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ABSTRACT: The dystonias are comprised of a group of disorders that share common neurological abnormalities of involuntary twisting or repetitive movements and postures. The most common inherited primary dystonia is DYT1 dystonia, which is due to loss of a GAG codon in the TOR1A gene that encodes torsinA. Autopsy studies of brains from patients with DYT1 dystonia have revealed few abnormalities, although recent neuroimaging studies have implied the existence of microstructural defects that might not be detectable with traditional histopathological methods. The current studies took advantage of a knock-in mouse model for DYT1 dystonia to search for subtle anatomical abnormalities in the striatum, a region often implicated in studies of dystonia. Multiple abnormalities were identified using a combination of quantitative stereological measures of immunohistochemical stains for specific neuronal populations, morphometric studies of Golgi-stained neurons, and immuno-electron microscopy of synaptic connectivity. In keeping with other studies, there was no obvious loss of striatal neurons in the DYT1 mutant mice. However, interneurons immunoreactive for choline acetyltransferase or parvalbumin were larger in the mutants than in control mice. In contrast, interneurons immunoreactive for neuronal nitric oxide synthase were smaller in the mutants than in controls. Golgi histochemical studies of medium spiny projection neurons in the mutant mice revealed slightly fewer and thinner dendrites, and a corresponding loss of dendritic spines. Electron microscopic studies showed a reduction in the ratio of axo-spinous to axo-dendritic synaptic inputs from glutamatergic and dopaminergic sources in mutant mice compared with controls. These results suggest specific anatomical substrates for altered signaling in the striatum and potential correlates of the abnormalities implied by human imaging studies of DYT1 dystonia.
Neurobiology of Disease 01/2013; · 5.40 Impact Factor
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ABSTRACT: Describes a mouse model for Lesch-Nyhan syndrome that is based on calcium channel activation with the drug Bay K 8644. It is noted that this model provides a new tool for the investigation of self-injurious behavior (SIB) neurobiology. The authors suggest that calcium channel antagonists may be helpful as therapeutic agents for SIB. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
10/2012;
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ABSTRACT: Several episodic neurological disorders are caused by ion channel gene mutations. In patients, transient neurological dysfunction is often evoked by stress, caffeine and ethanol, but the mechanisms underlying these triggers are unclear because each has diverse and diffuse effects on the CNS. Attacks of motor dysfunction in the Ca(V)2.1 calcium channel mouse mutant tottering are also triggered by stress, caffeine and ethanol. Therefore, we used the tottering mouse attacks to explore the pathomechanisms of the triggers. Despite the diffuse physiological effects of these triggers, ryanodine receptor blockers prevented attacks induced by all of them. In contrast, compounds that potentiate ryanodine receptors triggered attacks suggesting a convergent biochemical pathway. Tottering mouse attacks were both induced and blocked within the cerebellum suggesting that the triggers act locally to instigate attacks. In fact, stress, caffeine and alcohol precipitated attacks in Ca(V)2.1 mutant mice in which genetic pathology was limited to cerebellar Purkinje cells, suggesting that the triggers initiate dysfunction within a specific brain region. The surprising biochemical and anatomical specificity of the triggers and the discovery that the triggers operate through shared mechanisms suggest that it is possible to develop targeted therapies aimed at blocking the induction of episodic neurological dysfunction, rather than treating the symptoms once provoked.
Neurobiology of Disease 09/2012; · 5.40 Impact Factor
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ABSTRACT: Dystonia is a complex neurological syndrome broadly characterized by involuntary twisting movements and abnormal postures. The anatomical distribution of the motor symptoms varies among dystonic patients and can range from focal, involving an isolated part of the body, to generalized, involving many body parts. Functional imaging studies of both focal and generalized dystonias in humans often implicate the cerebellum suggesting that similar pathological processes may underlie both. To test this, we exploited tools developed in mice to generate animals with gradients of cerebellar dysfunction. By using conditional genetics to regionally limit cerebellar dysfunction, we found that abnormalities restricted to Purkinje cells were sufficient to cause dystonia. In fact, the extent of cerebellar dysfunction determined the extent of abnormal movements. Dysfunction of the entire cerebellum caused abnormal postures of many body parts, resembling generalized dystonia. More limited regions of dysfunction that were created by electrical stimulation or conditional genetic manipulations produced abnormal movements in an isolated body part, resembling focal dystonia. Overall, these results suggest that focal and generalized dystonias may arise through similar mechanisms and therefore may be approached with similar therapeutic strategies.
Neurobiology of Disease 07/2012; 49C:200-210. · 5.40 Impact Factor
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ABSTRACT: The dystonias are a group of disorders characterized by involuntary twisting movements and abnormal posturing. The most common of the inherited dystonias is DYT1 dystonia, which is due to deletion of a single GAG codon (ΔE) in the TOR1A gene that encodes torsinA. Since some forms of dystonia have been linked with dysfunction of brain dopamine pathways, the integrity of these pathways was explored in a knock-in mouse model of DYT1 dystonia. In DYT1(ΔE) knock-in mice, neurochemical measures revealed only small changes in the content of dopamine or its metabolites in tissue homogenates from caudoputamen or midbrain, but microdialysis studies revealed robust decreases in baseline and amphetamine-stimulated extracellular dopamine in the caudoputamen. Quantitative stereological methods revealed no evidence for striatal or midbrain atrophy, but substantia nigra neurons immunopositive for tyrosine hydroxylase were slightly reduced in numbers and enlarged in size. Behavioral studies revealed subtle abnormalities in gross motor activity and motor coordination without overt dystonia. Neuropharmacological challenges of dopamine systems revealed normal behavioral responses to amphetamine and a minor increase in sensitivity to haloperidol. These results demonstrate that this DYT1(ΔE) knock-in mouse model of dystonia harbors neurochemical and structural changes of the dopamine pathways, as well as motor abnormalities.
Neurobiology of Disease 05/2012; 48(1):66-78. · 5.40 Impact Factor
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ABSTRACT: Lesch-Nyhan disease and its attenuated variants are caused by mutations in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase. The mutations are heterogeneous,
with more than 400 different mutations already documented. Prior efforts to correlate variations in the clinical phenotype
with different mutations have suggested that milder phenotypes typically are associated with mutants that permit some residual
enzyme function, whereas the most severe phenotype is associated with null mutants. However, multiple exceptions to this concept
have been reported. In the current studies 44 HPRT1 mutations associated with a wide spectrum of clinical phenotypes were reconstructed by site-directed mutagenesis, the mutant
enzymes were expressed in vitro and purified, and their kinetic properties were examined toward their substrates hypoxanthine, guanine, and phosphoribosylpyrophosphate.
The results provide strong evidence for a correlation between disease severity and residual catalytic activity of the enzyme
(kcat) toward each of its substrates as well as several mechanisms that result in exceptions to this correlation. There was no
correlation between disease severity and the affinity of the enzyme for its substrates (Km). These studies provide a valuable model for understanding general principles of genotype-phenotype correlations in human
disease, as the mechanisms involved are applicable to many other disorders.
Journal of Biological Chemistry 01/2012; 287(5):2997-3008. · 4.77 Impact Factor
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ABSTRACT: Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a spectrum of clinical phenotypes. All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. In between these two extremes is a continuous spectrum of phenotypes with varying degrees of motor and cognitive handicap but no self-injurious behavior. The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. The pathogenesis of the neurobehavioral problems is less well-understood, and effective treatments for them are lacking.
Current Rheumatology Reports 12/2011; 14(2):189-94.
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ABSTRACT: Dystonia is a neurological disorder characterized by involuntary muscle contractions that cause twisting movements and abnormal postures. Functional imaging consistently reveals cerebellar overactivity in dystonic patients regardless of the type or etiology of the disorder. To explore mechanisms that might explain the basis for the cerebellar overactivity in dystonia, normal mice were challenged with intracerebellar application of a variety of agents that induce hyperexcitability. A nonspecific increase in cerebellar excitability, such as that produced by picrotoxin, was not associated with dystonia. Instead, glutamate receptor activation, specifically AMPA receptor activation, was necessary to evoke dystonia. AMPA receptor agonists induced dystonia, and AMPA receptor antagonists reduced the dystonia induced by glutamate receptor agonists. AMPA receptor antagonists also ameliorated the dystonia exhibited by the dystonic mouse mutant tottering, suggesting that AMPA receptors may play a role in some other genetic models of dystonia. Furthermore, AMPA receptor desensitization mediated the expression of dystonia. Preventing AMPA receptor desensitization with cyclothiazide or the nondesensitizing agonist kainic acid exacerbated the dystonic response. These results suggest the novel hypothesis that the cerebellar overactivity observed in neuroimaging studies of patients with dystonia may be an indirect reflection of abnormal glutamate signaling. In addition, these results imply that reducing AMPA receptor activation by blocking AMPA receptors and promoting AMPA receptor desensitization or negative allosteric modulators may prove to be beneficial for treating dystonia.
Journal of Pharmacology and Experimental Therapeutics 12/2011; 340(3):733-41. · 3.83 Impact Factor
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ABSTRACT: INTRODUCTION: Dystonia is a neurological disorder associated with twisting motions and abnormal postures, which compromise normal movements and can be both painful and debilitating. It can affect a single body part (focal), several contiguous regions (segmental), or the entire body (generalized), and can arise as a result of numerous causes, both genetic and acquired. Despite the diversity of causes and manifestations, shared clinical features suggest that common mechanisms of pathogenesis may underlie many dystonias. AREAS COVERED: Shared themes in etiologically-diverse dystonias exist at several biological levels. At the cellular level, abnormalities in the dopaminergic system, mitochondrial function and calcium regulation are often present. At the anatomical level, the basal ganglia and the cerebellum are frequently implicated. Global CNS dysfunction, specifically aberrant neuronal plasticity, inhibition and sensorimotor integration, are also observed in a number of dystonias. Using clinical data and data from animal models, this article seeks to highlight shared pathways that may be critical in understanding mechanisms and identifying novel therapeutic strategies in dystonia. EXPERT OPINION: Identifying shared features of pathogenesis can provide insight into the biological processes that underlie etiologically diverse dystonias, and can suggest novel targets for therapeutic intervention that may be effective in a broad group of affected individuals.
Expert opinion on therapeutic targets 12/2011; 15(12):1387-403. · 3.72 Impact Factor
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ABSTRACT: Disproportionate anterocollis is a debilitating condition which occurs in the later stages of parkinsonian syndromes and for which there is no effective therapy. Multiple hypotheses have been proposed to explain its underlying etiology, including myopathy of the cervical extensors, and dystonia of the cervical flexors.
We examined the records of 39 patients (8 prospectively) with anterocollis and parkinsonian syndromes to explore demographics, historical and clinical data, findings from electromyography and response to therapies. We classified our patients based on whether or not they were weak on neck extension and also based on primary diagnosis (PD vs atypical parkinsonian syndrome). Demographic, clinical, historical and EMG features are reported for each group.
There were no significant demographic differences between clinical subtypes, or primary diagnosis. Electromyographic (EMG) findings demonstrated myopathic changes in both groups, although they were more prominent in the group which was weak in extension. Historical features were similar between groups except for dopamine agonist use, which was more common in the myopathic subgroup (p=0.02). There were no other significant clinical differences between clinical subtypes or primary diagnosis with the exception that patients with atypical parkinsonian syndromes had more advanced motor symptoms.
We conclude that anterocollis is a heterogeneous condition in which at least two distinct subtypes exist. Recognizing these subtypes may help guide therapy and future research.
Journal of the neurological sciences 11/2011; 315(1-2):100-3. · 2.32 Impact Factor
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Neurology 08/2011; 77(7):616-7. · 8.31 Impact Factor
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ABSTRACT: Dystonia is a neurological disorder characterized by involuntary twisting movements and postures. There are many different clinical manifestations, and many different causes. The neuroanatomical substrates for dystonia are only partly understood. Although the traditional view localizes dystonia to basal ganglia circuits, there is increasing recognition that this view is inadequate for accommodating a substantial portion of available clinical and experimental evidence. A model in which several brain regions play a role in a network better accommodates the evidence. This network model accommodates neuropathological and neuroimaging evidence that dystonia may be associated with abnormalities in multiple different brain regions. It also accommodates animal studies showing that dystonic movements arise with manipulations of different brain regions. It is consistent with neurophysiological evidence suggesting defects in neural inhibitory processes, sensorimotor integration, and maladaptive plasticity. Finally, it may explain neurosurgical experience showing that targeting the basal ganglia is effective only for certain subpopulations of dystonia. Most importantly, the network model provides many new and testable hypotheses with direct relevance for new treatment strategies that go beyond the basal ganglia. This article is part of a Special Issue entitled "Advances in dystonia".
Neurobiology of Disease 02/2011; 42(2):185-201. · 5.40 Impact Factor
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ABSTRACT: We have used microarray-based methods of global gene expression together with quantitative PCR and Western blot analysis to identify dysregulation of genes and aberrant cellular processes in human fibroblasts and in SH-SY5Y neuroblastoma cells made HPRT-deficient by transduction with a retrovirus stably expressing an shRNA targeted against HPRT. Analysis of the microarray expression data by Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) as well as significant pathway analysis by GeneSpring GX10 and Panther Classification System reveal that HPRT deficiency is accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/β-catenin and the Alzheimer's disease/presenilin signaling pathways. Dysregulation of the Wnt/β-catenin pathway is confirmed by Western blot demonstration of cytosolic sequestration of β-catenin during in vitro differentiation of the SH-SY5Y cells toward the neuronal phenotype. We also demonstrate that two key transcription factor genes known to be regulated by Wnt signaling and to be vital for the generation and function of dopaminergic neurons; i.e., Lmx1a and Engrailed 1, are down-regulated in the HPRT knockdown SH-SY5Y cells. In addition to the Wnt signaling aberration, we found that expression of presenilin-1 shows severely aberrant expression in HPRT-deficient SH-SY5Y cells, reflected by marked deficiency of the 23 kDa C-terminal fragment of presenilin-1 in knockdown cells. Western blot analysis of primary fibroblast cultures from two LND patients also shows dysregulated presenilin-1 expression, including aberrant proteolytic processing of presenilin-1. These demonstrations of dysregulated Wnt signaling and presenilin-1 expression together with impaired expression of dopaminergic transcription factors reveal broad pleitropic neuro-regulatory defects played by HPRT expression and suggest new directions for investigating mechanisms of aberrant neurogenesis and neuropathology in LND and potential new targets for restoration of effective signaling in this neuro-developmental defect.
PLoS ONE 01/2011; 6(1):e16572. · 4.09 Impact Factor
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ABSTRACT: Lesch-Nyhan disease is a neurogenetic disorder caused by mutation of the HPRT1 gene on the X chromosome. There is significant variation in the clinical phenotype, with more than 300 different known mutations. There are few studies that have addressed whether similar mutations result in similar phenotypes across different patients because hypoxanthine-guanine phosphoribosyltransferase (HGprt) deficiency is rare, and most mutations are unique or limited to individual families. However, recent studies have revealed multiple unrelated patients with similar mutations, providing an opportunity to examine genotype-phenotype correlations. We found significant variation among the clinical features of 10 patients from 8 unrelated families all carrying a mutation replacing guanine with adenine at base position 143 (c.143G>A) in the HPRT1 gene. This mutation results in replacement of arginine by histidine at amino acid position 48 (p.arg48his) in the HGprt enzyme. Biochemically, the enzyme exhibits reduced thermal integrity, a mechanism that may explain clinical variation. The literature reveals similar clinical variation among other patients with similar mutations, although the variation is relatively minor across the whole population of patients. Identifiable sources of clinical variation include known limitations of clinical ascertainment and mechanisms that affect residual enzyme activity and stability. These results are helpful for understanding genotype-phenotype correlations and discordance and likely are applicable to other neurogenetic disorders where similar variation occurs.
Human Genetics 10/2010; 129(1):71-8. · 5.07 Impact Factor
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Neurology 09/2010; 75(10):937; author reply 937-8. · 8.31 Impact Factor
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ABSTRACT: Increasing interest in rodent models for movement disorders has led to an increasing need for more accurate and precise methods for both delineating the nature of abnormal movements and measuring their severity. These studies describe application of simultaneous high-speed video kinematics with multichannel electromyography (EMG) to characterize the movement disorder exhibited by tottering mutant mice. These mice provide a uniquely valuable model, because they exhibit paroxysmal dystonia superimposed on mild baseline ataxia, permitting the examination of these two different problems within the same animals. At baseline with mild ataxia, the mutants exhibited poorly coordinated movements with increased variation of stance and swing times, and slower spontaneous walking velocities. The corresponding EMG showed reduced mean amplitudes of biceps femoris and vastus lateralis, and poorly modulated EMG activities during the step cycle. Attacks of paroxysmal dystonia were preceded by trains of EMG bursts with doublets and triplets simultaneously in the biceps femoris and vastus lateralis followed by more sustained coactivation. These EMG characteristics are consistent with the clinical phenomenology of the motor phenotype of tottering mice as a baseline of mild ataxia with intermittent attacks of paroxysmal dystonia. The EMG characteristics of ataxia and dystonia in the tottering mice also are consistent with EMG studies of other ataxic or dystonic animals and humans. These studies provide insights into how these methods can be used for delineating movement disorders in mice and for how they may be compared with similar disorders of humans.
Movement Disorders 02/2010; 25(3):265-74. · 4.51 Impact Factor
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H A Jinnah,
Irene Ceballos-Picot,
Rosa J Torres,
Jasper E Visser,
David J Schretlen,
Alfonso Verdu,
Laura E Laróvere,
Chung-Jen Chen,
Antonello Cossu,
Chien-Hui Wu,
Radhika Sampat,
Shun-Jen Chang,
Raquel Dodelson de Kremer,
William Nyhan,
James C Harris,
Stephen G Reich,
Juan G Puig
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ABSTRACT: Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch-Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch-Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine-guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch-Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine-guanine phosphoribosyltransferase deficiency.
Brain 02/2010; 133(Pt 3):671-89. · 9.46 Impact Factor
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ABSTRACT: Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency results in Lesch-Nyhan disease (LND), where affected individuals exhibit a characteristic neurobehavioral disorder that has been linked with dysfunction of dopaminergic pathways of the basal ganglia. Since the functions of HPRT, a housekeeping enzyme responsible for recycling purines, have no direct relationships with the dopaminergic pathways, the mechanisms whereby HPRT deficiency affect them remain unknown. The current studies demonstrate that HPRT deficiency influences early developmental processes controlling the dopaminergic phenotype, using several different cell models for HPRT deficiency. Microarray methods and quantitative PCR were applied to 10 different HPRT-deficient (HPRT(-)) sublines derived from the MN9D cell line. Despite the variation inherent in such mutant sublines, several consistent abnormalities were evident. Most notable were increases in the mRNAs for engrailed 1 and 2, transcription factors known to play a key role in the specification and survival of dopamine neurons. The increases in mRNAs were accompanied by increases in engrailed proteins, and restoration of HPRT reverted engrailed expression towards normal levels, demonstrating a functional relationship between HPRT and engrailed. The functional relevance of the abnormal developmental molecular signature of the HPRT(-) MN9D cells was evident in impoverished neurite outgrowth when the cells were forced to differentiate chemically. To verify that these abnormalities were not idiosyncratic to the MN9D line, HPRT(-) sublines from the SK-N-BE(2) M17 human neuroblastoma line were evaluated and an increased expression of engrailed mRNAs was also seen. Over-expression of engrailed occurred even in primary fibroblasts from patients with LND in a manner that suggested a correlation with disease severity. These results provide novel evidence that HPRT deficiency may affect dopaminergic neurons by influencing early developmental mechanisms.
Human Molecular Genetics 05/2009; 18(13):2317-27. · 7.64 Impact Factor
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ABSTRACT: Dystonia is a neurological disorder characterized by excessive involuntary muscle contractions that lead to twisting movements or abnormal posturing. Traditional views place responsibility for dystonia with dysfunction of basal ganglia circuits, yet recent evidence has pointed towards cerebellar circuits as well. In the current studies we used two strategies to explore the hypothesis that the expression of dystonic movements depends on influences from a motor network that includes both the basal ganglia and cerebellum. The first strategy was to evaluate the consequences of subthreshold lesions of the striatum in two different animal models where dystonic movements are thought to originate from abnormal cerebellar function. The second strategy employed microdialysis to search for changes in striatal dopamine release in these two animal models where the cerebellum has been already implicated. One of the animal models involved tottering mice, which exhibit paroxysmal dystonia due to an inherited defect affecting calcium channels. In keeping with prior results implicating the cerebellum in this model, surgical removal of the cerebellum eliminated their dystonic attacks. In contrast, subclinical lesions of the striatum with either 6-hydroxydopamine (6OHDA) or quinolinic acid (QA) exaggerated their dystonic attacks. Microdialysis of the striatum revealed dystonic attacks in tottering mice to be associated with a significant reduction in extracellular striatal dopamine. The other animal model involved the induction of dystonia via pharmacological excitation of the cerebellar cortex by local application of kainic acid in normal mice. In this model the site of stimulation determines the origin of dystonia in the cerebellum. However, subclinical striatal lesions with either 6OHDA or QA again exaggerated their generalized dystonia. When dystonic movements were triggered by pharmacological stimulation of the cerebellum, microdialysis revealed significant reductions in striatal dopamine release. These results demonstrate important functional relationships between cerebellar and basal ganglia circuits in two different animal models of dystonia. They suggest that expression of dystonic movements depends on influences from both basal ganglia and cerebellum in both models. These results support the hypothesis that dystonia may result from disruption of a motor network involving both the basal ganglia and cerebellum, rather than isolated dysfunction of only one motor system.
Brain 10/2008; 131(Pt 9):2499-509. · 9.46 Impact Factor
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ABSTRACT: 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.
One hundred eighty community-dwelling adults aged 20 to 96 years completed neuropsychological testing, laboratory blood studies, and a brain MRI scan.
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.
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.
Stroke 09/2008; 39(12):3418-20. · 5.73 Impact Factor
