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Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder.
CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D4 receptor (DRD4) gene has been frequently implicated in its pathogenesis. OBJECTIVE: To examine the effects of the 7-repeat microsatellite in the DRD4 gene on clinical outcome and cortical development in ADHD. We drew comparisons with a single nucleotide polymorphism in the dopamine D1 receptor (DRD1) gene, which was associated with ADHD within our cohort, and a polymorphism within the dopamine transporter (DAT1) gene, reported to have additive effects with the DRD4 7-repeat allele. DESIGN: Longitudinal cohort study. SETTING: National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: One hundred five children (with 222 neuroanatomical magnetic resonance images) with ADHD (mean age at entry, 10.1 years) and 103 healthy controls (total of 220 magnetic resonance images). Sixty-seven subjects with ADHD (64%) had follow-up clinical evaluations (mean follow-up, 6 years). MAIN OUTCOME MEASURES: Cortical thickness across the cerebrum and presence of DSM-IV-defined ADHD at follow-up. RESULTS: Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls. Participants with ADHD carrying the DRD4 7-repeat allele had a better clinical outcome and a distinct trajectory of cortical development. This group showed normalization of the right parietal cortical region, a pattern that we have previously linked with better clinical outcome. By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development. CONCLUSIONS: The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence.
Author Correction: Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice.
In the version of this article initially published, the Simons Foundation was missing from the list of sources of support to P.T.T. in the Acknowledgments. The error has been corrected in the HTML and PDF versions of the article.
Whole-brain mapping of behaviourally induced neural activation in mice.
The ability to visualize behaviourally evoked neural activity patterns across the rodent brain is essential for understanding the distributed brain networks mediating particular behaviours. However, current imaging methods are limited in their spatial resolution and/or ability to obtain brain-wide coverage of functional activity. Here, we describe a new automated method for obtaining cellular-level, whole-brain maps of behaviourally induced neural activity in the mouse. This method combines the use of transgenic immediate-early gene reporter mice to visualize neural activity; serial two-photon tomography to image the entire brain at cellular resolution; advanced image processing algorithms to count the activated neurons and align the datasets to the Allen Mouse Brain Atlas; and statistical analysis to identify the network of activated brain regions evoked by behaviour. We demonstrate the use of this approach to determine the whole-brain networks activated during the retrieval of fear memories. Consistent with previous studies, we identified a large network of amygdalar, hippocampal, and neocortical brain regions implicated in fear memory retrieval. Our proposed methods can thus be used to map cellular networks involved in the expression of normal behaviours as well as to investigate in depth circuit dysfunction in mouse models of neurobiological disease.
Self-injurious behaviours are associated with alterations in the somatosensory system in children with autism spectrum disorder.
Children with autism spectrum disorder (ASD) frequently engage in self-injurious behaviours, often in the absence of reporting pain. Previous research suggests that altered pain sensitivity and repeated exposure to noxious stimuli are associated with morphological changes in somatosensory and limbic cortices. Further evidence from postmortem studies with self-injurious adults has indicated alterations in the structure and organization of the temporal lobes; however, the effect of self-injurious behaviour on cortical development in children with ASD has not yet been determined. Thirty children and adolescents (mean age = 10.6 ± 2.5 years; range 7-15 years; 29 males) with a clinical diagnosis of ASD and 30 typically developing children (N = 30, mean age = 10.7 ± 2.5 years; range 7-15 years, 26 males) underwent T1-weighted magnetic resonance and diffusion tensor imaging. No between-group differences were seen in cerebral volume, surface area or cortical thickness. Within the ASD group, self-injury scores negatively correlated with thickness in the right superior parietal lobule t = 6.3, p < 0.0001, bilateral primary somatosensory cortices (SI) (right: t = 4.4, p = 0.02; left: t = 4.48, p = 0.004) and the volume of the left ventroposterior (VP) nucleus of the thalamus (r = -0.52, p = 0.008). Based on these findings, we performed an atlas-based region-of-interest diffusion tensor imaging analysis between SI and the VP nucleus and found that children who engaged in self-injury had significantly lower fractional anisotropy (r = -0.4, p = 0.04) and higher mean diffusivity (r = 0.5, p = 0.03) values in the territory of the left posterior limb of the internal capsule. Additionally, greater incidence of self-injury was associated with increased radial diffusivity values in bilateral posterior limbs of the internal capsule (left: r = 0.5, p = 0.02; right: r = 0.5, p = 0.009) and corona radiata (left: r = 0.6, p = 0.005; right: r = 0.5, p = 0.009). Results indicate that self-injury is related to alterations in somatosensory cortical and subcortical regions and their supporting white-matter pathways. Findings could reflect use-dependent plasticity in the somatosensory system or disrupted brain development that could serve as a risk marker for self-injury.
Mapping the development of the basal ganglia in children with attention-deficit/hyperactivity disorder.
OBJECTIVE: The basal ganglia are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), but little is known of their development in the disorder. Here, we mapped basal ganglia development from childhood into late adolescence using methods that define surface morphology with an exquisite level of spatial resolution. METHOD: Surface morphology of the basal ganglia was defined from neuroanatomic magnetic resonance images acquired in 270 youth with DSM-IV-defined ADHD and 270 age- and sex-matched typically developing controls; 220 individuals were scanned at least twice. Using linear mixed model regression, we mapped developmental trajectories from age 4 through 19 years at approximately 7,500 surface vertices in the striatum and globus pallidus. RESULTS: In the ventral striatal surfaces, there was a diagnostic difference in developmental trajectories (t = 5.6, p < .0001). Here, the typically developing group showed surface area expansion with age (estimated rate of increase of 0.54 mm(2) per year, standard error [SE] 0.29 mm(2) per year), whereas the ADHD group showed progressive contraction (decrease of 1.75 mm(2) per year, SE 0.28 mm(2) per year). The ADHD group also showed significant, fixed surface area reductions in dorsal striatal regions, which were detected in childhood at study entry and persisted into adolescence. There was no significant association between history of psychostimulant treatment and developmental trajectories. CONCLUSIONS: Progressive, atypical contraction of the ventral striatal surfaces characterizes ADHD, localizing to regions pivotal in reward processing. This contrasts with fixed, nonprogressive contraction of dorsal striatal surfaces in regions that support executive function and motor planning.
Disrupted prefrontal interhemispheric structural coupling in schizophrenia related to working memory performance.
BACKGROUND: Prominent regional cortical thickness reductions have been shown in schizophrenia. In contrast, little is known regarding alterations of structural coupling between regions in schizophrenia and how these alterations may be related to cognitive impairments in this disorder. METHODS: T1-weighted magnetic resonance images were acquired in 54 patients with schizophrenia and 68 healthy control subjects aged 18-55 years. Cortical thickness was compared between groups using a vertex-wise approach. To assess structural coupling, seeds were selected within regions of reduced thickness, and brain-wide cortical thickness correlations were compared between groups. The relationships between identified patterns of circuit structure disruption and cognitive task performance were then explored. RESULTS: Prominent cortical thickness reductions were found in patients compared with controls at a 5% false discovery rate in a predominantly frontal and temporal pattern. Correlations of the left dorsolateral prefrontal cortex (DLPFC) with right prefrontal regions were significantly different in patients and controls. The difference remained significant in a subset of 20 first-episode patients. Participants with stronger frontal interhemispheric thickness correlations had poorer working memory performance. CONCLUSIONS: We identified structural impairment in a left-right DLPFC circuit in patients with schizophrenia independent of illness stage or medication exposure. The relationship between left-right DLPFC thickness correlations and working memory performance implicates prefrontal interhemispheric circuit impairment as a vulnerability pathway for poor working memory performance. Our findings could guide the development of novel therapeutic interventions aimed at improving working memory performance in patients with schizophrenia.
Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease.
Models of Huntington disease (HD) recapitulate some neuropathological features of the disease. However, a global natural history of neuroanatomy in a mouse expressing full-length huntingtin has not been conducted. We investigated neuropathological changes in the YAC128 murine model of HD using magnetic resonance imaging (MRI). Structures affected in human HD are reduced in the YAC128 mice both in absolute terms and in terms of percentage of brain volume. Structures resistant to degeneration in HD, including the cerebellum and hippocampus, are spared in the YAC128 mice. Segmentation of major white matter structures confirms specific, progressive, loss of white matter in HD. In parallel with their specific volume loss, the YAC128 mice also show progressive increases in total ventricular volume, similarly to human HD patients. Cortical atrophy in the YAC128 mice is layer specific, which is the observed pattern of cortical loss in human HD patients. Finally, we have used a classification tree analysis to maximize separation of genotypes using all 62 structure volumes in an objective manner. This analysis demonstrates that sub-cortical gray matter structures (striatum, globus pallidus, thalamus) and cerebral white matter structures (corpus callosum, anterior commisure, fimbria) are the most discriminatory. The high resolution of the current study enables robust measurement of subtle early pathological changes. The use of mice furthermore enables us to address questions difficult to address in humans, including the sequential changes of HD from baseline and the relation between MRI and stereological measures.
Neuroanatomical correlates of musicianship as revealed by cortical thickness and voxel-based morphometry.
We used a multimethod approach to investigate the neuroanatomical correlates of musicianship and absolute pitch (AP). Cortical thickness measures, interregional correlations applied to these thicknesses, and voxel-based morphometry (VBM) were applied to the same magnetic resonance imaging data set of 71 musicians (27 with AP) and 64 nonmusicians. Cortical thickness was greater in musicians with peaks in superior temporal and dorsolateral frontal regions. Correlations between 2 seed points, centered on peaks of thickness difference within the right frontal cortex, and all other points across the cortex showed greater specificity of significant correlations among musicians, with fewer and more discrete areas correlating with the frontal seeds, including the superior temporal cortex. VBM of gray matter (GM)-classified voxels yielded a strongly right-lateralized focus of greater GM concentration in musicians centered on the posterolateral aspect of Heschl's gyrus. Together, these results are consistent with functional evidence emphasizing the importance of a frontotemporal network of areas heavily relied upon in the performance of musical tasks. Among musicians, contrasts of AP possessors and nonpossessors showed significantly thinner cortex among possessors in a number of areas, including the posterior dorsal frontal cortices that have been previously implicated in the performance of AP tasks.
Focal decline of cortical thickness in Alzheimer's disease identified by computational neuroanatomy.
Alzheimer's disease (AD) is characterized by a heterogeneous distribution of pathological changes throughout the brain. Magnetic resonance imaging can be used to investigate the regional distribution of cortical atrophy in AD in vivo. One marker for the disease-specific atrophy is the thickness of the cortical mantle across the brain, obtained with automated 3-D image processing. Here, we present data from 36 subjects (17 controls and, 19 patients diagnosed as probable AD) investigated for cortical thickness across the entire brain. We show significant cortical thickness decline in AD in temporal, orbitofrontal and parietal regions, with the most pronounced changes occurring in the allocortical region of the medial temporal lobes, outlining the parahippocampal gyrus, and representing a loss of >1.25 millimeters of cortical thickness. Moreover, focal cortical areas decline with progression of the disease as measured by time from baseline scan as well as the Mini-Mental State Exam. The results demonstrate the ability of this method to detect changes in cortical thickness in AD, across the entire brain, without need of prior anatomical definitions. The regional distribution of changes reported here is consistent with independent findings on the distribution of neuropathological alterations in AD. Using cortical thickness, moreover, we provide a direct quantitative index of atrophy in the disease.
Fetal brain sparing in a mouse model of chronic maternal hypoxia.
Hypoxic stress is a common occurrence during human pregnancy, yet little is known about its effects on the fetal brain. This study examined the fetal hemodynamic responses to chronic hypoxia in an experimental mouse model of chronic maternal hypoxia (11% O2 from E14.5 to E17.5). Using high-frequency Doppler ultrasound, we found fetal cerebral and ductus venosus blood flow were both elevated by 69% and pulmonary blood flow was decreased by 62% in the fetuses exposed to chronic hypoxia compared to controls. This demonstrates that brain sparing persists during chronic fetal hypoxia and is mediated by "streaming," where highly oxygenated blood preferentially flows through the ductus venosus towards the cerebral circulation, bypassing the liver and the lungs. Consistent with these changes in blood flow, the fetal brain volume measured by MRI is preserved, while the liver and lung volumes decreased compared to controls. However, hypoxia exposed fetuses were rendered vulnerable to an acute hypoxic challenge (8% O2 for 3 min), demonstrating global blood flow decreases consistent with imminent fetal demise rather than elevated cerebral blood flow. Despite this vulnerability, there were no differences in adult brain morphology in the mice exposed to chronic maternal hypoxia compared to controls.
MRI to Assess Neurological Function.
This article describes a detailed set of protocols for mouse brain imaging using MRI. We focus primarily on measuring changes in neuroanatomy, and provide both instructions for mouse preparation and details on image acquisition, image processing, and statistics. Practical details as well as theoretical considerations are provided. © 2018 by John Wiley & Sons, Inc.
MRI-detectable changes in mouse brain structure induced by voluntary exercise.
Physical exercise, besides improving cognitive and mental health, is known to cause structural changes in the brain. Understanding the structural changes that occur with exercise as well as the neuroanatomical correlates of a predisposition for exercise is important for understanding human health. This study used high-resolution 3D MR imaging, in combination with deformation-based morphometry, to investigate the macroscopic changes in brain structure that occur in healthy adult mice following four weeks of voluntary exercise. We found that exercise induced changes in multiple brain structures that are involved in motor function and learning and memory including the hippocampus, dentate gyrus, stratum granulosum of the dentate gyrus, cingulate cortex, olivary complex, inferior cerebellar peduncle and regions of the cerebellum. In addition, a number of brain structures, including the hippocampus, striatum and pons, when measured on MRI prior to the start of exercise were highly predictive of subsequent exercise activity. Exercise tended to normalize these pre-existing differences between mice.
Automated pipeline for anatomical phenotyping of mouse embryos using micro-CT.
The International Mouse Phenotyping Consortium (IMPC) plans to phenotype 20,000 single-gene knockout mice to gain an insight into gene function. Approximately 30% of these knockout mouse lines will be embryonic or perinatal lethal. The IMPC has selected three-dimensional (3D) imaging to phenotype these mouse lines at relevant stages of embryonic development in an attempt to discover the cause of lethality using detailed anatomical information. Rate of throughput is paramount as IMPC production centers have been given the ambitious task of completing this phenotyping project by 2021. Sifting through the wealth of data within high-resolution 3D mouse embryo data sets by trained human experts is infeasible at this scale. Here, we present a phenotyping pipeline that identifies statistically significant anatomical differences in the knockout, in comparison with the wild type, through a computer-automated image registration algorithm. This phenotyping pipeline consists of three analyses (intensity, deformation, and atlas based) that can detect missing anatomical structures and differences in volume of whole organs as well as on the voxel level. This phenotyping pipeline was applied to micro-CT images of two perinatal lethal mouse lines: a hypomorphic mutation of the Tcf21 gene (Tcf21-hypo) and a knockout of the Satb2 gene. With the proposed pipeline we were able to identify the majority of morphological phenotypes previously published for both the Tcf21-hypo and Satb2 mutant mouse embryos in addition to novel phenotypes. This phenotyping pipeline is an unbiased, automated method that highlights only those structural abnormalities that survive statistical scrutiny and illustrates them in a straightforward fashion.
The influence of fetal ethanol exposure on subsequent development of the cerebral cortex as revealed by magnetic resonance imaging.
BACKGROUND: Fetal alcohol syndrome and related disorders (commonly referred to as fetal alcohol spectrum disorder, or FASD) cause significant hardships to the individuals affected. Previously, histological studies in animals have characterized developmental cerebral cortical abnormalities that result from prenatal ethanol (EtOH) exposure. Additionally, magnetic resonance imaging (MRI) studies have identified abnormalities associated with fetal EtOH exposure in the cerebral cortices of human children and adolescents. However, there is still a need to bridge the gap between human MRI studies and animal histological studies. The goal of the research presented here was to perform postmortem MRI experiments on rodents, during time periods relative to late human gestation through adulthood, to characterize anomalies associated with FASD throughout development. Additionally, by determining how histologically identified abnormalities are manifest in MRI measurements specifically during the critical early time points, neuroimaging-based biomarkers of FASD can potentially be identified at much earlier ages in humans, thus reducing the impact of these disorders. METHODS: Cerebral cortical volume, thickness, and surface area were characterized by ex vivo MRI in Long-Evans rat pups born from dams that were EtOH-treated, maltose/dextrin-treated, or untreated throughout gestation at 6 developmental time points (postnatal day [P] 0, P3, P6, P11, P19, and P60). RESULTS: Brain volume, isocortical volume, isocortical thickness, and isocortical surface area were all demonstrated to be reduced following prenatal exposure to EtOH. Significant differences among the treatment groups were observed throughout the range of time points studied, allowing for a comprehensive view of FASD influenced MRI outcomes throughout development. Isocortical surface area and isocortical thickness results contributed independent information important to interpreting effects of prenatal EtOH exposure on cerebral cortical development. Additionally, regional patterns in cortical thickness differences suggested primary sensory areas were particularly vulnerable to gestational EtOH exposure. CONCLUSIONS: Structural MRI measurements were in accordance with previous histological studies performed in animal models of FASD. In addition to establishing a summary of MRI outcomes throughout development in FASD, this research suggests that MRI techniques are sufficiently sensitive to detect neuroanatomical effects of fetal EtOH exposure on development of the cerebral cortex during the period of time corresponding to late gestation in humans. Importantly, this research provides a link between animal histological data and human MRI data.
The effect of diagnosis, age, and symptom severity on cortical surface area in the cingulate cortex and insula in autism spectrum disorders.
Functional activity in the anterior cingulate cortex and insula has been reported to be abnormal during social tasks in autism spectrum disorders. However, few studies have examined surface morphometry in these regions and how this may be related to autism spectrum disorder symptomatology. In this study, 27 individuals with autism spectrum disorders and 25 controls between the ages of 7 to 39 years underwent structural magnetic resonance imaging. Our primary analysis examined differences in surface area in the cingulate and insula, between individuals with and without autism spectrum disorders, as well as age-related changes and associations with social impairments. Surface area in the right cingulate was significantly different between groups and decreased more rapidly with age in autism spectrum disorder participants. In addition, greater surface area in the insula and isthmus was associated with poorer social behaviors. Results suggest atypical surface morphometry in brain regions involved in social function, which appeared to be related to poorer social ability scores.
Cortical atrophy and hypoperfusion in a transgenic mouse model of Alzheimer's disease.
Magnetic resonance imaging studies have revealed distinct patterns of cortical atrophy and hypoperfusion in patients with Alzheimer's disease. The relationship between these in vivo imaging measures and the corresponding underlying pathophysiological changes, however, remains elusive. Recently, attention has turned to neuroimaging of mouse models of Alzheimer's disease in which imaging-pathological correlations can be readily performed. In this study, anatomical and arterial spin labeling perfusion magnetic resonance imaging scans of amyloid precursor protein transgenic and age-matched wild-type mice were acquired at 3, 12, and 18 months of age. Fully-automated image processing methods were used to derive quantitative measures of cortical thickness and perfusion. These studies revealed increased regional cortical thickness in young transgenic mice relative to age-matched wild-type mice. However, the transgenic mice generally demonstrated a greater rate of cortical thinning over 15 months. Cortical perfusion was significantly reduced in young transgenic mice in comparison with wild-type mice across most brain regions. Previously unreported regional genotype differences and age-related changes in cortical thickness and cerebral perfusion were identified in amyloid precursor protein transgenic and wild-type mice.
Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[(11)C]DASB and structural brain imaging study.
Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [(11)C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range -19 to -46%) and hippocampus (-21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although 'grossly behaviourally normal', reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the 'typical'/low dose (one to two tablets/session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson's disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in 'heavier' users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions.
Time course and nature of brain atrophy in the MRL mouse model of central nervous system lupus.
OBJECTIVE: Similar to patients with systemic lupus erythematosus, autoimmune MRL/lpr mice spontaneously develop behavioral deficits and pathologic changes in the brain. Given that the disease-associated brain atrophy in this model is not well understood, the present study was undertaken to determine the time course of morphometric changes in major brain structures of autoimmune MRL/lpr mice. METHODS: Computerized planimetry and high-resolution magnetic resonance imaging (MRI) were used to compare the areas and volumes of brain structures in cohorts of mice that differ in severity of lupus-like disease. RESULTS: A thinner cerebral cortex and smaller cerebellum were observed in the MRL/lpr substrain, even before severe autoimmunity developed. With progression of the disease, the brain area of coronal sections became smaller and the growth of the hippocampus was retarded, which likely contributed to the increase in the ventricle area:brain area ratio. MRI revealed reduced volume across different brain regions, with the structures in the vicinity of the ventricular system particularly affected. The superior colliculus, periaqueductal gray matter, pons, and midbrain were among the regions most affected, whereas the volumes of the parietal-temporal lobe, parts of the cerebellum, and lateral ventricles in autoimmune MRL/lpr mice were comparable with values in congenic controls. CONCLUSION: These results suggest that morphologic alterations in the brains of MRL/lpr mice are a consequence of several factors, including spontaneous development of lupus-like disease. A periventricular pattern of parenchymal damage is consistent with the cerebrospinal fluid neurotoxicity, limbic system pathologic features, and deficits in emotional reactivity previously documented in this model.
Cortical thickness measured from MRI in the YAC128 mouse model of Huntington's disease.
A recent study found differences in localised regions of the cortex between the YAC128 mouse model of Huntington's Disease (HD) and wild-type mice. There are, however, few tools to automatically examine shape differences in the cortices of mice. This paper describes an algorithm for automatically measuring cortical thickness across the entire cortex from MRI of fixed mouse brain specimens. An analysis of the variance of the method showed that, on average, a 50 microm (0.05 mm) localised difference in cortical thickness can be measured using MR scans. Applying these methods to 8-month-old YAC128 mouse model mice representing an early stage of HD, we found an increase in cortical thickness in the sensorimotor cortex, and also revealed regions wherein decreasing striatal volume correlated with increasing cortical thickness, indicating a potential compensatory response.
Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study.
BACKGROUND: Alleles of the apolipoprotein E (APOE) gene modulate risk for Alzheimer's disease, with carriers of the epsilon4 allele being at increased risk and carriers of the epsilon2 allele possibly at decreased risk compared with non-carriers. Our aim was to determine whether possession of an epsilon4 allele would confer children with a neural substrate that might render them at risk for Alzheimer's disease, and whether carriers of the epsilon2 allele might have a so-called protective cortical morphology. METHODS: 239 healthy children and adolescents were genotyped and had repeated neuroanatomic MRI (total 530 scans). Mixed model regression was used to determine whether the developmental trajectory of the cortex differed by genotype. FINDINGS: Cortical thickness of the left entorhinal region was significantly thinner in epsilon4 carriers than it was in non-epsilon4 carriers (3.79 [SE 0.06] mm, range 1.54-5.24 vs 3.94 [0.03] mm, 2.37-6.11; p=0.03). There was a significant stepwise increase in cortical thickness in the left entorhinal regions, with epsilon4 carriers having the thinnest cortex and epsilon2 carriers the thickest, with epsilon3 homozygotes occupying an intermediate position (left beta 0.11 [SE 0.05], p=0.02). Neuroanatomic effects seemed fixed and non-progressive, with no evidence of accelerated cortical loss in young healthy epsilon4 carriers. INTERPRETATION: Alleles of the apolipoprotein E gene have distinct neuroanatomic signatures, identifiable in childhood. The thinner entorhinal cortex in individuals with the epsilon4 allele might contribute to risk of Alzheimer's disease.