Tracy D. Vannorsdall

Serum uric acid and brain ischemia in normal elderly adults.

Background: Uric acid (UA) has antioxidant properties yet when elevated is associated with vascular disease and stroke. Further, even high normal UA is associated with increased risk of mild cognitive dysfunction in elderly adults. Method: In this cross-sectional, observational study, we examined the relationship between serum UA and aggregate volume of white matter hyperintense (WMH) signals observed on proton density and T2-weighted brain MR images in a community sample of 177 adults ages 20 to 92. Using logistic regression, we tested whether participants with UA concentrations in the highest quartile of the sample—but still normal—would have increased WMH volumes. Results: Compared with those with low to moderate levels, participants with high normal serum UA were more likely to fall in the highest quartile of WMH volume. The odds ratios (95% CIs) of increased WMH were 2.6 (1.2 to 5.4) for total, 2.5 (1.2 to 5.1) for periventricular, and 2.8 (1.4 to 5.9) for subcortical WMH volume. After controlling for age, sex, race, education, body mass, hypertension, and diabetes, the multivariate-adjusted odds of large total and subcortical WMH volumes remained elevated. Finally, high normal UA increased the odds of having excessive ischemic burden four- to fivefold in adults ages 60 and older. Conclusions: These findings demonstrate that mildly elevated serum uric acid is associated with increased burden of cerebral ischemic pathology, particularly in older adults. We outline the potential pathogenesis of this association. A clinical trial of antihyperuricemic medication to treat or prevent chronic brain ischemia might be warranted. GLOSSARY: ICC = intraclass correlation; OR = odds ratio; UA = uric acid; WMH = white matter hyperintense.

Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function

Background and Purpose— High normal concentrations of serum uric acid (UA) are associated with mild cognitive dysfunction and increased cerebral ischemia as indexed by white matter hyperintensity volumes. We hypothesized that individual differences in white matter hyperintensities mediate the association between UA and mild cognitive dysfunction. Methods— One hundred eighty community-dwelling adults aged 20 to 96 years completed neuropsychological testing, laboratory blood studies, and a brain MRI scan. Results— Serum UA was associated (P<0.05) with greater white matter hyperintensities and poorer working memory, processing speed, fluency, and verbal memory. Associations remained after controlling for age, sex, race, education, hypertension, diabetes, alcohol abuse, smoking, and body mass. Adding a term for white matter hyperintensity attenuated these associations such that UA no longer predicted cognitive performance. Conclusions— Severity of cerebral ischemia might mediate the association between UA and cognitive dysfunction. Even mild elevations in UA appear to contribute to structural and functional brain changes.

Target Optimization in Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is an emerging neuromodulation therapy that has been experimentally determined to affect a wide range of behaviors and diseases ranging from motor, cognitive, and memory processes to depression and pain syndromes. The effects of tDCS may be inhibitory or excitatory, depending on the relative polarities of electrodes and their proximity to different brain structures. This distinction is believed to relate to the interaction of current flow with activation thresholds of different neural complexes. tDCS currents are typically applied via a single pair of large electrodes, with one (the active electrode) sited close to brain structures associated with targeted processes. To efficiently direct current toward the areas presumed related to these effects, we devised a method of steering current toward a selected area by reference to a 19-electrode montage applied to a high-resolution finite element model of the head. We used a non-linear optimization procedure to maximize mean current densities inside the left inferior frontal gyrus (IFG), while simultaneously restricting overall current, and median current densities within the accumbens. We found that a distributed current pattern could be found that would indeed direct current toward the IFG in this way, and compared it to other candidate 2-electrode configurations. Further, we found a combination of four anterior-posterior electrodes could direct current densities to the accumbens. We conclude that a similar method using multiple electrodes may be a useful means of directing current toward or away from specific brain regions and also of reducing tDCS side effects.

White matter abnormalities and cognition in a community sample

White matter hyperintensities (WMH) can compromise cognition in older adults, but differences in sampling, WMH measurements, and cognitive assessments contribute to discrepant findings across studies. We examined linear and nonlinear effects of WMH volumes on cognition in 253 reasonably healthy adults. After adjusting for demographic characteristics and total brain volumes, WMH burden was not associated with cognition in those aged 20-59. In participants aged 60 and older, models accounted for > or =58% of the variance in performance on tests of working memory, processing speed, fluency, and fluid intelligence, and WMH volumes accounted for variance beyond that explained by age and other demographic characteristics. Larger increases in WMH burden over 5 years also were associated with steeper cognitive declines over the same interval. Results point to both age-related and age-independent effects of WMH on cognition in later life and suggest that the accumulation of WMH might partially explain normal age-related declines in cognition.

Neuroanatomic and cognitive abnormalities related to herpes simplex virus type 1 in schizophrenia

Herpes simplex virus 1 (HSV-1) tends to replicate in the temporal cortex and can damage the limbic system. The presence of serum antibodies to HSV-1 is associated with cognitive impairment in adults with schizophrenia, suggesting that cerebral gray matter abnormalities might distinguish patient subgroups defined by HSV-1 exposure. We assessed 43 adult outpatients with schizophrenia. The assessment included clinical interviews, neurocognitive testing, anatomic brain magnetic resonance imaging and measures of serum IgG antibodies specific to herpes simplex viruses 1 and 2. We then compared 25 patients who tested positive for antibodies to HSV-1 with 15 who were seronegative for both HSV-1 and HSV-2. The seropositive patients performed significantly worse than the seronegative patients on four neuropsychological measures of psychomotor speed, executive functioning, and explicit verbal memory. Voxel-based morphometric analyses revealed that the same patients showed reduced gray matter volume in the anterior cingulate and areas of the cerebellum. Finally, performance on the test of psychomotor speed and executive functioning that showed the largest between- group effect size correlated with reduced gray matter volume in some of the same brain regions (cingulate and cerebellum) that distinguished the two HSV-1 subgroups. In these outpatients with schizophrenia, HSV-1 seropositivity and performance on a cognitive test that is highly sensitive to it co-localize to closely overlapping brain regions.

Altering automatic verbal processes with transcranial direct current stimulation.

Background: Word retrieval during verbal fluency tasks invokes both automatic and controlled cognitive processes. A distinction has been made between the generation of words clusters and switches between such clusters on verbal fluency tasks. Clusters, defined by the reporting of contiguous words that constitute semantic or phonemic subcategories, are thought to reflect relatively automatic processing. In contrast, switching from one subcategory to another is thought to require a more controlled, effortful form of cognitive processing. Objective: In this single-blind, sham-controlled experiment, we investigated whether anodal and cathodal transcranial direct current stimulation (tDCS) can differentially modify controlled or automatic processes that support lexical retrieval, as assessed by clustering and switching on verbal fluency tasks, in 24 healthy right-handed adults. Methods: Participants were randomly assigned to receive 1 mA of either anodal (excitatory) or cathodal (inhibitory) active tDCS over the left dorsolateral prefrontal cortex in addition to sham stimulation over the same region in counterbalanced order. Participants engaged in various cognitive activities during the first 23 min of stimulation. Then, during the final segment of each 30-min session, they completed letter- and category-cued word fluency tasks. Results: Participants reported more words on category-cued word fluency tasks during anodal than sham stimulation (25.9 vs. 23.0 words; p = 0.055). They also showed a net increase in the number of clustered words during anodal stimulation compared to a net decrease during cathodal stimulation (1.3 vs. −1.5 words; p = 0.038). Conclusion: tDCS can selectively alter automatic aspects of speeded lexical retrieval in a polarity-dependent fashion during a category-guided fluency task.

Cranial Volume, Mild Cognitive Deficits, and Functional Limitations Associated with Diabetes in a Community Sample

Diabetes is associated with dementia in older adults, but it remains unclear whether nondemented adults with type 2 diabetes show subtle abnormalities across cognition, neuroanatomy, and everyday functioning. Using the Aging, Brain Imaging, and Cognition study sample of 301 community-dwelling, middle-aged and older adults, we conducted a secondary analysis on 28 participants with and 150 participants without diabetes. We analyzed brain magnetic resonance imaging data, cognitive test performance, and informant ratings of personal and instrumental activities of daily living (PADL/IADL). Relative to controls, participants with diabetes had lower brain-to-intracranial volume ratios (69.3 +/- 4.5% vs. 71.7 +/- 4.6%; p < .02), and performed more poorly on measures of working memory, processing speed, fluency, and crystallized intelligence (all p <.05). Decrements in working memory and processing speed were associated with IADL limitations (p < .01). Nondemented adults with diabetes exhibit neuroanatomic and cognitive abnormalities. Their cognitive deficits correlate with everyday functional limitations.

Regional brain volume abnormalities in Lesch-Nyhan disease and its variants: a cross-sectional study

BACKGROUND Lesch-Nyhan disease is a rare, X-linked, neurodevelopmental metabolic disorder that is caused by abnormalities in the levels of hypoxanthine-guanine phosphoribosyltransferase enzyme activity. The neural substrates associated with Lesch-Nyhan disease remain poorly understood. We aimed to use voxel-based morphometry to identify affected brain regions in classic Lesch-Nyhan disease and Lesch-Nyhan variant disease, and to identify regions that differ between the two disease types. METHODS In this cross-sectional study, we recruited patients with classic Lesch-Nyhan disease or Lesch-Nyhan variant disease from clinics, referrals, the Lesch-Nyhan Syndrome Registry, and the Matheny School and Hospital (Peapack, NJ, USA), and healthy controls from the Baltimore metropolitan area (MD, USA). We used voxel-based morphometry to analyse grey matter volume between groups using a three-group ANCOVA, followed by six pairwise post-hoc group comparisons. FINDINGS Between Oct 3, 1993, and April 29, 2013, we recruited 21 patients with classic Lesch-Nyhan disease, 17 patients with variant disease, and 33 healthy controls. Patients with classic Lesch-Nyhan disease had a 20% reduction in intracranial volume (17% reduction in grey matter volume; 26% reduction in white matter volume) compared with healthy adults. The largest differences were in basal ganglia, and frontotemporal and limbic regions, with sparing of parieto-occipital regions. Grey matter volumes of patients with Lesch-Nyhan variant disease were invariably between those of patients with classic Lesch-Nyhan disease and healthy controls. Compared with healthy controls, patients with classic disease showed additional grey matter volume reductions in the temporal lobe and left lateralised structures, and patients with variant disease showed additional reductions in lingual and precuneus regions with sparing of right frontal and temporal regions. Patients with classic disease had reductions of volume in the ventral striatum and prefrontal areas compared with those with the variant form. INTERPRETATION We noted regional abnormalities associated with known neurological and behavioural deficits in patients with classic Lesch-Nyhan disease. Patients with Lesch-Nyhan variant disease show milder grey matter abnormalities in many of the same brain regions and preservation of grey matter volume in other regions, which could provide important clues to the neural substrates of differences between the phenotypes. FUNDING National Institute of Child Health and Human Development, Therapeutic Cognitive Neuroscience Fund, and Benjamin and Adith Miller Family Endowment on Aging, Alzheimers and Autism Research.

Comparing alternative metrics to assess performance on the Iowa Gambling Task

This study was conducted in response to calls to develop Iowa Gambling Task (IGT) metrics reflecting more homogeneous aspects of decision making, as well as to add to the literature on reliability and validity of the instrument. The conventional IGT metric, advantageous minus disadvantageous deck selections, was compared to alternatives in which Decks B and C or the first 40 selections were eliminated. We correlated these alternative metrics with performance on other neuropsychological tests in 214 healthy adults, and we compared participant subgroups stratified by health status (214 healthy and 43 unhealthy participants). Internal consistency of the IGT was low and could explain the modest levels of construct validity observed. Alternative metrics, especially Deck D minus Deck A selections (D–A), did improve construct and criterion validity of the IGT. They also showed different patterns of correlation with other neuropsychological measures and might enhance the clinical and scientific usefulness of this test. Future research with an eye to modifying the paradigm and/or administration procedures to increase intertrial consistency might also give a needed boost to construct and criterion validity.

Brain white matter volume abnormalities in Lesch-Nyhan disease and its variants

Objective: We sought to examine brain white matter abnormalities based on MRI in adults with Lesch-Nyhan disease (LND) or an attenuated variant (LNV) of this rare, X-linked neurodevelopmental disorder of purine metabolism. Methods: In this observational study, we compared 21 adults with LND, 17 with LNV, and 33 age-, sex-, and race-matched healthy controls using voxel-based morphometry and analysis of covariance to identify white matter volume abnormalities in both patient groups. Results: Patients with classic LND showed larger reductions of white (26%) than gray (17%) matter volume relative to healthy controls. Those with LNV showed comparable reductions of white (14%) and gray (15%) matter volume. Both patient groups demonstrated reduced volume in medial inferior white matter regions. Compared with LNV, the LND group showed larger reductions in inferior frontal white matter adjoining limbic and temporal regions and the motor cortex. These regions likely include such long association fibers as the superior longitudinal and uncinate fasciculi. Conclusions: Despite earlier reports that LND primarily involves the basal ganglia, this study reveals substantial white matter volume abnormalities. Moreover, white matter deficits are more severe than gray matter deficits in classic LND, and also characterize persons with LNV. The brain images acquired for these analyses cannot precisely localize white matter abnormalities or determine whether they involve changes in tract orientation or anisotropy. However, clusters of reduced white matter volume identified here affect regions that are consistent with the neurobehavioral phenotype.