Agnosia

New findings suggest that not all cases of Parkinson’s disease may be driven by alpha-synuclein accumulation. A new test could make it possible to diagnose Parkinson’s disease before symptoms appear, paving the way for early intervention. According to the results of a nearly decadelong study published April 12 in The Lancet Neurology, a team of scientists with the Parkinson’s Progression Markers Initiative—a longstanding biomarkers study backed by actor Michael J. Fox’s Parkinson’s research nonprofit—described how they developed an assay to detect deposits of a protein called alpha-synuclein in the cerebrospinal fluid of hundreds of at-risk and early-stage patients. The test, recently commercialized by Amprion as SYNTap, was able to distinguish them from non-Parkinson’s patients 88% of the time and had a specificity of 96%. “It would be difficult to overstate the implications of this discovery,” Deborah Brooks, CEO of the Michael J. Fox Foundation for Parkinson’s Research (MJFF) and a study participant herself, said in a press release. “With development and scaling, αSyn-SAA can usher in the era of objectively and biologically defining Parkinson’s disease—revolutionizing every aspect of research and care.” SYNTap is a seed amplification assay, or SAA, which were previously used to diagnose neurodegenerative prion diseases like Creutzfeldt-Jakob disease, setting a precedent for their use in diagnosing other brain pathologies involving misfolded proteins. In Parkinson’s, misfolded alpha-synuclein accumulates in the brain as part of what are known as Lewy bodies, which leads to the loss of neurons that signal using the neurotransmitter dopamine. Many of these are in the region of the brain that controls movement, which helps explain why the disease manifests in tremors and other motion problems. To develop the test, MJFF neuroscience researchers tapped scientists from the University of Texas who were working on an SAA to help diagnose Alzheimer’s. Between 2010 and 2019, they tested it out on cerebrospinal fluid samples from 1,123 individuals, about half of whom had been diagnosed with Parkinson’s. Another 310 had gene changes associated with Parkinson’s but had not yet developed the disease; 51 had early clinical symptoms but didn’t have an official diagnosis, and 163 were healthy controls. The test was positive for alpha-synuclein deposits at a rate of nearly 99% in patients who had a sporadic form of Parkinson’s—a form without a known genetic cause that makes up about 90% of cases—and who had also lost their sense of smell, one of the condition’s earliest symptoms. It was positive about 78% of the time in individuals who had sporadic Parkinson’s but didn’t have the olfactory deficit and 68% in those who had a form of the disease involving a mutation in the gene LRRK2. LRRK2 is a common target of drugs that are currently in clinical trials for Parkinson's, like Biogen and Denali Therapeutics’ BIIB122 and a small molecule from Qiagen and Neuron23. To the scientists, these results suggest that not all cases of Parkinson’s may be driven by alpha-synuclein accumulation. LRRK2 mutations are found in a relatively small subset of the Parkinson’s patient population: just 0.5 to 2% of those with the sporadic form and 5% of those with the familial form. Identifying which patients have alpha-synuclein deposits could help researchers find better ways to treat them—potentially before they develop symptoms. The deposits showed up in patients with smell loss and other early hallmarks, such as REM sleep behavior disorder, before dysfunction in the dopamine system was visible on brain scans. That finding validates the notion that alpha-synuclein is part of the disease process that leads to symptoms down the line and that it could potentially be targeted to stave off Parkinson’s altogether, the researchers noted in the press release. The SYNTap test was granted breakthrough-device designation by the U.S. FDA in February 2022. Physicians can now order the test for people exhibiting Parkinson’s symptoms, though it’s currently not covered by insurance. Amprion offers financial assistance for the test according to patient need, per the company’s website, and is in the process of setting up reimbursement from insurance payers.

MONDAY, April 17, 2023 -- α-synuclein seed amplification assays (SAAs) can classify people with Parkinson disease with high sensitivity and specificity, according to a study published in the May issue of The Lancet Neurology . Andrew Siderowf, M.D., from the University of Pennsylvania in Philadelphia, and colleagues assessed the diagnostic performance of the α-synuclein SAA in a cross-sectional analysis based on assessments conducted at enrollment for Parkinson's Progression Markers Initiative (PPMI) cohort participants from 33 participating academic neurology outpatient practices worldwide. The sensitivity and specificity of the α-synuclein SAA was examined in participants with Parkinson disease and healthy controls. The analysis included 1,123 participants: 545 with Parkinson disease, 163 healthy controls, 54 participants with scans without evidence of dopaminergic deficit, 51 prodromal participants, and 310 nonmanifesting carriers. The researchers found that for Parkinson disease, sensitivity was 87.7 percent and specificity was 96.3 percent for healthy controls. Overall, α-synuclein SAA had sensitivity of 98.6 percent in sporadic Parkinson disease with the typical olfactory deficit. In subgroups including LRRK2 Parkinson disease and participants with sporadic Parkinson disease without olfactory deficit, the proportion of positive α-synuclein SAA was lower (67.5 and 78.3 percent, respectively). An even lower α-synuclein SAA positivity rate was seen for participants with the LRRK2 variant and normal olfaction (34.7 percent). Eighty-six percent of participants with rapid eye movement sleep behavior disorder and hyposmia (prodromal individuals) had positive α-synuclein SAA. Of the nonmanifesting carriers, 8 percent were positive. "These findings have immediate implications for clinical trial design, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts," the authors write. Several authors disclosed financial ties to the pharmaceutical industry; PPMI is funded by multiple partners, including biopharmaceutical companies. Abstract/Full Text (subscription or payment may be required) Editorial (subscription or payment may be required) Posted April 2023

New paper in The Lancet Neurology confirms that a key Parkinson's pathology can now be identified by examining spinal fluid from living patients Test validated in the gold-standard Parkinson's Progression Markers Initiative demonstrates greater than 90% sensitivity in people with typical Parkinson's pathology, and is frequently positive even before onset of symptoms Findings show differences in disease subtypes and among people with Parkinson's risk factors, providing a novel tool for precision medicine approaches, earlier intervention and improved clinical trial design Michael J. Fox "deeply moved by breakthrough," "making a cure for Parkinson's inevitable" NEW YORK, April 12, 2023 /PRNewswire/ -- A landmark paper published today in The Lancet Neurology journal by leaders of the Parkinson's Progression Markers Initiative (PPMI), the gold-standard Parkinson's biomarker study sponsored by The Michael J. Fox Foundation for Parkinson's Research (MJFF), confirms the most significant breakthrough yet in the search for a Parkinson's biomarker: a biological test for Parkinson's disease that demonstrates high diagnostic accuracy, differentiates molecular subtypes and detects disease in individuals before cardinal movement symptoms arise. The new test, known as the alpha-synuclein seed amplification assay (αSyn-SAA), heralds the revolutionary ability for research to define Parkinson's disease biologically, offering a critical tool for clinical trial design and assessment of treatment effects, and for early detection of disease pathology. As authors from PPMI detail in The Lancet Neurology, the test detects synuclein pathology, one of the two biological hallmarks of Parkinson's disease (alongside dopaminergic transport dysfunction, which can be visualized using DaTScan). As a result, for the first time since James Parkinson first characterized the disorder in 1817, researchers and clinicians can use biology (vs. clinical assessments and patient-reported outcomes) to identify, define and monitor Parkinson's objectively, based on cellular pathology in the living body. "Validation of this biomarker launches a new, biological era in Parkinson's research," said Kenneth Marek, MD, PPMI Principal Investigator and president and senior scientist at the Institute for Neurodegenerative Disorders. "Using αSyn-SAA, we are already unlocking new understanding of Parkinson's, which will transform every aspect of drug development and ultimately clinical care. We will rapidly be in a position to test new therapies in the right populations, target the right therapy to the right patient at the right time, and launch studies of agents with potential to prevent Parkinson's disease altogether. This is what PPMI was built to do, and we are especially grateful to the thousands of study participants whose contributions have enabled this watershed moment." The paper, co-led by Andrew Siderowf, MD, PPMI Investigator and Director, Parkinson Disease and Movement Disorders Center at the University of Pennsylvania and Luis Concha, PhD, Director, Research and Development at Amprion, outlines αSyn-SAA results from more than 1,100 PPMI participants including individuals with Parkinson's disease, those with genetic and/or clinical risk factors but not diagnosed with Parkinson's, and control volunteers. The large-scale analysis in PPMI confirms previous reports — including from MJFF-funded work — that αSyn-SAA can distinguish Parkinson's from control volunteers with a stunningly robust sensitivity of 88 percent and specificity of 96 percent. As an objective and reliable biomarker of Parkinson's biology, αSyn-SAA will significantly decrease the risk for industry to invest in the development of potential blockbuster therapies, including preventive agents, and increase the speed and efficiency with which these therapies can be developed, tested and brought to market. With αSyn-SAA in hand, it will be possible to establish objective endpoints for clinical trials of Parkinson's treatments, ensure study participants exhibit appropriate pathology, and detect therapy-induced changes in their status. This already is reworking the design of clinical trials and can induce greater pharma and biotech investment in the space — creating more "shots on goal" to benefit people at every stage of disease. Subtypes of Parkinson's Biology Linked to Genetic and Clinical Factors The authors reported findings related to olfactory deficit, or smell loss (enduring and significant smell loss is a common symptom of Parkinson's often seen years before a diagnosis) and to carrying a mutation in the Parkinson's-associated LRRK2 gene: The assay accurately diagnosed disease in 99 percent (274 of 278) of people with smell loss and sporadic Parkinson's (without a known causal genetic mutation). The proportion of positive results was lower in people with Parkinson's and a LRRK2 mutation [68 percent (83 of 123)]. Positive results also were lower in people with sporadic Parkinson's without olfactory deficit (78 percent). People with Parkinson's, a LRRK2 mutation and normal smell ability were even less likely to show positive assay results. This was particularly true among females; only 12.5 percent of females in this population (three of 24) showed synuclein pathology on the test. In people with Parkinson's enrolled in PPMI who consented to post-mortem examination and who have passed since joining the study, all those with positive assay results (14) showed typical alpha-synuclein aggregation pathology in brain cells; the single such PD participant who did not show positive assay results was a LRRK2 mutation carrier with preserved olfaction. These results suggest that not all cases of clinical Parkinson's symptoms are associated with the accumulation of alpha-synuclein aggregates as detected by this assay, and that LRRK2 variant carriers, in particular, may not show this pathology. This insight opens new avenues of investigation toward treatments to benefit more people with PD. It also will enable deeper studies of the cellular pathways and cascades occurring in LRRK2-associated Parkinson's, some of which may be protective against synuclein dysfunction and Parkinson's toxicity. This could lead to breakthroughs to benefit everyone with Parkinson's, not just those who carry a genetic mutation. (Three therapies targeting dysfunction in the LRRK2 pathway are currently in clinical trials.) New Evidence that Biological Changes in Synuclein Predate Both Symptoms and Dopamine Dysfunction, Setting Stage for First Prevention Trials The αSyn-SAA also has been validated in individuals enrolled in PPMI who have not been diagnosed with Parkinson's, but are age 60 or older and living with increased relative risk of developing Parkinson's due to genetic mutations, smell loss, or diagnosed REM sleep behavior disorder (RBD). (RBD is a sleep disorder of acting out dreams by hitting, punching or kicking, and is tied to significant risk of developing Parkinson's or a similar neurodegenerative disease.) PPMI reopened enrollment in 2020 and is building a longitudinal cohort of 2000 such at-risk individuals. Most people with olfactory deficit [88 percent (16 of 18)] or RBD [84 percent (28 of 33)] showed positive assay results. The authors also compared results to dopamine transporter (DAT) brain imaging scans, a tool for assessing dopamine transporter system dysfunction and thereby Parkinson's pathology, including in at-risk individuals. Only about 30 percent of at-risk individuals with a positive seed amplification assay result also had significant dopamine loss. This finding suggests that synuclein pathology could be detectable by this assay earlier than dopamine dysfunction is seen with DAT imaging, extending the window in which it may be possible to intervene with preventive therapies. On the other hand, undiagnosed but at-risk carriers of a LRRK2 or GBA mutation (the most common known genetic link to Parkinson's disease) were less likely to show positive assay results: 8.8 percent (14 of 159) and 7.3 percent (11 of 151) respectively. This finding suggests that RBD and olfactory deficit arise closer to onset of Parkinson's movement symptoms. It also suggests that alpha-synuclein aggregation in spinal fluid is not a life-long trait but rather acquired as part of a disease biology process that ultimately gives rise to symptoms. By exploiting this understanding to intervene in this process, drugmakers hope to make Parkinson's a preventable condition. Biomarker Test Available for Diagnostic Assessment The αSyn-SAA was developed when MJFF on-staff neuroscience PhDs approached researchers at University of Texas working on seed amplification assays in Alzheimer's. The Foundation offered funding to experiment with developing an alpha-synuclein assay using PPMI cerebrospinal fluid samples. The University of Texas team that developed the assay has since launched biotech Amprion, which partnered with PPMI on its analysis of αSyn-SAA. The company has commercialized the assay as the SYNTap® test, which is available for order by physicians for people exhibiting symptoms of Parkinson's or related disorders. When the test is positive, a person likely has Parkinson's or a related disorder of alpha-synuclein, such as Dementia with Lewy Bodies (DLB) or Multiple System Atrophy (MSA). The test, on its own, cannot differentiate between these diseases. It also may not be covered by insurance. But, in conjunction with a doctor's examination, the test might help support a specific diagnosis. "The Michael J. Fox Foundation has always recognized the indisputable need for biomarkers of Parkinson's disease, and has relentlessly pursued them as a mission-critical goal," said Deborah W. Brooks, MJFF's chief executive officer (and a PPMI control volunteer at the University of Pennsylvania since 2010). "It would be difficult to overstate the implications of this discovery. With development and scaling, αSyn-SAA can usher in the era of objectively and biologically defining Parkinson's disease — revolutionizing every aspect of research and care." Michael J. Fox said: "There are many ways I am involved with the work of the Foundation, but I come to this result first and foremost as a Parkinson's patient. I am deeply moved by this breakthrough and endlessly grateful to the researchers, study participants and funders who have endeavored to bring us this far. When we started PPMI, we weren't casting about for fish — we were going after a whale. Now, here we are. Together we are making a cure for Parkinson's inevitable." PPMI: The Study that's Changing Everything MJFF launched the Parkinson's Progression Markers Initiative (, michaeljfox.org/ppmi) in 2010 at 18 clinical sites in the United States and Europe with a lead gift from the late Mrs. Lily Safra, a visionary friend, partner, and board member of MJFF. A longitudinal observational study, PPMI has built the most robust dataset and biosample library ever assembled in Parkinson's research, which is shared with the broader research community in real time for ongoing discovery and validation studies. Today the study has enrolled nearly 2000 participants and is actively enrolling Parkinson's patients, at-risk individuals and control volunteers at 51 clinical sites around the globe. Study data are downloaded by researchers worldwide for independent studies on average 2200 times a day. With the publication of αSyn-SAA, The Michael J. Fox Foundation announced that the tagline of the PPMI study will change from "The Study that Could Change Everything" about how Parkinson's disease is diagnosed, managed and treated to "The Study that's Changing Everything." Major funding for PPMI comes from Aligning Science Across Parkinson's (ASAP) (), a coordinated research initiative focused on accelerating the pace of discovery and informing the path to a cure for Parkinson's disease. ASAP support is enabling the seismic expansion of PPMI to increase recruitment efforts and remote testing for those at-risk for PD as well as expanding assay development efforts to enable breakthroughs such as αSyn-SAA. This infrastructure provides a ready platform for future discoveries. In addition to ASAP, PPMI is supported by the Edmond J. Safra Foundation, the Farmer Family Foundation and Connie and Steve Ballmer. The study is additionally funded by a consortium of more than 40 biotech and pharmaceutical firms providing financial and in-kind support, and by tens of thousands of individual donors to The Michael J. Fox Foundation. About The Michael J. Fox Foundation for Parkinson's Research (MJFF) As the world's largest nonprofit funder of Parkinson's research, The Michael J. Fox Foundation is dedicated to accelerating a cure for Parkinson's disease and improved therapies for those living with the condition today. The Foundation pursues its goals through an aggressively funded, highly targeted research program coupled with active global engagement of scientists, Parkinson's patients, business leaders, clinical trial participants, donors and volunteers. In addition to funding $1.75 billion in research to date, the Foundation has fundamentally altered the trajectory of progress toward a cure. Operating at the hub of worldwide Parkinson's research, the Foundation forges groundbreaking collaborations with industry leaders, academic scientists and government research funders; creates a robust open-access data set and biosample library to speed scientific breakthroughs and treatment with its landmark clinical study, PPMI; increases the flow of participants into Parkinson's disease clinical trials with its online tool, Fox Trial Finder; promotes Parkinson's awareness through high-profile advocacy, events and outreach; and coordinates the grassroots involvement of thousands of Team Fox members around the world. For more information, visit us at , Facebook, Twitter, LinkedIn. Logo - SOURCE The Michael J. Fox Foundation for Parkinson's Research