Hyperinsulinemia and hyperglycemia due to insulin resistance may accelerate the formation of neuritic plaques in combination with the effects of apolipoprotein (APOE) e4, as reported in the August 25 online Neurology. This is the conclusion from autopsy studies of 135 residents of Hisayama, Japan, who died between 1998 and 2003. In 1988, the subjects underwent a 75-g oral glucose tolerance test in which measurements of diabetes-related factors, including fasting glucose, two-hour postload plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were taken. The investigators found that higher levels of postload glucose, fasting insulin, and HOMA-IR were associated with an increased risk for neuritic plaques. In addition, “the coexistence of hyperglycemia and APOE e4 increased the risk for neuritic plaque formation,” the researchers reported. “A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.”

A novel gamma-secretase activating protein (GSAP) that “drastically and selectively increases beta-amyloid production” without impairing Notch cleavage was reported in the September 1 online Nature. According to the paper, GSAP stimulates beta-amyloid production in vitro, while mouse models have shown that reducing GSAP decreases beta-amyloid concentrations. The researchers demonstrated that the anti-cancer drug imatinib prevents GSAP interaction with the gamma-secretase substrate amyloid precursor protein carboxy-terminal fragment, without affecting Notch cleavage, and thereby may provide a new therapeutic target for the treatment and prevention of Alzheimer’s disease.
Brain games aimed at stimulating mental acuity appear to slow cognitive decline prior to the onset of dementia, but accelerate it afterward, according to a study in the September 1 online Neurology. Researchers assessed cognitive performance of older subjects at three-year intervals as a composite measure of global cognition, while a subset was sampled for clinical evaluation. Subjects were dementia-free at baseline, at which point they rated the frequency at which they engaged in cognitively stimulating activity. “During follow-up, the annual rate of global cognitive decline in persons without cognitive impairment was reduced by 52% for each additional point on the cognitive activity scale,” the investigators reported. “In the mild cognitive impairment group, cognitive decline rate was unrelated to cognitive activity. In Alzheimer’s disease, the mean rate of decline per year increased by 42% for each point on the cognitive activity scale.”
Researchers have found a new genetic risk factor for amyotrophic lateral sclerosis (ALS), as reported in the August 26 Nature. The study authors showed that ataxin 2 (ATXN2) is a potent modifier of TDP-43 toxicity in animal and cellular models and analyzed the length of the polyQ repeat in the ATXN2 gene in 915 patients with ALS. “We found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS,” the investigators stated. “These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43 ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.”
Two studies in the August 27 online Lancet Neurology have identified genetic variations on chromosome 9 as having a role in the development of amyotrophic lateral sclerosis (ALS). In one study of 442 Finnish patients with ALS, researchers found data suggesting the presence of a founder mutation for chromosome 9p21-linked ALS. “The overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.” A second study of 599 patients with ALS from the UK found “strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent genome-wide association studies of ALS and linkage studies of ALS-frontotemporal dementia.”
Infants born at 37 or 38 weeks gestation or at 42 weeks or later have an increased risk for cerebral palsy, compared with those born at 40 weeks, researchers reported in the September 1 JAMA. Among 1,938 children with cerebral palsy, infants born at 40 weeks had the lowest risk of the disease, with a prevalence of 0.99/1,000. At 37 weeks, the prevalence was 1.91 (relative risk [RR], 1.9), at 38 weeks the prevalence was 1.25 (RR, 1.3), at 42 weeks the prevalence was 1.36 (RR, 1.4), and after 42 weeks the prevalence was 1.44 (RR, 1.4). “These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1,000 and the RR was 3.7,” the investigators reported. “At 42 weeks the prevalence was 0.85/1,000 and the RR was 2.4.”
Use of anticholinergic medications may increase the risk of cognitive impairment, according to a study in the July 13 Neurology. In a six-year longitudinal, observational study of 1,652 community-dwelling African American subjects older than 70, investigators found the number of definite anticholinergics used was associated with a 1.46-fold increased risk of cognitive impairment. Possible anticholinergics were not associated with an increased risk of cognitive impairment. Medications were rated as possible or definite based on the Anticholinergic Cognitive Burden scale. In addition, the investigators found that the increased risk of cognitive impairment was evident among definite anticholinergic users regardless of their apolipoprotein (APOE) e4 allele status. “Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans,” the study authors wrote.
Veterans who experienced post-traumatic stress disorder (PTSD) have a higher incidence and prevalence of dementia, researchers reported in the September Journal of the American Geriatrics Society. In an administrative database study of veterans enrolled in the South Central VA Healthcare Network, which comprises Arkansas, Louisiana, Mississippi, Oklahoma, and parts of Alabama, Florida, Missouri, and Texas, the investigators identified subjects 65 and older who had a diagnosis of PTSD or received a Purple Heart to compare with a group of contemporaries without PTSD or a Purple Heart. After controlling for confounding factors in a multivariate logistic regression, those with PTSD who had not received a Purple Heart had the highest rates of dementia. “It is unclear whether this is due to a common risk factor underlying PTSD and dementia or to PTSD being a risk factor for dementia,” the investigators wrote. “Regardless, this study suggests that veterans with PTSD should be screened more closely for dementia. Because PTSD is so common in veterans, this association has important implications for veteran care.”
The FDA has approved Silenor (doxepin) for the treatment of insomnia characterized by difficulty with sleep maintenance. The first and only prescription sleep medicine approved for treating patients who have episodes of frequent waking during the night or waking too early and being unable to return to sleep, the oral tablet formulation is now commercially available by prescription in 3-mg and 6-mg doses. According to a representative for Somaxon Pharmaceuticals, Inc, in San Diego, “clinical studies demonstrate that Silenor supports seven to eight hours of sleep with no next-day residual effects in most patients and no evidence of abuse potential or physical dependence.”
Subclinical multiple sclerosis (MS) activity may have a strong seasonal pattern, peaking during the spring and summer months, according to a study published in the August 31 issue of Neurology. Basing their findings on noncontrast brain MRI, researchers reported that “the observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.” New T2 activity showed a likelihood of occurring two to three times higher from March to August than during the rest of the year, which “correlated strongly with regional climate data, in particular solar radiation,” the investigators wrote. In addition, disease intensity was elevated during the summer season. “The elevated risk season appears to lessen for progressive MS and occur about two months earlier,” the authors wrote.
An association between Parkinson’s disease and a gene in the human leukocyte antigen (HLA) region was found in a genome-wide association study (GWAS), researchers reported in the September issue of Nature Genetics. The finding links the involvement of the immune system in Parkinson’s disease and offers new targets for drug development, the investigators stated. The GWAS of 2,000 subjects and 1,986 controls, all of whom were Americans of European ancestry, found an association peak at rs3129882. The findings lend “strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis,” the researchers wrote. The study also confirmed associations with SNCA2,6-8 and MAPT3,7-9 genes, and replicated an association with GAK9.
Drinking alcohol temporarily increases the risk of acute ischemic stroke, per a study that was published in the September Stroke. In a multicenter study of 209 men and 181 women who recently had a stroke, investigators questioned subjects regarding alcohol consumption in relation to stroke onset. “We found the risk of ischemic stroke was transiently elevated for two hours after drinking as little as one serving of alcohol,” they wrote. Fourteen patients reported alcohol consumption within one hour of stroke onset, for a 2.3-fold increased risk of stroke compared to periods of nonuse. The relative risk of stroke onset was 1.6 within two hours of alcohol consumption, and by three hours, the risk returned to baseline. By 24 hours, there was a 30% lower stroke risk. “Although speculative, it is possible that the transiently increased stroke risk from moderate alcohol consumption may be outweighed by the health benefits for the next 24 hours, but consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well,” the researchers stated.

—Rebecca K. Abma and Colby Stong

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