Citations

Abstract It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene-set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol-dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the ‘synthesis and degradation of ketone bodies’ pathway. Our results also support the potential involvement of the ‘neuroactive ligand–receptor interaction’ pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence.

Spinal dural arteriovenous fistulas (AVFs), the most common type of spinal cord vascular malformation, can be a challenge to diagnose and treat promptly. The disorder is rare, and the presenting clinical symptoms and signs are nonspecific and insidious at onset. Spinal dural AVFs preferentially affect middle-aged men, and patients most commonly present with gait abnormality or lower-extremity weakness and sensory disturbances. Symptoms gradually progress or decline in a stepwise manner and are commonly associated with pain and sphincter disturbances. Surgical or endovascular disconnection of the fistula has a high success rate with a low rate of morbidity. Motor symptoms are most likely to improve after treatment, followed by sensory disturbances, and lastly sphincter disturbances. Patients with severe neurological deficits at presentation tend to have worse posttreatment functional outcomes than those with mild or moderate pretreatment disability. However, improvement or stabilization of symptoms is seen in the vast majority of treated patients, and thus treatment is justified even in patients with substantial neurological deficits. The extent of intramedullary spinal cord T2 signal abnormality does not correlate with outcomes and should not be used as a prognostic factor.

BackgroundThe progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) are associated with relatively specific patterns of atrophy; the former predominantly involving the brainstem, the latter frontoparietal regions. However, it has become apparent that there are subjects that meet criteria for PSPS and CBS. We refer to subjects with this presentation as Hybrids. The hybrid presentation is not rare, yet there are no studies that have assessed the neuroanatomical correlates of the hybrid syndrome to explain its occurrence.MethodIn this study of 41 subjects and controls, we utilized the technique of voxel‐based morphometry to assess both gray and white matter volume loss in six prospectively recruited Hybrids that underwent 3.0 T volumetric head magnetic resonance image scanning to determine the neuroanatomical correlates of the syndrome. We compared patterns of atrophy in three prospectively recruited groups: the Hybrid group (n = 6), a PSPS group (n = 10), and CBS group (n = 5). All 21 subjects had completed the same standardized batteries assessing cognition, and motor, behavioral, executive, oculomotor and limb praxis function.ResultsThe Hybrid group showed imaging features of both PSPS and CBS, with volume loss observed in the brainstem (superior cerebellar peduncle) and cortex (medial and lateral premotor, prefrontal and motor cortex). As expected, typical patterns of loss were observed in PSPS and CBS.ConclusionsThese findings explain the neuroanatomical basis of the overlapping presenting signs and symptoms of PSPS and CBS, in Hybrids.