Rebecca L. Koscik

Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease

IMPORTANCE Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET). OBJECTIVES To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance. DESIGN, SETTING, AND PARTICIPANTS This population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimers Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake. MAIN OUTCOMES AND MEASURES Regional glucose uptake determined using FDG-PET and neuropsychological factors. RESULTS Higher HOMA-IR was associated with lower global glucose metabolism (β = -0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P < .001) and delayed memory (β = 0.305; t148 = 3.895; P < .001) factor scores. CONCLUSIONS AND RELEVANCE Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

Psychosocial Risk Associated With Newborn Screening for Cystic Fibrosis: Parents’ Experience While Awaiting the Sweat-Test Appointment

Background. The psychosocial effects on parents of infants with abnormal results in cystic fibrosis (CF) newborn screening (NBS) that uses genetic testing remain unclear. Methods. Twenty-eight individuals representing 14 families participated in grounded theory interviews ∼6 months after their child’s positive NBS results for CF. Participants also completed the Center for Epidemiologic Studies Depression Scales (CES-D) at their infant’s sweat-test appointment (n = 51) and/or ∼6 months after the sweat test (n = 35). Results. Most parents experienced high levels of emotional distress during their wait for the sweat-test appointment (CES-D score, mean ± SD: 16.5 ± 6.7; 43.1% in the clinical range; median wait: 7 days; range: 3–35 days). CES-D scores of these parents were also significantly higher than those of comparison parents. Interviews showed that parental cognitive uncertainty and emotional distress were influenced by the parents’ prior knowledge of NBS, CF, and their carrier status; parents’ adjustment to their new baby; and the physicians’ approach to informing parents. Parents’ coping strategies involved requesting a sweat test as soon as possible, searching for information, assessing the infant’s risk/health, seeking support, praying, or not talking with others. Conclusions. The waiting period from notification regarding positive NBS results to diagnostic test results can be psychologically distressing to parents, causing depressive symptoms that vary depending on their perceptions about the likelihood that their infant has CF. Implications for future research examining psychosocial interventions for NBS are discussed.

Insulin resistance predicts brain amyloid deposition in late middle-aged adults

Insulin resistance (IR) increases Alzheimers disease (AD) risk. IR is related to greater amyloid burden post‐mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle‐aged participants at risk for AD.

The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ɛ3/ɛ3 genotype

Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late‐onset Alzheimers disease (LOAD), with APOE epsilon 4 (APOE ɛ4) having higher risk. A variable poly‐T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly‐T length associated with earlier disease onset, and short poly‐T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism.

Effects of Simvastatin on Cerebrospinal Fluid Biomarkers and Cognition in Middle-Aged Adults at Risk for Alzheimer's Disease

BACKGROUND Statins reduce amyloid-beta (Abeta) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Abeta metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD. METHODS In a 4-month randomized, double-blind, controlled study, we evaluated the effects of simvastatin 40 mg daily vs. placebo on CSF Abeta42 levels and cognition in 57 asymptomatic middle-aged adult children of persons with AD. RESULTS Compared to placebo, individuals randomized to simvastatin for 4 months had similar changes in CSF Abeta42 (p=0.344) and total tau levels (p=0.226), yet greater improvements in some measures of verbal fluency (p=0.024) and working memory (p=0.015). APOE4 genotype, gender, and vascular risk factors were associated with CSF biomarker levels, but did not modify treatment effects. CONCLUSION In asymptomatic middle-aged adults at increased risk for AD, simvastatin use improved selected measures of cognitive function without significantly changing CSF Abeta42 or total tau levels. Further studies are needed to clarify the impact of higher dose and/or longer duration statin therapy on not only Abeta metabolism, but also other preclinical processes related to the development of AD.

Amyloid burden is associated with self-reported sleep in nondemented late middle-aged adults

Midlife may be an ideal window for intervention in Alzheimers disease (AD). To determine whether sleep is associated with early signs of AD neuropathology (amyloid deposition) in late midlife, we imaged brain amyloid deposits using positron emission tomography with [C-11]Pittsburgh Compound B (PiB), and assessed sleep with the Epworth Sleepiness Scale and the Medical Outcomes Study Sleep Scale in 98 cognitively healthy adults (aged 62.4 ± 5.7 years) from the Wisconsin Registry for Alzheimers Prevention. We used multiple regressions to test the extent to which sleep scores predicted regional amyloid burden. Participants reporting less adequate sleep, more sleep problems, and greater somnolence on the Medical Outcomes Study had greater amyloid burden in AD-sensitive brain regions (angular gyrus, frontal medial orbital cortex, cingulate gyrus, and precuneus). Amyloid was not associated with reported sleep amount, symptoms of sleep-disordered breathing, trouble falling asleep, or Epworth Sleepiness Scale. Poor sleep may be a risk factor for AD and a potential early marker of AD or target for preventative interventions in midlife.

Low cerebral blood flow is associated with lower memory function in metabolic syndrome

Metabolic syndrome (MetS)—a cluster of cardiovascular risk factors—is linked with cognitive decline and dementia. However, the brain changes underlying this link are presently unknown. In this study, we tested the relationship between MetS, cerebral blood flow (CBF), white matter hyperintensity burden, and gray matter (GM) volume in cognitively healthy late middle‐aged adults. Additionally, the extent to which MetS was associated with cognitive performance was assessed.

Surgical versus balloon therapy for aortic coarctation in infants ≤ 3 months old☆

OBJECTIVES This study compared the efficacy and safety of balloon angioplasty with surgical correction of native aortic coarctation in infants < or = 3 months old. BACKGROUND There is a controversy with regard to the role of balloon angioplasty in the treatment of aortic coarctation, especially in young infants. METHODS Data from 29 infants < or = 3 months old undergoing therapy for aortic coarctation during the decade ending 1992 were analyzed. Fourteen infants underwent surgery, and 15 had balloon angioplasty. The sole criterion for allotment to the balloon group was the availability of an interventional cardiologist at the time of presentation of the infant. RESULTS The surgical and balloon groups were comparable (p > 0.1) with regard to age (27 +/- 35 [mean +/- SD] vs. 29 +/- 27 days), weight (3.5 +/- 0.9 vs. 3.8 +/- 1.0 kg) and prevalence (7 of 14 vs. 8 of 15) and type of associated defects. Operative (1 of 14 vs. 1 of 15) and late (3 of 13 vs. 3 of 14) mortality, immediate gradient relief (36 +/- 25 to 10 +/- 9 mm Hg vs. 41 +/- 14 to 6 +/- 6 mm Hg) and follow-up gradient (27 +/- 27 vs. 24 +/- 19 mm Hg) were similar (p > 0.1). Infants with a gradient > 20 mm Hg at follow-up (6 of 13 vs. 7 of 14) and need for reintervention (6 of 13 vs. 7 of 14) were also similar (p > 0.1) in both groups. Duration of hospital stay during the first intervention was higher (p < 0.05) in the surgical (32 +/- 37 days) than the balloon (7 +/- 6 days) group. Similarly, duration of endotracheal intubation and mechanical ventilation was longer (p < 0.05) in the surgical (12 +/- 16 days) than the balloon (2 +/- 3 days) group. Complications after surgical intervention (0.86 events/patient) were higher (p < 0.01) than those seen after balloon angioplasty (0.27 events/patient). However, the lack of significant differences observed for mortality rates and residual gradients may be due to low statistical power to detect differences (16% to 49%), implying that this may be due to either actual lack of statistical difference or small sample size. CONCLUSIONS The data indicate that the degree of relief from aortic coarctation and the frequency with which reintervention is needed are similar in both groups. However, the morbidity and complication rates are lower with balloon than with surgical therapy. These data suggest that balloon angioplasty may be an acceptable alternative to surgical correction in the treatment of symptomatic aortic coarctation in infants < or = 3 months old.

Echocardiographic predictors of success of catheter closure of atrial septal defect with the buttoned device

Transcatheter occlusion of ostium secundum atrial septal defects (ASD) with the buttoned device has been shown to be feasible, effective, and safe. The final decision to implant the device is largely based on the balloon sizing of the ASD during cardiac catheterization. Only subjective criteria of ASD size and the septal rims on echocardiography have been used before catheterization, balloon sizing, and transcatheter occlusion. The purpose of this study was to determine whether objective echo criteria could be developed to predict successful occlusion of the ASD. During a 46-month period ending August 1992, 29 children with secundum ASD were evaluated for transcatheter occlusion. The device was successfully implanted in 15 (group A); in the remaining 14 children, this procedure could not be performed (group B). Preocclusion echos were analyzed by independent investigators who had no knowledge of outcome of the procedure. Echo parameters studied included size of ASD, length of atrial septum (LAS), and size of the superior and inferior rims in precordial and subcostal views and maximum jet width by color flow mapping. From these measurements several ratios were derived, and the data were compared. A smaller (p < 0.05) ASD was present in the group of patients with successful implantation of the device; LAS was similar (p > 0.1) in both groups. A lower (p < 0.05) ratio of ASD to LAS and a higher (p < 0.05) ratio of the superior and inferior septal rims to ASD were associated with the group of patients with successful implantation of the device.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional white matter hyperintensities: aging, Alzheimer's disease risk, and cognitive function.

White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimers disease (AD). The cognitive implications of these common markers are not well understood. Previous research has primarily focused on global measures of WMH burden and broad localizations that contain multiple white matter tracts. The aims of this study were to determine the pattern of WMH accumulation with age, risk for AD, and the relationship with cognitive function utilizing a voxel-wise analysis capable of identifying specific white matter regions. A total of 349 participants underwent T1-weighted and high-resolution T2-weighted fluid attenuated inversion recovery magnetic resonance imaging and neuropsychological testing. Increasing age and lower cognitive speed and flexibility (a component of executive function), were both significantly associated with regional WMH throughout the brain. When age was controlled, lower cognitive speed and flexibility was independently associated with WMH in the superior corona radiata. Apolipoprotein E ε4 and parental family history of AD were not associated with higher burden of WMH. The results contribute to a larger body of literature suggesting that white matter measures are linked with processing speed, and illustrate the utility of voxel-wise analysis in understanding the effect of lesion location on cognitive function.