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Parkinson’s disease is a debilitating neurodegenerative movement disorder, characterized by the progressive and selective loss of dopaminergic neurons located in the substantia nigra, leading to clinical motor symptoms. The factors involved in PD are rather multifaceted. There are many cellular pathways contributing to its neuro-pathogenesis, which include abnormal protein aggregation, impaired ubiquitin proteasome system, autophagy, and neuroinflammation. However, despite years of investigation, still little is known about early events in the molecular pathogenesis. MicroRNAs are small non-coding RNAs that can regulate post-transcriptional expression of mRNAs. Since they somewhat modulate many mRNA targets simultaneously, many cellular pathways may be affected by one individual miRNA. Moreover, miRNAs can stably circulate in cerebrospinal fluid and blood, and their expression pattern can reflect the molecular pathophysiology, thus making them promising biomarkers in PD diagnosis and prognosis. In this review, we will review the recent progress on miRNA’s mechanism in PD pathogenesis and discuss the possibilities of miRNAs as PD molecular biomarkers.

SCarlet RoAD (NCT01224106; WN25203), a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-year study of gantenerumab in prodromal AD, was the first global registration-enabling study using biomarker screening for entry and a single clinical endpoint for outcome. Dosing was terminated in December 2014 following a pre-planned futility analysis; patients continue to be followed. Efficacy data for 2-year completers (n=312) and all ITT safety data (n=797) are presented. Patients were 50–85 years old with MMSE scores ≥24, CDR-Global scores of 0.5 (memory box scores of 0.5 or 1.0) and evidence of amyloid pathology (CSF Aβ42 <600 ng/mL, Innotest®), with cognition and functional performance largely preserved to exclude a diagnosis of AD dementia. Patients were randomized to monthly subcutaneous injections of placebo, or 105 mg or 225 mg gantenerumab, depending on their APOEe4 allele status (no APOEe4 homozygotes received 225 mg). Primary endpoint at 2 years was CDR-Sum of Boxes (SB) total score; secondary endpoints included ADAS-Cog 13, FAQ and MMSE. Biomarker results are presented separately. No differences in CDR-SB scores between placebo and gantenerumab treatment groups over 2 years were found, with similar findings for ADAS-Cog 13, FAQ and MMSE. PK/PD modeling showed an exposure-dependent trend for clinical benefit in patients that were predicted to have a faster rate of progression over the duration of the trial. Serious adverse events were reported in 19.5%, 17.3% and 16.9% of patients in the placebo, 105 mg and 225 mg gantenerumab arms, respectively. ARIA were dose- and APOEε4allele-dependent. Overall incidence of ARIA for placebo, 105 mg and 225 mg gantenerumab groups was 0.8%, 6.6% and 12.3% for ARIA-E, and 10.9%, 19.2% and 13.1% for ARIA-H, respectively. Additional exploratory analyses will be presented. Gantenerumab, a human anti-Aβ antibody with high affinity to aggregated Aβ, was well tolerated by patients with prodromal AD over the dose range tested in this dataset, one of the larger controlled datasets in prodromal AD patients available to date. No significant differences in primary efficacy endpoints between treatment arms were observed. Exploratory analyses are ongoing and will help guide further development of gantenerumab.

Gantenerumab, a human anti-Aβ antibody designed to bind aggregated Aβ and promote plaque removal, was studied in SCarlet RoAD (NCT01224106; WN25203)—a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-year trial in prodromal AD. Dosing was terminated in December 2014 following a pre-planned futility analysis; patients continue to be followed. CSF biomarker data and amyloid PET sub-study results are presented (patients completing 2-year treatment). Eligible patients were 50–85 years old, had MMSE scores ≥24, CDR-Global scores of 0.5 (memory box scores of 0.5 or 1.0) and evidence of amyloid pathology (CSF Aβ42 <600 ng/mL, Innotest®), with cognitive and functional performance largely preserved to exclude a diagnosis of dementia. Patients were randomized to monthly subcutaneous injections of placebo, or 105 mg or 225 mg gantenerumab, based on APOEe4 allele status (no APOEe4 homozygotes received 225 mg). CSF biomarkers were analyzed using Elecsys® β-Amyloid(1–42), tTau and pTau(181P) immunoassays (Roche Diagnostics; these products are in development and not available in the USA). 114 patients were enrolled in a PET sub-study (AmyvidTM). Standardized uptake value (SUVr), normalized to different reference regions, was assessed. Clinical results are presented separately. Amyloid-PET observed mean % change (± SD) from baseline in cortical composite SUVr (using mean cerebellar grey as reference region) at Week 100: placebo (n=20) -1.11 ± 8.02; 105 mg gantenerumab (n=11) +0.19 ± 12.70; 225 mg gantenerumab (n=18) -5.37 ± 7.92. No changes in CSF Aβ42 levels were found. CSF p-Tau mean % change (± SD) from baseline at Week 104: placebo (n=63) +2.62 ± 21.89; 105 mg gantenerumab (n=62) -4.85 ± 12.42; 225 mg gantenerumab (n=58) -7.52 ± 9.85. CSF t-Tau: mean % change (± SD) from baseline at Week 104: placebo (n=62) +3.11 ± 21.12; 105 mg gantenerumab (n=60) -1.45 ± 13.55; 225 mg gantenerumab (n=57) -2.94 ± 10.37. At the doses tested, gantenerumab treatment was associated with dose-dependent reductions in brain Aβ SUVr and CSF p-Tau and t-Tau, compared with placebo. As expected, CSF Aβ42 levels were unaltered. These findings are consistent with brain amyloid clearance and an effect on downstream markers of neurodegeneration.

IMPORTANCEIn schizophrenia, the severity of negative symptoms is a key predictor of long-term disability. Deficient signaling through the N-methyl-D-aspartate receptor is hypothesized to underlie many signs and symptoms associated with schizophrenia in particular negative symptoms. Glycine acts as an N-methyl-D-aspartate receptor coagonist. Blockade of the glycine transporter type 1 to inhibit glycine reuptake and elevate synaptic glycine concentrations represents an effective strategy to enhance N-methyl-D-aspartate receptor transmission.OBJECTIVETo determine the efficacy and safety of bitopertin (RG1678), a glycine reuptake inhibitor, in patients with schizophrenia and predominant negative symptoms who were stable while taking an antipsychotic treatment.DESIGN, SETTING, AND PARTICIPANTSThis randomized, double-blind, placebo-controlled, phase 2 proof-of-concept trial involved 323 patients with schizophrenia and predominant negative symptoms across 66 sites worldwide.INTERVENTIONSBitopertin (10, 30, or 60 mg/d) or placebo added to standard antipsychotic therapy for a treatment duration of 8 weeks.MAIN OUTCOMES AND MEASURESChange from baseline in the Positive and Negative Syndrome Scale negative factor score.RESULTSIn the per-protocol population, 8 weeks of treatment with bitopertin was associated with a significant reduction of negative symptoms in the 10-mg/d (mean [SE] reduction in negative symptoms score, -25% [2%]; P = .049) and 30-mg/d (mean [SE], -25% [2%]; P = .03) bitopertin groups, a significantly higher response rate and a trend toward improved functioning in the 10-mg/d group when compared with placebo (mean [SE], -19% [2%]). Results reached trend-level significance in the intent-to-treat population. Estimates of bitopertin binding to glycine transporter type 1 showed that low to medium levels of occupancy yielded optimal efficacy in patients, consistent with findings in preclinical assays.CONCLUSIONS AND RELEVANCEBitopertin-mediated glycine reuptake inhibition may represent a novel treatment option for schizophrenia, with the potential to address negative symptoms.TRIAL REGISTRATIONclinicaltrials.gov Identifier: NCT00616798.

Cytology-based cervical screening had unequivocal success in reducing the incidence and mortality of cervical cancer in the last century. The recognition of the role of human papillomavirus (HPV) as a necessary cause of cervical cancer led to the development of HPV testing. Gradually, there has been a shift from reflex HPV testing for mild cytological abnormalities, to co-testing with cytology and HPV, and lately to primary HPV screening, based on evidence from well-designed large randomized controlled trials and meta-analyses. Advantages of primary HPV screening include higher sensitivity to detect pre-neoplastic lesions, better re-assurance with a negative test, and safe prolongation of screening intervals. However, clinicians and policy makers must ensure the availability of clinically validated HPV assays and triage protocols of screen positive cases prior to implementation of primary HPV screening. This is likely to reduce potential harm from over-treatment as well as extra burden on the health care system.

A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR®), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of ≥1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs.

In this double-blind, placebo-controlled trial, we investigated the effect of the catechol-O-methyltransferase inhibitor tolcapone 100 or 200 mg three times daily on activities of daily living and motor function in 298 patients with parkinsonism receiving levodopa but without motor fluctuations. At 6 months, both dosages of tolcapone produced significant reductions in the Unified Parkinson's Disease Rating Scale scores for activities of daily living (Subscale II) and motor function (Subscale III) and in the total score for Subscales I to III. These improvements were maintained up to the 12-month assessment. At 6 months, both tolcapone groups had changes in levodopa dosage that were significantly different from placebo: the tolcapone groups had decreases in mean total daily dose of levodopa, whereas the placebo group had a mean increase. Tolcapone was well tolerated. The principal adverse events were levodopa-related, but these were generally mild or moderate. Diarrhea was the most frequent nondopaminergic adverse event. Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations.

We studied the new catechol-O-methyltransferase inhibitor tolcapone, 100 and 200 mg, three times daily (tid) in a randomized, double-blind, parallel-group trial involving 202 parkinsonian patients who were experiencing the "wearing-off" phenomenon on levodopa therapy. After 3 months, patients receiving tolcapone had a significant decrease in mean daily levodopa dose requirement compared with placebo-treated patients (p< 0.01). In patients treated with tolcapone 200 mg tid, daily "off" time, measured using patient diaries, was reduced from baseline by 3.25 hours; this reduction was significantly different from that seen in the placebo group(p < 0.01). Moreover, the number of daily levodopa intakes was reduced significantly in each tolcapone group compared with placebo(p < 0.01). We found significant improvements in motor function and overall efficacy in the tolcapone groups (p < 0.01). The most frequent adverse events were associated with levodopa treatment. Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study. Diarrhea was the most frequent nondopaminergic event, occurring in 14% on placebo, 13% on tolcapone 100 mg tid, and 19% on 200 mg tid. Overall 18% of patients withdrew because of adverse events: 15% on placebo, 17% on tolcapone 100 mg tid, and 22% on 200 mg tid. We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off" phenomenon in levodopa-treated parkinsonian patients.

Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demonstrated to improve motor function and allow levodopa dose reductions in Parkinson's disease (PD) patients who are experiencing either a stable response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because shiatal dopamine is metabolized by COMT and monoamine oxidase (MAO), central COMT inhibition alone or in combination with MAO inhibition might provide symptomatic benefit for patients not receiving levodopa. We conducted a pilot study to evaluate the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in early untreated PD patients. Patients were randomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the morning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups according to the investigator's assessment of tolerability at week 4. Ninety-five percent of tolcapone-treated patients and 98% of placebo-treated patients experienced excellent or good tolerability during the first 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A decrease in tolerability occurred in the tolcapone group during the second 4 weeks of the study following the addition of selegiline. The most commonly reported side effects were diarrhea (31% tolcapone, 7% placebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tolcapone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% placebo). We did not identify symptomatic benefit associated with tolcapone alone or in combination with oral selegiline in this group of otherwise untreated PD patients.

Objective: To assess the efficacy and tolerability of the catechol-O-methyltransferase inhibitor tolcapone in reducing "off/on" fluctuations in levodopa-treated parkinsonian patients.Design: A randomized, double-blind, placebo-controlled, parallel-group study.Setting: Fifteen Parkinson disease clinics.Patients: Two hundred fifteen referred outpatients with Parkinson disease who showed predictable end-of-dose motor fluctuations that were not controlled by a stable levodopa-carbidopa (Sinemet) regimen of at least 4 weeks' duration.Interventions: In addition to their usual levodopa-carbidopa regimen, patients received placebo or tolcapone, 100 or 200 mg, 3 times daily orally for 6 weeks.Primary Outcome Measure: Change in daily off/on time.Results: Tolcapone, 100 and 200 mg 3 times daily, reduced off time by 2.0 and 2.5 hours per day, respectively, and increased on time by 2.1 and 2.3 hours per day, respectively (P < .001 vs placebo). Investigators' global measures of disease severity indicated that significantly more tolcapone-treated patients had reduced wearing off and symptom severity (P < .001 vs placebo). No significant change in quality-of-life measures occurred. Clinical improvements occurred despite a reduction in total daily levodopa dose of 185.5 mg (23%) in the tolcapone, 100 mg 3 times daily, group and 251.5 mg (29%) in the 200 mg 3 times daily group. Principal adverse events (mainly dyskinesia and nausea) were levodopa related, were not treatment limiting, and were seldom reported as reasons for withdrawal. The frequency of withdrawals because of adverse events was similar in all groups (3% to 7%).Conclusions: Tolcapone was well tolerated and substantially increased on time and reduced off time in patients with fluctuating Parkinson disease. Additionally, levodopa requirements were significantly decreased.

Tolcapone is a potent catechol-O-methyltransferase inhibitor that prolongs the plasma half-life of levodopa. This multicenter, double-blind, placebo-controlled study used two 10-hour clinical evaluations to compare the efficacy and safety of three doses of tolcapone (50, 200, and 400 mg tid) with placebo in patients with Parkinson's disease (PD) experiencing motor fluctuations from levodopa/carbidopa. One hundred fifty-one patients completed the study. Clinical evaluations lasting 10 hours were performed on day -1 and day 42 using United Parkinson's Disease Rating Scale motor subscale and "on/off" and dyskinesia assessments every 30 minutes. Tolcapone significantly reduced "off" time an average of 40% and increased total "on" time by about 25% at all dose levels, as compared to placebo treatment. Levodopa/carbidopa dosage and frequency were significantly reduced. Tolcapone was well tolerated, with patients experiencing typical dopaminergic side effects that could be reduced or eliminated by lowering levodopa/carbidopa dosages. Tolcapone was effective at prolonging the clinical benefit of levodopa and reducing total levodopa requirements in PD patients with motor fluctuations.