SynNeurGe model is intended for research purposes only and is not ready for immediate application in the clinic.
Both groups acknowledged the need for studies to test and validate the proposed classification systems.
Caveats, Cautionary Notes
Adopting a biological definition of PD would represent a shift as the field has prompted considerable discussion and healthy debate.
Commenting for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, said the principle behind the proposed classifications is where “the field needs to go.”
“Right now, people with Parkinson’s take too long to get a confirmed diagnosis of their disease, and despite best efforts, clinicians can get it wrong, not diagnosing people or maybe misdiagnosing people,” Dr. Beck said. “Moving to a biological basis, where we have better certainty, is going to be really important.”
Beck noted that the NSD-ISS “goes all in on alpha-synuclein,” which does play a big role in PD, but added, “I don’t know if I want to declare a winner after the first heat. There are other biomarkers that are coming to fruition but still need validation, and alpha-synuclein may be just one of many to help determine whether someone has Parkinson’s disease or not.”
Un Kang, MD, director of translational research at the Fresco Institute for Parkinson’s & Movement Disorders at NYU Langone Health, New York City, told this news organization that alpha-synuclein has “very high diagnostic accuracy” but cautioned that the adoption of a biological definition for PD would not usurp a clinical diagnosis.
“We need both,” Dr. Kang said. “But knowing the underlying pathology is important for earlier diagnosis and testing of potential therapies to treat the molecular pathology. If a patient doesn’t have abnormal synuclein, you may be treating the wrong disease.”
The coauthors of recent JAMA Neurology perspective said the biological definitions are “exciting, but there is “wisdom” in tapping the brakes when attempting to establish a biological definition and classification system for PD.
“Although these two proposals represent significant steps forward, a sprint toward the finish line may not be wise,” wrote Njideka U. Okubadejo, MD, with University of Lagos, Nigeria; Joseph Jankovic, MD, with Baylor College of Medicine, Houston; and Michael S. Okun, MD, with University of Florida Health, Gainesville, Florida.
“A process that embraces inclusivity and weaves in evolving technological advancements will be important. Who benefits if implementation of a biologically based staging system for PD is hurried?” they continued.
The proposals rely heavily on alpha-synuclein assays, they noted, which currently require subjective interpretation and lack extensive validation. They also worry that the need for expensive and, in some regions, unattainable biological fluids (CSF) or imaging studies (dopamine transporter scan) may limit global access to both PD trials and future therapeutics.
They also worry about retiring the name Parkinson’s disease.
“Beyond the historical importance of the term Parkinson disease, any classification that proposes abandoning the two words in either clinical or research descriptions could have unintended global repercussions,” Dr. Okubadejo, Dr. Jankovic, and Dr. Okun cautioned.
Dr. Beck told this news organization he’s spoken to clinicians at meetings about this and “no one really likes the idea” of retiring the term Parkinson’s disease.
Frederick Ketchum, MD, and Nathaniel Chin, MD, with University of Wisconsin–Madison, worry about the “lived” experience of the asymptomatic patient after receiving a biological diagnosis.
“Biological diagnosis might enable effective prognostication and treatment in the future but will substantially change the experience of illness for patients now as new frameworks are slowly adopted and knowledge is gained,” they said in a correspondence in The Lancet Neurology.
“Understanding and addressing this lived experience remains a core task for health professionals and must be made central as we begin an era in which neurological diseases are redefined on a biological basis,” Dr. Ketchum and Dr. Chin advised.
A complete list of agencies that supported this work and author disclosures are available with the original articles. Dr. Beck and Dr. Kang had no relevant disclosures.
A version of this article first appeared on Medscape.com.
Parkinson’s disease (PD) and dementia with Lewy bodies are currently defined by clinical features, which can be heterogeneous and do not capture the presymptomatic phase of neurodegeneration.
Recent advances have enabled the detection of misfolded and aggregated alpha-synuclein protein (synucleinopathy) — a key pathologic feature of these diseases — allowing for earlier and more accurate diagnosis. This has led two international research groups to propose a major shift from a clinical to a biological definition of the disease.
Both groups emphasized the detection of alpha-synuclein through recently developed seed amplification assays as a key diagnostic and staging tool, although they differ in their approaches and criteria.
NSD-ISS
NSD is defined by the presence during life of pathologic neuronal alpha-synuclein (S, the first biological anchor) in cerebrospinal fluid (CSF), regardless of the presence of any specific clinical syndrome. Individuals with pathologic neuronal alpha-synuclein aggregates are at a high risk for dopaminergic neuronal dysfunction (D, the second key biological anchor).
Dr. Simuni and colleagues also proposed the NSD integrated staging system (NSD-ISS) rooted in the S and D biological anchors coupled with the degree of functional impairment caused by clinical signs or symptoms.
Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B).
The presence of clinical manifestations marks the transition to stage 2 and beyond, with stage 2 characterized by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment.
“An advantage of the NSD-ISS will be to reduce heterogeneity in clinical trials by requiring biological consistency within the study cohort rather than identifying study participants on the basis of clinical criteria for Parkinson’s disease and dementia with Lewy bodies,” Dr. Simuni and colleagues pointed out in a position paper describing the NSD-ISS published online earlier this year in The Lancet Neurology.
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.”
For now, the NSD-ISS is intended for research use only and not in the clinic.
The SynNeurGe Research Diagnostic Criteria
Separately, a team led by Anthony Lang, MD, with the Krembil Brain Institute at Toronto Western Hospital, Toronto, Ontario, Canada, proposed the SynNeurGe biological classification of PD.
Described in a companion paper published online in The Lancet Neurology, their “S-N-G” classification emphasizes the important interactions between three biological factors that contribute to disease: The presence or absence of pathologic alpha-synuclein (S) in tissues or CSF, an evidence of underlying neurodegeneration (N) defined by neuroimaging procedures, and the documentation of pathogenic gene variants (G) that cause or strongly predispose to PD.
These three components link to a clinical component, defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features.
As with the NSD-ISS, the SynNeurGe model is intended for research purposes only and is not ready for immediate application in the clinic.
Both groups acknowledged the need for studies to test and validate the proposed classification systems.
Caveats, Cautionary Notes
Adopting a biological definition of PD would represent a shift as the field has prompted considerable discussion and healthy debate.
Commenting for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, said the principle behind the proposed classifications is where “the field needs to go.”
“Right now, people with Parkinson’s take too long to get a confirmed diagnosis of their disease, and despite best efforts, clinicians can get it wrong, not diagnosing people or maybe misdiagnosing people,” Dr. Beck said. “Moving to a biological basis, where we have better certainty, is going to be really important.”
Beck noted that the NSD-ISS “goes all in on alpha-synuclein,” which does play a big role in PD, but added, “I don’t know if I want to declare a winner after the first heat. There are other biomarkers that are coming to fruition but still need validation, and alpha-synuclein may be just one of many to help determine whether someone has Parkinson’s disease or not.”
Un Kang, MD, director of translational research at the Fresco Institute for Parkinson’s & Movement Disorders at NYU Langone Health, New York City, told this news organization that alpha-synuclein has “very high diagnostic accuracy” but cautioned that the adoption of a biological definition for PD would not usurp a clinical diagnosis.
“We need both,” Dr. Kang said. “But knowing the underlying pathology is important for earlier diagnosis and testing of potential therapies to treat the molecular pathology. If a patient doesn’t have abnormal synuclein, you may be treating the wrong disease.”
The coauthors of recent JAMA Neurology perspective said the biological definitions are “exciting, but there is “wisdom” in tapping the brakes when attempting to establish a biological definition and classification system for PD.
“Although these two proposals represent significant steps forward, a sprint toward the finish line may not be wise,” wrote Njideka U. Okubadejo, MD, with University of Lagos, Nigeria; Joseph Jankovic, MD, with Baylor College of Medicine, Houston; and Michael S. Okun, MD, with University of Florida Health, Gainesville, Florida.
“A process that embraces inclusivity and weaves in evolving technological advancements will be important. Who benefits if implementation of a biologically based staging system for PD is hurried?” they continued.
The proposals rely heavily on alpha-synuclein assays, they noted, which currently require subjective interpretation and lack extensive validation. They also worry that the need for expensive and, in some regions, unattainable biological fluids (CSF) or imaging studies (dopamine transporter scan) may limit global access to both PD trials and future therapeutics.
They also worry about retiring the name Parkinson’s disease.
“Beyond the historical importance of the term Parkinson disease, any classification that proposes abandoning the two words in either clinical or research descriptions could have unintended global repercussions,” Dr. Okubadejo, Dr. Jankovic, and Dr. Okun cautioned.
Dr. Beck told this news organization he’s spoken to clinicians at meetings about this and “no one really likes the idea” of retiring the term Parkinson’s disease.
Frederick Ketchum, MD, and Nathaniel Chin, MD, with University of Wisconsin–Madison, worry about the “lived” experience of the asymptomatic patient after receiving a biological diagnosis.
“Biological diagnosis might enable effective prognostication and treatment in the future but will substantially change the experience of illness for patients now as new frameworks are slowly adopted and knowledge is gained,” they said in a correspondence in The Lancet Neurology.
“Understanding and addressing this lived experience remains a core task for health professionals and must be made central as we begin an era in which neurological diseases are redefined on a biological basis,” Dr. Ketchum and Dr. Chin advised.
A complete list of agencies that supported this work and author disclosures are available with the original articles. Dr. Beck and Dr. Kang had no relevant disclosures.
A version of this article first appeared on Medscape.com.