09 Feb 2024

Just as fluid biomarkers for amyloidosis and tau have revolutionized clinical studies of Alzheimer’s disease, α-synuclein markers are poised to do the same for Parkinson’s. With the advent of sensitive assays that reflect α-synuclein pathology brewing in the brain, the time is ripe to center our view of PD and related disorders around their underlying biology, argue a Personal View and a separate Position Paper in the February issue of Lancet Neurology. Each proposes a system to classify and, in one case, also stage Parkinson’s and related diseases based on their pathology. Both hope that shifting toward a biology-based framework will help scientists zero in on specific mechanisms underlying disease, better-characterize people with parkinsonism, and streamline therapeutic development. Curiously, though, the two proposals are not a unison, consensus effort by the same authors, but parallel efforts.

Scientists led by Anthony Lang, University of Toronto, lay out the so-called SynNeurGe classification system in the Personal View paper. Pronounced “synergy,” the framework categorizes disease based on the presence or absence of α-synuclein (Syn) pathology as gauged by biomarkers, neurodegeneration (Neur) based on neuroimaging, and PD-associated genetic variants (Ge). This classification system does not limit itself to Syn+ cases. Rather it casts a wide net by including those people who lose dopaminergic neurons and have clinical manifestations of PD but who have no α-synuclein pathology on autopsy or based on biomarkers. The authors contend that α-synuclein is not necessary for the development of clinical Parkinson’s disease. They therefore classify different forms of PD, rather than define the disease based on α-synuclein pathology.

In the Position Paper, a working group spearheaded by the Michael J. Fox Foundation proposes starting from scratch. It ditched clinical definitions of PD and DLB altogether. The authors include academic and industry scientists, FDA regulators, and patient advocates. They suggest using fluid biomarkers of α-synuclein to define what they call neuronal α-synuclein disease (NSD). It would include most people who suffer from what is now known as PD or DLB. Led by Kenneth Marek at the Institute for Neurodegenerative Disorders in New Haven, Connecticut, these authors developed a six-stage system in which α-synuclein pathology and dopaminergic loss emerge in Stage 1, clinical symptoms in Stage 2, and functional impairment in Stages 3-6.

While the two schemes take different stances on the primacy of α-synuclein pathology in PD, both incorporate biomarkers of pathological α-synuclein to characterize the underlying biology. The most sensitive biomarkers tested so far pick up minuscule concentrations of α-synuclein aggregates by amplifying them. These so-called seed amplification assays (SAAs) are being tested in different peripheral tissues, with CSF furthest developed (Apr 2023 conference news; Aug 2023 conference news).

Both frameworks allow for a diagnosis based on underlying pathology, even in asymptomatic individuals, according to Sirwan Darweesh and Bastiaan Bloem of Radboud University Medical Center, the Netherlands, and Cristina Sampaio of the Cure Huntington’s Disease Initiative (CHDI) in Princeton, New Jersey. In one of three Lancet Neurology editorials, they write, “This new conceptualization is a radical shift in the traditional understanding of Parkinson’s disease and opens research opportunities, in particular for designing trials to delay or prevent parkinsonism.”

To David Standaert of the University of Alabama in Birmingham, who was not involved in either classification, both approaches have merit. “One is homing in on a single, α-synuclein-based mechanism of disease, and putting α-synuclein-negative cases to the side for now,” he said. “The other takes a big-tent approach, which provides a way to classify different biological drivers of what we recognize as clinical PD.” 

Classify, but Don’t Define
SynNeurGe was borne out of a collaboration between Lang and first author Günter Höglinger of the German Center for Neurodegenerative Diseases in Munich. Both brought experts from Canada, Germany, Austria, and the U.S. to the task. Together, they designed SynNeurGe to encompass the pathological heterogeneity underlying PD and its related clinical syndromes.

SynNeurGe starts by classifying based on the presence or absence of α-synuclein pathology. The authors propose using seed amplification assays of CSF or skin samples, although they leave open the possibility of using other assays as they are developed. While synucleinopathy underlies the majority of PD cases, a minority are found to have scant Lewy bodies upon autopsy, despite displaying the classic dopaminergic loss and clinical symptoms (Schneider and Alcalay, 2017; Madsen et al., 2021). Some people test negative on α-synuclein SAAs as well (Brockmann et al., 2021; Siderowf et al., 2023). These Lewy-less, biomarker-negative PD cases include most homozygous carriers of pathogenic mutations in the Parkin (PRKN) gene, and a proportion of LRRK2 mutation carriers.

The authors propose categorizing these cases as α-synuclein-negative (S-) forms of PD. “We believe that defining PD exclusively as a synucleinopathy misrepresents our understanding of its pathogenesis, and the formal acknowledgment of S– cases will advance our understanding of the disease,” the authors wrote.

Next, SynNeurGe classifies cases by the presence or absence of neurodegeneration. This is most commonly done via neuroimaging methods such as a dopamine transporter (DaT) scan, which reveals loss of dopaminergic neurons. Other measures can also be used to infer PD-related neurodegeneration within the SynNeurGe system; these include FDG-PET and MIBG scans that pick up denervation of the heart (Dec 2015 conference news).

The third classification step considers genetic variants. Here, a person's case goes into one of three buckets based on the level of pathogenicity conferred by genetic variants they carry. Those with a fully penetrant variant, such as having four copies of SNCA due to duplications, a SNCA missense variant, or variants in PRKN, PINK1, or PRK7 genes, are designated as “G_F+.” People with variants that predispose them to PD, such as having three copies of SNCA due to duplication, or variants in LRRK2, VPS35, CHCHD2, or GBA1, are classified as “G_p+. Finally, people who carry no known PD variants, or whose variants are only weakly associated with PD, are considered “G-.”

In addition to these three layers of biological classification, the authors also propose a broad clinical category. Called the “C+” state, this is when a person exhibits symptoms associated with PD. These encompass motor and non-motor symptoms that arise from the prodromal phase to the final stages of the disease. Notably, Höglinger et al.'s system does not have a staging scheme, nor does it distinguish the order in which symptoms arise. As such, it lumps together a range of clinical manifestations, such as PD, PDD, and DLB. The authors wrote that they decided against sequential stages because evidence from longitudinal studies is insufficient to do so. 

Classified by Biology. In SynNeurGe, Parkinson’s disease is classified by the presence or absence of disease-associated genetic variants (Gf, Gp, or G-), α-synuclein pathology (S+/S-), and PD-associated neurodegeneration (N+/N-). Clinical status is classified separately. Green bars indicate physiological conditions; other colors indicate pathogenic conditions. Gradients suggest gradual transition over time. [Courtesy of Höglinger et al., Lancet Neurology, 2024.]

Time for Something New?
In their position paper, Marek and colleagues, including co-first authors Tanya Simuni of Northwestern University and Lana Chahine of the University of Pittsburgh, scrap clinical definitions of disease altogether. Instead, they spell out a new, biologically defined disorder called neuronal α-synuclein disease. NSD's defining characteristic is the presence of misfolded, seeding-competent α-synuclein that predominantly plagues neurons.

They base the concept largely on biomarker abnormality. For now, this means α-synuclein seeds that can be amplified from the CSF, but other assays might be added as they become validated.

Carriers of fully penetrant SNCA mutations are the lone exception to the requirement for a positive α-synuclein seeding test. This is because these rare mutations invariably spark neuronal α-synuclein aggregation. The researchers include asymptomatic carriers within the NSD framework, whether or not they are biomarker positive.

What about people who have symptoms of dopaminergic dysfunction and clinical PD, yet test negative for α-synuclein biomarkers? Estimated to represent about 10 to 15 percent of people with clinical PD, these cases stand outside the NSD framework. So do people with multiple system atrophy (MSA), a synucleinopathy that affects glia more than neurons. Importantly, seed amplification assays can distinguish between PD/DLB and MSA (Concha-Marambio et al., 2023).

With this definition in hand, Simuni and colleagues developed a scheme to stage it. Called the NSD integrated staging system (NSD-ISS), it considers neurodegeneration, clinical symptoms, and functional impairment. Even if they test negative for α-synuclein seeds, carriers of fully penetrant SNCA mutations are designated Stage 0. For everyone else, the disease clock starts at Stage 1A, when an asymptomatic person tests positive for α-synuclein pathology. Evidence of dopaminergic dysfunction, currently measured most commonly by DaT SPECT, signals Stage 1B. The emergence of clinical symptoms heralds Stage 2. These include subtle motor symptoms, as well as non-motor signs, such as loss of smell, hypotension, constipation, depression, mild cognitive impairment, and REM sleep behavior disorder. Finally, Stages 3-6 are characterized by the emergence and progressive worsening of functional impairment, which can be driven by motor, cognitive, or other non-motor deficits (image below). Details about how to stage functional impairments need to be ironed out, the authors wrote.

The Stages of NSD. Neuronal α-synuclein pathology, as detected by seed amplification assay, emerges in Stage 1A, followed by dopaminergic dysfunction in Stage 1B. Clinical symptoms signal Stage 2A/B, while functional impairments emerge in Stage 3 and worsen from there. [Courtesy of Simuni et al., Lancet Neurology, 2024.]

Just as Alzheimer's disease biomarkers enabled the amyloid/tau/neurodegeneration (ATN) framework that is now broadly applied in AD research, Simuni and colleagues hope that the biomarker-based definition for NSD will streamline studies of synucleinopathies.

In a commentary in Lancet Neurology, Clifford Jack of the Mayo Clinic in Rochester, Minnesota, drew parallels between the two. “By separating the syndrome from the biology, the […] criteria also recognize that syndromic presentation is not always specific for neuronal α-synuclein pathology,” Jack wrote. “The analogy in Alzheimer’s disease is that patients with characteristic syndromic presentations but who have normal biomarker testing do not have Alzheimer’s disease,” he wrote.

For his part, Lang believes that excluding α-synuclein-negative PD cases from the NSD-ISS framework could relegate them to a research backwater, where less attention, and less funding, are funneled in their direction. Although they represent a small proportion of PD, they may have much to teach us about the disease, he added. “For example, how is it that LRRK2 variants can cause Parkinson’s without α-synuclein pathology?” He also fears those people would be excluded from clinical trials.

To Jose Obeso of Universidad San Pablo CEU, Madrid, and Paolo Calabresi of Universitá Cattolica del Sacro Cuore in Rome, the idea of having a unifying, common disorder purely driven by synuclein pathology might inadvertently lump together clinical syndromes which, despite the presence of Lewy bodies, might be fundamentally different in nature. For example, they noted that consensus is still lacking on whether PD and DLB denote the same pathological process with different clinical expressions.

Simuni and Marek believe that α-synuclein-positive and -negative cases represent fundamentally different diseases, and should be treated as such, hence the new neuronal α-synuclein disease definition. “Right now, we’re lumping α-synuclein negative and positive cases together,” Simuni said. Splitting them based on the underlying biology will allow researchers to home in on the distinct culprits of dopaminergic destruction wrought in each disorder, she told Alzforum. In particular, they see the new staging system as a way to improve selection and monitoring in clinical trials. FDA regulators are among the position paper’s co-authors.

Lang agrees that the biomarkers will be useful tools for stratifying clinical trial participants, but, as he told Alzforum, “You don’t need to create a new disease to do that.”

Bloem and colleagues wrote that the proposed nixing of clinical terms like PD and DLB by the authors of the NSD-ISS framework is contentious because some people with the full clinical spectrum of Parkinson’s disease do not have α-synucleinopathy. They also took issue with defining a disease based solely on a single biomarker or pathology, given that many people with Lewy bodies never develop clinical symptoms.

They added that although both classification systems were developed with research use in mind, their publication carries the risk that they could be applied prematurely in the clinic. Similar situations have caused controversy and confusion in the AD field, particularly as doctors grapple with how to interpret biomarker findings for their patients (Nov 2023 news; van der Schaar et al., 2022; Jan 2024 news). “To avoid this scenario, we need clear guidance on the settings in which the proposed Parkinson’s disease classification is applied, and on how to communicate a research diagnosis of early stage Parkinson’s disease pathology to research participants,” they wrote.—Jessica Shugart

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References

News Citations

1. Synuclein Assay Passes the Sniff Test—What of Other Seeds? 21 Apr 2023
2. Finally, a Diagnostic Marker for Lewy Body Disease? 15 Aug 2023
3. Through the Heart? Cardiology Tracer to Nail DLB Diagnosis 23 Dec 2015
4. New Alzheimer’s Diagnostic Criteria Remain ‘Research Only’ 28 Nov 2023
5. AD Blood Tests Are Here. Now, Let's Grapple With How to Use Them 25 Jan 2024

Paper Citations

1. Schneider SA, Alcalay RN. Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature. Mov Disord. 2017 Nov;32(11):1504-1523. PubMed.
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4. Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, Nguyen H, Alcalay RN, Chahine LM, Foroud T, Galasko D, Kieburtz K, Merchant K, Mollenhauer B, Poston KL, Seibyl J, Simuni T, Tanner CM, Weintraub D, Videnovic A, Choi SH, Kurth R, Caspell-Garcia C, Coffey CS, Frasier M, Oliveira LM, Hutten SJ, Sherer T, Marek K, Soto C, Parkinson's Progression Markers Initiative. Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023 May;22(5):407-417. PubMed.
5. Concha-Marambio L, Pritzkow S, Shahnawaz M, Farris CM, Soto C. Seed amplification assay for the detection of pathologic alpha-synuclein aggregates in cerebrospinal fluid. Nat Protoc. 2023 Apr;18(4):1179-1196. Epub 2023 Jan 18 PubMed.
6. van der Schaar J, Visser LN, Bouwman FH, Ket JC, Scheltens P, Bredenoord AL, van der Flier WM. Considerations regarding a diagnosis of Alzheimer's disease before dementia: a systematic review. Alzheimers Res Ther. 2022 Feb 10;14(1):31. PubMed.

Further Reading

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