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1.  Trail Making Test A Improves Performance Characteristics of the International HIV-Dementia Scale to Identify Symptomatic HAND 
Journal of neurovirology  2013;19(2):137-143.
Although HIV-Associated Dementia (HAD) occurs in less than 5% of individuals with access to combination antiretroviral therapy (cART), rates of milder forms of HIV-Associated Neurocognitive Disorder (HAND) are much higher. We sought to define an optimal cut-point for the International HIV-Dementia Scale (IHDS) in Thailand for the identification of symptomatic HAND, defined as both HAD and Mild Neurocognitive Disorder (MND). We then sought to determine if adding a simple test from a larger neuropsychological battery could improve the performance characteristics for identifying symptomatic HAND. In this study 75 seropositive adults in Bangkok, Thailand, subjects completed neuropsychological tests and underwent a full neurological assessment. HAND diagnoses were determined by consensus conference using the 2007 Frascati criteria, blinded to the IHDS results. The optimal IHDS cut-point was determined by Receiver Operating Characteristic analysis with cross-validation. Individual neuropsychological tests were then evaluated and combined with the IHDS to test performance characteristics. The IHDS was poor at detecting symptomatic HAND at the optimized cut-point of ≤10 (sensitivity: 53.3%, specificity: 89.8%). The Trail Making Test A was most effective in improving performance characteristics when combined with the IHDS, with net sensitivity of 86% and specificity of 79%. In this setting, the IHDS performed poorly in identifying symptomatic HAND, but was substantially improved by the addition of Trail Making Test A, which typically requires less than two minutes to complete. This combination should be validated in a larger setting since it may address the critical need for HAND screening instruments in international settings.
doi:10.1007/s13365-013-0151-4
PMCID: PMC3644005  PMID: 23483520
HIV Dementia; Neuropsychology; Asia; Neuropsychological Tests; Trail Making Test
2.  Reduced memory in fat mass and obesity-associated allele carriers among older adults with cardiovascular disease 
Background
Much attention has been paid to the prevalence and predisposition of the fat mass and obesity-associated (FTO) gene to obesity, although only a few studies have characterized the extent to which this affects cognitive function. This study examined differences between risk allele carriers (i.e. FTO-AC/AA) and non-carriers (i.e. FTO-CC) on indices of attention/executive function/psychomotor speed, memory, language, and visual-spatial ability in a sample of older patients with cardiovascular disease.
Methods
We recruited 120 older adults from an outpatient cardiology clinic who underwent blood draw and completed neuropsychological testing. Participants were classified into two groups: one for those who were homozygous for the non-risk-conferring allele (i.e. FTO-CC) (n = 49) and the other for those who had at least one copy of the obesity risk-conferring A allele (i.e. FTO-AC/AA) (n = 71).
Results
Mancova analyses adjusting for age and years of education revealed the FTO-AC/AA group performed significantly worse on indices of memory (λ = 0.94, F(2, 115) = 3.58, P = 0.03, partial η2 = 0.06). Follow-up tests revealed a significant effect for the FTO-AC/AA group, relative to the non-carrier group, on encoding (i.e. California Verbal Learning Test Total Learning) and California Verbal Learning Test long-delay free recall (P < 0.05). No such differences between FTO carriers and non-carriers emerged on tests of attention/executive function/psychomotor speed, language, or visual-spatial ability (P > 0.05 for all).
Conclusions
These findings suggest that the FTO risk allele is associated with reduced memory performance, particularly on aspects of memory encoding and delayed recall. To elucidate underlying mechanisms, these findings will need to be replicated in larger samples that utilize neuroimaging.
doi:10.1111/j.1479-8301.2012.00424.x
PMCID: PMC3806216  PMID: 23551410
cardiovascular disease; cognitive function; FTO risk allele; memory; obesity
3.  Drug Abuse and Hepatitis C Infection as Comorbid Features of HIV Associated Neurocognitive Disorder: Neurocognitive and Neuroimaging Features 
Neuropsychology review  2009;19(2):215-231.
Substance abuse and co-infection with hepatitis C (HCV) are two highly relevant determinants of neurocognitive and neuroimaging abnormalities associated with HIV. Substance abuse and HCV are common in the HIV population and there is increasing evidence that the CNS is directly compromised by these comorbid conditions via additive or synergistic processes. In this article we review the current literature regarding mechanisms of neuronal injury as well as the neuropsychological and neuroimaging signatures associated with substance abuse and HCV status among HIV patients. We discuss specific methodological challenges and threats to validity associated with studies of HIV and comorbid substance use disorders or HCV and review potential strategies for minimizing their confounding effects. Efforts to understand the interactions between HIV, substance abuse and HCV co-infection will lead to more complete models of neuropathogenesis of HIV and a greater understanding of the variability in neuropsychological expression of HIV Associated Neurocognitive Disorder.
doi:10.1007/s11065-009-9101-6
PMCID: PMC3635478  PMID: 19468837
HIV; Drug abuse; Hepatitis C; Addiction; Neurocognition; Neuroimaging; Dementia
4.  Recent Clinical History and Cognitive Dysfunction for Attention and Executive Function among Human Immunodeficiency Virus-Infected Patients 
This study examined the association between recent trends in CD4 and viral loads and cognitive test performance with the expectation that recent history could predict cognitive performance. Eighty-three human immunodeficiency virus (HIV)-infected patients with a mean CD4 count of 428 copies/ml were examined in this study (62% with undetectable plasma viral load [PVL]). We investigated the relationships between nadir CD4 cell count, 1-year trends in immunologic function/PVLs, and cognitive performance across several domains using linear regression models. Nadir CD4 cell count was predictive of current executive function (p = .004). One year clinical history for CD4 cell counts and/or PVLs were predictive of executive function, attention/working memory, and learning/memory measures (p < .05). Models that combined recent clinical history trends and nadir CD4 cell counts suggested that recent clinical trends were more important in predicting current cognitive performance for all domains except executive function. This research suggests that recent CD4 and viral load history is an important predictor of current cognitive function across several cognitive domains. If validated, clinical variables and cognitive dysfunction models may improve our understanding of the dynamic relationships between disease evolution and progression and CNS involvement.
doi:10.1093/arclin/acr065
PMCID: PMC3243921  PMID: 21873325
HIV; Cognition; Neuropsychology; Executive function; Recent clinical history
5.  Improved Memory Function 12 Weeks after Bariatric Surgery 
Background
There is growing evidence that obesity is associated with poor neurocognitive outcome. Bariatric surgery is an effective intervention for morbid obesity and improves many comorbid medical conditions that are associated with cognitive dysfunction. The effects of bariatric surgery on cognition are unknown.
Methods
Prospective study total of 150 individuals (109 bariatric surgery patients enrolled in the Longitudinal Assessment of Bariatric Surgery (LABS) project and 41 obese controls that did not undergo surgery) completed cognitive evaluation at baseline and 12 week follow-up. Demographic, medical, and psychosocial information was also collected to elucidate possible mechanisms of change.
Results
Many bariatric surgery patients exhibited impaired performance on cognitive testing at baseline (range from 4.6%–23.9%). However, surgery patients were no more likely to exhibit decline on two or more cognitive tests at 12-week follow-up than obese controls [12.84% vs. 23.26%; χ2 (1) = 2.51, p = .11]. Group comparisons using repeated measures MANOVA showed surgery patients had improved memory performance at 12 week follow-up [λ = .86, F(4, 147) = 5.88, p<.001], whereas obese controls actually declined. Regression analyses showed surgery patients without hypertension had better short delay recall at 12 weeks than those that did [β = 0.31, p = .005], though other demographic and medical variables were largely unrelated to test performance.
Conclusion
The current results suggest that cognitive impairment is common in bariatric surgery patients, though these deficits may be at least partly reversible. Future studies are needed to clarify underlying mechanisms, particularly longitudinal studies employing neuroimaging and blood markers.
doi:10.1016/j.soard.2010.09.015
PMCID: PMC3117085  PMID: 21145295
obesity; cognitive function; bariatric surgery; Integneuro
7.  Neuroimaging and Cardiac Correlates of Cognitive Function among Patients with Cardiac Disease 
In the present study, we examined the relationships between whole brain volume (WBV), subcortical hyperintensities (SH), indices of cardiac disease and cognitive function in nondemented cardiac patients with evidence of mild cerebrovascular disease. A total of 27 individuals with evidence of cardiac disease underwent neuropsychological examination, neuroimaging, and cardiac assessment. Cognition was assessed with the Dementia Rating Scale-2 (DRS). WBV and SH were quantified using a semi-automated thresholding program based on MRI. Correlational analyses revealed that WBV predicted performance on the overall DRS score, the attention subscale and the initiation/perseveration scale. SH were significantly associated with performance on the attention subscale, and the initiation/perseveration subscale. Regression analyses revealed that SH accounted for most of the variance in the initiation/perseveration scale, whereas WBV accounted for most of the variance in the attention scale. The only cardiac structural or functional variable related to the neurological indices was aortic diameter, which was strongly related to both neuroimaging variables, as well as performances on the DRS attention and initiation/perseveration subscales. Our results highlight the importance of overall brain parenchyma in determining cognitive status among patients at risk for cognitive decline and suggest that select indices of structural cardiac morphology may be related to the early phases of cerebrovascular disease and cognitive status.
doi:10.1159/000086803
PMCID: PMC3222237  PMID: 16006761
Cardiac disease; MRI; Cognition; Neuropsychology; Subcortical hyperintensities
8.  Blood pressure variability and white matter hyperintensities in older adults with cardiovascular disease 
Blood pressure  2005;14(6):353-358.
The present study examined the relationship between multiple blood pressure (BP) indices and white matter hyperintensities (WMH) in a sample of 39 older adults with cardiovascular disease (CVD). Resting BP was measured using an automated monitor every 10 min for 2 h. WMH were quantified on FLAIR images and separate indices were generated for neocortical, periventricular and subcortical brain regions. Correlation analyses revealed systolic BP variability was related to neocortical and total WMH. A function of systolic BP variability and average diastolic pressure showed the strongest relationships, including significant correlation to neocortical, subcortical and total WMH. No BP index was related to WMH in periventricular regions. Exploratory analyses showed only the function of systolic BP variability and average diastolic pressure predicted total WMH, whereas as age, CVD conditions and psychosocial factors did not. These findings demonstrate BP variability is an important contributor to WMH in older adults with CVD and suggests it may have differential relationships to WMH in different brain regions. Additional studies are needed to examine the role of autoregulatory systems in the development of WMH, particularly those using beat-to-beat measures of BP.
doi:10.1080/08037050500364117
PMCID: PMC3215278  PMID: 16403689
Blood pressure; cardiovascular disease; cerebrovascular disease
9.  Link Between Change in Cognition and Left Ventricular Function following Cardiac Resynchronization Therapy 
PURPOSE
In patients with heart failure, reduced cardiac ejection fraction has been associated with impaired cognition. Improving cardiac function may have beneficial effects on cognition; however, no controlled intervention studies have examined this possibility. Cardiac resynchronization therapy (CRT) is 1 intervention that has been shown to increase cardiac function. The goals of the current study were to: 1) evaluate neuropsychological performance before and 3-months after CRT and 2) examine follow-up neuropsychological performance of patients classified based on extent of improved left ventricular ejection fraction (LVEF).
METHODS
Twenty-seven patients with moderate to severe heart failure completed a neuropsychological assessment, 6-minute walk test, and transthoracic echocardiogram prior to and 3-months post-CRT. Patients were classified based on improvement in LVEF. Results of a MANOVA revealed a significant effect of improvement in LVEF on change in cognition (Wilk’s lambda, P=.031).
RESULTS
Patients with improved LVEF demonstrated significant increases on measures of executive functioning (F=8.57, P=.007) and visuospatial function (F=7.52, P=.011) and less decline on global cognition (F=5.73, P=.024) than those without LVEF improvement.
CONCLUSIONS
Findings provide preliminary evidence that improved LVEF in response to CRT is associated with enhanced cognitive outcomes within 3 months of CRT. Patients with improved LVEF showed better outcomes on measures of executive functioning, global cognition, and visuospatial functioning. Future controlled large scale trials will be necessary to determine whether there is an underlying causal relationship linking increase in LVEF and cognition.
doi:10.1097/HCR.0b013e3181e1739a
PMCID: PMC2978265  PMID: 20562712
Heart failure; Cardiac resynchronization therapy; Cognition; Neuropsychology; Left ventricular ejection fraction
10.  Quantitative Diffusion Tensor Imaging Tractography Metrics are Associated with Cognitive Performance Among HIV-Infected Patients 
Brain imaging and behavior  2010;4(1):68-79.
There have been many studies examining HIV-infection-related alterations of magnetic resonance imaging (MRI) diffusion metrics. However, examining scalar diffusion metrics ignores the orientation aspect of diffusion imaging, which can be captured with tractography. We examined five different tractography metrics obtained from global tractography maps (global tractography FA, average tube length, normalized number of streamtubes, normalized weighted streamtube length, and normalized total number of tubes generated) for differences between HIV positive and negative patients and the association between the metrics and clinical variables of disease severity. We also examined the relationship between these metrics and cognitive performance across a wide range of cognitive domains for the HIV positive and negative patient groups separately. The results demonstrated a significant difference between the groups for global tractography FA (t=2.13, p= 0.04), but not for any of the other tractography metrics examined (p-value range=0.39 to 0.95). There were also several significant associations between the tractography metrics and cognitive performance (i.e., tapping rates, switching 1 and 2, verbal interference, mazes; r≥0.42) for HIV infected patients. In particular, associations were noted between tractography metrics, speed of processing, fine motor control/speed, and executive function for the HIV-infected patients. These findings suggest that tractography metrics capture clinically relevant information regarding cognitive performance among HIV infected patients and suggests the importance of subtle white matter changes in examining cognitive performance.
doi:10.1007/s11682-009-9086-z
PMCID: PMC2909656  PMID: 20503115
HIV; DTI; Neuropsychological performance; Tractography
11.  Vascular Health and Cognitive Function in Older Adults with Cardiovascular Disease 
Artery research  2008;2(1):35-43.
Background
We hypothesized that changes in vascular flow dynamics resulting from age and cardiovascular disease (CVD) would correlate to neurocognitive capacities, even in adults screened to exclude dementia and neurological disease. We studied endothelial-dependent as well as endothelial-independent brachial responses in older adults with CVD to study the associations of vascular responses with cognition. Comprehensive neurocognitive testing was used to discern which specific cognitive domain(s) correlated to the vascular responses.
Methods
Eighty-eight independent, community-dwelling older adults (70.02+7.67 years) with mild to severe CVD were recruited. Enrollees were thoroughly screened to exclude neurological disease and dementia. Flow-mediated (endothelial-dependent) and nitroglycerin-mediated (endothelial-independent) brachial artery responses were assessed using 2-d ultrasound. Cognitive functioning was assessed using comprehensive neuropsychological testing. Linear regression analyses were used to evaluate the relationships between the endothelial-dependent and endothelial-independent vascular flow dynamics and specific domains of neurocognitive function.
Results
Endothelial-dependent and endothelial-independent brachial artery responses both correlated with neurocognitive testing indices. The strongest independent relationship was between endothelial function and measures of attention-executive functioning.
Conclusions
Endothelial-dependent and endothelial-independent vascular responsiveness correlate with neurocognitive performance among older CVD patients, particularly in the attention-executive domain. While further study is needed to substantiate causal relationships, our data demonstrate that brachial responses serve as important markers of risk for common neurocognitive changes. Learning and behavior-modifying therapeutic strategies that compensate for such common, insidious neurocognitive limitations will likely improve caregiving efficacy.
doi:10.1016/j.artres.2008.01.001
PMCID: PMC3004172  PMID: 21179381
Cardiovascular Disease; vascular function; age; endothelium; neurocognitive performance
12.  Subjective Cognitive Complaints Relate to White Matter Hyperintensities and Future Cognitive Decline in Patients with Cardiovascular Disease 
Objective
Elderly patients with cardiovascular disease (CVD) often report cognitive difficulties including reduced cognitive processing speed and attention. On cross-sectional examination, such reports relate more closely to mood than to objective measures of cognitive performance, thus questioning the validity of subjective cognitive complaints as a marker of neurodegenerative processes. This study examined the longitudinal relationship between self-reported cognitive difficulties, depression, and performance on objective tests of global cognition in patients with CVD.
Participants and Methods
Forty-seven CVD patients (ages 55 to 85 years) completed a measure of perceived cognitive dysfunction (Cognitive Difficulties Scale), a medical history questionnaire, the Dementia Rating Scale (DRS), and the Beck Depression Inventory (BDI) at baseline and 12 months later. Baseline brain imaging was available on a small sub-sample (n = 17).
Results
Hierarchical linear regression revealed that increased report of cognitive difficulties at baseline was significantly associated with poorer DRS performance at follow-up (F(3, 43) = 4.45, p = .008, CDS partial r = −.30, p = .048), independent of age, education, baseline DRS and BDI scores. Greater perceived cognitive dysfunction at baseline also related to higher level of white matter lesions (r = .53, df = 15, p = .028).
Conclusions
Self-reported cognitive difficulties may reflect early changes in cognitive aging that are difficult to detect using global cognitive screening measures at a single time point. Yet, these perceived difficulties relate to objectively measured cognitive decline over time. Thus, they may provide important clinical information about early neurodegenerative processes that should be carefully monitored.
doi:10.1097/JGP.0b013e3181b208ef
PMCID: PMC2813459  PMID: 20104055
Subjective Cognitive Complaints; Cognition; Cardiovascular Diseases; Dementia Ratings Scale; White Matter Hyperintensities
13.  SELP 1087G/A Polymorphism is Associated with Neuropsychological Test Performance in Older Adults with Cardiovascular Disease 
Background and Purpose
There is growing evidence that the cell adhesion molecule P-selectin (SELP) contributes to the adverse vascular processes that promote cognitive impairment in individuals with cardiovascular disease. Previous research has shown that SELP genotypes moderate circulating levels of P-selectin and that coronary artery bypass graft (CABG) patients with the SELP 1087A allele were less likely to show post-operative cognitive decline and more likely to exhibit lower levels of C-reactive protein (CRP) than non-carriers. Thus, we expected that carriers of the 1087A allele (n = 43) would exhibit better cognitive functioning than persons with two 1087G alleles (n = 77) and that CRP levels would be important for this relationship.
Methods
120 older adults with diagnosed cardiovascular disease (CVD) were recruited from outpatient cardiology clinics. Each participant underwent a comprehensive neuropsychological test battery and a blood draw.
Results
Participants with the SELP 1087A allele performed more poorly on tests of attention [TMT-A: t(116)=3.20, p=.002], executive function [TMT-B: t(116)=2.89, p=.005], psychomotor speed [Digit-Symbol Coding: t(117)=2.54, p=.012], and memory [CVLT Discrimination: t(116)=2.05, p=.04]. There were no significant differences between the SELP genotype groups on demographic/medical variables or CRP levels.
Conclusions
Contrary to expectations, the present analyses showed that older CVD patients with the SELP 1087A allele performed more poorly on neuropsychological testing. Findings from the present study were counter to previous research with CABG candidates. Further work using neuroimaging and alternative measures of cardiovascular function is needed to clarify the mechanisms of this association.
doi:10.1161/STROKEAHA.109.553339
PMCID: PMC2752956  PMID: 19590054
P-selectin; Cognitive Function; Heart Disease
14.  Blood Pressure and Cognitive Function in Older adults with Cardiovascular Disease 
Background
Past studies link elevated blood pressure (BP) and BP variability to adverse neurocognitive changes in community samples. However, little is known about the relationship between BP indices and cognitive function in older CVD patients.
Methods
A total of 99 older adults with CVD completed a comprehensive neuropsychological test battery. Resting BP measurements were collected every 10 minutes for two hours during a separate cardiac assessment. Five BP indices were generated: average and standard deviation of systolic blood pressure, average and standard deviation of diastolic blood pressure, and a function of systolic variability and average diastolic pressure. We examined the relationship between these BP indices and cognitive function.
Results
Partial correlation adjusting for age and education revealed that the function of systolic variability and average diastolic pressure (systolic BP standard deviation divided by the average diastolic BP) was most closely related to test performance, showing significant associations to both Learning/Memory (r = 0.25) and Language functioning (r = 0.22). Systolic BP indices were also related to Language functioning (SBP avg, r = 0.22; SBP sd, r = 0.25), though diastolic BP indices were unrelated to performance in any cognitive domain.
Conclusions
The current findings indicate that BP is modestly related to cognitive function in older CVD patients. Contrary to expectations, greater BP variability was associated with better, not poorer, cognitive test performance. Such findings suggest that the relationship between BP and cognitive function is more complicated than typically hypothesized and requires further examination.
doi:10.3109/00207450903139713
PMCID: PMC2899480  PMID: 19916851
Blood Pressure; Cognitive Function; Heart Disease
15.  Normative scores for a brief neuropsychological battery for the detection of HIV-associated neurocognitive disorder (HAND) among South Africans 
BMC Research Notes  2010;3:28.
Background
There is an urgent need to more accurately diagnose HIV-associated neurocognitive disorder (HAND) in Africa. Rapid screening tests for HIV-associated dementia are of limited utility due to variable sensitivity and specificity. The use of selected neuropsychological tests is more appropriate, but norms for HIV seronegative people are not readily available for sub-Saharan African populations. We sought to derive normative scores for two commonly used neuropsychological tests that generate four test scores -- namely the Trail-Making Test (Parts A and B) and the Digit Span Test [Forward (DSF) and Backward (DSB)]. To assess memory and recall, we used the memory item of the International HIV Dementia Scale (IHDS).
Findings
One hundred and ten HIV seronegative participants were assessed at McCord Hospital, Durban, South Africa between March 3rd and October 31st, 2008. We excluded people with major depressive disorder, substance use abuse and dependence and head injuries (with or without loss of consciousness). All the participants in this study were African and predominantly female with an average age of 28.5 years and 10 years of education. Age and gender influenced neuropsychological functioning, with older people performing worse. The effect of gender was not uniform across all the tests.
Conclusion
These two neuropsychological tests can be administered with the IHDS in busy antiretroviral clinics. Their performance can be measured against these norms to more accurately diagnose the spectrum and progression of HAND.
doi:10.1186/1756-0500-3-28
PMCID: PMC2843737  PMID: 20181051
16.  Category and letter verbal fluency across the adult lifespan: relationship to EEG theta power 
The purpose of this study was to examine the impact of age, sex, and education on category and letter verbal fluency task performance. A secondary goal was to examine whether resting EEG theta power in bilateral frontal and temporal lobes impacts age-associated decline in verbal fluency task performance. A large sample (N=471) of healthy, normal participants, age 21–82, was assessed for letter fluency (i.e., FAS), and for category fluency (i.e., Animal Naming), and with a 32-channel EEG system for ‘eyes-open’ resting theta power. The effects of age, sex, and education were examined using analyses of variance. Correlation analyses were used to test the impact of theta power on age and fluency performance by controlling for the effects of theta when examining the relationship between the other two variables. The results indicated that performance on both fluency tests declined linearly with age, but that the rate of decline was greater for category fluency. These age changes were not associated with education level, and there were no sex differences. While theta power was negatively associated with age and positively associated with Animal Naming performance, it did not moderate the relationship between the two. The differential age-associated decline between category and letter fluency suggests separate neurobiological substrates underlying the two domains of performance, which is not related to theta activity.
doi:10.1016/j.acn.2004.12.006
PMCID: PMC2758771  PMID: 15939182
Normal aging; Category fluency; Letter fluency; EEG; Theta
17.  C-reactive protein, but not homocysteine, is related to cognitive dysfunction in older adults with cardiovascular disease 
Cardiovascular disease (CVD) is a risk factor for cognitive impairment and dementia. Recent studies implicate homocysteine (HCY) and C-reactive protein (CRP) in this increased risk, as both are associated with cognitive dysfunction in demented and non-demented patients. However, it remains unclear whether they confer added risk in older adults with CVD. A total of 126 older CVD patients underwent blood and neuropsychological evaluation as part of a prospective examination of the neurocognitive consequences of CVD. A subset of these participants (n = 37) also underwent neuroimaging to quantify the degree of white matter disease. After adjusting for demographic and medical factors, no significant relationship emerged between HCY and cognitive performance. In contrast, CRP showed significant independent relationships to test performance, including global cognitive performance, attention/psychomotor function, executive function, memory, and visuospatial abilities. Neither HCY nor CRP was related to extent of white matter disease or whole brain volume on magnetic resonance imaging. Further study is needed to identify mechanisms by which inflammatory processes impact on cognitive function and to determine whether reducing circulating levels of inflammatory markers results in improved cognition.
doi:10.1016/j.jocn.2005.08.010
PMCID: PMC2748307  PMID: 16723232
Homocysteine; C-reactive protein; Cognition
18.  Relation of Brain Natriuretic Peptide Levels to Cognitive Dysfunction in Adults >55 Years of Age With Cardiovascular Disease 
Cardiovascular disease (CVD) is associated with cognitive deficits long before the onset of stroke or dementia. Recent work has extended these findings and shown that patients with congestive heart failure also exhibit reduced cognitive performance. Brain natriuretic peptide (BNP) is used to help diagnose heart failure, but no study has examined whether BNP predicts cognitive dysfunction in older patients with CVD. BNP values and performance on the Dementia Rating Scale were assessed in 56 older adults with documented CVD. Forty-eight percent of the participants were women, and their average age was 70 ± 8 years. All participants had Mini-Mental State Examination scores greater than the cutoff for dementia and no histories of neurologic or severe psychiatric disorders. The average BNP level was 122 ± 202 pg/ml. Hierarchical regression analyses showed that log-transformed BNP levels predicted Dementia Rating Scale total score after adjusting for possible demographic and medical confounders (ΔR2 = 0.09, F[1, 44] = 6.14, p = 0.017). Partial correlation analysis adjusting for these possible confounders showed a particularly strong relation to the conceptualization subtest (r = −0.44, p = 0.002), a measure of verbal and nonverbal abstraction abilities. In conclusion, the results of the present study provide the first evidence for an independent relation between BNP and cognitive dysfunction in older adults with CVD.
doi:10.1016/j.amjcard.2006.02.062
PMCID: PMC2748274  PMID: 16893713
19.  Endothelial Function and White Matter Hyperintensities in Older Adults With Cardiovascular Disease 
Background and Purpose
The presence of white matter hyperintensities on brain MRI is common among elderly individuals. Previous research suggests that cardiovascular risk factors are associated with increased white matter hyperintensities. Examining the role of direct physiological measures of vascular function will help to clarify the vascular mechanisms related to white matter hyperintensities. The aim of the present study was to examine the association between endothelial-dependent and endothelial-independent vasodilatation and white matter hyperintensity volume.
Methods
Twenty-five older adults with a range of cardiovascular diseases underwent brain MRI and completed assessments of blood vessel integrity using endothelial-dependent and independent flow-mediated dilation of the brachial artery. A semi-automated pixel-based method was used to quantify total brain volume and white matter hyperintensity volume, with white matter hyperintensity volume corrected for total brain volume. The association between measures of flow-mediated dilation and log-transformed white matter hyperintensities was examined.
Results
Correlation analysis revealed that endothelial-dependent vasodilatation was significantly and inversely associated with white matter hyperintensity volume. In contrast, endothelial-independent vasodilatation was not associated with white matter hyperintensities. Neither endothelial-dependent nor endothelial-independent vasodilatation was associated with total brain volume.
Conclusions
These data provide preliminary evidence that the integrity of the vascular endothelium is associated with white matter hyperintensities in older adults with cardiovascular disease. Impaired vascular function may be one mechanism that contributes to the development of white matter hyperintensities in the brain. Additional longitudinal research combining measures of vessel function, neuroimaging and cognition will be helpful in clarifying this potential mechanism.
doi:10.1161/01.STR.0000254517.04275.3f
PMCID: PMC2748266  PMID: 17204686
cardiovascular disease; endothelium; magnetic resonance; white matter disease
20.  Object Perception Impairments Predict Instrumental Activities of Daily Living Dependence in Alzheimer's Disease 
This study examined the contribution of object perception and spatial localization to functional dependence among Alzheimer's disease (AD) patients. Forty patients with probable AD completed measures assessing verbal recognition memory, working memory, object perception, spatial localization, semantic knowledge, and global cognition. Primary caregivers completed a measure of activities of daily living (ADLs) that included instrumental and basic self-care subscales (i.e., IADLs and BADLs, respectively). Stepwise multiple regressions revealed that global cognition accounted for significant portions of variance among the ADL total, IADL, and BADL scores. However, when global cognition was removed from the model, object perception was the only significant cognitive predictor of the ADL total and IADL subscale scores, accounting for 18.5% and 19.3% of the variance, respectively. When considering multiple cognitive components simultaneously, object perception and the integrity of the inferotemporal cortex is important in the completion of functional abilities in general and IADLs in particular among AD patients.
doi:10.1080/13803390591001034
PMCID: PMC2746422  PMID: 16822730
21.  Cognitive predictors of functional decline in vascular dementia 
SUMMARY
Background
This study examined changes in cognitive-functional relationships in vascular dementia (VaD) over the course of one year.
Methods
Twenty-four patients with probable VaD were administered the Dementia Rating Scale (DRS). Caregivers completed an informant-based measure of instrumental (IADL) and basic activities of daily living (BADL). Follow-up assessment was conducted one-year post-baseline.
Results
Logistic regression revealed that changes in the DRS Initiation/Perseveration and DRS Memory subscales were significantly associated with declines in IADLs and BADLs, respectively.
Conclusions
Among patients with VaD, longitudinal changes in IADLs and BADLs are most strongly associated with changes in executive functioning and memory abilities, respectively. Findings suggest that different cognitive functions subserve complex instrumental and rote, habituated basic functional activities, and neuropsychological screening measures are useful in the prediction of such functional changes.
doi:10.1002/gps.1556
PMCID: PMC2746410  PMID: 16906630
activities of daily living (ADLs); vascular dementia (VaD); functional decline; neuropsychology; cognition; memory; executive function; Dementia Rating Scale (DRS)
22.  Evaluating elements of executive functioning as predictors of instrumental activities of daily living (IADLs) 
OBJECTIVE
Executive functioning has been repeatedly linked to the integrity of instrumental activities of daily living (IADL). The present study examined the association of multiple executive functioning elements (i.e., working memory, generation, inhibition, planning, and sequencing) to IADLs among an older adult cohort at risk for future cognitive and functional decline.
METHODS
Seventy-two participants with prevalent but stable cardiovascular disease completed a neuropsychological protocol assessing multiple elements of executive functioning, including COWA, PASAT, DKEFS Color-Word Interference Test, DKEFS Trail-Making Test, DKEFS Tower Test, and Ruff Figural Fluency Test. Reliable informants completed a measure of IADLs.
RESULTS
Stepwise logistic regression selected a model involving a single significant predictor, a measure of inhibition (i.e., DKEFS Color-Word Interference Test), which had a significant regression coefficient. Subsequent correlation analyses confirmed an association between the inhibition measure and multiple IADL items. Inter-item comparisons among the IADLs revealed significant differences, such that telephone use and laundry were significantly more intact than most other IADLs while shopping and housekeeping were most compromised.
CONCLUSIONS
Our data suggest that inhibition, also known as susceptibility to interference, is most strongly related to IADL impairment among patients at risk for future cognitive and functional decline.
doi:10.1016/j.acn.2006.03.007
PMCID: PMC2746400  PMID: 16814980
Cardiovascular disease; Neuropsychology; Cognition; Executive functioning; Instrumental activities of daily living (IADLs); Delis-Kaplan Executive Function System (D-KEFS); Inhibition; Geriatric
23.  Quantitative Tractography Metrics of White Matter Integrity in Diffusion-Tensor MRI 
NeuroImage  2008;42(2):568-581.
We present new quantitative diffusion-tensor imaging (DTI) tractography-based metrics for assessing cerebral white matter integrity. These metrics extend prior work in this area. Tractography models of cerebral white matter were produced from each subject's DTI data. The models are a set of curves (e.g., “streamtubes”) derived from DTI data that represent the underlying topography of the cerebral white matter. Nine metrics were calculated in whole brain tractography models and in three “tracts-of-interest” (TOI): transcallosal fibers, and the left and right cingulum bundles. The metrics included the number of streamtubes and several metrics based on the summed length of streamtubes in including some that were weighted by scalar anisotropy metrics and normalized for estimated intracranial volume. We then tested whether patients with subcortical ischemic vascular disease (i.e., vascular cognitive impairment or VCI) vs. healthy controls (HC) differed on the metrics. The metrics were significantly lower in the VCI group in whole brain and in transcallosal TOI but not in the left or right cingulum bundles. The metrics correlated significantly with cognitive functions known to be impacted by white matter abnormalities (e.g., processing speed) but not with those more impacted by cortical disease (e.g., naming). These new metrics help bridge the gap between DTI tractography and scalar analytical methods and provide a potential means for examining group differences in white matter integrity in specific tracts-of-interest.
doi:10.1016/j.neuroimage.2008.05.022
PMCID: PMC2745947  PMID: 18617421
24.  Systemic hypoperfusion is associated with executive dysfunction in geriatric cardiac patients 
Neurobiology of aging  2006;28(3):477-483.
The present study examines the relationship between systemic hypoperfusion via cardiac output (CO) and neuropsychological performances emphasizing executive function in an aging cohort. Geriatric outpatients with treated, stable cardiovascular disease (CVD) and no history of neurological illness (n = 72, ages 56-85) were administered cognitive measures with an emphasis on executive functioning. Echocardiogram findings were used to stratify participants into two groups: low CO (<4.0 L/min) and normal CO (≥4.0 L/min). Between-group comparisons were made using ANCOVAs adjusting for systolic blood pressure. The low CO group performed significantly worse than the normal CO group on DKEFS Tower Test and DKEFS Trail Making Test. No significant between-group differences were noted for any of the other cognitive indices. Findings suggest that reduced CO is associated with poorer executive functioning among geriatric outpatients with stable CVD, as the cognitive profile emphasizes a relationship between systemic hypoperfusion and problems with sequencing and planning. The executive dysfunction profile may be secondary to reduced blood flow to vulnerable subcortical structures implicated in frontal-subcortical circuitry.
doi:10.1016/j.neurobiolaging.2006.01.001
PMCID: PMC2741683  PMID: 16469418
Cardiovascular disease; Neuropsychology; Cognition; Executive functioning; Cardiac output; Systemic perfusion; Heart failure
25.  Vascular and cognitive functions associated with cardiovascular disease in the elderly 
This study examines the relationship between systemic vascular function, neurocognitive performance, and structural brain abnormalities on magnetic resonance imaging (MRI) among geriatric outpatients with treated, stable cardiovascular disease and no history of neurological illness (n = 88, ages 56–85 years). Vascular function was assessed by cardiac ejection fraction and output, sequential systolic and diastolic blood pressures, flow mediated brachial artery reactivity (BAR), and carotid intima media thickness (IMT). White matter hyperintensities (WMH) on MRI were quantified and examined relative to cognitive and vascular function. Principal component analysis revealed two primary vascular components: one associated with cardiac function, the other with atherosclerotic burden/endothelial dysfunction. Both factors were significantly associated with cognitive function and WMH volume. Reduced systolic variability and increased IMT were most strongly related to reduced attention, executive function, and information-processing speed. These findings suggest the possibility that systemic vascular indices may provide proxy measures of cerebrovascular dysfunction and reinforce the importance of achieving greater understanding of interaction between systemic vascular disease and brain dysfunction among elderly people with cardiovascular disease.
doi:10.1080/13803390802014594
PMCID: PMC2739675  PMID: 18608677
Cardiovascular disease; Cerebrovascular disease; White matter hyperintensities; Magnetic resonance imaging; Flow mediated dilatation intima lamina thickness; Blood pressure variability; Cardiac output; Cognition; Attention; Executive function; Psychomotor function

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