If a strong and stable association can be firmly established between cognitive and MR variables in appropriate subsets of MS patients, it might aid in the investigation of interventions to enhance cognition and modify the course of the disease.

The relation between self-reported cognitive dysfunction and neuropsychological performance over 24 weeks was assessed in a sample of 53 multiple sclerosis patients. Subjects were assessed at Weeks Zero and 24 as part of a clinical trial to enhance cognition. At baseline, subjects had at least mild cognitive impairment on the Rey Auditory Verbal Learning Test and an absence of depression. Neuropsychological performance was assessed with a modification of the well standardized Brief Repeatable Battery. The 5-item Perceived Deficits Questionnaire and a 2-item memory and attention/concentration questionnaire assessed self-perceived cognitive impairment. Self-assessed cognition did not correlate with neuropsychological performance at either baseline or 24 weeks. However, changes in the self-assessment measures did correlate with changes in neuropsychological performance. Patients accurately perceived some changes in their level of cognitive dysfunction, though they were insensitive to the degree of their current dysfunction. Possible explanations of this pattern of results are discussed.

Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04–1×10−17). Except for total HDL particles (r = −0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07–0.17, P = 5×10−5–1×10−19). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE±0.22 mg/dl/allele, P = 8×10−5, P interaction = 0.02) in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE±0.22 mg/dl/allele, P = 0.35) or metformin (β = −0.03, SEE±0.22 mg/dl/allele, P = 0.90; P interaction = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE±0.012 ln nmol/L/allele, P = 0.01, P interaction = 0.01) but not in the placebo (β = −0.002, SEE±0.008 ln nmol/L/allele, P = 0.74) or metformin (β = +0.013, SEE±0.008 nmol/L/allele, P = 0.12; P interaction = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss.

We examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS). RESEARCH DESIGN AND METHODS During the DPP (1996-2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002-present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA 1c. Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs). RESULTS During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA 1c levels, respectively. Metformin's effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD 24.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD 20.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA 1c , metformin was more effective in subjects with higher baseline HbA 1c by RD, with metformin RD 21.03 cases/100 person-years with baseline HbA 1c <6.0% (42 mmol/mol) and 23.88 cases/100 person-years with 6.0-6.4% (P = 0.0001). CONCLUSIONS Metformin reduces the development of diabetes over 15 years. The subsets that benefitted the most include subjects with higher baseline fasting glucose or HbA 1c and women with a history of GDM.