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1.  Cerebrovascular Perfusion among Older Adults is Moderated by Strength Training and Gender 
Neuroscience letters  2013;560:26-30.
Cerebral perfusion is important in older adults as it is linked to cognitive declines. Physical activity can improve blood flow in the body but little is known about the relationship between physical activity and cerebral perfusion in older adults. In particular, no study has investigated the relation between strength training and cerebral perfusion. We examined whether different types of physical activity (assessed with the Rapid Assessment of Physical Activity questionnaire) were associated with MRI cerebrovascular perfusion in 59 older adults. There was a significant interaction between gender and strength training, such that women who engaged in strength training (weight lifting or calisthenics) at least once per week exhibited significantly greater cerebrovascular perfusion than women who did not. This interaction remained significant after controlling for other physical activity, demographics, and health variables. These findings suggest that regular strength training can be beneficial for cerebrovascular health in women.
PMCID: PMC3920729  PMID: 24355360
cerebral perfusion; strength training; sex; physical activity; ASL
2.  Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies 
Journal of neurovirology  2011;17(4):368-379.
Recent reports suggest that a growing number of human immunodeficiency virus (HIV)-infected persons show signs of persistent cognitive impairment even in the context of combination antiretroviral therapies (cART). The basis for this finding remains poorly understood as there are only a limited number of studies examining the relationship between CNS injury, measures of disease severity, and cognitive function in the setting of stable disease. This study examined the effects of HIV infection on cerebral white matter using quantitative morphometry of the midsagittal corpus callosum (CC) in 216 chronically infected participants from the multisite HIV Neuroimaging Consortium study currently receiving cART and 139 controls. All participants underwent MRI assessment, and HIV-infected subjects also underwent measures of cognitive function and disease severity. The midsagittal slice of the CC was quantified using two semi-automated procedures. Group comparisons were accomplished using ANOVA, and the relationship between CC morphometry and clinical covariates (current CD4, nadir CD4, plasma and CSF HIV RNA, duration of HIV infection, age, and ADC stage) was assessed using linear regression models. HIV-infected patients showed significant reductions in both the area and linear widths for several regions of the CC. Significant relationships were found with ADC stage and nadir CD4 cell count, but no other clinical variables. Despite effective treatment, significant and possibly irreversible structural loss of the white matter persists in the setting of chronic HIV disease. A history of advanced immune suppression is a strong predictor of this complication and suggests that antiretroviral intervention at earlier stages of infection may be warranted.
PMCID: PMC4309645  PMID: 21556960
HIV; Corpus callosum; Nadir CD4; White matter; CART
3.  Hormones as “difference makers” in cognitive and socioemotional aging processes 
Frontiers in Psychology  2015;5:1595.
Aging is associated with well-recognized alterations in brain function, some of which are reflected in cognitive decline. While less appreciated, there is also considerable evidence of socioemotional changes later in life, some of which are beneficial. In this review, we examine age-related changes and individual differences in four neuroendocrine systems—cortisol, estrogen, testosterone, and oxytocin—as “difference makers” in these processes. This suite of interrelated hormonal systems actively coordinates regulatory processes in brain and behavior throughout development, and their level and function fluctuate during the aging process. Despite these facts, their specific impact in cognitive and socioemotional aging has received relatively limited study. It is known that chronically elevated levels of the stress hormone cortisol exert neurotoxic effects on the aging brain with negative impacts on cognition and socioemotional functioning. In contrast, the sex hormones estrogen and testosterone appear to have neuroprotective effects in cognitive aging, but may decrease prosociality. Higher levels of the neuropeptide oxytocin benefit socioemotional functioning, but little is known about the effects of oxytocin on cognition or about age-related changes in the oxytocin system. In this paper, we will review the role of these hormones in the context of cognitive and socioemotional aging. In particular, we address the aforementioned gap in the literature by: (1) examining both singular actions and interrelations of these four hormonal systems; (2) exploring their correlations and causal relationships with aspects of cognitive and socioemotional aging; and (3) considering multilevel internal and external influences on these hormone systems within the framework of explanatory pluralism. We conclude with a discussion of promising future research directions.
PMCID: PMC4302708  PMID: 25657633
hormones; aging; cognitive functioning; socioemotional functioning; cortisol; estrogen; testosterone; oxytocin
4.  Improved Serum Leptin and Ghrelin Following Bariatric Surgery Predict Better Postoperative Cognitive Function 
Background and Purpose
Bariatric surgery is associated with improved cognitive function, but the mechanisms underlying these gains remain poorly understood. Disturbed leptin and ghrelin systems are common in obese individuals and are associated with impaired cognitive function in other samples. Bariatric surgery has been shown to improve serum leptin and ghrelin levels, and these changes may underlie postoperative cognitive improvements.
Eighty-four patients completed a computerized cognitive test battery prior to bariatric surgery and at 12 months postoperatively. Participants also submitted to an 8-hour fasting blood draw to quantify serum leptin and ghrelin concentrations at these same time points.
Baseline cognitive impairments and disturbed leptin and ghrelin levels improved at the 12-month follow-up compared to presurgery. Higher leptin levels were associated with worse attention/executive function at baseline; no such findings emerged for ghrelin. Regression analyses controlling for baseline factors and demographic characteristics showed that both decreased leptin and increased ghrelin following surgery was associated with better attention/executive function at the 12-month follow-up. These effects diminished after controlling for the postoperative change in body mass index (BMI); however, BMI change did not predict 12-month cognitive function.
Improvements in leptin and ghrelin levels following bariatric surgery appear to contribute to postoperative cognitive benefits. These gains may involve multiple mechanisms, such as reduced inflammation and improved glycemic control. Future studies that employ neuroimaging are needed to clarify the underlying mechanisms and determine whether the effects of bariatric surgery on leptin and ghrelin levels can attenuate adverse brain changes and/or risk of dementia in severely obese individuals.
PMCID: PMC4302179  PMID: 25628737
obesity; bariatric surgery; cognitive function; leptin; ghrelin
5.  Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Cognitive Function in Persons with Cardiovascular Disease 
Cognitive impairment is common among persons with cardiovascular disease (CVD) and several potential etiological mechanisms have been described, including contributions of genetic markers such as variations in the brain-derived neurotrophic (BDNF) gene. The current study examined the associations of BDNF genotype with cognitive function among individuals with CVD.
110 participants with CVD completed a comprehensive neuropsychological battery that assessed global cognitive function, attention/executive function, memory, language, and visuospatial abilities. All participants also underwent blood draw to provide a DNA sample that was used to determine BDNF genotype. Carriers of either one or two copies of the MET allele of BDNF were categorized into one group (N = 33), while non-carriers were categorized into a second group (N = 77).
After adjustment for demographic and medical characteristics, hierarchical regression analyses revealed persons with one or more Met alleles displayed better performance than Val/Val individuals for attention/executive function (β = .22, p = .047), memory (β = .25, p = .03) and a trend for language (β = .19, p = .08) and visuospatial abilities (β = .21, p = .06).
BDNF VAL66MET had little impact on cognitive functioning in a sample of older adults with CVD and significant findings were actually opposite of that predicted by past work. Future work is much needed to clarify the mechanisms for these findings, particularly studies examining both circulating BDNF levels and genetic variation in the BDNF gene and cognitive function over time.
PMCID: PMC3847660  PMID: 24289461
BDNF; cardiovascular disease; cognitive function; genetics; MET allele
6.  Are Apathy and Depression Independently Associated with Longitudinal Trajectories of Cortical Atrophy in Mild Cognitive Impairment? 
We sought to examine whether depression and apathy are independently associated with longitudinal trajectories of cortical atrophy in entorhinal cortex compared to frontal subregions previously implicated in late-life mood disturbance.
Data from 334 participants classified as having Mild Cognitive Impairment (MCI) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed using multilevel models for change adjusted for age, global cognitive status, and total intracranial volume at enrollment.
Participants in ADNI were recruited from over 50 clinical research sites in the United States and Canada.
Depression and apathy were identified by informants with the Neuropsychiatric Inventory Questionnaire. Serial MRI was carried out on 1.5T scanners according to standardized ADNI-1 protocol on an average of 5 occasions over an average of 2.5 years. Regional cortical thickness values were derived from longitudinal data processing in Freesurfer version 4.4.
Depression was associated with reduced cortical thickness in the entorhinal cortex at baseline and accelerated atrophy in anterior cingulate cortex. Similarly-sized relationships between depression and orbitofrontal cortex and between apathy and anterior cingulate cortex were not significant.
In MCI, depression signs are a better marker of longitudinal cortical atrophy than apathy. Results are consistent with hypotheses that depression is an early sign of a more aggressive neurodegenerative process or that depression lowers brain reserve capacity, allowing for more rapid progression of AD neuropathology.
PMCID: PMC3797189  PMID: 23636003
MRI; Alzheimer’s disease; mild cognitive impairment; apathy; depression
7.  Laminin α4 Deficient Mice Exhibit Decreased Capacity for Adipose Tissue Expansion and Weight Gain 
PLoS ONE  2014;9(10):e109854.
Obesity is a global epidemic that contributes to the increasing medical burdens related to type 2 diabetes, cardiovascular disease and cancer. A better understanding of the mechanisms regulating adipose tissue expansion could lead to therapeutics that eliminate or reduce obesity-associated morbidity and mortality. The extracellular matrix (ECM) has been shown to regulate the development and function of numerous tissues and organs. However, there is little understanding of its function in adipose tissue. In this manuscript we describe the role of laminin α4, a specialized ECM protein surrounding adipocytes, on weight gain and adipose tissue function. Adipose tissue accumulation, lipogenesis, and structure were examined in mice with a null mutation of the laminin α4 gene (Lama4−/−) and compared to wild-type (Lama4+/+) control animals. Lama4−/− mice exhibited reduced weight gain in response to both age and high fat diet. Interestingly, the mice had decreased adipose tissue mass and altered lipogenesis in a depot-specific manner. In particular, epididymal adipose tissue mass was specifically decreased in knock-out mice, and there was also a defect in lipogenesis in this depot as well. In contrast, no such differences were observed in subcutaneous adipose tissue at 14 weeks. The results suggest that laminin α4 influences adipose tissue structure and function in a depot-specific manner. Alterations in laminin composition offers insight into the roll the ECM potentially plays in modulating cellular behavior in adipose tissue expansion.
PMCID: PMC4195691  PMID: 25310607
8.  Bariatric Surgery Patients Exhibit Improved Memory Function 12 Months Post-Operatively 
Obesity surgery  2013;23(10):1527-1535.
Previous work from our group demonstrated improved memory function in bariatric surgery patients at 12 weeks post-operatively relative to controls. However, no study has examined longer term changes in cognitive functioning following bariatric surgery.
Materials and Methods
A total of 137 individuals (95 bariatric surgery patients, 42 obese controls) were followed prospectively to determine whether post-surgery cognitive improvements persist. Potential mechanisms of change were also examined. Bariatric surgery participants completed self-report measurements and a computerized cognitive test battery prior to surgery and at 12-week and 12-month follow-up; obese controls completed measures at equivalent time points.
Bariatric surgery patients exhibited cognitive deficits relative to well established standardized normative data prior to surgery, and obese controls demonstrated similar deficits. Analyses of longitudinal change indicated an interactive effect on memory indices, with bariatric surgery patients demonstrating better performance post-operatively than obese controls.
While memory performance was improved 12 months post-bariatric surgery, the mechanisms underlying these improvements were unclear and did not appear attributable to obvious post-surgical changes, such as reductions in BMI or co-morbid medical conditions. Future studies employing neuroimaging, metabolic biomarkers, and more precise physiological measurements are needed to determine the mechanisms underlying memory improvements following bariatric surgery.
PMCID: PMC3773052  PMID: 23636994
obesity; cognitive function; bariatric surgery; longitudinal assessment
9.  The effects of cigarette smoking on learning and memory performance among people living with HIV/AIDS 
AIDS care  2013;25(10):1308-1316.
The purpose of the present study was to examine the effects of smoking (past and current) on multiple domains of cognitive functioning in a sample of people living with HIV/AIDS (PLWHA). We hypothesized that among PLWHA, current smokers would demonstrate poorer cognitive functioning when compared to non-smokers, specifically in the cognitive domains of auditory-verbal (AV) learning and memory, visuospatial memory, overall cognitive efficiency, executive skills, processing speed and working memory. Results suggest that in patients being treated for HIV infection, current smoking is negatively associated with learning, memory and global cognitive functioning. There also was some evidence that cognitive deficits in learning associated with smoking were more pronounced among men compared to women. However, the cause of these effects is not at all clear. In multivariate models, the differences associated with smoking were non-significant when adjusting for education and hepatitis C (HCV) infection. Therefore, smoking may simply reflect a general tendency to more widespread deficits and comorbidities rather than directly impacting cognitive function. Future studies should attempt to examine a priori cognitive factors which contribute to smoking debut and other associated risk factors in order to understand why smoking may be a marker for other risk factors and may ultimately influence neurocognitive functioning critical to daily activities and adherence.
PMCID: PMC3672313  PMID: 23394125
10.  Lung Aeration Changes After Lung Recruitment in Children With Acute Lung Injury: A Feasibility Study 
Pediatric pulmonology  2012;47(8):771-779.
There are several adult studies using computed tomography (CT-scan) to examine lung aeration changes during or after a recruitment maneuver (RM) in ventilated patients with acute lung injury (ALI). However, there are no published data on the lung aeration changes during or after a RM in ventilated pediatric patients with ALI.
To describe CT-scan lung aeration changes and gas exchange after lung recruitment in pediatric ALI and assess the safety of transporting patients in the acute phase of ALI to the CT-scanner.
We present a case series completed in a subset of six patients enrolled in our previously published study of efficacy and safety of lung recruitment in pediatric patients with ALI.
RM using incremental positive end-expiratory pressure.
There was a variable increase in aerated and poorly aerated lung after the RM ranging from 3% to 72% (median 20%; interquartile range 6, 47; P = 0.03). All patients had improvement in the ratio of partial pressure of arterial oxygen over fraction of inspired oxygen (PaO2/FiO2) after the RM (median 14%; interquartile range: 8, 72; P = 0.03). There was a decrease in the partial pressure of arterial carbon dioxide (PaCO2) in four of six subjects after the RM (median −5%; interquartile range: −9, 2; P = 0.5). One subject had transient hypercapnia (41% increase in PaCO2) during the RM and this correlated with the smallest increase (3%) in aerated and poorly aerated lung. All patients tolerated the RM without hemodynamic compromise, barotrauma, hypoxemia, or dysrhythmias.
Lung recruitment results in improved lung aeration as detected by lung tomography. This is accompanied by improvements in oxygenation and ventilation. However, the clinical significance of these findings is uncertain. Transporting patients in early ALI to the CT-scanner seems safe and feasible.
PMCID: PMC4169705  PMID: 22298419
ARDS; respiratory distress syndrome; ALI; recruitment maneuvers
11.  Left Atrial Size is Independently Associated with Cognitive Function 
Left atrial (LA) diameter is easily attainable from echocardiograph and sensitive to underlying cardiovascular disease severity, though its association with neurocognitive outcomes is not well understood. Fifty older adults (64.50 ± 9.41 years) recruited from outpatient cardiology clinics and local papers underwent magnetic resonance imaging (MRI), were administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and completed psychosocial self-report measures. LA diameter was quantified using echocardiogram. Hierarchical regression analyses revealed greater LA size was independently associated with reduced performance on the following RBANS composites: language, delayed memory, and total index (p < .05 for all). Hierarchical regression analysis demonstrated no significant association between LA diameter and whole brain volume (p > .05). The current study suggests that greater LA size is associated with cognitive dysfunction in older adults and prospective studies are needed to validate these findings and elucidate underlying mechanisms.
PMCID: PMC4166650  PMID: 23394115
Left Atrial Diameter; Cognitive Function; Cardiovascular Disease; Echocardiogram; Neuroimaging; Cerebrovascular disease
12.  Patient reports of cognitive problems are not associated with neuropsychological test performance in bariatric surgery candidates 
Recent work shows that cognitive deficits are common in bariatric surgery candidates and associated with reduced weight loss at 12 months post-operatively. As pre-operatively neuropsychological assessment is not available for all patients at all sites, many care providers ask patients to self-report their level of cognitive dysfunction. However, the accuracy of patient self-report of cognitive abilities has not been empirically examined.
Longitudinal Assessment of Bariatric Surgery (LABS), United States; Medical Center
Eighty-one bariatric surgery candidates completed self-report measures of cognitive functioning and neuropsychological tests of memory and other cognitive abilities.
Analyses found no association between subjective report of cognitive function and objective performance on neuropsychological testing. However, persons with history of major depressive disorder reported experiencing greater cognitive deficits.
These findings suggest that bariatric surgery candidates have little insight into their current level of cognitive function. Future work is needed to confirm these findings and identify brief, objective measures of cognitive function that are sensitive to deficits in bariatric surgery candidates.
PMCID: PMC3610809  PMID: 23245496
Bariatric; Cognition; Self-report; Memory; Executive Function
13.  The Interactive Effects of Cerebral Perfusion and Depression on Cognitive Function in Older Adults with Heart Failure 
Psychosomatic medicine  2013;75(7):632-639.
Depression is common among persons with heart failure (HF) and has been linked to cognitive impairment in this population. The mechanisms of this relationship are unclear, and the current study examined whether cerebral perfusion moderates the association between depressive symptomatology and cognitive impairment in patients with HF.
Persons with HF (N=89; 67.61 (SD = 11.78) years of age) completed neuropsychological testing and impedance cardiography. Depressive symptomatology was assessed using the Beck Depression Inventory-II and transcranial doppler was used to quantify cerebral perfusion.
Depression was associated with reduced performance on tasks assessing attention/executive function (r=−0.28), language (r=−.0.30) and motor function (r=−.28) in unadjusted models (p-values < 0.05). Global cerebral blood flow was correlated with memory performance (r=0.22, p=.040) but not to other tasks. A moderation analysis was performed using hierarchical regression models for attention/executive function, memory, language, and motor function. For each model, medical and demographic characteristics were entered into the initial blocks, and the final block consisted of an interaction term between global cerebral blood flow velocity (CBF-V) and the BDI-II. The interaction between greater depressive symptomatology and decreased global CBF-V was associated with greater deficits in attention/executive function (β = .32, ΔR2 = .08, p = .003).
Depressive symptomatology and cerebral hypoperfusion interact to adversely affect cognitive performance in older adults with HF. Longitudinal studies are needed to clarify this relationship and elucidate subsequent neuropathology.
PMCID: PMC3770733  PMID: 23873714
Cognitive impairment; Cerebral Perfusion; Heart failure; Depression; Cardiovascular disease; Cerebral blood flow velocity
14.  Independent and Interactive Effects of Blood Pressure and Cardiac Function on Brain Volume and White Matter Hyperintensities in Heart Failure 
Reduced systemic perfusion and comorbid medical conditions are key contributors to adverse brain changes in heart failure (HF). Hypertension, the most common co-occurring condition in HF, accelerates brain atrophy in aging populations. However, the independent and interactive effects of blood pressure and systemic perfusion on brain structure in HF have yet to be investigated.
Forty-eight older adults with HF underwent impedance cardiography to assess current systolic blood pressure status, and cardiac index to quantify systemic perfusion. All participants underwent brain magnetic resonance imaging to quantify total brain, total and subcortical gray matter volume, and white matter hyperintensities (WMH) volume.
Regression analyses adjusting for medical and demographic factors showed decreased cardiac index was associated with smaller subcortical gray matter volume (p < .01) and higher systolic blood pressure predicted reduced total gray matter volume (p = .03). The combination of higher blood pressure and lower cardiac index exacerbated WMH (p = .048).
Higher blood pressure and systemic hypoperfusion are associated with smaller brain volume and these factors interact to exacerbate WMH in HF. Prospective studies are needed to clarify the effects of blood pressure on the brain in HF, including the role of long-term blood pressure fluctuations.
PMCID: PMC3770819  PMID: 23735419
Blood pressure; brain; cognition; heart failure; cardiac index; MRI
15.  Cognitive Function Predicts 24-Month Weight Loss Success Following Bariatric Surgery 
Clinically significant cognitive impairment, particularly in attention/executive and memory function, is found in many patients undergoing bariatric surgery. These difficulties have previously been linked to decreased weight loss 12 months post-surgery, but more protracted examination of this relationship has not yet been conducted.
The current study prospectively examined the independent contribution of cognitive function to weight loss 24 months following bariatric surgery. Given the rapid rate of cognitive improvement observed following surgery, postoperative cognitive function (i.e., cognition 12 weeks following surgery, controlling for baseline cognition) was expected to predict lower body mass index (BMI) and higher percent total weight loss (%WL) at 24-month follow-up.
Data were collected by three sites of the Longitudinal Assessment of Bariatric Surgery (LABS) parent project.
Fifty-seven individuals enrolled in the LABS project undergoing bariatric surgery completed cognitive evaluation at baseline, 12 weeks, and 24 months. %WL and BMI were calculated for 24-month postoperative follow-up.
Better cognitive function 12 weeks following surgery predicted higher %WL and lower BMI at 24 months, and specific domains of attention/executive and memory function were robustly related to decreased BMI and greater %WL at 24 months.
Results demonstrate that cognitive performance shortly after bariatric surgery predicts greater long-term %WL and lower BMI 24 months following bariatric surgery. Further work is needed to clarify the degree to which this relationship is mediated by adherence to postoperative guidelines.
PMCID: PMC3788845  PMID: 23816443
memory; cognition; executive function; adherence
16.  The LIFE Cognition Study: design and baseline characteristics 
Observational studies have shown beneficial relationships between exercise and cognitive function. Some clinical trials have also demonstrated improvements in cognitive function in response to moderate–high intensity aerobic exercise; however, these have been limited by relatively small sample sizes and short durations. The Lifestyle Interventions and Independence for Elders (LIFE) Study is the largest and longest randomized controlled clinical trial of physical activity with cognitive outcomes, in older sedentary adults at increased risk for incident mobility disability. One LIFE Study objective is to evaluate the effects of a structured physical activity program on changes in cognitive function and incident all-cause mild cognitive impairment or dementia. Here, we present the design and baseline cognitive data. At baseline, participants completed the modified Mini Mental Status Examination, Hopkins Verbal Learning Test, Digit Symbol Coding, Modified Rey–Osterrieth Complex Figure, and a computerized battery, selected to be sensitive to changes in speed of processing and executive functioning. During follow up, participants completed the same battery, along with the Category Fluency for Animals, Boston Naming, and Trail Making tests. The description of the mild cognitive impairment/dementia adjudication process is presented here. Participants with worse baseline Short Physical Performance Battery scores (prespecified at ≤7) had significantly lower median cognitive test scores compared with those having scores of 8 or 9 with modified Mini Mental Status Examination score of 91 versus (vs) 93, Hopkins Verbal Learning Test delayed recall score of 7.4 vs 7.9, and Digit Symbol Coding score of 45 vs 48, respectively (all P<0.001). The LIFE Study will contribute important information on the effects of a structured physical activity program on cognitive outcomes in sedentary older adults at particular risk for mobility impairment. In addition to its importance in the area of prevention of cognitive decline, the LIFE Study will also likely serve as a model for exercise and other behavioral intervention trials in older adults.
PMCID: PMC4154884  PMID: 25210447
exercise; physical activity; older adults; dementia
17.  Cerebral Perfusion is Associated with White Matter Hyperintensities in Older Adults with Heart Failure 
Cognitive impairment is common in heart failure (HF) and believed to be the result of cerebral hypoperfusion and subsequent brain changes including white matter hyperintensities (WMH). The current study examined the association between cerebral blood flow and WMH in HF patients and the relationship of WMH to cognitive impairment. Sixty-nine patients with HF completed the mini mental state examination (MMSE), echocardiogram, transcranial Doppler sonography (TCD) for cerebral blood flow velocity of the middle cerebral artery and brain magnetic resonance imaging (MRI). Multivariable hierarchical regression analyses controlling for medical and demographic characteristics as well as intracranial volume showed reduced cerebral blood flow velocity of the middle cerebral artery was associated with greater WMH (β = −.34, p = .02). Follow up regression analyses adjusting for the same medical and demographic factors in addition to cerebral perfusion also revealed marginal significance between increased WMH and poorer performance on the MMSE (β = −.26, p = .05). This study suggests that reduced cerebral perfusion is associated with greater WMH in older adults with HF. Our findings support the widely proposed mechanism of cognitive impairment in HF patients and prospective studies are needed to confirm our findings.
PMCID: PMC3692594  PMID: 23517434
Cardiovascular disease; cerebral blood flow; cognitive function; heat failure; white matter hyperintensities
18.  Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA-Binding Region: In Vitro Studies Reveal Different Pathogenic Mechanisms 
Thyroid  2013;23(7):791-796.
Mutations in PAX8, a transcription factor gene, cause thyroid dysgenesis (TD). The extreme variability of the thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q). We performed in vitro studies to functionally characterize these mutations.
Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)- and the thyroperoxidase (TPO)-promoters.
S54R had an impaired binding to DNA and a negligible activity on the TG- and the TPO-promoters. The DNA-binding property of R133Q, which is located in the highly conserved terminal portion of the PAX8 DNA-binding domain, was normal. Interestingly, it also exhibited dramatically impaired activation of the TG- and TPO-promoters. However, R133Q has no dominant negative effect on the WT protein in vitro. Thus, the underlying molecular mechanism by which the function of R133Q is impaired remains to be elucidated.
We identified and functionally characterized two novel mutations of the PAX8 gene that lead to TD by distinct mechanisms. A structural defect of the mutant R133Q leading to a reduced capability for induced fit upon DNA interaction might explain the disparity between its apparently normal binding to DNA, but lack of promoter activation.
PMCID: PMC3704082  PMID: 23308388
19.  Improved Memory Function Two Years After Bariatric Surgery 
Obesity (Silver Spring, Md.)  2013;22(1):32-38.
Obesity is as an independent risk factor for poor neurocognitive outcomes, including Alzheimer’s disease. Bariatric surgery has recently been shown to result in improved memory at 12-weeks post-operatively. However, the long-term effects of bariatric surgery on cognitive function remain unclear.
Design and Methods
86 individuals (63 bariatric surgery patients, 23 obese controls) were recruited from a prospective study examining the neurocognitive effects of bariatric surgery. All participants completed self-report measurements and a computerized cognitive test battery prior to surgery and at 12-week and 24-month follow-up; obese controls completed measures at equivalent time points.
Bariatric surgery patients exhibited high rates of pre-operative cognitive impairments in attention, executive function, memory, and language. Relative to obese controls, repeated measures ANOVA showed improvements in memory from baseline to 12-weeks and 24-months post-operatively (p < .05). Regression analyses controlling for baseline factors revealed that a lower BMI at 24-months demonstrated a trend toward significance for improved memory (β = -.30, p = .075).
These findings suggest that cognitive benefits of bariatric surgery may extend to 24-months post-operatively. Larger prospective studies with extended follow-up periods are needed to elucidate whether bariatric surgery decreases risk for cognitive decline and possibly the development of dementia.
PMCID: PMC4054602  PMID: 23625587
Obesity; bariatric surgery; cognitive function; weight loss
20.  Progressive Cerebral Injury in the Setting of Chronic HIV Infection and Antiretroviral Therapy 
Journal of neurovirology  2013;19(3):209-218.
Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet whether neurological injury can progress in this setting remains uncertain.
Magnetic resonance spectroscopy, neurocognitive and clinical assessments were performed over two years in 226 HIV-infected individuals on stable CART, including 138 individuals who were neurocognitively asymptomatic (NA). Concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol (MI), and glutamate/glutamine (Glx) were measured in the midfrontal cortex (MFC), frontal white matter (FWM) and basal ganglia (BG). Longitudinal changes in metabolite levels were determined using linear mixed effect models, as were metabolite changes in relation to global neurocognitive function.
HIV-infected subjects showed significant annual decreases in brain metabolite levels in all regions examined, including NAA (2.95%), Cho (2.61%) in the FWM; NAA (1.89%), Cr (1.84%), Cho (2.19%) and Glx (6.05%) in the MFC; and Glx (2.80%) in the BG. Similar metabolite decreases were observed in the NA and subclinically impaired subgroups, including subjects with virologic suppression in plasma and CSF. Neurocognitive decline was associated with longitudinal decreases in Glx in the FWM and the BG, and in NAA in the BG.
Widespread progressive changes in the brain, including neuronal injury, occur in chronically HIV-infected persons despite stable antiretroviral treatment and virologic suppression and can lead to neurocognitive declines. The basis for these findings is poorly understood and warrants further study.
PMCID: PMC3740160  PMID: 23613008
21.  Neurocognitive Effects of HIV, Hepatitis C, and Substance Use History 
HIV-associated neurocognitive dysfunction persists in the highly active antiretroviral therapy (HAART) era and may be exacerbated by comorbidities, including substance use and hepatitis C virus (HCV) infection. However, the neurocognitive impact of HIV, HCV, and substance use in the HAART era is still not well understood. In the current study, 115 HIV-infected and 72 HIV-seronegative individuals with significant rates of lifetime substance dependence and HCV infection received comprehensive neuropsychological assessment. We examined the effects of HIV serostatus, HCV infection, and substance use history on neurocognitive functioning. We also examined relationships between HIV disease measures (current and nadir CD4, HIV RNA, duration of infection) and cognitive functioning. Approximately half of HIV-infected participants exhibited neurocognitive impairment. Detectable HIV RNA but not HIV serostatus was significantly associated with cognitive functioning. HCV was among the factors most consistently associated with poorer neurocognitive performance across domains, while substance use was less strongly associated with cognitive performance. The results suggest that neurocognitive impairment continues to occur in HIV-infected individuals in association with poor virologic control and comorbid conditions, particularly HCV coinfection.
PMCID: PMC4031745  PMID: 22132928
Neuropsychology; HIV-1; Chronic hepatitis C; Viral load; Cocaine dependence; Opiate dependence
22.  Poorer Physical Fitness is Associated with Reduced Structural Brain Integrity in Heart Failure 
Physical fitness is an important correlate of structural and functional integrity of the brain in healthy adults. In heart failure (HF) patients, poor physical fitness may contribute to cognitive dysfunction and we examined the unique contribution of physical fitness to brain structural integrity among patients with HF.
Sixty-nine HF patients performed the Modified Mini Mental State examination (3MS) and underwent brain magnetic resonance imaging. All participants completed the 2-minute step test (2MST), a brief measure of physical fitness. We examined the associations between cognitive performance, physical fitness, and three indices of global brain integrity: Total cortical gray matter volume, total white matter volume, and whole brain cortical thickness.
Regression analyses adjusting for demographic characteristics, medical variables (e.g., left ventricular ejection fraction), and intracranial volume revealed reduced performance on the 2MST was associated with decreased gray matter volume and thinner cortex (p < .05). Follow up analyses showed that reduced gray matter volume and decreased cortical thickness were associated with poorer 3MS scores (p < .05).
Poor physical fitness is common in HF and associated with reduced structural brain integrity. Prospective studies are needed to elucidate underlying mechanisms for the influence of physical fitness on brain health in HF.
PMCID: PMC3625509  PMID: 23528350
Brain; cognitive function; heart failure; neuroimaging; physical fitness
23.  Brain dysfunction in the era of combination antiretroviral therapy: Implications for the treatment of the aging population of HIV-infected individuals 
Improvements in the treatment of HIV infection and in the advancement of combination antiretroviral therapy (cART) have led to an increase in the number of individuals with HIV who are surviving to an older age. Preventing the development of neurocognitive abnormalities has become an increasingly important issue in this aging patient population, which is already at risk for cognitive impairment as a result of the neuropathological effects of HIV. cART has been critical in reducing the overall severity of HIV-associated neurocognitive disorders (HAND), but numerous challenges remain, as the prevalence of HAND continues to be high. There are several key areas in which treatment could be improved to reduce the incidence and severity of HAND. The use of well-tolerated cART medications that are able to penetrate the blood-brain barrier hold particular promise, as these agents may enable increased viral suppression in the parenchyma and may reduce neurocognitive dysfunction. In addition, the improved treatment of comorbid medical conditions that are common in patient populations with HIV (eg, HCV, liver failure and metabolic syndrome) is critical, as several of these conditions are known to have a significant effect on neural functions. Various research approaches indicate that the development of agents that control free radicals, neurotoxicity, proinflammatory processes and apoptosis may also have substantial potential in this field.
PMCID: PMC4021717  PMID: 20721831
Aging; AIDS; antiretroviral therapy; brain; cART; cognition disorder; HAART; HCV; highly active; HIV-associated neurocognitive disorder; HIV infection
24.  Cognitive Function Predicts Weight Loss Following Bariatric Surgery 
Clinically significant cognitive impairment is found in a subset of patients undergoing bariatric surgery. These difficulties could contribute to reduced adherence to postsurgical lifestyle changes and decreased weight loss.
The current study is the first to prospectively examine the independent contribution of cognitive function to weight loss following bariatric surgery. Executive function/attention and verbal memory at baseline were expected to negatively predict percent excess weight loss (%EWL) and body mass index (BMI) at follow-up.
Three sites of the Longitudinal Assessment of Bariatric Surgery (LABS) parent project were used: Columbia, Cornell, and Neuropsychiatric Research Institute
Eighty-four individuals enrolled in the LABS project undergoing bariatric surgery completed cognitive evaluation at baseline. BMI and %EWL were calculated at 12-week and 12-month post-surgery follow-ups.
Clinical impairment in task performance was most prominent in tasks associated with verbal recall and recognition (14.3–15.5% of the sample) and perseverative errors (15.5%). After accounting for demographic and medical variables, baseline tests of attention/executive function and memory predicted BMI and %EWL at 12 months, but not at 12 weeks.
Results demonstrate that baseline cognition predicts greater %EWL and lower BMI 12 months following bariatric surgery. Further work is needed to clarify the degree to which cognition contributes to adherence, and the potential mediation of cognition on the relationship between adherence and weight loss in this group.
PMCID: PMC3294182  PMID: 22133580
memory; cognition; executive function
25.  The Adverse Impact of Type 2 Diabetes on Brain Volume in Heart Failure 
Heart failure (HF) is associated with structural brain abnormalities, including atrophy in multiple brain regions. Type 2 diabetes mellitus (T2DM) is a prevalent comorbid condition in HF and is associated with abnormalities on neuroimaging in other medical and elderly samples. The current study examined whether comorbid T2DM exacerbates brain atrophy in older adults with HF.
Seventy-five older adults with HF underwent echocardiogram, and completed a brief cognitive test battery. Participants then underwent brain magnetic resonance imaging (MRI) to quantify total brain volumes, cortical lobar volumes, and white matter hyperintensities (WMH).
Approximately 30% of HF patients had a comorbid T2DM diagnosis. A series of MANCOVA analyses adjusting for medical and demographic characteristics and intracranial volume showed that HF patients with T2DM had smaller total brain, gray matter, and subcortical gray matter volume than those without such history. No between group differences emerged for WMH. Persons with T2DM also had smaller cortical lobar volumes, including in frontal, temporal, and parietal lobes. Follow-up analyses revealed smaller total and cortical lobar brain volumes and WMH were associated with poorer performance on measures of global cognitive status, attention, executive functions, and memory.
T2DM is associated with smaller total and cortical lobar brain volumes in patients with HF and these structural brain indices were associated with cognitive test performance. Prospective studies that directly monitor glucose levels are needed to confirm our findings and clarify the mechanisms by which T2DM adversely impacts brain atrophy in this population.
PMCID: PMC3633205  PMID: 23419083
Brain; cognitive function; heart failure; type 2 diabetes; neuroimaging

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