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Item Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study(Elsevier, 2023) Siderowf, Andrew; Concha-Marambio, Luis; Lafontant, David-Erick; Farris, Carly M.; Ma, Yihua; Urenia, Paula A.; Nguyen, Hieu; Alcalay, Roy N.; Chahine, Lana M.; Foroud, Tatiana; Galasko, Douglas; Kieburtz, Karl; Merchant, Kalpana; Mollenhauer, Brit; Poston, Kathleen L.; Seibyl, John; Simuni, Tanya; Tanner, Caroline M.; Weintraub, Daniel; Videnovic, Aleksandar; Choi, Seung Ho; Kurth, Ryan; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Frasier, Mark; Oliveira, Luis M. A.; Hutten, Samantha J.; Sherer, Todd; Marek, Kenneth; Soto, Claudio; Parkinson's Progression Markers Initiative; Medical and Molecular Genetics, School of MedicineBackground: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. Methods: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. Findings: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. Interpretation: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts.Item Biomarkers of neurodegeneration and glial activation validated in Alzheimer’s disease assessed in longitudinal cerebrospinal fluid samples of Parkinson’s disease(PLOS, 2021-10-07) Bartl, Michael; Dakna, Mohammed; Galasko, Douglas; Hutten, Samantha J.; Foroud, Tatiana; Quan, Marian; Marek, Kenneth; Siderowf, Andrew; Franz, Jonas; Trenkwalder, Claudia; Mollenhauer, Brit; Medical and Molecular Genetics, School of MedicineAim: Several 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. Methods: Longitudinal cerebrospinal fluid (CSF) samples from PPMI (252 PD, 115 healthy controls, HC) were analyzed at six timepoints (baseline, 6, 12, 24, 36, and 48 months follow-up) using Elecsys® electrochemiluminescence immunoassays to quantify neurofilament light chain (NfL), soluble TREM2 receptor (sTREM2), chitinase-3-like protein 1 (YKL40), glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), S100, and total α-synuclein (αSyn). Results: αSyn was significantly lower in PD (mean 103 pg/ml vs. HC: 127 pg/ml, p<0.01; area under the curve [AUC]: 0.64), while all other biomarkers were not significantly different (AUC NfL: 0.49, sTREM2: 0.54, YKL40: 0.57, GFAP: 0.55, IL-6: 0.53, S100: 0.54, p>0.05) and none showed a significant difference longitudinally. We found significantly higher levels of all these markers between PD patients who developed cognitive decline during follow-up, except for αSyn and IL-6. Conclusion: 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.Item Dopamine transporter imaging predicts clinically-defined α-synucleinopathy in REM sleep behavior disorder(Wiley, 2021) Chahine, Lana M.; Brumm, Michael C.; Caspell-Garcia, Chelsea; Oertel, Wolfgang; Mollenhauer, Brit; Amara, Amy; Fernandez-Arcos, Ana; Tolosa, Eduardo; Simonet, Cristina; Hogl, Birgit; Videnovic, Aleksandar; Hutten, Samantha J.; Tanner, Caroline; Weintraub, Daniel; Burghardt, Elliot; Coffey, Christopher; Cho, Hyunkeun R.; Kieburtz, Karl; Poston, Kathleen L.; Merchant, Kalpana; Galasko, Douglas; Foroud, Tatiana; Siderowf, Andrew; Marek, Kenneth; Simuni, Tanya; Iranzo, Alex; Medical and Molecular Genetics, School of MedicineIntroduction: Individuals 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. Methods: The sample included individuals with iRBD, early Parkinson's Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow-up versus those not diagnosed. Results: The sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT-SPECT at baseline. Over 4.7 years of mean follow-up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79-83.3], P = 0.0003). Conclusion: We demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short-term risk of an aSN diagnosis.Item Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort(Springer, 2022-10-22) Simuni, Tanya; Merchant, Kalpana; Brumm, Michael C.; Cho, Hyunkeun; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Chahine, Lana M.; Alcalay, Roy N.; Nudelman, Kelly; Foroud, Tatiana; Mollenhauer, Brit; Siderowf, Andrew; Tanner, Caroline; Iwaki, Hirotaka; Sherer, Todd; Marek, Kenneth; Parkinson’s Progression Marker Initiative Authors; Medical and Molecular Genetics, School of MedicineWe examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.Item Parkinson's Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson's Disease Progression(IOS Press, 2023) Brumm, Michael C.; Siderowf, Andrew; Simuni, Tanya; Burghardt, Elliot; Choi, Seung Ho; Caspell-Garcia, Chelsea; Chahine, Lana M.; Mollenhauer, Brit; Foroud, Tatiana; Galasko, Douglas; Merchant, Kalpana; Arnedo, Vanessa; Hutten, Samantha J.; O’Grady, Alyssa N.; Poston, Kathleen L.; Tanner, Caroline M.; Weintraub, Daniel; Kieburtz, Karl; Marek, Kenneth; Coffey, Christopher S.; Parkinson’s Progression Markers Initiative; Medical and Molecular Genetics, School of MedicineBackground: 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 = 0.0030). Symptomatic treatment was not significantly associated with reaching a milestone (p = 0.1639). Conclusion: 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.Item Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression(Wiley, 2020-11) Mollenhauer, Brit; Dakna, Mohammed; Kruse, Niels; Galasko, Douglas; Foroud, Tatiana; Zetterberg, Henrik; Schade, Sebastian; Gera, Roland G.; Wang, Wenting; Gao, Feng; Frasier, Mark; Chahine, Lana M.; Coffey, Christopher S.; Singleton, Andrew B.; Simuni, Tanya; Weintraub, Daniel; Seibyl, John; Toga, Arthur W.; Tanner, Caroline M.; Kieburtz, Karl; Marek, Kenneth; Siderowf, Andrew; Cedarbaum, Jesse M.; Hutten, Samantha J.; Trenkwalder, Claudia; Graham, Danielle; Medical and Molecular Genetics, School of MedicineBackground: The objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker. Methods: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. Results: In the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. Conclusions: Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed.