The Brain Metabolic Signature in Superagers Using In Vivo 1H-MRS: A Pilot Study.

BACKGROUND AND PURPOSE: Youthful memory performance in older adults may reflect an underlying resilience to the conventional pathways of aging. Subjects having this unusual characteristic have been recently termed "superagers." This study aimed to explore the significance of imaging biomarkers acquired by 1H-MRS to characterize superagers and to differentiate them from their normal-aging peers. MATERIALS AND METHODS: Fifty-five patients older than 80 years of age were screened using a detailed neuropsychological protocol, and 25 participants, comprising 12 superagers and 13 age-matched controls, were statistically analyzed. We used state-of-the-art 3T 1H-MR spectroscopy to quantify 18 neurochemicals in the posterior cingulate cortex of our subjects. All 1H-MR spectroscopy data were analyzed using LCModel. Results were further processed using 2 approaches to investigate the technique accuracy: 1) comparison of the average concentration of metabolites estimated with Cramer-Rao lower bounds <20%; and 2) calculation and comparison of the weighted means of metabolites' concentrations. RESULTS: The main finding observed was a higher total N-acetyl aspartate concentration in superagers than in age-matched controls using both approaches (P = .02 and P = .03 for the weighted means), reflecting a positive association of total N-acetyl aspartate with higher cognitive performance. CONCLUSIONS: 1H-MR spectroscopy emerges as a promising technique to unravel neurochemical mechanisms related to cognitive aging in vivo and providing a brain metabolic signature in superagers. This may contribute to monitoring future interventional therapies to avoid or postpone the pathologic processes of aging.

Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism.

The brain-derived neurotrophic factor (BDNF), a neurotrophin fundamental for brain development and function, has previously been implicated in autism. In this study, the levels of BDNF in platelet-rich plasma were compared between autistic and control children, and the role of two genetic factors that might regulate this neurotrophin and contribute to autism etiology, BDNF and NTRK2, was examined. We found that BDNF levels in autistic children (n = 146) were significantly higher (t = 6.82; P < 0.0001) than in control children (n = 50) and were positively correlated with platelet serotonin distribution (r = 0.22; P = 0.004). Heritability of BDNF was estimated at 30% and therefore candidate genes BDNF and NTRK2 were tested for association with BDNF level distribution in this sample, and with autism in 469 trio families. Genetic association analysis provided no evidence for BDNF or NTRK2 as major determinants of the abnormally increased BDNF levels in autistic children. A significant association with autism was uncovered for six single nucleotide polymorphisms (SNPs) [0.004 (Z((1df)) = 2.85) < P < 0.039 (Z((1df)) = 2.06)] and multiple haplotypes [5 × 10(-4) (χ((3df)) = 17.77) < P < 0.042 (χ((9df)) = 17.450)] in the NTRK2 gene. These results do not withstand correction for multiple comparisons, however, reflect a trend toward association that supports a role of NTRK2 as a susceptibility factor for the disorder. Genetic variation in the BDNF gene had no impact on autism risk. By substantiating the previously observed increase in BDNF levels in autistic children in a larger patient set, and suggesting a genetic association between NTRK2 and autism, this study integrates evidence from multiple levels supporting the hypothesis that alterations in BDNF/tyrosine kinase B (TrkB) signaling contribute to an increased vulnerability to autism.

Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample.

Differences in metabolism of drugs can lead to severe toxicity or therapeutic failure. In addition to cytochrome P450 2D6, which plays a critical role in drug metabolism, ABCB1 encoded P-glycoprotein (PGP) is also an important determinant in drug bioavailability. The genes encoding these molecules are highly variable among populations and, given their clinical importance in drug therapy, determining CYP2D6 and ABCB1 allele frequencies in specific populations is very important for useful application in clinical settings. In this study the frequency of the pharmacologically relevant CYP2D6*3, *4, *5, *6 allelic variants and gene duplication, and ABCB1 C1236T and C3435T gene polymorphisms and their haplotypes was determined in a population sample of 100 Portuguese healthy subjects. CYP2D6 allele frequencies were 1.4% (*3), 13.3% (*4), 2.8% (*5), 1.8% (*6) and 6.1% (gene duplication), with 5% of the individuals classified as PM and 8.4% as UM. The frequencies obtained for the non-functional alleles and for the CYP2D6 gene duplication are in agreement with other South European populations, and reinforce the previously suggested south/north gradient of CYP2D6 duplications. Allelic frequencies for the ABCB1 polymorphisms were 52% (3435C) and 54% (1236C) and the most common haplotype (1236C-3435C) occurred with a frequency of 45.5%. Although allele and haplotype frequency data for ABCB1 in Southern Europe is limited, some discrepancies were found with other European populations, with possible therapeutic implications for PGP substrate drugs.

Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism.

The role of the serotonin system in the etiology and pathogenesis of autism spectrum disorders (ASD) is not clearly defined. High levels of platelet serotonin (5-HT) have been consistently found in a proportion of patients, and it is known that specific 5-HT transporter gene (SLC6A4) variants modulate transporter reuptake function, therefore possibly influencing the occurrence of hyperserotonemia in a subset of autistic patients. We have examined the association of platelet serotonin levels with two SLC6A4 polymorphisms, 5-HTT gene-linked polymorphic region (HTTLPR) in the promoter and intron 2 variable number of tandem repeats (VNTR), in a sample of 105 ASD patients, their parents, and 52 control children. Quantitative transmission disequilibrium test (QTDT) results showed a significant effect on 5-HT levels of each SLC6A4 marker (P=0.017 for HTTLPR; P=0.047 for intron 2 VNTR) and of haplotypes of the two markers (P=0.017), with a major contribution of the L.Stin2.10 haplotype (P=0.0013). A 5-HT mean value in the range of hyperserotonemia was associated with the homozygous L.Stin2.10 haplotype (H (1,N=97)=7.76, P=0.0054), which occurred in 33% of hyperserotonemic patients against 6% of patients with normal 5-HT levels (Fisher's exact test: P=0.013, OR=8). Allele interaction at the HTTLPR locus was found, with a significant dominance variance effect on 5-HT levels. We found no transmission disequilibrium of any of the SLC6A4 variants in ASD. Our results show that the SLC6A4 gene is a significant factor in the determination of 5-HT levels, and that specific SLC6A4 variants are associated with an increased risk for hyperserotonemia in our sample of autistic patients. The biological mechanism, however, is unlikely to involve the SLC6A4 gene solely. The associated SLC6A4 alleles likely interact with other genes or environmental factors to produce the abnormally high 5-HT levels observed in this subset of autistic patients, who possibly represent a separate etiological group.

[Injuries to the urinary tract]. / Traumatismos do aparelho urinário.

The aim of this paper is to briefly review recent data concerning urinary tract trauma. Upper urinary tract injuries occur in 1 to 1.5% of all trauma. Bladder trauma and urethral injuries are associated in 8 to 16% of pelvic fractures and perineal lesions. Functional and vital prognosis are reviewed and modern diagnostic management and treatment modalities are also mentioned. The association of urinary tract trauma with other injuries implies an interdisciplinary approach for these patients.