Plasma Neurofilament Light and p-tau181 and Risk of Psychosis in Parkinson's Disease

BACKGROUND: Neuropsychiatric symptoms are common and important to people with Parkinson's disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively which have yet to be explored in association with the affective and psychotic symptoms in PD. OBJECTIVE: To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD. METHODS: We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n = 63) was assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using Non-Motor Symptom Scale with affective symptoms measured in the Hospital Anxiety and Depression Scale. RESULTS: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40-47.4], p = 0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms. CONCLUSION: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD

Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase

Poly(ADP-ribosylation) of proteins following DNA damage is well studied and the use of poly(ADP-ribose) polymerase (PARP) inhibitors as therapeutic agents is an exciting prospect for the treatment of many cancers. Poly(ADP-ribose) glycohydrolase (PARG) has endo-and exoglycosidase activities which can cleave glycosidic bonds, rapidly reversing the action of PARP enzymes. Like addition of poly(ADP-ribose) (PAR) by PARP, removal of PAR by PARG is also thought to be required for repair of DNA strand breaks and for continued replication at perturbed forks. Here we use siRNA to show a synthetic lethal relationship between PARG and BRCA1, BRCA2, PALB2, FAM175A (ABRAXAS) and BARD1. In addition, we demonstrate that MCF7 cells depleted of these proteins are sensitive to Gallotannin and a novel and specific PARG inhibitor PDD00017273. We confirm that PARG inhibition increases endogenous DNA damage, stalls replication forks and increases homologous recombination, and propose that it is the lack of homologous recombination (HRR) proteins at PARG inhibitor-induced stalled replication forks that induces cell death. Interestingly not all genes that are synthetically lethal with PARP result in sensitivity to PARG inhibitors, suggesting that although there is overlap, the functions of PARP and PARG may not be completely identical. These data together add further evidence to the possibility that single treatment therapy with PARG inhibitors could be used for treatment of certain HRR deficient tumours and provide insight into the relationship between PARP, PARG and the processes of DNA repair

Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib

Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor. Here, a first in class, specific, and cell permeable PARG inhibitor, PDD00017273, is shown to radiosensitize. Further, PDD00017273 is compared with the PARP1/2/3 inhibitor olaparib. Both olaparib and PDD00017273 altered the repair of IR-induced DNA damage, resulting in delayed resolution of RAD51 foci compared with control cells. However, only PARG inhibition induced a rapid increase in IR-induced activation of PRKDC (DNA-PK) and perturbed mitotic progression. This suggests that PARG has additional functions in the cell compared with inhibition of PARP1/2/3, likely via reversal of tankyrase activity and/or that inhibiting the removal of poly(ADP-ribose) (PAR) has a different consequence to inhibiting PAR addition. Overall, our data are consistent with previous genetic findings, reveal new insights into the function of PAR metabolism following IR and demonstrate for the first time the therapeutic potential of PARG inhibitors as radiosensitizing agents

Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Risk factors for early psychosis in PD:insights from the Parkinson's Progression Markers Initiative

Parkinson's Disease (PD) psychosis refers to the spectrum of illusions, formed hallucinations and delusions that occur in PD. Visual hallucinations and illusions are thought to be caused by specific cognitive and higher visual function deficits and patients who develop such symptoms early in the disease course have greater rates of cognitive decline and progression to dementia. To date, no studies have investigated whether such deficits are found prior to the onset of PD psychosis. Here we compare baseline cognitive, biomarker (structural imaging and cerebrospinal fluid) and other PD psychosis risk factor data in patients who go on to develop illusions or hallucinations within 3-4 years of follow-up in the Parkinson's Progression Markers Initiative cohort of newly diagnosed PD. Of n=423 patients with PD, n=115 (27%) reported predominantly illusions with median onset at 19.5 months follow-up. At study entry these patients had reduced CSF amyloid Aß(1-42), lower olfaction scores, higher depression scores and increased REM sleep behaviour disorder symptoms compared to patients without early onset PD psychosis but no differences in cognitive, higher visual or structural imaging measures. A subset of patients with early onset formed hallucinations (n=21) had reduced higher visual function at baseline, cortical thinning in parietal, occipital and frontal cortex and reduced hippocampal volume. The findings suggest early onset illusions and formed hallucinations are linked to amyloid pathology in PD and point to a difference in the underlying pathophysiological mechanism of illusions and formed hallucinations, with implications for their respective links to future cognitive decline

Nonmotor symptom burden grading as predictor of cognitive impairment in Parkinson’s disease

Background: Identifying predictors of incident cognitive impairment (CI), one of the most problematic long-term outcomes, in Parkinson's disease (PD) is highly relevant for personalized medicine and prognostic counseling. The Nonmotor Symptoms Scale (NMSS) provides a global clinical assessment of a range of NMS, reflecting NMS burden (NMSB), and thus may assist in the identification of an "at-risk" CI group based on overall NMSB cutoff scores. Methods: To investigate whether specific patterns of PD NMS profiles predict incident CI, we performed a retrospective longitudinal study on a convenience sample of 541 nondemented PD patients taking part in the Nonmotor Longitudinal International Study (NILS) cohort, with Mini-Mental State Examination (MMSE), NMSS, and Scales for Outcomes in PD Motor Scale (SCOPA Motor) scores at baseline and last follow-up (mean 3.2 years) being available. Results: PD patients with incident CI (i.e., MMSE score ≤ 25) at last follow-up (n = 107) had severe overall NMSB level, significantly worse NMSS hallucinations/perceptual problems and higher NMSS attention/memory scores at baseline. Patients with CI also were older and with more advanced disease, but with no differences in disease duration, dopamine replacement therapy, sex, and comorbid depression, anxiety, and sleep disorders. Conclusions: Our findings suggest that a comprehensive baseline measure of NMS and in particular hallucinations and perceptual problems assessed with a validated single instrument can be used to predict incident CI in PD. This approach provides a simple, holistic strategy to predict future CI in this population.Albert‐Ludwigs‐Universität Freiburg: D637S