Adenosine A2A receptor in schizophrenia: an in vivo brain PET imaging study

Adenosine A2A receptors are highly enriched in the basal ganglia system, a region that is functionally implicated in schizophrenia. Preclinical evidence suggests a cross-regulation between adenosine A2A and dopamine D2 receptors in this region and that it is linked to the sensitization of the dopamine system. However, the relationship between A2A receptor availability and schizophrenia has not been directly examined in vivo in patients with this disorder. To investigate, using positron emission tomography (PET), the availability of A2A receptors in patients diagnosed with schizophrenia in comparison to matched healthy controls. A2A receptor availability was measured using the PET tracer [11C]SCH442416. Twelve male patients with chronic schizophrenia were compared to 13 matched healthy subjects. All patients were medicated with antipsychotics and none presented with any motor or extrapyramidal symptoms. Binding potential (BPND), a ratio measure between specific and non-specific tracer uptake, were compared between the groups for the caudate, putamen, accumbens and globus pallidum. There was no differences between A2A receptor binding potential (BPND) of schizophrenia patients in the caudate (p = 0.16), putamen (p = 0.86), accumbens (p = 0.44) and globus pallidum (p = 0.09) to that of matched healthy subjects. There was also no significant correlation between [11C]SCH442416 binding and severity of psychotic symptoms (p = 0.2 to 0.82) or antipsychotic dosage (p = 0.13 to 0.34). By showing that A2A receptor availability in medicated patients with chronic male schizophrenia is not different than in healthy controls, this study does not support the primary role of this receptor in the pathogenesis of schizophrenia.

Use of Functional Magnetic Resonance Imaging to Assess How Motor Phenotypes of Parkinson's Disease Respond to Deep Brain Stimulation

INTRODUCTION Deep brain stimulation (DBS) is a well-accepted treatment of Parkinson's disease (PD). Motor phenotypes include tremor-dominant (TD), akinesia-rigidity (AR), and postural instability gait disorder (PIGD). The mechanism of action in how DBS modulates symptom relief remains unknown. METHODS Subjects who were classified into TD, AR, or PIGD cohorts underwent task-based fMRI. The effects of the task [DBS (ON/OFF)] on BOLD activation in each phenotype were documented through general linear voxel-wise analysis. For group analysis, t-values were compared using ANOVA in regions of interest, including the primary motor cortex (MI), motor thalamus, primary somatosensory cortex (SI), globus pallidum externus (GPe), anterior and posterior cerebella, supplementary motor area (SMA), and caudate and putamen. A 2-way ANOVA analysis was performed to assess the impact of age, phenotype, and target nuclei. RESULTS BOLD activation with DBS-ON compared to the OFF state resulted in activation in the motor thalamus (P < .01) and GPe (P < .01) when analyzed as a group. Among phenotype, age of PD onset, and target nuclei, phenotype was most effective in determining activation levels. Specifically, AR patients had more activation in the SMA than PIGD patients (P = .002) and in MI compared to TD and PIGD subjects (P = .001 and P = .017, respectively). Further analysis demonstrated that the implant brain region affected activation patterns only in PIGD patients. Specifically, globus pallidum internus (GPi) DBS resulted in MI and SMA deactivation, while STN DBS led to MI activation with no changes in the SMA. CONCLUSION These data suggest that DBS modulates network activity differently based on patient motor phenotype. The nuclei where DBS is implanted affected activation patterns in the PIGD cohort. An improved understanding of these differences may allow us to further our knowledge about the mechanisms of DBS action on PD motor symptoms and to exploit connections to optimize treatment.

Degeneración Cortico-Estriatal del Tipo de Creutzfeldt-Jakob

Este artículo presenta los hallazgos clínico-patológicos de 3 pacientes preseniles, que murieron entre los 4 y 9 1/2 meses del inicio de una enfermedad subaguda, caracterizada clínicamente por el desarroll0 en forma progresivamente rápida, de deterioración mental, rigidez generalizada, hiperreflexia osteotendinosa y tremor de los dedos. Uno de los pacientes, que presentó además signo de Babinsky bilateral, mostró también sintomotoloqía de disfunción cerebelosa y en otro de ellos el examen clínico reveló la presencia de una ceguera de tipo cerebral. En los tres casos, el líquido céfalo raquídeo tuvo características normales; el electroencefalograma sugirió disfunción cerebral difusa y el pneumoencéfalograma mostró una moderada, pero generalizada dilatación del sistema ventricular. Al examen patológico, los tres cerebros aparecieron externamente negativos y las secciones coronales de ellos, sólo mostraron una dilatación moderada de los ventrículos laterales. Microscópicamente, se pudo observar una marcada hipertrofia e hiperplasia astrocitaria, presente en regiones del neo-cortex, neo-estriatum, núcleo anterior del tálamo óptico, hipotálamo y tubérculos cuadrigémínos pero, ausente o mínima en regiones del arquicortex, globus pallidum y otras porciones del tálamo óptico y tronco encefálico. Todas estas áreas, ya sea aquellas con cambios astrocitarios como las que no los mostraron, presentaron sin embargo, una degeneración neuronal inespecífica, de intensidad moderada y aproximadamente igual en todas ellas y así mismo revelaron discretas modificaciones en los axones, las vainas de mielina u otras estructuras neurales. En uno de los casos el grado de compromiso neuronal fue particularmente más intenso en la corteza occipital posiblemente condicionando la ceguera cortical que este paciente presentaba y en otro, una pérdida entre moderada y marcada de células granulares y de Purkinje de la corteza cerebelosa estaba relacionada posiblemente a la sintomatología cerebelosa que dicho paciente presentó. Este pattern de cambios hístolócicos, bien podría delinear una entidad específica dentro del grupo heterogéneo de casos actualmente incluídos en el síndrome de Creutzfeldt-Jakob y por otro lado sugeriría la posibilidad de que los cambios en los astrocitos observados, representen una reacción primaria o mejor una reacción a un efecto nocivo directo de los factores patogenéticos operantes en estos casos; más que un fenómeno secundario sea a los cambios neuronales o a los de otros componentes del sistema nervioso central.

Abstract 2254: Very Brief Focal Ischemia Simulating Human TIAs Induces Aβ Aggregate and Activates Prolonged Autophagy in Rats

Objective Very brief periods of focal ischemia in humans called Transient Ischemic Attacks (TIAs) are viewed as being benign. However, our recent animal studies demonstrate that brief periods of focal ischemia can produce microinfarcts associated with neuronal apoptosis and glial Hsp70 positive inclusions. Recent studies of inclusions show they are associated with misfolded proteins that can aggregate and form inclusions, or the proteins can be destroyed via the catabolic process of autophagy. These processes have been shown to occur in Alzheimer’s Disease (AD) where evidence of β amyloid (Aβ) aggregates and cellular autophagy are described. Since there is increasing evidence that cerebral ischemia is linked to AD, we postulated that protein aggregates possibly including Aβ and autophagy would occur following cerebral ischemia. The aims of this study were to demonstrate that brief focal cerebral ischemia induces: Aβ aggregation; Aβ cleavage into “non-toxic” and toxic Aβ 1-42 fragments; and autophagy of cells in brain. Methods Middle cerebral artery occlusion (MCAO) was produced in adult SD rats using the suture method. Rats subjected to 20 minutes of ischemia were sacrificed at 4 or 8 weeks. Antibodies against Rodent Aβ (R Aβ, detects all cleaved fragments of Aβ), Aβ 1-42 (detects only the toxic fragment), and LC3b (Atg8 marker of autophagy) were used. Results All immunoreactive cells were ipsilateral to the MCAO. No immunoreactivity was observed contralateral to the MCAO in the opposite hemisphere. 1. At 4 weeks post ischemia, R Aβ was expressed in focal areas of the caudate-putamen, globus pallidum and cortex. Aβ 1-42 staining was negative at 4 weeks in all structures. At 8 weeks post ischemia, the pattern of the R Aβ expression was similar to 4 weeks except that it appeared in CA1 hippocampal neurons. At 8 weeks Aβ 1-42 was induced in caudate-putamen, globus pallidum, hippocampal CA1 region, and cortex where it partially co-localized with R Aβ. R Aβ and Aβ 1-42 co-localization in hippocampus occurred in few cells, possibly GABAergic interneurons. 2. LC3b, an autophagy marker, was expressed in the penumbra of microinfarcts of the cortex at 8 weeks. Almost all Aβ 1-42 positive aggregates co-localized with LC3b. Conclusions 1. Brief focal ischemia induced Aβ only on the ischemic side of the brain; 2. Brief ischemia produced “non-toxic” and toxic Aβ 1-42 fragments; 3. Most cells expressing Aβ 1-42 are undergoing autophagy.