Parkinson’s Progression Markers Initiative: A Milestone-Based Strategy to Monitor PD Progression
By onChallenge: Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge. Objective: To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones. Methods: Using data from the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we monitored 25 milestones across six domains ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living"). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression. Results: Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at the next annual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p<0.0001), greater MDS-UPDRS total scores (p<0.0001), higher GDS-15 depression scores (p=0.0341), lower dopamine transporter binding (p=0.0043), and lower CSF total α-synuclein levels (p=0.0033). Symptomatic treatment was not significantly associated with reaching a milestone (p=0.1639). Conclusions: Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.
Impact of the dopamine system on long-term cognitive impairment in Parkinson disease: an exploratory study
By onBackground Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). Using data from a multi-site, international, prospective cohort study, authors explored the impact of dopamine system-related biomarkers on CI in PD. The study provides preliminary evidence that alterations in the dopamine system predict the development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course.
Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson’s Disease
By onThe aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis. Baseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single-photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug-naive individuals, but some changed on starting levodopa treatment.
Biomarkers of neurodegeneration and glial activation validated in Alzheimer’s disease assessed in longitudinal cerebrospinal fluid samples of Parkinson’s disease
By onSeveral pathophysiological processes are involved in Parkinson’s disease (PD) and could inform in vivo biomarkers. We assessed an established biomarker panel, validated in Alzheimer’s Disease, in a PD cohort. Except for αSyn, the additional biomarkers did not differentiate PD and HC, and none showed longitudinal differences, but most markers predict cognitive decline in PD during follow-up.
The longitudinal progression of autonomic dysfunction in Parkinson’s disease: a 7-year study
By onAutonomic dysfunction, including gastrointestinal, cardiovascular, and urinary dysfunction, is often present in early Parkinson's Disease (PD). However, the knowledge of the longitudinal progression of these symptoms, and the connection between different autonomic domains, is limited. Using data collected from PPMI, autonomic dysfunction was measured using the Scales for Outcomes in Parkinson's Disease (SCOPA-AUT). Symptom frequency and mean scores over 7 years were determined. At baseline, greater SCOPA-AUT total score was associated with lower UPSIT scores (r = −0.209, p = 0.006) and with greater total MDS-UDPRS III score (r = 0.218, p = 0.004).
Urinary bis(monacylglycerol) phosphate (BMP) levels are higher in LRRK2 and GBA1 variant carriers but do not predict disease progression in PPMI cohorts
By onWe quantified concentrations of three isoforms of the endolysosomal lipid, bis(monoacylglycerol) phosphate (BMP) in urine of deeply phenotyped cohorts in the Parkinson’s Progression Markers Initiative: LRRK2 G2019S PD (N = 134) and non-manifesting carriers (NMC) (G2019S + NMC; N = 182), LRRK2 R1441G PD (N = 15) and R1441G + NMC (N = 15), GBA1 N409S PD (N = 76) and N409S + NMC (N = 178), sporadic PD (sPD, N = 379) and healthy controls (HC) (N = 190). Effects of each mutation and disease status were analyzed using nonparametric methods. Longitudinal changes in BMP levels were analyzed using linear mixed models. At baseline, all LRRK2 carriers had 3-7x higher BMP levels compared to HC, irrespective of the disease status. GBA1 N409S carriers also showed significant, albeit smaller, elevation (~ 30–40%) in BMP levels compared to HC. In LRRK2 G2019S PD, urinary BMP levels remained stable over two years. Furthermore, baseline BMP levels did not predict disease progression as measured by striatal DaT imaging, MDS-UPDRS III Off or MoCA in any of the cohorts. These data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.
Dopamine transporter imaging predicts clinically‐defined α‐synucleinopathy in REM sleep behavior disorder
By onIndividuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α‐synucleinopathy (aSN). They could serve as a key population for disease‐modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically‐defined aSN in iRBD.
High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease
By onAlpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson’s Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods
Updated Percentiles for the University of Pennsylvania Smell Identification Test in Adults 50 Years of Age and Older
By onThe University of Pennsylvania Smell Identification Test (UPSIT) is commonly used to assess olfaction and screen for early detection of disorders including Parkinson (PD) and Alzheimer disease. Our objective was to develop updated percentiles, based on substantially larger samples than previous norms, to more finely discriminate age- and sex-specific UPSIT performance among ≥50-year-old adults who may be candidates for studies of prodromal neurodegenerative diseases.
Assessment of heterogeneity and disease onset in the Parkinson’s Progression Markers Initiative (PPMI) cohort using the α-synuclein seed amplification assay: a cross-sectional study
By onBackground Recent research demonstrates that α-synuclein seed amplification assays (αSyn-SAA) accurately differentiate Parkinson’s disease (PD) patients from healthy controls (HC). We used the well-characterized, multicenter Parkinson’s Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of αSyn-SAA and to examine whether the assay identifies heterogeneity among patients and enables early identification in at-risk groups. Methods αSyn-SAA analysis of cerebrospinal fluid (CSF) was performed using previously described methods. We assessed sensitivity and specificity in PD and HC, including subgroups based on genetic and clinical features. We determined the frequency of positive αSyn-SAA results in prodromal participants (REM sleep behavior disorder and hyposmia) and non-manifesting carriers (NMCs) of genetic variants associated with PD and compared αSyn-SAA to clinical measures and other biomarkers. Findings 1,123 participants were included: 545 PD, 163 HCs, 54 participants with scans without evidence of dopaminergic deficit (SWEDDs), 51 prodromal participants, and 310 NMCs. Sensitivity and specificity for PD versus HC were 88% and 96%, respectively. Sensitivity in sporadic PD with the typical olfactory deficit was 99%. The proportion of positive αSyn-SAA was lower in subgroups including LRRK2 PD (68%) and sporadic PD patients without olfactory deficit (78%). Participants with LRRK2 variant and normal olfaction had an even lower αSyn-SAA positivity rate (35%). Among prodromal and at-risk groups, 86% of RBD and hyposmic cases had positive αSyn-SAA. 8% of NMC (either LRRK2 or GBA) were positive. Interpretation This study represents the largest analysis of αSyn-SAA for biochemical diagnosis of PD. Our results demonstrate that the assay classifies PD patients with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals prior to diagnosis. These findings suggest a crucial role for αSyn-SAA in therapeutic development, both to identify pathologically defined subgroups of PD patients and to establish biomarker-defined at-risk cohorts. (Initial Preprint DOI: 10.1101/2023.02.27.23286156 )
2024: A Year in Review
ASAP is excited to share how we pushed the Parkinson’s disease research field forward. Together, our supported programs worked to funnel new ideas into Parkinson’s disease R&D, facilitate the rapid exchange of ideas, ensure researchers can build upon ASAP-funded work, and establish a diverse pipeline for the next generation of researchers.
Why Acting Out in Dreams May Signal a Health Issue
Read this article from The Washington Post on how REM sleep behavior disorder (RBD) can be a sign of early-onset Parkinson’s disease and how the Michael J. Fox Foundation is inviting people who act out their dreams to participate in the Parkinson’s Progression Markers Initiative (PPMI).
2023: A Year in Review
ASAP reflects on the results our initiative, network, and supported programs have had on providing new insights into Parkinson’s disease in 2023. Together, we have uncovered novel discoveries and made progress toward our vision of advancing collaborative, transparent research processes, and environments that deliver faster and better outcomes in PD research.
A Parkinson’s ‘Game Changer,’ Backed by Michael J. Fox, Could Lead to New Diagnostics and, Someday, Treatments
STAT highlights how The Parkinson’s Progression Markers Initiative (PPMI) recently discovered how αSyn-SAA could be a novel tool for precision medicine approaches, earlier intervention, and improved clinical trial design for Parkinson's disease.
2022: A Year in Review
ASAP reflects on the progress made in 2022 toward our vision of advancing collaborative, transparent research processes and environments that deliver faster and better outcomes in Parkinson’s disease research.
