Browsing by Author "Coffey, Christopher S."
Now showing 1 - 9 of 9
Results Per Page
Sort Options
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 Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for α-Synuclein in Parkinson's Disease: The Systemic Synuclein Sampling Study (S4)(IOS Press, 2018) Chahine, Lana M.; Beach, Thomas G.; Seedorff, Nicholas; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Brumm, Michael; Adler, Charles H.; Serrano, Geidy E.; Linder, Carly; Mosovsky, Sherri; Foroud, Tatiana; Riss, Holly; Ecklund, Dixie; Seibyl, John; Jennings, Danna; Arnedo, Vanessa; Riley, Lindsey; Dave, K.D.; Mollenhauer, Brit; SystemicSynuclein Sampling study; Medical and Molecular Genetics, School of MedicineBACKGROUND: α-synuclein is a lead Parkinson's disease (PD) biomarker. There are conflicting reports regarding accuracy of α-synuclein in different tissues and biofluids as a PD biomarker, and the within-subject anatomical distribution of α-synuclein is not well described. The Systemic Synuclein Sampling Study (S4) aims to address these gaps in knowledge. The S4 is a multicenter, cross-sectional, observational study evaluating α-synuclein in multiple tissues and biofluids in PD and healthy controls (HC). OBJECTIVE: To describe the baseline characteristics of the S4 cohort and safety and feasibility of this study. METHODS: Participants underwent motor and non-motor clinical assessments, dopamine transporter SPECT, biofluid collection (cerebrospinal fluid, saliva, and blood), and tissue biopsies (skin, sigmoid colon, and submandibular gland). Biopsy adequacy was determined based on presence of adequate target tissue. Tissue sections were stained with the 5C12 monoclonal antibody against unmodified α-synuclein. All specimens were acquired and processed in a standardized manner. Adverse events were systematically recorded. RESULTS: The final cohort consists of 82 participants (61 PD, 21 HC). In 68 subjects (83%), all types of specimens were obtained but only 50 (61%) of subjects had all specimens both collected and evaluable for α-synuclein. Mild adverse events were common, especially for submandibular gland biopsy, but only 1 severe adverse event occurred. CONCLUSION: Multicenter tissue and biofluid sampling for α-synuclein is feasible and generally safe. S4 will inform understanding of the concurrent distribution of α-synuclein pathology and biomarkers in biofluids and peripheral nervous system in PD.Item Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease(Wiley, 2021-08) Kremer, Thomas; Taylor, Kirsten I.; Siebourg-Polster, Juliane; Gerken, Thomas; Staempfli, Andreas; Czech, Christian; Dukart, Juergen; Galasko, Douglas; Foroud, Tatiana; Chahine, Lana M.; Coffey, Christopher S.; Simuni, Tanya; Weintraub, Daniel; Seibyl, John; Poston, Kathleen L.; Toga, Arthur W.; Tanner, Caroline M.; Marek, Kenneth; Hutten, Samantha J.; Dziadek, Sebastian; Trenkwalder, Claudia; Pagano, Gennaro; Mollenhauer, Brit; Medical and Molecular Genetics, School of MedicineBackground: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD). Objective: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis. Methods: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies. Results: 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. Conclusions: HVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD.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 Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study(Wolters Kluwer, 2022-01-25) Nowak, Richard J.; Coffey, Christopher S.; Goldstein, Jonathan M.; Dimachkie, Mazen M.; Benatar, Michael; Kissel, John T.; Wolfe, Gil I.; Burns, Ted M.; Freimer, Miriam L.; Nations, Sharon; Granit, Volkan; Smith, A. Gordon; Richman, David P.; Ciafaloni, Emma; Al-Lozi, Muhammad T.; Sams, Laura Ann; Quan, Dianna; Ubogu, Eroboghene; Pearson, Brenda; Sharma, Aditi; Yankey, Jon W.; Uribe, Liz; Shy, Michael; Amato, Anthony A.; Conwit, Robin; O'Connor, Kevin C.; Hafler, David A.; Cudkowicz, Merit E.; Barohn, Richard J.; NeuroNEXT NN103 BeatMG Study Team; Neurology, School of MedicineObjective: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). Methods: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks. Results: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified. Conclusions: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG. Classification of evidence: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year.Item Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial(Oxford University Press, 2021-12-24) Griguer, Corinne E.; Oliva, Claudia R.; Coffey, Christopher S.; Cudkowicz, Merit E.; Conwit, Robin A.; Gudjonsdottir, Anna L.; Ecklund, Dixie J.; Fedler, Janel K.; Neill-Hudson, Tina M.; Nabors, Louis B.; Benge, Melanie; Hackney, James R.; Chase, Marianne; Leonard, Timothy P.; Patel, Toral; Colman, Howard; de la Fuente, Macarena; Chaudhary, Rekha; Marder, Karen; Kreisl, Teri; Mohile, Nimish; Chheda, Milan G.; McNeill, Katharine; Kumthekar, Priya; Dogan, Aclan; Drappatz, Jan; Puduvalli, Vinay; Kowalska, Agnes; Graber, Jerome; Gerstner, Elizabeth; Clark, Stephen; Salacz, Michael; Markert, James; Neurology, School of MedicineBackground: Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods: This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results: OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions: Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.Item Staged Screening Identifies People with Biomarkers Related to Neuronal Alpha-Synuclein Disease(Wiley, 2025) Brown, Ethan G.; Chahine, Lana M.; Siderowf, Andrew; Gochanour, Caroline; Kurth, Ryan; Marshall, Micah J.; Caspell-Garcia, Chelsea; Brumm, Michael C.; Stanley, Craig E., Jr.; Korell, Monica; McMahon, Bridget; Kuhl, Maggie; Fabrizio, Kimberly; Heathers, Laura; Concha-Marambio, Luis; Soto, Claudio; Chowdhury, Sohini; Coffey, Christopher S.; Foroud, Tatiana M.; Simuni, Tanya; Marek, Kenneth; Tanner, Caroline M.; Parkinson Progression Marker Initiative; Medical and Molecular Genetics, School of MedicineObjective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation. Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in longitudinal assessments and further biomarker evaluation including cerebrospinal fluid alpha-synuclein seed amplification assay (aSynSAA). Results: As of January 29, 2024, 49,843 participants were sent an UPSIT and 31,293 (63%) completed it. Of UPSIT completers, 8,301 (27%) scored <15th percentile. Of 1,546 who completed DAT-SPECT, 1,060 (69%) had DAT-SPECT binding <100% expected for age and sex. Participants with an UPSIT <10th percentile (n = 1,221) had greater likelihood of low DAT-SPECT binding compared to participants with an UPSIT in the 10th to 15th percentile (odds ratio, 3.01; 95% confidence interval, 1.85-4.91). Overall, 55% (198/363) of cases with UPSIT <15th percentile and DAT-SPECT <100% had positive aSynSAA, which increased to 70% (182/260) when selecting for more severe hyposmia (UPSIT <10th percentile). Interpretation: Remote screening for hyposmia and reduced DAT-SPECT binding identifies participants with a high proportion positive aSynSAA. Longitudinal data will be essential to define progression patterns in these individuals to ultimately inform recruitment into disease modification clinical trials.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.