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Identification of individuals at high risk for rapid progression of motor and cognitive signs in Parkinson disease (PD) is clinically significant. Postural instability and gait dysfunction (PIGD) are associated with greater motor and cognitive deterioration. We examined the relationship between baseline clinical factors and the development of postural instability using 5-year longitudinal de-novo idiopathic data (n = 301) from the Parkinson's Progressive Markers Initiative (PPMI). Logistic regression analysis revealed baseline features associated with future postural instability, and we designated this cohort the emerging postural instability (ePI) phenotype. We evaluated the resulting ePI phenotype rating scale validity in two held-out populations which showed a significantly higher risk of postural instability. Emerging PI phenotype was identified before onset of postural instability in 289 of 301 paired comparisons, with a median progression time of 972 days. Baseline cognitive performance was similar but declined more rapidly in ePI phenotype. We provide an ePI phenotype rating scale (ePIRS) for evaluation of individual risk at baseline for progression to postural instability.

BackgroundThe Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.MethodsThis cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FindingsBetween Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

Parkinson's disease (PD) is a progressive neurodegenerative condition associated with a broad scope of motor and nonmotor symptoms (NMS). Excessive daytime sleepiness (EDS) is one of the most common and debilitating manifestations of NMS in PD. The reported prevalence of EDS in the overall PD population is widely variable (16%-74%) and depends on EDS criteria, disease stage, and ascertainment methods, but it is consistently higher than in the general population.1,2 Respective data on EDS stem largely from studies on patients with advanced PD, whereas hardly any data exist on EDS in early, specifically untreated, PD. The cause of EDS in advanced and treated PD is multifactorial.3 Disease variables that have been reported to be associated with EDS in PD populations include longer disease duration, older age, older age at PD onset, sex, more severe motor manifestations, nontremor dominant motor phenotype, depression, anxiety, cognitive impairment, and hallucinations.4-10 In addition, dopaminergic medications have been shown to have a major negative impact on EDS in PD.4,11-14 The presence of EDS predicts a greater decline over time in motor impairment, cognition, and greater risk of developing dementia.15 Very limited information is available on EDS in early, specifically untreated, PD.16-18 Three small studies assessed EDS in de novo PD patients.16-18 Each of them enrolled fewer than 25 de novo PD patients, and only one had healthy controls (HCs). Excessive daytime sleepiness was defined by Epworth Sleepiness Scale (ESS ≥ 10). All studies came to the same conclusion: that EDS does not seem to be a trait of untreated PD.16-18 More recent studies assessed EDS as part of the overall NMS by using a validated NMS questionnaire.19,20 Prevalence of EDS in the cohort of 97 de novo PD subjects was 3.3% and did not change significantly 2 y later with initiation of dopaminergic therapy (4.4%).20 However, prevalence was substantially higher (28% of 109 subjects) in another de novo cohort compared with 15% of 107 HCs.19 Thus, uncertainty remains regarding the prevalence and clinicobiological correlates of EDS in de novo PD. That is specifically relevant considering that EDS was shown to be one of the risk factors for development of PD in prospective epidemiological studies and may precede onset of motor manifestations of PD,4,21 theoretically corresponding to Braak et al.'s data22 on early involvement of the brainstem sleep wakefulness control system in the disease pathological process.22 We aimed to systematically explore prevalence, clinical, and for the first time biological correlates of EDS in a large group of subjects with early untreated PD compared with HCs.

Importance We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not β-amyloid 1-42 (Aβ1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. Objective To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aβ1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau 181 ], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI) study. Design, Setting, and Participants Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. Main Outcomes and Measures The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aβ1-42, T-tau, and P-tau 181 ; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. Results Slightly, but significantly, lower levels of Aβ1-42, T-tau, P-tau 181 , α-synuclein, and T-tau/Aβ1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower Aβ1-42 and P-tau 181 levels were associated with PD diagnosis and that decreased CSF T-tau and α-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aβ1-42 and P-tau 181 concentrations were associated with the postural instability–gait disturbance–dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau 181 . Conclusions and Relevance In this first report of CSF biomarkers in PPMI study subjects, we found that measures of CSF Aβ1-42, T-tau, P-tau 181 , and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression.

The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials. The PPMI cohort will comprise 400 recently diagnosed PD and 200 healthy subjects followed longitudinally for clinical, imaging and biospecimen biomarker assessment using standardized data acquisition protocols at twenty-one clinical sites. All study data will be integrated in the PPMI study database and will be rapidly and publically available through the PPMI web site- www.ppmi-info.org. Biological samples including longitudinal collection of blood, cerebrospinal fluid (CSF) and urine will be available to scientists by application to an independent PPMI biospecimen review committee also through the PPMI web site. PPMI will rely on a partnership of government, PD foundations, industry and academics working cooperatively. This approach is crucial to enhance the potential for success of this ambitious strategy to develop PD progression biomarkers that will accelerate research in disease modifying therapeutics.

Parkinson’s Disease (PD) is an age-related, chronic neurodegenerative disorder. Activated microglia/macrophages is associated with the pathogenesis of PD. Accumulation of α-synuclein (α-syn) leads to microglial activation and neurodegeneration. We have recently shown that inhibiting the JAK/STAT pathway prevents inflammation and neurodegeneration by suppressing activation of immune responses, and iNOS, TNF-α and IL-6 expression in an a-syn overexpression PD model. Studies from patients and animal models suggest that M1-polarized macrophage activation promotes the loss of dopaminergic neurons. As such, we investigated the function of M1-polarized macrophages in PD, especially how aggregated a-syn affects M1 phenotype. Our results indicate that expression levels of IFN-γ-induced MHC Class II, CD40, iNOS, TNF-α and IL-6 are synergistically enhanced by α-syn stimulation, along with higher activation of STAT1 and STAT3. We have previously shown that macrophages deficient in SOCS3 have heightened STAT3 activation and M1 phenotype. Stimulation of SOCS3-/- macrophages with a combination of α-syn and IFN-γ promotes a more pronounced M1 phenotype that promote neuronal degeneration. We hypothesize that hyperactivation of JAK/STAT and M1 macrophages promotes more severe synucleinopathy, including neuroinflammation and neurodegeneration. The characteristics of PD pathology in SOCS3fl/fl and LysMCre-SOCS3fl/fl mice with α-syn overexpression is currently under investigation.

Extracellular adenosine critically modulates ischemic brain injury, at least in part through activation of the A(1) adenosine receptor. However, the role played by the A(2A) receptor has been obscured by intrinsic limitations of A(2A) adenosinergic agents. To overcome these pharmacological limitations, we explored the consequences of deleting the A(2A) adenosine receptor on brain damage after transient focal ischemia. Cerebral morphology, as well as vascular and physiological measures (before, during, and after ischemia) did not differ between A(2A) receptor knock-out and wild-type littermates. The volume of cerebral infarction, as well as the associated neurological deficit induced by transient filament occlusion of the middle cerebral artery, were significantly attenuated in A(2A) receptor knock-out mice. This neuroprotective phenotype of A(2A) receptor-deficient mice was observed in different genetic backgrounds, confirming A(2A) receptor disruption as its cause. Together with complimentary pharmacological studies, these data suggest that A(2A) receptors play a prominent role in the development of ischemic injury within brain and demonstrate the potential for anatomical and functional neuroprotection against stroke by A(2A) receptor antagonists