Mismatches in resident and stranger serotonin transporter genotypes lead to escalated aggression, and the target for aggression is mediated by sex differences in male and female rhesus monkeys (Macaca mulatta).

A variety of studies show that the s-allele of the serotonin transporter genotype (5-HTT) is related to aggression. However, influences of sex and 5-HTT genotype of both subject and opponent have not received as much attention in aggression research. Using a nonhuman primate model, the present study explores differences in rates of aggression exhibited by 201 group-housed male and female rhesus monkeys (Macaca mulatta; 122 females; 79 males) exposed to an unfamiliar age- and sex-matched stranger while in the presence of other same-sex members of their social group. The study also assesses whether the rates of aggression increase when the home-cage resident, the unfamiliar stimulus animal, or both possess the short (s) allele of the 5-HTT. Results showed that, when compared to females, males exhibited higher rates of physical aggression toward the stranger, and when both the male resident and the male stranger possessed the s-allele, rates of physical aggression toward the stranger increased five-fold. Resident females also engaged in higher rates of physical aggression when they possessed the s-allele, although unlike the males, their physical aggression was directed toward familiar same-sex members of their social group. The findings of this study indicate that rates of physical aggression are modulated by 5-HTT resident and stranger suggest a role of sexual competition in the phenotype of the 5-HTT genotype. Importantly, when two males with impulse deficits, as a function of the s-allele, are placed together, rates of violence exhibited by the dyad escalate substantially.

A non-human primate system for large-scale genetic studies of complex traits.

Non-human primates provide genetic model systems biologically intermediate between humans and other mammalian model organisms. Populations of Caribbean vervet monkeys (Chlorocebus aethiops sabaeus) are genetically homogeneous and large enough to permit well-powered genetic mapping studies of quantitative traits relevant to human health, including expression quantitative trait loci (eQTL). Previous transcriptome-wide investigation in an extended vervet pedigree identified 29 heritable transcripts for which levels of expression in peripheral blood correlate strongly with expression levels in the brain. Quantitative trait linkage analysis using 261 microsatellite markers identified significant (n = 8) and suggestive (n = 4) linkages for 12 of these transcripts, including both cis- and trans-eQTL. Seven transcripts, located on different chromosomes, showed maximum linkage to markers in a single region of vervet chromosome 9; this observation suggests the possibility of a master trans-regulator locus in this region. For one cis-eQTL (at B3GALTL, beta-1,3-glucosyltransferase), we conducted follow-up single nucleotide polymorphism genotyping and fine-scale association analysis in a sample of unrelated Caribbean vervets, localizing this eQTL to a region of <200 kb. These results suggest the value of pedigree and population samples of the Caribbean vervet for linkage and association mapping studies of quantitative traits. The imminent whole genome sequencing of many of these vervet samples will enhance the power of such investigations by providing a comprehensive catalog of genetic variation.

Risk factors for behavioral abnormalities in mild cognitive impairment and mild Alzheimer's disease.

BACKGROUND: Behavioral symptoms are common in both mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: We analyzed the Neuropsychiatric Inventory Questionnaire data of 3,456 MCI and 2,641 mild AD National Alzheimer's Coordinating Center database participants. Using factor analysis and logistic regression we estimated the effects of age, sex, race, education, Mini-Mental State Examination, functional impairment, marital status and family history on the presence of behavioral symptoms. We also compared the observed prevalence of behavioral symptoms between amnestic and nonamnestic MCI. RESULTS: Four factors were identified: affective behaviors (depression, apathy and anxiety); distress/tension behaviors (irritability and agitation); impulse control behaviors (disinhibition, elation and aberrant motor behavior), and psychotic behaviors (delusions and hallucinations). Male gender was significantly associated with all factors. Younger age was associated with a higher prevalence of distress/tension, impulse control and psychotic behaviors. Being married was protective against psychotic behaviors. Lower education was associated with the presence of distress/tension behaviors. Caucasians showed a higher prevalence of affective behaviors. Functional impairment was strongly associated with all behavioral abnormalities. Amnestic MCI patients had more elation and agitation relative to nonamnestic MCI patients. CONCLUSIONS: Younger age, male gender and greater functional impairment were associated with higher overall presence of behavioral abnormalities in MCI and mild AD. Marital status, lower education and race had an effect on selected behaviors.

Younger age of dementia diagnosis in a Hispanic population in southern California.

OBJECTIVE: Prior studies of US Hispanics, largely performed on the East Coast, have found a younger age of dementia onset than in White non-Hispanics. We performed a cross-sectional study to examine clinical and sociodemographic variables associated with age of dementia diagnosis in older Hispanics and White, non-Hispanics in southern California. METHODS: Two hundred ninety (110 Hispanic and 180 White non-Hispanic) community dwelling, cognitively symptomatic subjects, aged 50 years and older, were assessed and diagnosed with probable Alzheimer's disease or probable vascular dementia. Apolipoprotein E (APOE) genotype was assessed in a subset of cases. Analysis of variance and multiple stepwise linear regression were used to assess main effects and interactions of ethnicity with dementia severity (indexed by mini mental state examination scores) and other sociodemographic and clinical variables on age of dementia diagnosis. RESULTS: Hispanics were younger by an average of 4 years at the time of diagnosis, regardless of dementia subtype, despite a similar prevalence of the APOE ε4 genotype. The earlier age at diagnosis for Hispanics was not explained by gender, dementia severity, years of education, history of hypercholesterolemia, hypertension, or diabetes. Only ethnicity was significantly associated with age of onset. CONCLUSIONS: These findings confirm that US Hispanics living in the southwestern USA tend to be younger at the time of dementia diagnosis than their White non-Hispanic counterparts. As this is not explained by the presence of the APOE ε4 genotype, further studies should explore other cultural, medical, or genetic risk factors influencing the age of dementia onset in this population.

Significant genotype by diet (G × D) interaction effects on cardiometabolic responses to a pedigree-wide, dietary challenge in vervet monkeys (Chlorocebus aethiops sabaeus).

Nutrient composition of a diet (D) has been shown to interact with genetic predispositions (G) to affect various lipid phenotypes. Our aim in this study was to confirm G × D interaction and determine whether the interaction extends to other cardiometabolic risk factors such as glycemic measures and body weight. Subjects were vervet monkeys (Chlorocebus aethiops sabaeus; n = 309) from a multigenerational pedigreed colony initially fed with a plant-based diet, standard primate diet (18% calories from protein, 13% from fat, and 69% from carbohydrates), and subsequently challenged for 8 weeks with a diet modeled on the typical American diet (18% calories from protein, 35% from fat, and 47% from carbohydrates). Our results showed that although exposure to the challenge diet did not result in significant changes in weight, most lipid and glycemic biomarkers moved in an adverse direction (P < 0.01). Quantitative genetic analyses showed that cardiometabolic phenotypes were significantly heritable under both dietary conditions (P < 0.05), and there was significant evidence of G × D interaction for these phenotypes. We observed significant differences in the additive genetic variances for most lipid phenotypes (P < 10(-4) ), indicating that the magnitude of genetic effects varies by diet. Furthermore, genetic correlations between diets differed significantly from 1 with respect to insulin, body weight, and some lipid phenotypes (P < 0.01). This implied that distinct genetic effects are involved in the regulation of these phenotypes under the two dietary conditions. These G × D effects confirm and extend previous observations in baboons (Papio sp.) and suggest that mimicking the typical human nutritional environment can reveal genetic influences that might not be observed in animals consuming standard, plant-based diets.

Maternal and offspring dopamine D4 receptor genotypes interact to influence juvenile impulsivity in vervet monkeys.

The merging of psychological and genetic methodologies has led to an increasing appreciation of environmental moderators of the relationships between genotype and phenotype. Here we used a nonhuman-primate model to study the moderating effect of the mother's genotype on the association of a dopamine D4 receptor (DRD4) gene polymorphism with juvenile impulsivity, assessed in a standardized social-challenge test. The results showed that juvenile carriers of the rare 5-repeat variant of the exon III 48-base-pair repeat polymorphism scored significantly higher in social impulsivity than juveniles homozygous for the common 6-repeat allele. In addition, juvenile genotype interacted with maternal genotype to influence impulsivity, with the highest rates of impulsivity found in variant offspring with variant mothers. These results highlight the importance of considering the genotype of the parents in studies of early experience and vulnerability genes for impulsivity-related traits.

A web-based brain atlas of the vervet monkey, Chlorocebus aethiops.

Vervet monkeys are a frequently studied animal model in neuroscience research. Although equally distantly related to humans, the ancestors of vervets diverged from those of macaques and baboons more than 11 million years ago, antedating the divergence of the ancestors of humans, chimpanzees and gorillas. To facilitate anatomic localization in the vervet brain, two linked on-line electronic atlases are described, one based on registered MRI scans from hundreds of vervets (http://www.loni.ucla.edu/Research/Atlases/Data/vervet/vervetmratlas/vervetmratlas.html) and the other based on a high-resolution cryomacrotome study of a single vervet (http://www.loni.ucla.edu/Research/Atlases/Data/vervet/vervetatlas/vervetatlas.html). The averaged MRI atlas is also available as a volume in Neuroimaging Informatics Technology Initiative format. In the cryomacrotome atlas, various sulcal and subcortical structures have been anatomically labeled and surface rendered views are provided along the primary planes of section. Both atlases simultaneously provide views in all three primary planes of section, rapid navigation by clicking on the displayed images, and stereotaxic coordinates in the averaged MRI atlas space. Despite the extended time period since their divergence, the major sulcal and subcortical landmarks in vervets are highly conserved relative to those described in macaques.

Identification of brain transcriptional variation reproduced in peripheral blood: an approach for mapping brain expression traits.

Genome-wide gene expression studies may provide substantial insight into gene activities and biological pathways differing between tissues and individuals. We investigated such gene expression variation by analyzing expression profiles in brain tissues derived from eight different brain regions and from blood in 12 monkeys from a biomedically important non-human primate model, the vervet (Chlorocebus aethiops sabaeus). We characterized brain regional differences in gene expression, focusing on transcripts for which inter-individual variation of expression in brain correlates well with variation in blood from the same individuals. Using stringent criteria, we identified 29 transcripts whose expression is measurable, stable, replicable, variable between individuals, relevant to brain function and heritable. Polymorphisms identified in probe regions could, in a minority of transcripts, confound the interpretation of the observed inter-individual variation. The high heritability of levels of these transcripts in a large vervet pedigree validated our approach of focusing on transcripts that showed higher inter-individual compared with intra-individual variation. These selected transcripts are candidate expression Quantitative Trait Loci, differentially regulating transcript levels in the brain among individuals. Given the high degree of conservation of tissue expression profiles between vervets and humans, our findings may facilitate the understanding of regional and individual transcriptional variation and its genetic mechanisms in humans. The approach employed here-utilizing higher quality tissue and more precise dissection of brain regions than is usually possible in humans-may therefore provide a powerful means to investigate variation in gene expression relevant to complex brain related traits, including human neuropsychiatric diseases.

Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics.

A dramatic rise in obesity has occurred among humans within the last several decades. Little is known about whether similar increases in obesity have occurred in animals inhabiting human-influenced environments. We examined samples collectively consisting of over 20 000 animals from 24 populations (12 divided separately into males and females) of animals representing eight species living with or around humans in industrialized societies. In all populations, the estimated coefficient for the trend of body weight over time was positive (i.e. increasing). The probability of all trends being in the same direction by chance is 1.2 × 10(-7). Surprisingly, we find that over the past several decades, average mid-life body weights have risen among primates and rodents living in research colonies, as well as among feral rodents and domestic dogs and cats. The consistency of these findings among animals living in varying environments, suggests the intriguing possibility that the aetiology of increasing body weight may involve several as-of-yet unidentified and/or poorly understood factors (e.g. viral pathogens, epigenetic factors). This finding may eventually enhance the discovery and fuller elucidation of other factors that have contributed to the recent rise in obesity rates.

Identifying heritable brain phenotypes in an extended pedigree of vervet monkeys.

The area and volume of brain structural features, as assessed by high-resolution three-dimensional magnetic resonance imaging (MRI), are among the most heritable measures relating to the human CNS. We have conducted MRI scanning of all available monkeys >2 years of age (n = 357) from the extended multigenerational pedigree of the Vervet Research Colony (VRC). Using a combination of automated and manual segmentation we have quantified several correlated but distinct brain structural phenotypes. The estimated heritabilities (h(2)) for these measures in the VRC are higher than those reported previously for such features in humans or in other nonhuman primates: total brain volume (h(2) = 0.99, SE = 0.06), cerebral volume (h(2) = 0.98, SE = 0.06), cerebellar volume (h(2) = 0.86, SE = 0.09), hippocampal volume (h(2) = 0.95, SE = 0.07) and corpus callosum cross-sectional areas (h(2) = 0.87, SE = 0.07). These findings indicate that, in the controlled environment and with the inbreeding structure of the VRC, additive genetic factors account for almost all of the observed variance in brain structure, and suggest the potential of the VRC for genetic mapping of quantitative trait loci underlying such variance.

High-fiber diet promotes weight loss and affects maternal behavior in vervet monkeys.

The dramatic increase in obesity in western societies has shifted the emphasis in nutrition research from the problems of undernutrition to the adverse consequences of being overweight. As with humans, Old World monkeys are at increased risk for type II diabetes and other chronic diseases when they gain excessive weight. To prevent overweight and obesity, promote animal health, and provide a more natural level of fiber in the diet, the standard commercial monkey chow diet at a vervet monkey breeding colony was changed to a higher fiber formulation in 2004. The new diet was also higher in protein and lower in carbohydrate and energy density than the standard diet. Because maternal behavior is known to be sensitive to differences in resource availability, data on weight and mother-infant interactions for 147 mothers with 279 infants born from 2000 through 2006 were assessed for effects of the diet change. The results showed that, even though food was provided ad libitum, the mean body weight of breeding females was 10% lower after the transition to the high-fiber diet. Behaviorally, mothers on the high-fiber diet were significantly more rejecting to their infants, and their infants had to play a greater role in maintaining ventral contact in the first few months of their lives. The effects of the diet change on maternal rejection were significantly related to the mother's body weight, with lower-weight mothers scoring higher in maternal rejection. These results demonstrate that maternal behavior is responsive to changes in maternal condition, and that beneficial changes in the diet may have unintended consequences on behavior.

Dimensions of impulsivity are associated with poor spatial working memory performance in monkeys.

Impulsive behavior and novelty seeking are dimensions of temperament that are behavioral determinants of risk for attention deficit/hyperactivity disorder and its neurocognitive endophenotypes, and variation in the dopamine D4 receptor gene (DRD4) explains at least a portion of the variance in the traits. To further characterize the dimensional phenotype associated with impulsiveness, adolescent male monkeys were evaluated using ecologically valid tests of impulsive approach and aggression in response to social or nonsocial stimuli; subsequently, a delayed response task was implemented to assess spatial working memory performance. Subjects were selected into this study based on their response to the social challenge task or by DRD4 genotype, resulting in three groups: low-impulsivity/common DRD4 allele, high-impulsivity/common DRD4 allele, or rare DRD4 allele. All animals acquired the delayed response task and could perform at near ceiling levels when a approximately 0 s delay version was imposed, but as delays were lengthened, high-impulsive animals, regardless of DRD4 genotype, made fewer correct responses than did low-impulsive subjects; an inverse relationship existed for working memory and impulsivity. Notably, impulsive behavior evoked by social and nonsocial stimuli explained overlapping and independent portions of the variance in working memory performance. CSF levels of monoamine metabolites did not significantly differentiate the high- and low-impulsive animals, although monkeys carrying the DRD4 rare allele tended to exhibit higher monoamine turnover. These data indicate that dimensions of impulsivity may impact on working memory performance in qualitatively similar ways but through different mechanisms.

Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles.

Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1-3 microM, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on 'injection' days. Anxiety increased on 'no injection' days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [3H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [3H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [3H]SCH 23390 and [3H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.

The association of DRD4 and novelty seeking is found in a nonhuman primate model.

OBJECTIVE: The association of novelty seeking with a repeat polymorphism in the coding region of the dopamine D4 receptor gene (DRD4) has been demonstrated in several human populations, but not in others. The objective of this study was to test the generality of the association in a captive nonhuman primate population of known history, using objective methods for assessing novelty seeking and a pedigree-based association design. METHODS: Four hundred and fifty two socially-living vervet monkeys (Cercopithecus aethiops) from a large multigenerational pedigree at the UCLA-VA Vervet Research Colony were studied. Two variants in the 48 base pair repeat in exon III of the DRD4 gene have been found in this population, a six-repeat (92%) and a less common five-repeat (8%). Novelty seeking was measured by the latency to approach a large and potentially threatening novel object placed in the home enclosure. Heritability of novelty seeking and the association of novelty seeking with the DRD4 polymorphism were assessed using variance component modeling as implemented in Sequential Oligogenic Linkage Analysis Routines. RESULTS: The variance component analysis indicated that the DRD4 variant explained a significant portion of the total variance in novelty seeking. The final model included a significant effect of the DRD4 polymorphism (P=0.03), which explained 13% of the phenotypic variance, and a significant remaining genetic effect (h=0. 467+/-0.095, P<0.0001). CONCLUSIONS: The association of DRD4 with novelty seeking has now been replicated in a nonhuman primate species, the vervet monkey.

Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study.

OBJECTIVE: Pilot study examining the effects of estrogen therapy (ET) on antidepressant response in postmenopausal women with major depressive disorder (MDD). METHODS: Twenty-two subjects received sertraline at 50mg/day for one week, with an increase to 100mg/day at week 2 for a 10-week trial. Transdermal estrogen or placebo patches 0.1mg were randomly administered concurrent with the initiation of sertraline treatment. The 21 item Hamilton Depression Rating Scale (HDRS-21) was administered to all patients at baseline and weekly thereafter. RESULTS: Both groups showed a similar significant reduction in HDRS-21 scores by the end of the study. There was no significant difference between the two treatment groups at the end of the 10-week trial, but the women receiving sertraline with ET showed significantly greater early improvement (weeks 2-4) compared to the women receiving sertraline with placebo. CONCLUSIONS: Sertraline is an effective antidepressant for postmenopausal women with MDD. ET does not alter the response rate to antidepressant therapy however ET may play a role in accelerating the antidepressant response.

Early-onset Alzheimer's disease is associated with greater pathologic burden.

Two subtypes of Alzheimer's disease (AD) have been commonly identified: early- and late-onset forms. Previous studies suggest that early-onset AD patients have more neuritic plaques (NPs) and neurofibrillary tangles (NFTs). In the current study, NP and NFT counts were performed for 8 brain regions in 25 subjects with definite AD. A repeated-measures analysis of variance of mean regional NP and NFT counts for early- and late-onset groups was performed. A significant between-subject effect indicating greater overall NP and NFT burden in the early-onset group was observed (NP: F = 6.8, df = 1, P = .015; NFT: F = 7.5, df = 1, P = .012). This analysis supports the hypothesis that early-onset AD is associated with greater pathologic burden than late-onset AD. This suggests that late-onset AD patients have less cognitive reserve than early-onset patients and require fewer pathologic changes to exhibit cognitive deterioration.

Genetic variation and gene expression across multiple tissues and developmental stages in a nonhuman primate.

By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

Considerations in the selection and conditioning of Old World monkeys for laboratory research: animals from domestic sources.

Nonhuman primates from domestic sources constitute an important resource for the research community. The life history of the Old World monkey species that comprise the bulk of this resource is described, and issues that colony managers and researchers alike should consider regarding animal selection (e.g., species, age, sex, rearing history, temperament, genotype, viral status, geographic origin) are discussed. Preparation of domestically bred animals for research usually involves some combination of social separation, relocation, resocialization, alterations in physical space, photoperiod, and diet, as well as exposure to novel environments. The research literature that has focused on these issues is reviewed, and authors suggest that once animals have been assigned to their project housing situation, a period ranging up to 3 mo (depending on the magnitude of the change in housing) might be warranted before an experimental protocol should begin. Attention to issues of animal selection and conditioning by both researchers and colony managers can lead to the shared goal of high-quality research that utilizes the minimal number of animals.

Effects of age and sex on hematologic and serum biochemical values of vervet monkeys (Chlorocebus aethiops sabaeus).

Hematologic and serum biochemical values are of great importance in assessing animal health. Normal reference ranges for vervet monkeys (Chlorocebus aethiops sabaeus) have seldom been reported, making it difficult for clinicians to interpret blood values. The purpose of this study was to determine what effects age and sex have on hematologic and serum biochemical values of vervet monkeys and to establish clinically relevant reference ranges for all life stages of each gender. Blood samples were collected from 140 healthy vervet monkeys of Caribbean origin consisting of 60 females and 80 males. Male and female data were displayed separately within six life-stage categories (yearlings, juveniles, adolescents, young adults, adults, and aged). The effects of sex and age on these values were examined statistically. Significant age-related factors included red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, alkaline phosphatase, albumin, total protein, globulin, direct bilirubin, blood urea nitrogen, creatinine, glucose, calcium, phosphorus, potassium, albumin/globulin ratio, blood urea nitrogen/creatinine ratio, and sodium/potassium ratio values. Significant sex-related values included red blood cell count, hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophil count, total bilirubin, direct bilirubin, creatinine, glucose, calcium, phosphorus, total carbon dioxide, chloride, potassium, and sodium/potassium ratio values.

Vitamin E as a treatment for ulcerative dermatitis in C57BL/6 mice and strains with a C57BL/6 background.

In this study, we fed a standard NIH-31 diet fortified with vitamin E to C57BL/6 mice and strains of mice with a C57BL/6 background that had spontaneously developed ulcerative dermatitis (UD). In addition to the therapeutic response to increased levels of vitamin E, we also defined the occurrence of UD within our facility in terms of age, sex, coat color, and lesion location on the body. Mice with spontaneous UD were fed a vitamin E-fortified diet (3000 IU/kg) for a period of 8 weeks and entered the study without regard to vendor source, age, sex, coat color, or the site or number of UD lesions. We found that lesions occurred most commonly on the dorsal cervical and scapular regions and spared the ventral abdomen and thorax. No sex or coat color predilection was noted for the development of UD, however males were older than females at the time of lesion development. Of 71 mice, 32 (45%) had complete lesion re-epithelialization with hair regrowth. Complete lesion repair was not influenced by sex, age, or coat color. The average time to complete lesion repair ranged from 2 to 5 weeks, and there was no correlation with sex or coat color. The positive response to vitamin E suggests that protection from oxidative injury may play a role in the resolution of UD lesions and offers veterinarians and investigators a new treatment option with ease of compliance.