Temporal Cortex Tissue Research Articles

An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer's disease

The endocannabinoids and their attending cannabinoid (CB)1 receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear. In the present study, we used liquid chromatography/mass spectrometry to conduct an endocannabinoid-targeted lipidomic analysis of postmortem brain samples from 38 Alzheimer's disease (AD) patients and 17 control subjects, matched for age and postmortem interval. The analysis revealed that midfrontal and temporal cortex tissue from AD patients contains, relative to control subjects, significantly lower levels of the endocannabinoid anandamide and its precursor 1-stearoyl, 2-docosahexaenoyl-sn-glycero-phosphoethanolamine-N-arachidonoyl (NArPE). No such difference was observed with the endocannabinoid 2-arachidonoyl-sn-glycerol or 15 additional lipid species. In AD patients, but not in control subjects, statistically detectable positive correlations were found between (1) anandamide content in midfrontal cortex and scores of the Kendrick's Digit Copy test (p = 0.004, r = 0.81; n = 10), which measures speed of information processing; and (2) anandamide content in temporal cortex and scores of the Boston Naming test (p = 0.027, r = 0.52; n = 18), which assesses language facility. Furthermore, anandamide and NArPE levels in midfrontal cortex of the study subjects inversely correlated with levels of the neurotoxic amyloid peptide, amyloid β-protein (Aβ)42, while showing no association with Aβ40 levels, amyloid plaque load or tau protein phosphorylation. Finally, high endogenous levels of Aβ42 in Swedish mutant form of amyloid precursor protein (APPSWE)/Neuro-2a cells directly reduced anandamide and NArPE concentrations in cells lysates. The results suggest that an Aβ42-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD.

Genomic and epigenetic evidence for oxytocin receptor deficiency in autism

BackgroundAutism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.MethodsWe describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR).ResultsOur analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls.ConclusionTogether, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder.See the related commentary by Gurrieri and Neri:

Selective loss of dopamine D2 receptors in temporal cortex in dementia with Lewy bodies, association with cognitive decline

Dementia with Lewy bodies (DLB) is a progressive dementia frequently accompanied by psychotic symptoms. Similar symptoms can occur in Alzheimer's disease (AD) to a lesser extent. The use of neuroleptic medication to treat psychosis in both diseases is of modest efficacy and can induce severe adverse reactions in DLB. Dopamine D2 receptors in the cerebral cortex are the putative target for the antipsychotic action of these drugs, but the status of these receptors in DLB is unknown. Autoradiography was used to examine the density D2 receptors in postmortem temporal cortex tissue from prospectively assessed patients with neuropathologically confirmed DLB and AD. D2 receptors were substantially (over 40%) and significantly (P < 0.001) reduced in temporal cortex in DLB, and in DLB with concomitant Alzheimer pathology, but was not significantly changed in AD. This reduction correlated with greater cognitive decline (P < 0.01), but was not significantly related to visual or auditory hallucinations or delusions. D2 receptor density was inversely correlated with cortical Lewy body pathology in the neocortex (P < 0.001). The specific loss of D2 receptors associated with Lewy body pathology, in conjunction with our previous finding of low D2 receptors in striatum in DLB, provides a possible explanation for neuroleptic intolerance. That the reduction of D2 receptors correlated with cognitive decline suggests that neuroleptics, as dopamine D2 receptor antagonists, may have a deleterious effect on cognition in DLB.

Association of Increased Cortical Soluble Aβ42 Levels With Diffuse Plaques After Severe Brain Injury in Humans

Traumatic brain injury (TBI) is an environmental risk factor for developing Alzheimer disease. This may be due, in part, to changes associated with beta-amyloid (Abeta) plaque formation, which can occur within hours after injury, regardless of the patient's age. In addition to being precursors of toxic fibrils that deposit into plaques, soluble (nonfibrillar) Abeta peptides are posited to disrupt synaptic function and are associated with cognitive decline in Alzheimer disease. Changes in soluble Abeta levels and their relationship to Abeta plaque formation following TBI are unknown. To quantify brain tissue levels of soluble Abeta peptides and their precursor protein in relation to Abeta plaque formation after TBI in humans. Surgically resected temporal cortex tissue from patients with severe TBI was processed for biochemical assays of soluble Abeta peptides with COOH-termini ending in amino acid 40 (Abeta(40)) or 42 (Abeta(42)) and Abeta precursor protein to compare patients with cortical Abeta plaques and those without. Patients Nineteen subjects admitted to the University of Pittsburgh Medical Center for treatment of severe closed head injury. Patients with severe TBI and cortical plaques had higher levels of soluble Abeta(1-42) but not Abeta(1-40); half of them were apolipoprotein E (APOE) epsilon4 allele carriers. The lowest Abeta levels were in 1 patient without plaques who was the only subject with an APOE epsilon2 allele. beta-Amyloid precursor protein levels were comparable in the 2 TBI groups. Selective increases in soluble Abeta(1-42) after TBI may predispose individuals with a brain injury to Alzheimer disease pathology. This may be influenced by the APOE genotype, and it may confer increased risk for developing Alzheimer disease later in life.