Age-Related Changes in Sleep-Dependent Consolidation of Visuo-Spatial Memory

Healthy aging is associated with a reduction in slow-wave sleep (SWS), crucial for declarative memory consolidation in young adults; consequently, previously observed benefits of sleep on declarative learning in older adults could reflect a passive role of sleep in protecting memories from waking interference, rather than an active, stabilizing effect. To dissociate the passive and active roles of sleep, a visuo-spatial task was administered; memory was probed after a 12 hr interval consisting of either daytime wake or overnight sleep and post-wake/post-sleep stability of the memories was tested following task-related interference. Ninety five older adults (mean=65.43 yrs; SD=7.6 yrs) and 137 young adults (mean= 21.22yrs; SD=2.62 yrs) were tested across either an “Interference” or a “No Interference” condition (without exposure to the interference). In both young and older adults, sleep significantly benefitted performance compared to wake, such that the memories were more resistant to subsequent interference. For young adults, post-sleep performance was correlated with time spent in SWS and delta power density during SWS early in the night. Additionally, the interaction between NREM and REM early in the night played an important role in stabilizing the memories. There were no significant correlations between sleep parameters and over-sleep performance changes in older adults; however, high performing older adults benefitted from greater amounts of REM sleep early in the night, and from the interaction between NREM and REM during this time period. These results suggest that the active role of sleep in declarative memory consolidation persists in an aging population

Sleep, and its Relation to Non-Motor Deficits in Patients with Cerebellar Ataxia

The cerebellum is a highly connected structure, and its involvement in sleep – which is a dynamic process that is modulated by a complex set of neural systems – can come about through a number of neural pathways. We conducted two studies aimed at furthering our understanding of cerebellar involvement in sleep behavior and physiology, as well as measuring the impact of poor sleep on mood and cognition in patients with cerebellar degeneration. First, by means of an online battery including measures of sleep and neuropsychiatric function, we collected data from 176 patients with cerebellar ataxia. We found strong evidence of poor subjective sleep quality, symptoms of movement-related sleep disorders, and excessive daytime sleepiness in this sample. Importantly, poor subjective sleep was associated with both diminished perceptions of cognitive abilities and depression symptomatology. Second, in order to determine whether the benefit of sleep on declarative associative learning, previously observed in healthy controls, was affected by cerebellar degeneration, we compared overnight changes in performance on a word-pair association task between patients with pure cerebellar syndrome and matched-controls. By means of polysomnography recordings, we demonstrated significantly greater fragmentation of sleep and periodic limb movement indices in patients relative to controls. Although patients demonstrated impaired learning of the word-pair association task – which was significantly correlated with sleep fragmentation – there were no differences between patients and controls with respect to overnight change in accuracy on the word-pair task. Taken together, these findings suggest that inefficient sleep and the presence of sleep disorders in patients with cerebellar ataxia might exacerbate deficits in certain non-motor domains, while other processes – namely those associated with sleep-dependent declarative memory consolidation – remain intact

Naps Do Not Change Delay Discounting Behavior in Young Adults

When offered a choice of $40 today or$50 later, many would choose the immediate reward over the greater delayed reward. Such behavior is a result of future gains being discounted such that their value is rendered less than that of the immediate gain. Extreme discounting behaviors are associated with impulsivity and addiction. Given recent evidence of sleep’s role in decision making, we tested the hypothesis that sleep would reduce delayed discounting behavior. Twenty young adults (M = 20.19 years, SD = 0.98 years; 6 males) performed a hypothetical delay discounting task, making a series of choices between an immediate reward (from $0 to$50) or a larger reward ($50) available at a delay of 2, 4, 8, 14, or 22 weeks. Participants performed the task before and after a mid-day nap, and before and after an equivalent interval of wake (within subject, order counterbalanced, wake, and sleep conditions separated by 1 week). As expected, indifference points decreased with longer delays both prior to and following the nap/wake interval. However, the impact of a nap interval on discounting did not differ from the impact of a wake interval. Thus, while sleep has been shown to play an active role in some financial decision-making tasks, a nap is not sufficient to change delay discounting behavior

Variants at APOE influence risk of deep and lobar intracerebral hemorrhage

Objective Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50–2.23, p = 6.6 × 10 −10 ; and OR = 2.20, 95%CI = 1.85–2.63, p = 2.4 × 10 −11 , respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08–1.36, p = 2.6 × 10 −4 ). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78478/1/22134_ftp.pd

Independent susceptibility markers for atrial fibrillation on chromosome 4q25

Background-: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. Methods and results-: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2×10) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. Conclusions-: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF

Independent susceptibility markers for atrial fibrillation on chromosome 4q25

Background-: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. Methods and results-: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2×10) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. Conclusions-: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF

Principal-Component Analysis for Assessment of Population Stratification in Mitochondrial Medical Genetics

Although inherited mitochondrial genetic variation can cause human disease, no validated methods exist for control of confounding due to mitochondrial population stratification (PS). We sought to identify a reliable method for PS assessment in mitochondrial medical genetics. We analyzed mitochondrial SNP data from 1513 European American individuals concomitantly genotyped with the use of a previously validated panel of 144 mitochondrial markers as well as the Affymetrix 6.0 (n = 432), Illumina 610-Quad (n = 458), or Illumina 660 (n = 623) platforms. Additional analyses were performed in 938 participants in the Human Genome Diversity Panel (HGDP) (Illumina 650). We compared the following methods for controlling for PS: haplogroup-stratified analyses, mitochondrial principal-component analysis (PCA), and combined autosomal-mitochondrial PCA. We computed mitochondrial genomic inflation factors (mtGIFs) and test statistics for simulated case-control and continuous phenotypes (10,000 simulations each) with varying degrees of correlation with mitochondrial ancestry. Results were then compared across adjustment methods. We also calculated power for discovery of true associations under each method, using a simulation approach. Mitochondrial PCA recapitulated haplogroup information, but haplogroup-stratified analyses were inferior to mitochondrial PCA in controlling for PS. Correlation between nuclear and mitochondrial principal components (PCs) was very limited. Adjustment for nuclear PCs had no effect on mitochondrial analysis of simulated phenotypes. Mitochondrial PCA performed with the use of data from commercially available genome-wide arrays correlated strongly with PCA performed with the use of an exhaustive mitochondrial marker panel. Finally, we demonstrate, through simulation, no loss in power for detection of true associations with the use of mitochondrial PCA