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Purpose: to explore and describe the health care situation, the use of aids, the way of communicating and the quality of life of Locked-in syndrome patients in Flanders (Belgium) and to collect information on their fulfilled and unfulfilled needs. Method: in depth interviews with eight LIS-patients by means of an extensive questionnaire consisting of five parts: (i) general information and medical history, (ii) health care, rehabilitation and follow-up, (iii) speech and communication, (iv) quality of life, (v) needs and problems experienced. Results: the patients' condition, mostly caused by ischemic stroke, persisted for a mean period of 6 years 8 months. Their mean age was 41;10 years. At the moment of our study all the patients were living at home. Care was provided by an extensive care team. Some recovery of head and neck movements was mentioned, recovery of upper and lower limb mobility however was very limited. Most patients use an alphabet system to communicate, all of them had access to and made use of a PC with internet connection. Except for the domain of physical functioning, the quality of life scores of our patient group are rather high. As for unfulfilled needs, half of the patients experience a lack of information on their condition and a lack of appropriate information on (communication) aids. Conclusion: most results seem to be in line with those of other studies, though larger scale and follow-up studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

To curb viral epidemics and pandemics, antiviral drugs are needed with activity against entire genera or families of viruses. Here, we develop a cell-based multiplex antiviral assay for high-throughput screening against multiple viruses at once, as demonstrated by using three distantly related orthoflaviviruses: dengue, Japanese encephalitis and yellow fever virus. Each virus is tagged with a distinct fluorescent protein, enabling individual monitoring in cell culture through high-content imaging. Specific antisera and small-molecule inhibitors are employed to validate that multiplexing approach yields comparable inhibition profiles to single-virus infection assays. To facilitate downstream analysis, a kernel is developed to deconvolute and reduce the multidimensional quantitative data to three cartesian coordinates. The methodology is applicable to viruses from different families as exemplified by co-infections with chikungunya, parainfluenza and Bunyamwera viruses. The multiplex approach is expected to facilitate the discovery of broader-spectrum antivirals, as shown in a pilot screen of approximately 1200 drug-like small-molecules., (© 2024. The Author(s).)

Whereas most infants infected with respiratory syncytial virus (RSV) show no or only mild symptoms, an estimated 3 million children under five are hospitalized annually due to RSV disease. This study aimed to investigate biological mechanisms and associated biomarkers underlying RSV disease heterogeneity in young infants, enabling the potential to objectively categorize RSV-infected infants according to their medical needs. Immunophenotypic and functional profiling demonstrated the emergence of immature and progenitor-like neutrophils, proliferative monocytes (HLA-DR Low , Ki67+), impaired antigen-presenting function, downregulation of T cell response and low abundance of HLA-DR Low B cells in severe RSV disease. HLA-DR Low monocytes were found as a hallmark of RSV-infected infants requiring hospitalization. Complementary transcriptomics identified genes associated with disease severity and pointed to the emergency myelopoiesis response. These results shed new light on mechanisms underlying the pathogenesis and development of severe RSV disease and identified potential new candidate biomarkers for patient stratification., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16 + and granzyme B + NK cells, and higher frequency of TIM-3 + and HLA-DR + NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells., Competing Interests: MCM has a consultancy or advisory role for Gilead Sciences, BMS, Alnylam, Janssen Cilag, Takeda, and Servier; all paid to employer, hospitality from Celgene. MDL serves in advisory boards for Roche, Janssen and Abbvia. AB receives honoraria from Celgene, Janssen, Amgen, Takeda, and Sanofi. MJK has received research support from Kite/Gilead, and honoraria from Kite/Gilead, Novartis, BMS/Celgene, Takeda, Roche, and Miltenyi Biotec (all paid to institution). MK, TC, YA, RIV, TS, GV, DCS, LvS, and ER are employed by Janssen. PS has received honoraria from Amgen, BMS, Celgene, Janssen, Karyopharm, Takeda, and receives research funding from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, Takeda. SZ has received research funding from Celgene, Takeda, Janssen, and serves in advisory boards for Janssen, Takeda, BMS, Oncopeptides and Sanofi, all paid to institution. TM has received research support from Janssen Pharmaceuticals, Takeda, Genmab, Novartis, and ONK Therapeutics. NWCJvdD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS, and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

CD38-targeted antibody, daratumumab, is approved for the treatment of multiple myeloma (MM). Phase 1/2 studies GEN501/SIRIUS revealed a novel immunomodulatory mechanism of action (MOA) of daratumumab that enhanced the immune response, reducing natural killer (NK) cells without affecting efficacy or safety. We further evaluated daratumumab's effects on immune cells in whole blood samples of relapsed/refractory MM patients from both treatment arms of the phase 3 POLLUX study (lenalidomide/dexamethasone [Rd] or daratumumab plus Rd [D-Rd]) at baseline (D-Rd, 40; Rd, 45) and after 2 months on treatment (D-Rd, 31; Rd, 33) using cytometry by time-of-flight. We confirmed previous reports of NK cell reduction with D-Rd. Persisting NK cells were phenotypically distinct, with increased expression of HLA-DR, CD69, CD127, and CD27. The proportion of T cells increased preferentially in deep responders to D-Rd, with a higher proportion of CD8 + versus CD4 + T cells. The expansion of CD8 + T cells correlated with clonality, indicating generation of adaptive immune response with D-Rd. D-Rd resulted in a higher proportion of effector memory T cells versus Rd. D-Rd reduced immunosuppressive CD38 + regulatory T cells. This study confirms daratumumab's immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.

We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5- a ]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC 50 's from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC 50 of 1.3 ± 0.39 nM, ∼100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.

Daratumumab is a CD38-targeted human monoclonal antibody with direct anti-myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T-cell expansion and reduction of immune-suppressive populations, suggesting immune modulation as an additional mechanism of action. Here, we performed an in-depth analysis of the effects of daratumumab on immune-cell subpopulations using high-dimensional mass cytometry. Whole-blood and bone-marrow baseline and on-treatment samples from RRMM patients who participated in daratumumab monotherapy studies (SIRIUS and GEN501) were evaluated with high-throughput immunophenotyping. In daratumumab-treated patients, the intensity of CD38 marker expression decreased on many immune cells in SIRIUS whole-blood samples. Natural killer (NK) cells were depleted with daratumumab, with remaining NK cells showing increased CD69 and CD127, decreased CD45RA, and trends for increased CD25, CD27, and CD137 and decreased granzyme B. Immune-suppressive population depletion paralleled previous findings, and a newly observed reduction in CD38 + basophils was seen in patients who received monotherapy. After 2 months of daratumumab, the T-cell population in whole-blood samples from responders shifted to a CD8 prevalence with higher granzyme B positivity (P = 0.017), suggesting increased killing capacity and supporting monotherapy-induced CD8 + T-cell activation. High-throughput cytometry immune profiling confirms and builds upon previous flow cytometry data, including comparable CD38 marker intensity on plasma cells, NK cells, monocytes, and B/T cells. Interestingly, a shift toward cytolytic granzyme B + T cells was also observed and supports adaptive responses in patients that may contribute to depth of response. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry., (© 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.)

Mass cytometry has emerged as a new state-of-the-art technology that enables in-depth characterization of cellular populations and functions at a single cell resolution. We describe the application of this technology to deeply phenotype the blood and bone marrow components of multiple myeloma patients in a clinical setting. This technology allows for simultaneous quantification of more than 40 markers, overcoming the challenges of traditional fluorescence-based flow cytometry.

The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDE5 represents an important therapeutic and/or prognostic target, but noninvasive assessment of PDE5 expression is lacking. The purpose of this study was to develop and evaluate pyridopyrazinone derivatives labeled with carbon-11 or fluorine-18 as PDE5-specific PET tracers. In biodistribution studies, highest PDE5-specific retention was observed for [ 11 C]-12 and [ 18 F]-17 in the lungs of wild-type mice and in the myocardium of transgenic mice with cardiomyocyte-specific PDE5 overexpression at 30 min postinjection. In vivo dynamic microPET images in rats revealed that both tracers crossed the blood-brain barrier but brain retention was not PDE5-specific. Both [ 11 C]-12 and [ 18 F]-17 showed specific binding to PDE5 in myocardium of transgenic mice; however [ 18 F]-17 showed significantly higher PDE5-specific inhibitable binding than [ 11 C]-12.

Behavioral and event-related potential (ERP) studies on aphasia patients showed that lexical information is not lost but rather its integration into the working context is hampered. Studies have been conducted on the processing of sentence-level information (meaningful versus meaningless) and of word-level information (related versus unrelated) in aphasia patients, but we are not aware of any study that assesses the relationship between the two. In healthy subjects the processing of a single word in a sentence context has been studied using the N400 ERP. It was shown that, even when there is only a weak expectation of a final word in a sentence, this expectation will dominate word relatedness. In order to study the effect of semantic relatedness between words in sentence processing in aphasia patients, we conducted a crossed-design ERP study, crossing the factors of word relatedness and sentence congruity. We tested aphasia patients with mild to minimum comprehension deficit and healthy young and older (age-matched with our patients) controls on a semantic anomaly judgment task when simultaneously recording EEG. Our results show that our aphasia patient's N400 amplitudes in response to the sentences of our crossed-design study were similar to those of our age-matched healthy subjects. However, we detected an increase in the N400 ERP latency in those patients, indicating a delay in the integration of the new word into the working context. Additionally, we observed a positive correlation between comprehension level of those patients and N400 effect in response to meaningful sentences without word relatedness contrasted to meaningless sentences without word relatedness.

Background: Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission. However, little is known on the effect of alterations in DA neurotransmission on PDE10A availability. Here, we used [ 18 F]JNJ42259152 PET to measure changes in PDE10A availability, secondary to pharmacological alterations in DA release and to investigate whether these are D 1 - or D 2 -receptor driven., Results: Acute treatment of rats using D-amphetamine (5 mg, s.c. and 1 mg/kg i.v.) did not result in a significant change in PDE10A BP ND compared to baseline conditions. 5-day D-amphetamine treatment (5 mg/kg, s.c.) increased striatal PDE10A BP ND compared to the baseline (+24 %, p  = 0.03). Treatment with the selective D2 antagonist SCH23390 (1 mg/kg) and D-amphetamine decreased PDE10A binding (-22 %, p  = 0.03). Treatment with only SCH23390 further decreased PDE10A binding (-26 %, p  = 0.03). No significant alterations in PDE10A mRNA levels were observed., Conclusions: Repeated D-amphetamine treatment significantly increased PDE10A binding, which is not observed upon selective D 1 receptor blocking. This study suggests a potential pharmacological interaction between PDE10A enzymes and drugs modifying DA neurotransmission. Therefore, PDE10A binding in patients with neuropsychiatric disorders might be modulated by chronic DA-related treatment.

There is increasing evidence that a bilingual person should not be considered as two monolinguals in a single body, a view that has gradually been adopted in the diagnosis and treatment of bilingual aphasia. However, its investigation is complicated due to the large variety in possible language combinations, pre- and postmorbid language proficiencies, and age of second language acquisition. Furthermore, the tests and tasks used to assess linguistic capabilities differ in almost every study, hindering a direct comparison of their outcomes. Behavioral, electrophysiological, and neuroimaging data from healthy population show that the processing of second language domains (semantics, syntax, morphology) depends on factors such as age and method of acquisition, proficiency level and environment in which the second language was acquired. A number of single and multiple case reports that rely on behavioral testing of bilingual aphasics replicate these results. Additionally, they show that the patient's performance depends on the size and location of the lesion, as well as language typology and morphological characteristics. Furthermore, the impairment and recovery patterns and recovery generalization from treated to untreated language depend on the lexical and orthographic distances between the two languages. For healthy bilinguals, language processing is usually studied in comparison to monolinguals. We advocate that a good starting point for identifying patterns specific for bilingual aphasia is to compare patient studies of bilinguals and monolinguals., (© 2016 Wiley Periodicals, Inc.)

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.

A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12.

The enzyme phosphodiesterase 10A (PDE10A) regulates the activity of striatal, medium spiny neurons (MSNs), which are divided into a behaviorally stimulating, Gs-coupled D1 receptor-expressing "direct" pathway and a behaviorally suppressant, Gi-coupled D2 receptor-expressing "indirect" pathway. Activating both pathways, PDE10A inhibitors (PDE10AIs) combine functional characteristics of D2 antagonists and D1 agonists. While the effects of PDE10AIs on spontaneous and stimulated behavior have been extensively reported, the present study investigates their effects on suppressed behavior under various conditions of reduced dopaminergic neurotransmission: blockade of D1 receptors with SCH-23390, blockade of D2 receptors with haloperidol, or depletion of dopamine with RO-4-1284 or reserpine. In rats, PDE10AIs displayed relatively low cataleptic activity per se. After blocking D1 receptors, however, they induced pronounced catalepsy at low doses close to those required for inhibition of apomorphine-induced behavior; slightly higher doses resulted in behavioral stimulant effects, counteracting the catalepsy. PDE10AIs also counteracted catalepsy and related behaviors induced by D2 receptor blockade or dopamine depletion; catalepsy was replaced by behavioral stimulant effects under the latter but not the former condition. Similar interactions were observed at the level of locomotion in mice. At doses close to those inhibiting d-amphetamine-induced hyperlocomotion, PDE10AIs reversed hypolocomotion induced by D1 receptor blockade or dopamine depletion but not hypolocomotion induced by D2 receptor blockade. It is concluded that PDE10AIs stimulate or inhibit motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways.

Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.

The striatum is the main input structure to the basal ganglia and consists mainly out of medium spiny neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal medium spiny neurons and hydrolyses cAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal medium spiny neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.

The new phosphodiesterase 10A inhibitor (PDE10AI) JNJ-42314415 [3-[6-(2-methoxyethyl)pyridin-3-yl]-2-methyl-8-morpholin-4-ylimidazo[1,2-a]pyrazine] was compared with three reference PDE10AIs and eight dopamine 2 (D(2)) receptor blockers. Despite displaying relatively low PDE10A activity in vitro, JNJ-42314415 was found to be a relatively potent and specific PDE10AI in vivo. The compound was devoid of effects on prolactin release and of receptor interactions associated with other commonly observed adverse effects of available antipsychotics. Similar to D(2) receptor blockers, the tested PDE10AIs antagonized stimulant-induced behavior and inhibited conditioned avoidance behavior; these effects were observed at doses close to the ED(50) for striatal PDE10A occupancy. Relative to the ED(50) for inhibition of apomorphine-induced stereotypy, PDE10AIs blocked conditioned avoidance behavior and behaviors induced by nondopaminergic stimulants (phencyclidine, scopolamine) more efficiently than did D(2) receptor blockers; however, they blocked behaviors induced by dopaminergic stimulants (apomorphine, d-amphetamine) less efficiently. PDE10AIs also induced less pronounced catalepsy than D(2) receptor blockers. The effects of PDE10A inhibition against dopaminergic stimulants and on catalepsy were potentiated by the D(1) antagonist SCH-23390 (8-chloro-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol), suggesting that enhancement of D(1) receptor-mediated neurotransmission contributes to the behavioral profile of PDE10AIs. By reducing dopamine D(2) and concomitantly potentiating dopamine D(1) receptor-mediated neurotransmission, PDE10AIs may show antipsychotic activity with an improved side-effect profile relative to D(2) receptor blockers. However, the clinical implications of this dual mechanism must be further explored.

Introduction: The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) is considered to play an important role in various etiologies such as pulmonary arterial hypertension (PAH) and chronic heart failure. This PDE5 modulation represents an important prognostic and/or therapeutic target; however, there is currently no method to non-invasively evaluate the PDE5 expression levels in vivo., Methods: Radiolabeled tracers were prepared by N-alkylation of the corresponding precursors with [(11)C]methyl trifluoromethanesulfonate ([(11)C]CH3OTf) or 2-[(18)F]fluoroethyl trifluoromethanesulfonate ([(18)F]FEtOTf). Biodistribution of radiolabeled tracers was studied in NMRI mice and their specific binding to PDE5 was investigated by comparing their lung retention as the enzyme is abundantly expressed in this organ., Results: The overall radiochemical yields ranged between 24% and 60% for labeled radiotracers with radiochemical purity of>99%. The highest retention in the lungs at 30min post injection was observed for vardenafil derivatives [(11)C]-7 and [(18)F]-11 and the retention of the ethoxyethyl pyrazolopyrimidine derivative [(11)C]-37 was moderate. The other investigated compounds [(11)C]-8, [(11)C]-14, [(11)C]-21 and [(11)C]-33 showed lower retention in lungs in agreement with their lower in-vitro affinity for PDE5., Conclusion: Among the different radiolabeled PDE5 inhibitors evaluated in this study, the vardenafil derivatives [(11)C]-7 and [(18)F]-11 are found to be promising tracers for in vivo visualization of PDE5., (© 2014.)

The pharmacological effect of the selective PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline succinic acid (MP-10) on aversively and appetitively motivated behavior in C57BL/6J mice was examined. MP-10 dose-dependently impaired performance on a highly demanding reward schedule during appetitive conditioning. The compound further affected cue-based, but not contextual aversive conditioning. Finally, dose-dependent impaired performance in an instrumentally conditioned reinforcement (ICR) task was found. This suggests that the observed behavioral effects of MP-10 can be at least partially ascribed to impaired incentive salience attribution. MP-10 administration dose-dependently enhanced striatal expression of the immediate early gene Zif268, which suggest that MP-10 affects the studied motivated behaviors by enhancing PDE10A-regulated striatal signaling. Striatal signaling thus appears to be crucial in processes that control reward-motivated behavior in general, and incentive salience attribution in particular. Continued research will prove valuable towards a better understanding of psychopathologies that affect reward-motivated behaviors, such as drug addiction and schizophrenia., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: We study the applicability of a visual P3-based and a Steady State Visually Evoked Potentials (SSVEP)-based Brain-Computer Interfaces (BCIs) for mental text spelling on a cohort of patients with incomplete Locked-In Syndrome (LIS)., Methods: Seven patients performed repeated sessions with each BCI. We assessed BCI performance, mental workload and overall satisfaction for both systems. We also investigated the effect of the quality of life and level of motor impairment on the performance., Results: All seven patients were able to achieve an accuracy of 70% or more with the SSVEP-based BCI, compared to 3 patients with the P3-based BCI, showing a better performance with the SSVEP BCI than with the P3 BCI in the studied cohort. Moreover, the better performance of the SSVEP-based BCI was accompanied by a lower mental workload and a higher overall satisfaction. No relationship was found between BCI performance and level of motor impairment or quality of life., Conclusion: Our results show a better usability of the SSVEP-based BCI than the P3-based one for the sessions performed by the tested population of locked-in patients with respect to all the criteria considered. The study shows the advantage of developing alternative BCIs with respect to the traditional matrix-based P3 speller using different designs and signal modalities such as SSVEPs to build a faster, more accurate, less mentally demanding and more satisfying BCI by testing both types of BCIs on a convenience sample of LIS patients.

The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described. From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes. Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed. These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Phosphodiesterase 10A (PDE10A) inhibitors have recently been proposed as a new therapy for schizophrenia. The aim of this study was to enhance our understanding of the role of PDE10A inhibitors and potentially identify a clinically useful mechanistic/functional biomarker by using 2-deoxyglucose (2-DG) autoradiography. PDE10A inhibitors papaverine (10 and 40 mg/kg), 6,7-dimethoxy-4-[(3R)-3-(2-quinoxalinyloxy)-1-pyrrolidinyl]quinazoline (PQ-10), (0.16-10 mg/kg), and 2-[{4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy}methyl]quinoline (MP-10) (0.16-40 mg/kg) induced region-specific hypermetabolism in the globus pallidus and lateral habenula of C57BL/6 mice. Studies with MP-10 revealed a dose-dependent relative increase in globus pallidus activation, whereas a bell-shaped curve was observed for the lateral habenula. Although the relative increase in 2-DG uptake in the lateral habenula was also characteristic of the D(2) antagonist haloperidol (0.01-0.63 mg/kg), relative 2-DG changes were absent in the globus pallidus. This observation probably is explained by the interaction of PDE10A inhibitors with the D(1) direct pathway as suggested by experiments in combination with the D(1) agonist (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-82958) (0.16 mg/kg). The absence of an effect of MP-10 (2.5 mg/kg) on relative glucose metabolism in the globus pallidus and lateral habenula of PDE10A knockout mice confirmed the specificity of the signal induced by PDE10A inhibitors. These studies substantiate the regulatory role of PDE10A in the basal ganglia circuit and as such support the potential of PDE10A inhibitors for treating psychiatric disorders. Moreover, we could differentiate PDE10A inhibitors from haloperidol based on specific patterns of hypermetabolism probably caused by its combined action at both direct and indirect dopaminergic pathways. Finally, these specific changes in brain glucose metabolism may act as a translational biomarker for target engagement in future clinical studies.

We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a series of related pyridinyl analogues that exhibit high potency and selectivity as PDE10A inhibitors. The most interesting compounds were injected in rats to measure their levels of PDE10A occupancy through an in vivo occupancy assay. The 3,5-dimethylpyridine derivative 3 and the 5-methoxypyridine derivative 4 showed a comparable level of occupancy to that of 1a. Because these derivatives showed lower in vitro activity and are slightly less lipophilic than 1a, we hypothesized that they could behave as better PET imaging ligands. Compounds [(18)F]3, [(18)F]4, and [(11)C]4 were radiosynthesized and subjected to biodistribution studies in rats for a preliminary evaluation as candidate PET radioligands for in vivo imaging of PDE10A in the brain., (© 2011 American Chemical Society)

Phosphodiesterase 10A (PDE10A) hydrolyzes both cAMP and cGMP, and is a key element in the regulation of medium spiny neuron (MSN) activity in the striatum. In the present report, we investigated the effects of targeted disruption of PDE10A on spatial learning and memory as well as aversive and appetitive conditioning in C57BL/6J mice. Because of its putative role in motivational processes and reward learning, we also determined the expression of the immediate early gene zif268 in striatum and anterior cingulate cortex. Animals showed decreased response rates in scheduled appetitive operant conditioning, as well as impaired aversive conditioning in a passive avoidance task. Morris water maze performance revealed not-motor related spatial learning and memory deficits. Anxiety and social explorative behavior was not affected in PDE10A-deficient mice. Expression of zif268 was increased in striatum and anterior cingulate cortex, which suggests alterations in the neural connections between striatum and anterior cingulate cortex in PDE10A-deficient mice. The changes in behavior and plasticity in these PDE10A-deficient mice were in accordance with the proposed role of striatal MSNs and corticostriatal connections in evaluative salience attribution., (Copyright © 2010 Elsevier Inc. All rights reserved.)