News Roundup: New and Noteworthy Information

Stable isotope labeling of CNS proteins can be used to assess the effects of potential disease-modifying treatments for Alzheimer’s disease and other CNS disorders, as reported in the March 18 online Annals of Neurology. The study was conducted in healthy men, ages 21 to 50. The γ-secretase inhibitor “LY450139 significantly decreased the production of CNS β-amyloid in a dose-dependent fashion, with inhibition of β-amyloid generation of 47%, 52%, and 84% over a 12-hour period with doses of 100, 140, and 280 mg, respectively,” researchers stated. No difference in β-amyloid clearance was observed. “Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer’s disease, and may accelerate effective drug validation,” the researchers concluded.

Use of platelet aggregation inhibitors is associated with the presence of cerebral microbleeds, according to findings in the April 13 online Archives of Neurology. In the Rotterdam Scan Study, researchers used MRI to assess the location of possible microbleeds in 1,062 persons ages 60 and older who were free of dementia. “Compared with nonusers of antithrombotic drugs, cerebral microbleeds were more prevalent among users of platelet aggregation inhibitors (adjusted odds ratio [OR], 1.71),” investigators commented. Aspirin users had a higher prevalence of strictly lobular microbleeds (adjusted OR compared with nonusers, 2.70) than those using carbasalate calcium (adjusted OR, 1.16). “This difference was even more pronounced when comparing persons who had used similar dosages of both drugs,” the researchers stated.”

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α could become a novel therapeutic target for patients with Alzheimer’s disease, researchers reported in the March Archives of Neurology. “Using genome-wide complementary DNA microarray analysis, we found that PGC-1α messenger RNA expression was significantly decreased as a function of progression of clinical dementia in the Alzheimer’s disease brain,” the investigators stated. “Most importantly, we found that the reconstitution of exogenous PGC-1α expression in Tg2576 neurons attenuated the hyperglycemic-mediated β-amyloidogenesis through mechanisms involving the promotion of the ‘nonamyloidogenic' α-secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression.”

Investigators have identified a common brain-derived neurotrophic factor (BDNF) polymorphism that is a genetic modifier of Rett syndrome severity, according to a report in the April 7 Neurology. The researchers evaluated the association between disease severity and BDNF polymorphism in 125 mutation-positive patients with Rett syndrome from the Australian Rett Syndrome Database and an Israeli cohort. “Those who were heterozygous (Val/Met) had significantly more severe disease than those who were homozygous for the wild-type (Val/Val) BDNF polymorphism (increased severity score, 2.1),” the study authors stated. “In those with p.R168X, a commonly occurring MECP2 mutation in Rett syndrome, there was a six-point increase in severity score for those who were heterozygous for the BDNF polymorphism, both unadjusted and adjusted for age.”

The apolipoprotein E (APOE) ε 4 allele, a risk factor for early- and late-onset Alzheimer’s disease and age-related cognitive impairment, modulates brain function long before any clinical or neurophysiologic expression of neurodegenerative processes is observed, according to findings in the April 8 online edition of Proceedings of the National Academy of Sciences. Investigators assessed structural and functional effects of the APOE polymorphism in 18 healthy APOE ε 4 carriers and 18 matched controls (ages 20 to 35). Blood oxygen level–dependent fMRI was used to study the brain at rest and during an encoding memory paradigm. “Resting fMRI revealed increased ‘default mode network’ … coactivation in ε 4 carriers relative to noncarriers,” researchers stated. “The encoding task produced greater hippocampal activation in ε 4 carriers relative to noncarriers.”

A genetic locus on chromosome 12p14 is associated with an increased risk for stroke, according to data published in the April 15 New England Journal of Medicine. Investigators analyzed genomewide association data from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, which included 19,602 white persons (mean age, 63) in whom 1,544 incident strokes (1,164 of which were ischemic strokes) occurred during an average of 11 years. Markers most strongly associated with stroke were tested in a replication cohort of 2,430 black persons with 215 incident strokes (191 ischemic strokes), 574 black persons with 85 incident strokes (68 ischemic strokes), 652 Dutch persons with ischemic stroke, and 3,613 unaffected participants. “Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke,” the investigators stated.

Statins have no preventative effect for Alzheimer’s disease or dementia when given to at-risk individuals in late life, per results reported in the April 15 Cochrane Database of Systematic Reviews. In the Heart Protection Study (patients 70 and older), no difference in incidence of dementia (31 cases in the simvastatin group and 31 cases in the placebo group) nor on the modified Telephone Interview for Cognitive Status at final follow-up (23.7% in the simvastatin group were cognitively impaired vs 24.2% in the placebo group) was shown. There was no difference between groups in cognition in relation to age at study entry or history of cerebrovascular disease. In the Prospective Study of Pravastatin in the Elderly at Risk (patients aged 70 to 82), cognitive function declined at the same rate in both treatment cohorts.