Genome-wide scan of copy number variation in late-onset Alzheimer's disease.

Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE epsilon4 risk allele, identified a novel variant that influences disease risk within the APOE epsilon4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.

Application of a rank-based genetic association test to age-at-onset data from the Collaborative Study on the Genetics of Alcoholism study.

Association studies of quantitative traits have often relied on methods in which a normal distribution of the trait is assumed. However, quantitative phenotypes from complex human diseases are often censored, highly skewed, or contaminated with outlying values. We recently developed a rank-based association method that takes into account censoring and makes no distributional assumptions about the trait. In this study, we applied our new method to age-at-onset data on ALDX1 and ALDX2. Both traits are highly skewed (skewness > 1.9) and often censored. We performed a whole genome association study of age at onset of the ALDX1 trait using Illumina single-nucleotide polymorphisms. Only slightly more than 5% of markers were significant. However, we identified two regions on chromosomes 14 and 15, which each have at least four significant markers clustering together. These two regions may harbor genes that regulate age at onset of ALDX1 and ALDX2. Future fine mapping of these two regions with densely spaced markers is warranted.

Adjunctive albuterol enhances the response to enzyme replacement therapy in late-onset Pompe disease.

Effective dosages for enzyme replacement therapy (ERT) in Pompe disease are much higher than for other lysosomal storage disorders, which has been attributed to low cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle. We have previously demonstrated the benefit of increased CI-MPR-mediated uptake of recombinant human acid-α-glucosidase during ERT in mice with Pompe disease following addition of albuterol therapy. Currently we have completed a pilot study of albuterol in patients with late-onset Pompe disease already on ERT for >2 yr, who were not improving further. The 6-min walk test (6MWT) distance increased in all 7 subjects at wk 6 (30±13 m; P=0.002), wk 12 (34±14 m; P=0.004), and wk 24 (42±37 m; P=0.02), in comparison with baseline. Grip strength was improved significantly for both hands at wk 12. Furthermore, individual subjects reported benefits; e.g., a female patient could stand up from sitting on the floor much more easily (time for supine to standing position decreased from 30 to 11 s), and a male patient could readily swing his legs out of his van seat (hip abduction increased from 1 to 2+ on manual muscle testing). Finally, analysis of the quadriceps biopsies suggested increased CI-MPR at wk 12 (P=0.08), compared with baseline. With the exception of 1 patient who succumbed to respiratory complications of Pompe disease in the first week, only mild adverse events have been reported, including tremor, transient difficulty falling asleep, and mild urinary retention (requiring early morning voiding). Therefore, this pilot study revealed initial safety and efficacy in an open label study of adjunctive albuterol therapy in patients with late-onset Pompe disease who had been stable on ERT with no improvements noted over the previous several years.

Differences in onset and abuse/dependence episodes between prescription opioids and heroin: results from the National Epidemiologic Survey on Alcohol and Related Conditions.

OBJECTIVES: To examine patterns of onset and abuse/dependence episodes of prescription opioid (PO) and heroin use disorders in a national sample of adults, and to explore differences by gender and substance abuse treatment status. METHODS: Analyses of data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). RESULTS: Of all respondents, 5% (n = 1815) reported a history of nonmedical PO use (NMPOU) and 0.3% (n = 150) a history of heroin use. Abuse was more prevalent than dependence among NMPOUs (PO abuse, 29%; dependence, 7%) and heroin users (heroin abuse, 63%; dependence, 28%). Heroin users reported a short mean interval from first use to onset of abuse (1.5 years) or dependence (2.0 years), and a lengthy mean duration for the longest episode of abuse (66 months) or dependence (59 months); the corresponding mean estimates for PO abuse and dependence among NMPOUs were 2.6 and 2.9 years, respectively, and 31 and 49 months, respectively. The mean number of years from first use to remission from the most recent episode was 6.9 years for PO abuse and 8.1 years for dependence; the mean number of years from first heroin use to remission from the most recent episode was 8.5 years for heroin abuse and 9.7 years for dependence. Most individuals with PO or heroin use disorders were remitted from the most recent episode. Treated individuals, whether their problem was heroin or POs, tended to have a longer mean duration of an episode than untreated individuals. CONCLUSION: Periodic remissions from opioid or heroin abuse or dependence episodes occur commonly but take a long time. Timely and effective use of treatment services are needed to mitigate the many adverse consequences from opioid/heroin abuse and dependence.