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Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).

Synucleinopathies are neurodegenerative disorders defined by the pathological aggregation of α-synuclein. Several α-synuclein biomarkers have been developed to aid diagnosis and research, such as cerebrospinal fluid (CSF) and blood-based measurements, seed amplification assays (SAAs), and immunohistochemical detection from skin biopsies. While these existing biomarkers have important uses, they face limitations in diagnostic specificity, spatial localization, and the ability to monitor disease progression or response to therapy. The development of α-synuclein PET tracers, which would allow for the direct in vivo imaging of α-synuclein, represents an important unmet need in both research and the clinical care of patients with movement disorders. This review outlines the current landscape of α-synuclein biomarkers and discusses both the scientific and technical challenges in developing α-synuclein PET imaging tracers.

Parkinson disease patients develop clinically significant cognitive impairment at variable times over their disease course, which is often preceded by milder deficits in memory, visuo-spatial, and executive domains. The significance of amyloid-β accumulation to these problems is unclear. We hypothesized that amyloid-β PET imaging by 18F-florbetapir, a radiotracer that detects fibrillar amyloid-β plaque deposits, would identify subjects with global cognitive impairment or poor performance in individual cognitive domains in non-demented Parkinson disease patients. We assessed 61 non-demented Parkinson disease patients with detailed cognitive assessments and 18F-florbetapir PET brain imaging. Scans were interpreted qualitatively (positive or negative) by two independent nuclear medicine physicians blinded to clinical data, and quantitatively by a novel volume-weighted method. The presence of mild cognitive impairment was determined through an expert consensus process using Level 1 criteria from the Movement Disorder Society. Nineteen participants (31.2%) were diagnosed with mild cognitive impairment and the remainder had normal cognition. Qualitative 18F-florbetapir PET imaging was positive in 15 participants (24.6%). Increasing age and presence of an APOE ε4 allele were associated with higher composite 18F-florbetapir binding. In multivariable models, an abnormal 18F-florbetapir scan by expert rating was not associated with a diagnosis of mild cognitive impairment. However, 18F-florbetapir retention values in the posterior cingulate gyrus inversely correlated with verbal memory performance. Retention values in the frontal cortex, precuneus, and anterior cingulate gyrus retention values inversely correlated with naming performance. Regional cortical amyloid-β amyloid, as measured by 18F-florbetapir PET, may be a biomarker of specific cognitive deficits in non-demented Parkinson disease patients.

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. 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 [alpha]-synuclein ([alpha]Syn). [alpha]Syn was significantly lower in PD (mean 103 pg/ml vs. HC: 127 pg/ml, p0.05) 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 [alpha]Syn and IL-6. Except for [alpha]Syn, 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.

Now that wearable sensors have become more commonplace, it is possible to monitor individual healthcare-related activity outside the clinic, unleashing potential for early detection of events in diseases such as Parkinson’s disease (PD). However, the unsupervised and “open world” nature of this type of data collection make such applications difficult to develop. In this proof-of-concept study, we used inertial sensor data from Verily Study Watches worn by individuals for up to 23 h per day over several months to distinguish between seven subjects with PD and four without. Since motor-related PD symptoms such as bradykinesia and gait abnormalities typically present when a PD subject is walking, we initially used human activity recognition (HAR) techniques to identify walk-like activity in the unconstrained, unlabeled data. We then used these “walk-like” events to train one-dimensional convolutional neural networks (1D-CNNs) to determine the presence of PD. We report classification accuracies near 90% on single 5-s walk-like events and 100% accuracy when taking the majority vote over single-event classifications that span a duration of one day. Though based on a small cohort, this study shows the feasibility of leveraging unconstrained wearable sensor data to accurately detect the presence or absence of PD.

Recent findings question our present understanding of Parkinson's disease and suggest that new research criteria for the diagnosis of Parkinson's disease are needed, similar to those recently defined in Alzheimer's disease. However, our ability to redefine Parkinson's disease is hampered by its complexity and heterogeneity in genetics, phenotypes, and underlying molecular mechanisms; the absence of biochemical markers or ability to image Parkinson's disease-specific histopathological changes; the long prodromal period during which non-motor manifestations might precede classic motor manifestations; and uncertainty about the status of disorders diagnosed clinically as Parkinson's disease but without Lewy pathology. Although it is too early to confidently redefine Parkinson's disease, the time has come to establish a research framework that could lead to new diagnostic criteria. We propose the establishment of three tiers encompassing clinical features, pathological findings, and genetics or molecular mechanisms. Specific advances in each tier, bridged by neuroimaging and biochemical data, will eventually lead to a redefinition of Parkinson's disease.

To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments. We longitudinally assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta [Aβ], tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition. Additionally, longitudinal structural MRI and DAT scan data were included. Univariate analyses were run initially, with false discovery rate = 0.2, to select biomarker variables for inclusion in multivariable longitudinal mixed-effect models. By year 3, cognitive impairment was diagnosed in 15-38% participants depending on the criteria applied. Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer's disease Aβ amyloid pathology (lower CSF Aβ 1-42); and (4) genes (COMT val/val and BDNF val/val genotypes). Cognitive impairment in PD increases in frequency 50-200% in the first several years of disease, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer's disease plaque pathology, and genetic factors.

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression. In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 × 10-2, Replication FDR-corrected p = 1.03 × 10-4), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 × 10-2, Replication FDR-corrected p = 9.14 × 10-5), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 × 10-3, Replication FDR-corrected p = 2.18 × 10-2), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 × 10-4, Replication FDR-corrected p = 2.97 × 10-3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04-5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24-7.0, p = 0.014] for ACY1). GHR's association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20-11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts. In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD.

Purpose This study examined the feasibility of using quantitation to augment interpretation of florbetapir PET amyloid imaging. Methods A total of 80 physician readers were trained on quantitation of florbetapir PET images and the principles for using quantitation to augment a visual read. On day 1, the readers completed a visual read of 96 scans (46 autopsy-verified and 50 from patients seeking a diagnosis). On day 2, 69 of the readers reinterpreted the 96 scans augmenting their interpretation with quantitation (VisQ method) using one of three commercial software packages. A subset of 11 readers reinterpreted all scans on day 2 based on a visual read only (VisVis control). For the autopsy-verified scans, the neuropathologist’s modified CERAD plaque score was used as the truth standard for interpretation accuracy. Because an autopsy truth standard was not available for scans from patients seeking a diagnosis, the majority VisQ interpretation of the three readers with the best accuracy in interpreting autopsy-verified scans was used as the reference standard. Results Day 1 visual read accuracy was high for both the autopsy-verified scans (90%) and the scans from patients seeking a diagnosis (87.3%). Accuracy improved from the visual read to the VisQ read (from 90.1% to 93.1%, p  < 0.0001). Importantly, access to quantitative information did not decrease interpretation accuracy of the above-average readers (>90% on day 1). Accuracy in interpreting the autopsy-verified scans also increased from the first to the second visual read (VisVis group). However, agreement with the reference standard (best readers) for scans from patients seeking a diagnosis did not improve with a second visual read, and in this cohort the VisQ group was significantly improved relative to the VisVis group (change 5.4% vs. −1.1%, p  < 0.0001). Conclusion These results indicate that augmentation of visual interpretation of florbetapir PET amyloid images with quantitative information obtained using commercially available software packages did not reduce the accuracy of readers who were already performing with above average accuracy on the visual read and may improve the accuracy and confidence of some readers in clinically relevant cases.

The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7-8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.