Perfil cognitivo en el Mareo Perceptual Postural Persistente: Implicancias sobre su fisiopatología como disfunción cognitiva viso-vestibular superior

Introducción: El mareo perceptual postural persistente (MPPP) es, probablemente, la causa más prevalente de mareo crónico. Sin embargo, su fisiopatología es aún motivo de duda y debate. En el presente artículo, proponemos que el MPPP se caracteriza por disfunciones cognitivas de orden superior, al punto de diferenciarse en estas dimensiones de controles sanos y pacientes con patologías vestibulares no-MPPP. Objetivo: Determinar si pacientes con MPPP presentan alteraciones discriminantes respecto a grupos controles, en ámbitos de atención, memoria de trabajo visoespacial, planificación espacial, funciones ejecutivas y rendimiento cognitivo global. Material y Método: Estudio descriptivo transversal con sujetos de entre 18 y 65 años, reclutados de una unidad de otoneurología ambulatoria. Se aplicaron pruebas Montreal Cognitive Assessment (MoCA), tarea de retención de dígitos, Trail Making Test, Corsi Block-Tapping Task y Torre de Londres. Resultados: 30 pacientes fueron categorizados en tres grupos: grupo MPPP (n = 14), grupo vestibular no-MPPP (n = 11) y grupo control (n = 5). El grupo MPPP exhibió un rendimiento significativamente inferior en pruebas de planificación, velocidad de procesamiento y funciones ejecutivas en ámbitos visoespaciales, mientras que en atención y memoria visoespacial no hubo diferencias entre grupos. Conclusión: El MPPP podría caracterizarse por una disfunción de procesos cognitivos superiores de construcción espacial de mayor complejidad, respetando funciones visoespaciales de menor orden como la memoria de trabajo. Estos hallazgos ofrecen nuevas luces para comprender la fisiopatología del MPPP y sus implicancias clínicas.

Introduction: Persistent postural-perceptual dizziness (PPPD) is probably the most prevalent cause of chronic dizziness. However, its pathophysiology is still a matter of uncertainty and debate. In this article, we propose that PPPD is characterized by higher-order cognitive dysfunctions, to the point of differentiating it from healthy controls and patients with non-PPPD vestibular pathologies. Aim: To determine whether patients with PPPD exhibit discriminant alterations compared to control groups in the areas of attention, visuospatial working memory, spatial planning, executive functions, and global cognitive performance. Materials and Methods: A cross-sectional descriptive study was conducted with subjects between the ages of 18 and 65 years, recruited from an outpatient otoneurology unit. Tests included the Montreal Cognitive Assessment (MoCA), digit retention task, Trail Making Test, Corsi Block-Tapping Task, and the Tower of London. Results: 30 patients were categorized into three groups: PPPD group (n = 14), non-PPPD vestibular group (n = 11), and control group (n = 5). The PPPD group showed significantly lower performance on tests of planning, processing speed, and executive function in visuospatial domains, while there were no differences between groups in attention and visuospatial memory. Conclusion: PPPD may be characterized by dysfunction of higher-order cognitive processes related to spatial construction of greater complexity, while sparing lower-order visuospatial functions such as working memory. These findings offer new insights into the pathophysiology of PPPD and its clinical implications.

Functional Dizziness as a Spatial Cognitive Dysfunction.

(1) Background: Persistent postural-perceptual dizziness (PPPD) is a common chronic dizziness disorder with an unclear pathophysiology. It is hypothesized that PPPD may involve disrupted spatial cognition processes as a core feature. (2) Methods: A cohort of 19 PPPD patients underwent psycho-cognitive testing, including assessments for anxiety, depression, memory, attention, planning, and executive functions, with an emphasis on spatial navigation via a virtual Morris water maze. These patients were compared with 12 healthy controls and 20 individuals with other vestibular disorders but without PPPD. Vestibular function was evaluated using video head impulse testing and vestibular evoked myogenic potentials, while brain magnetic resonance imaging was used to exclude confounding pathology. (3) Results: PPPD patients demonstrated unique impairments in allocentric spatial navigation (as evidenced by the virtual Morris water maze) and in other high-demand visuospatial cognitive tasks that involve executive functions and planning, such as the Towers of London and Trail Making B tests. A factor analysis highlighted spatial navigation and advanced visuospatial functions as being central to PPPD, with a strong correlation to symptom severity. (4) Conclusions: PPPD may broadly impair higher cognitive functions, especially in spatial cognition. We discuss a disruption in the creation of enriched cognitive spatial maps as a possible pathophysiology for PPPD.

A high-throughput screening campaign to identify inhibitors of DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD).

The rise of antibacterial resistance among human pathogens represents a problem that could change the landscape of healthcare unless new antibiotics are developed. The methyl erythritol phosphate (MEP) pathway represents an attractive series of targets for novel antibiotic design, considering each enzyme of the pathway is both essential and has no human homologs. Here we describe a pilot scale high-throughput screening (HTS) campaign against the first and second committed steps in the pathway, catalyzed by DXP reductoisomerase (IspC) and MEP cytidylyltransferase (IspD), using compounds present in the commercially available LOPAC1280 library as well as in an in-house natural product extract library. Hit compounds were characterized to deduce their mechanism of inhibition; most function through aggregation. The HTS workflow outlined here is useful for quickly screening a chemical library, while effectively identifying false positive compounds associated with assay constraints and aggregation.

Kinetic characterization and allosteric inhibition of the Yersinia pestis 1-deoxy-D-xylulose 5-phosphate reductoisomerase (MEP synthase).

The methylerythritol phosphate (MEP) pathway found in many bacteria governs the synthesis of isoprenoids, which are crucial lipid precursors for vital cell components such as ubiquinone. Because mammals synthesize isoprenoids via an alternate pathway, the bacterial MEP pathway is an attractive target for novel antibiotic development, necessitated by emerging antibiotic resistance as well as biodefense concerns. The first committed step in the MEP pathway is the reduction and isomerization of 1-deoxy-D-xylulose-5-phosphate (DXP) to methylerythritol phosphate (MEP), catalyzed by MEP synthase. To facilitate drug development, we cloned, expressed, purified, and characterized MEP synthase from Yersinia pestis. Enzyme assays indicate apparent kinetic constants of KMDXP = 252 µM and KMNADPH = 13 µM, IC50 values for fosmidomycin and FR900098 of 710 nM and 231 nM respectively, and Ki values for fosmidomycin and FR900098 of 251 nM and 101 nM respectively. To ascertain if the Y. pestis MEP synthase was amenable to a high-throughput screening campaign, the Z-factor was determined (0.9) then the purified enzyme was screened against a pilot scale library containing rationally designed fosmidomycin analogs and natural product extracts. Several hit molecules were obtained, most notably a natural product allosteric affector of MEP synthase and a rationally designed bisubstrate derivative of FR900098 (able to associate with both the NADPH and DXP binding sites in MEP synthase). It is particularly noteworthy that allosteric regulation of MEP synthase has not been described previously. Thus, our discovery implicates an alternative site (and new chemical space) for rational drug development.