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ABSTRACT: With the ever-increasing amount of anatomical information radiologists have to evaluate for routine diagnoses, computational support that facilitates more efficient education and clinical decision making is highly desired. Despite the rapid progress of image analysis technologies for magnetic resonance imaging of the human brain, these methods have not been widely adopted for clinical diagnoses. To bring computational support into the clinical arena, we need to understand the decision-making process employed by well-trained clinicians and develop tools to simulate that process. In this review, we discuss the potential of atlas-based clinical neuroinformatics, which consists of annotated databases of anatomical measurements grouped according to their morphometric phenotypes and coupled with the clinical informatics upon which their diagnostic groupings are based. As these are indexed via parametric representations, we can use image retrieval tools to search for phenotypes along with their clinical metadata. The review covers the current technology, preliminary data, and future directions of this field. Expected final online publication date for the Annual Review of Biomedical Engineering Volume 15 is July 11, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Annual review of biomedical engineering 04/2013; · 11.24 Impact Factor
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ABSTRACT: Background:Diffusion tensor imaging (DTI) can be used to predict outcome following perinatal arterial ischemic stroke (PAIS), though little is known about white matter changes over time.Methods:Infants with PAIS were serially scanned in the neonatal period (n=15), at 3 months (n=16), and at 24 months (n=8). Fractional anisotropy (FA) values in five regions of interest (anterior and posterior limb of the internal capsule, corpus callosum, optic radiation and posterior thalamic radiation) were obtained and compared with FA values of healthy controls and neurodevelopmental outcome.Results:In the neonatal period, no differences in FA were found. At three months, the six infants who ultimately developed motor deficits showed lower FA-values in all affected regions. Four infants developed a visual field defect and showed lower FA values in the affected optic radiation at three months (0.22 vs 0.29, p=0.03). Finally, a correlation between FA-values of the corpus callosum at three months and the Griffiths developmental quotients was found (r =.66 p=0.03). At 24 months a similar pattern was observed.Conclusion:Neonatal FA measurements may underestimate the extent of injury following PAIS. FA measurements at three months could be considered a more reliable predictor of neurodevelopmental outcome and correlate with DTI findings at 24 months.Pediatric Research (2013); doi:10.1038/pr.2013.45.
Pediatric Research 03/2013; · 2.70 Impact Factor
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ABSTRACT: Huntington's disease (HD) is a fatal neurodegenerative disease characterized by abnormal motor coordination, cognitive decline and psychiatric disorders. This disease is caused by an expanded CAG trinucleotide repeat in the gene encoding the protein huntingtin. Reduced levels of brain-derived neurotrophic factor (BDNF) in the brain, which results from transcriptional inhibition and axonal transport deficits mediated by mutant huntingtin, have been suggested as critical factors underlying selective neurodegeneration in both HD patients and HD mouse models. BDNF activates its high-affinity receptor TrkB and promotes neuronal survival; restoring BDNF signaling is thus of particular therapeutic interest. In the present study, we evaluated the ability of a small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and its synthetic derivative 4'-dimethylamino-7,8- dihydroxyflavone (4'-DMA-7,8-DHF) to protect neurons in the well-characterized N171-82Q HD mouse model. We found that chronic administration of 7, 8-DHF (5 mg/kg) or 4'-DMA-7,8-DHF (1 mg/kg) significantly improved motor deficits, ameliorated brain atrophy and extended survival in these N171-82Q HD mice. Moreover, 4'-DMA-7,8-DHF preserved DARPP32 levels in the striatum and rescued mutant huntingtin-induced impairment of neurogenesis in the N171-82Q HD mice. These data highlight consideration of TrkB as a therapeutic target in HD and suggest that small-molecule TrkB agonists that penetrate the brain have high potential to be further tested in clinical trials of HD.
Human Molecular Genetics 03/2013; · 7.64 Impact Factor
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ABSTRACT: A three-dimensional stereotaxic atlas of the human brainstem based on high resolution ex vivo diffusion tensor imaging (DTI) is introduced. The atlas consists of high resolution (125-255μm isotropic) three-dimensional DT images of the formalin-fixed brainstem acquired at 11.7T. The DTI data revealed microscopic neuroanatomical details, allowing three-dimensional visualization and reconstruction of fiber pathways including the decussation of the pyramidal tract fibers, and interdigitating fascicles of the corticospinal and transverse pontine fibers. Additionally, strong grey-white matter contrasts in the apparent diffusion coefficient (ADC) maps enabled precise delineation of grey matter nuclei in the brainstem, including the cranial nerve and the inferior olivary nuclei. Comparison with myelin-stained histology shows that at the level of resolution achieved in this study, the structural details resolved with DTI contrasts in the brainstem were comparable to anatomical delineation obtained with histological sectioning. Major neural structures delineated from DTI contrasts in the brainstem are segmented and three-dimensionally reconstructed. Further, the ex vivo DTI data are nonlinearly mapped to a widely-used in vivo human brain atlas, to construct a high-resolution atlas of the brainstem in the Montreal Neurological Institute (MNI) stereotaxic coordinate space. The results demonstrate the feasibility of developing a 3D DTI based atlas for detailed characterization of brainstem neuroanatomy with high resolution and contrasts, which will be a useful resource for research and clinical applications.
NeuroImage 02/2013; · 5.89 Impact Factor
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ABSTRACT: Diffusion tensor imaging (DTI) is an MRI technique that can measure the macroscopic structural organization in brain tissues. DTI has been shown to provide information complementary to relaxation-based MRI about the changes in the brain's microstructure. In the pediatric population, DTI enables quantitative observation of the maturation process of white matter structures. Its ability to delineate various brain structures during developmental stages makes it an effective tool with which to characterize both the normal and abnormal anatomy of the developing brain. This review will highlight the advantages, as well as the common technical pitfalls of pediatric DTI. In addition, image quantification strategies for various DTI-derived parameters and the normal brain developmental changes associated with these parameters are discussed.
Pediatric Radiology 01/2013; 43(1):15-27. · 1.67 Impact Factor
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ABSTRACT: BACKGROUND: Diffusion tensor imaging (DTI) is a promising method for identifying significant cross-sectional differences of white-matter tracts in normal controls (NC) and those with mild cognitive impairment (MCI) or Alzheimer's disease (AD). There have not been many studies establishing its longitudinal utility. METHODS: Seventy-five participants (25 NC, 25 amnestic MCI, and 25 AD) had 3-Tesla MRI scans and clinical evaluations at baseline and 3, 6, and 12 months. Fractional anisotropy (FA) and mean diffusivity (MD) were analyzed at each time-point and longitudinally in eight a priori-selected areas taken from four regions of interest (ROIs). RESULTS: Cross-sectionally, MD values were higher, and FA values lower in the fornix and splenium of the AD group compared with either MCI or NC (P < .01). Within-group change was more evident in MD than in FA over 12 months: MD increased in the inferior, anterior cingulum, and fornix in both the MCI and AD groups (P < .01). CONCLUSIONS: There were stable, cross-sectional, region-specific differences between the NC and AD groups in both FA and MD at each time-point over 12 months. Longitudinally, MD was a better indicator of change than FA. Significant increases of fornix MD in the MCI group suggest this is an early indicator of progression.
Alzheimer's & dementia: the journal of the Alzheimer's Association 12/2012; · 5.90 Impact Factor
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ABSTRACT: PURPOSE: To improve image registration accuracy in neurodegenerative populations. MATERIALS AND METHODS: This study used primary progressive aphasia, aged control, and young control T1-weighted images. Mapping to a template image was performed using single-channel Large Deformation Diffeomorphic Metric Mapping (LDDMM), a dual-channel method with ventricular anatomy in the second channel, and a dual-channel with appendage method, which utilized a priori knowledge of template ventricular anatomy in the deformable atlas. RESULTS: Our results indicated substantial improvement in the registration accuracy over single-contrast-based brain mapping, mainly in the lateral ventricles and regions surrounding them. Dual-channel mapping significantly (P < 0.001) reduced the number of misclassified lateral ventricle voxels (based on a manually defined reference) over single-channel mapping. The dual-channel (w/appendage) method further reduced (P < 0.001) misclassification over the dual-channel method, indicating that the appendage provides more accurate anatomical correspondence for deformation. CONCLUSION: Brain anatomical mapping by shape normalization is widely used for quantitative anatomical analysis. However, in many geriatric and neurodegenerative disorders, severe tissue atrophy poses a unique challenge for accurate mapping of voxels, especially around the lateral ventricles. In this study we demonstrate our ability to improve mapping accuracy by incorporating ventricular anatomy in LDDMM and by utilizing a priori knowledge of ventricular anatomy in the deformable atlas. J. Magn. Reson. Imaging 2012;. © 2012 Wiley Periodicals, Inc.
Journal of Magnetic Resonance Imaging 09/2012; · 2.70 Impact Factor
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Paul G Unschuld,
Suresh E Joel,
James J Pekar,
Sarah A Reading,
Kenichi Oishi,
Julie McEntee,
Megan Shanahan,
Arnold Bakker,
Russell L Margolis,
Susan S Bassett,
Adam Rosenblatt, Susumu Mori,
Peter C van Zijl,
Christopher A Ross,
Graham W Redgrave
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ABSTRACT: Huntington's Disease (HD) is a neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) triplet repeat-expansion in the Huntingtin (HTT) gene. Diagnosis of HD is classically defined by the presence of motor symptoms; however, cognitive and depressive symptoms frequently precede motor manifestations, and may occur early in the prodromal phase. There are sparse data so far on functional brain correlates of depressive symptoms in prodromal HD. A Stroop color-naming test was administered to 32 subjects in the prodromal phase of HD and 52 expansion-negative controls while performing functional magnetic resonance imaging at 3Tesla. Networks of functional connectivity were identified using group independent component analysis, followed by an analysis of functional network interactions. A contrast of temporal regression-based beta-weights was calculated as a reflection of Stroop-interference related activity and correlated with Center for Epidemiologic Studies Depression (CES-D) scores. For secondary analysis, patients were stratified into two subgroups by median split of CAG repeat-length. Stroop performance was independent of HTT mutation-carrier status and CES-D score. Stroop-interference-related activity of the ventromedial prefrontal cortex-node of the default-mode network, calculated by temporal-regression beta-weights, was more highly correlated with depressive symptoms in subjects in the prodromal phase of HD than in controls, differing significantly. The strength of this correlation and its difference from controls increased when a subgroup of patients with longer CAG repeat lengths was analyzed. These findings suggest that depressive symptoms in prodromal HD subjects may reflect altered functional brain network activity in the context of early HD-related brain alterations.
Psychiatry research. 09/2012; 203(2-3):166-74.
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ABSTRACT: Neuropsychiatric symptoms (NPS) occur frequently in mild cognitive impairment (MCI) and Alzheimer's dementia (AD). The authors examined the relationship between NPS and white-matter integrity in these conditions. Twenty-two individuals with MCI and 23 with mild AD underwent clinical assessments including the Neuropsychiatric Inventory Questionnaire and 3.0-tesla magnetic resonance scans. Fractional anisotropy (FA) was measured in the following manually-drawn regions of interest (ROI): fornix, cingulum bundle, splenium, and cerebral peduncles (control region). The probability of having NPS by tertile of ROI FA was assessed by logistic regression. Because associations were similar within MCI and AD groups, the two groups were combined. Compared with those in the highest tertile, participants within the lowest anterior cingulum (AC) FA tertile were more likely to exhibit irritability, agitation, dysphoria, apathy, and nighttime behavioral disturbances. After adjusting for Mini-Mental State Exam status, participants in the lowest versus highest tertile of AC FA were more likely to report irritability. Using DTI, low AC FA was associated with increased odds of irritability in mild AD and MCI participants. Further imaging studies are necessary to elucidate the role of the AC in the pathophysiology of neuropsychiatric symptoms in AD and MCI.
The Journal of neuropsychiatry and clinical neurosciences 09/2012; 24(4):484-8. · 2.34 Impact Factor
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Hao Huang,
Tina Jeon,
Goran Sedmak,
Mihovil Pletikos,
Lana Vasung,
Xuming Xu,
Paul Yarowsky,
Linda J Richards,
Ivica Kostovic,
Nenad Sestan, Susumu Mori
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ABSTRACT: As a prominent component of the human fetal brain, the structure of the cerebral wall is characterized by its laminar organization which includes the radial glial scaffold during fetal development. Diffusion tensor imaging (DTI) is useful to quantitatively delineate the microstructure of the developing brain and to clearly identify transient fetal layers in the cerebral wall. In our study, the spatio-temporal microstructural changes in the developing human fetal cerebral wall were quantitatively characterized with high-resolution DTI data of postmortem fetal brains from 13 to 21 gestational weeks. Eleven regions of interest for each layer in the entire cerebral wall were included. Distinctive time courses of microstructural changes were revealed for 11 regions of the neocortical plate. A histological analysis was also integrated to elucidate the relationship between DTI fractional anisotropy (FA) and histology. High FA values correlated with organized radial architecture in histological image. Expression levels of 17565 genes were quantified for each of 11 regions of human fetal neocortex from 13 to 21 gestational weeks to identify transcripts showing significant correlation with FA change. These correlations suggest that the heterogeneous and regionally specific microstructural changes of the human neocortex are related to different gene expression patterns.
Cerebral Cortex 08/2012; · 6.54 Impact Factor
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ABSTRACT: Abnormal neuroimmune responses have been reported to be associated with autism and could be appropriate targets for pharmacologic intervention. Our previous studies showed that neuroimmune factor, interleukin (IL)-6, was significantly elevated in the fontal cortex and cerebellum of autistic subjects. The IL-6 overexpressing mice displayed several autism-like features as well as an abnormal dendritic spine morphology and synaptic function. The purpose of this study was to examine the volumetric differences in the brain of IL-6 overexpressing mice and compare with corresponding control mice using magnetic resonance imaging. Here we show that IL-6 overexpressing mice display an increase in the total brain volume. In addition, the lateral ventricle is also enlarged in the IL-6 overexpressing mice. The brain structures surrounding the lateral ventricle were squeezed and deformed from the normal location. These results indicate that IL-6 elevation in the brain could mediate neuroanatomical abnormalities. Taking together with our previous findings, a mechanism by which IL-6 may be involved in the pathogenesis of autism is proposed.
International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 08/2012; 30(7):554-9. · 2.03 Impact Factor
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ABSTRACT: Diffusion tensor imaging (DTI) is a useful tool for studying anatomy and pathology in the rodent central nervous system (CNS).The unique tissue contrasts provided by DTI are well suited for monitoring disease progression, studying brain development, and characterizing anatomical phenotypes. Recent technical developments have vastly improved the speed and resolution of rodent DTI. Ongoing research efforts exploring the microstructural basis of DTI signals have provided useful insights into its capabilities to delineate brain structures and detect neuropathology. Significant progress has also been made in combining DTI results with data acquired using other imaging modalities to enhance our understanding of the rodent CNS.
Trends in Neurosciences 05/2012; 35(7):412-21. · 14.23 Impact Factor
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ABSTRACT: Resting state functional connectivity MRI (rsfc-MRI) reveals a wealth of information about the functional organization of the brain, but poses unique challenges for quantitative image analysis, mostly related to the large number of voxels with low signal-to-noise ratios. In this study, we tested the idea of using a prior spatial parcellation of the entire brain into various structural units, to perform an analysis on a structure-by-structure, rather than voxel-by-voxel, basis. This analysis, based upon atlas parcels, potentially offers enhanced SNR and reproducibility, and can be used as a common anatomical framework for cross-modality and cross-subject quantitative analysis. We used Large Deformation Diffeomorphic Metric Mapping (LDDMM) and a deformable brain atlas to parcel each brain into 185 regions. To investigate the precision of the cross-subject analysis, we computed inter-parcel correlations in 20 participants, each of whom was scanned twice, as well as the consistency of the connectivity patterns inter- and intra-subject, and the intersession reproducibility. We report significant inter-parcel correlations consistent with previous findings, and high test-retest reliability, an important consideration when the goal is to compare clinical populations. As an example of the cross-modality analysis, correlation with anatomical connectivity is also examined.
NeuroImage 04/2012; 61(3):613-21. · 5.89 Impact Factor
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ABSTRACT: We report patterns of dysgraphia in participants with primary progressive aphasia that can be explained by assuming disruption of one or more cognitive processes or representations in the complex process of spelling. These patterns are compared to those described in participants with focal lesions (stroke). Using structural imaging techniques, we found that damage to the left extrasylvian regions, including the uncinate, inferior fronto-occipital fasciculus, and sagittal stratum (including geniculostriate pathway and inferior longitudinal fasciculus), as well as other deep white and grey matter structures, was significantly associated with impairments in access to orthographic word forms and semantics (with reliance on phonology-to-orthography to produce a plausible spelling in the spelling to dictation task). These results contribute not only to our understanding of the patterns of dysgraphia following acquired brain damage but also the neural substrates underlying spelling.
Behavioural neurology 03/2012; · 1.77 Impact Factor
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ABSTRACT: Williams syndrome is a developmental disorder with a genetic basis, which results in an uneven cognitive profile with relatively strong language skills and severely impaired visuospatial abilities. To better understand the brain structure underlying this profile, we compared individuals with Williams syndrome with controls using multimodal neuroimaging data and new analytic methods (diffeomorphic mapping and atlas-based analysis). People with Williams syndrome had basal ganglia atrophy, while the fusiform, the medium temporal gyri, and the cerebellar cortex were relatively preserved. The right superior longitudinal fasciculus, the left frontooccipital fasciculus, the caudate, and the cingulum demonstrated increased fractional anisotropy, whereas the corticospinal tract revealed decreased values. These findings may be linked to the uneven cognitive profile evident in Williams syndrome.
Neuroreport 03/2012; 23(5):283-9. · 1.66 Impact Factor
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ABSTRACT: The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer's disease (AD). The aims of the present study were to: (1) examine the cross-sectional relationship between fornix diffusion tensor imaging (DTI) measurements (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity, and radial diffusivity), hippocampal volume, and memory performance, and (2) compare fornix DTI measures with hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment to AD dementia.
Twenty-three mild cognitive impairment participants for whom hippocampal volumetry and DTI were conducted at baseline received detailed evaluations at baseline; 3, 6, and 12 months; and 2.5 years. Six participants converted to AD over the follow-up period. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the Mini-Mental State Examination, Clinical Dementia Rating-sum of boxes, and memory z scores; receiver operating characteristic analyses examined the predictive value for conversion to AD.
There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, radial diffusivity, and axial diffusivity) were cross-sectionally correlated with memory z scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression, with likelihood ratios >83, and better than 90% accuracy.
Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually drawn region of interest within the fornix shows promise comparable with hippocampal volume as a predictive biomarker of progression, and this finding warrants replication in a larger study.
Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2012; 8(2):105-13. · 5.90 Impact Factor
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ABSTRACT: Mouse models of Huntington's disease (HD) that recapitulate some of the phenotypic features of human HD, play a crucial role in investigating disease mechanisms and testing potential therapeutic approaches. Longitudinal studies of these models can yield valuable insights into the temporal course of disease progression and the effect of drug treatments on the progressive phenotypes. Atrophy of the brain, particularly the striatum, is a characteristic phenotype of human HD, is known to begin long before the onset of motor symptoms, and correlates strongly with clinical features. Elucidating the spatial and temporal patterns of atrophy in HD mouse models is important to characterize the phenotypes of these models, as well as evaluate the effects of neuroprotective treatments at specific time frames during disease progression. In this study, three dimensional in vivo magnetic resonance imaging (MRI) and automated longitudinal deformation-based morphological analysis was used to elucidate the spatial and temporal patterns of brain atrophy in the R6/2 and N171-82Q mouse models of HD. Using an established MRI-based brain atlas and mixed-effects modeling of deformation-based metrics, we report the rates of progression and region-specificity of brain atrophy in the two models. Further, the longitudinal analysis approach was used to evaluate the effects of sertraline and coenzyme Q(10) (CoQ(10)) treatments on progressive atrophy in the N171-82Q model. Sertraline treatment resulted in significant slowing of atrophy, especially in the striatum and frontal cortex regions, while no significant effects of CoQ(10) treatment were observed. Progressive cortical and striatal atrophy in the N171-82Q mice showed significant positive correlations with measured functional deficits. The findings of this report can be used for future testing and comparison of potential therapeutics in mouse models of HD.
NeuroImage 02/2012; 60(4):2086-95. · 5.89 Impact Factor
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ABSTRACT: This article describes the potentials and challenges of quantitative analyses of human neonatal brain images using structural magnetic resonance (MR) imaging and diffusion tensor imaging. To maximize the potential of MR imaging for neonatal brain studies, the combination of both contrasts is highly beneficial. Based on the multicontrast data, a neonate brain atlas was created, which allows automated segmentation of neonate brain MR images. The accuracy, advantages, and potential pitfalls of this atlas-based segmentation approach are discussed. The accurate and reproducible MR imaging quantification achieved by this approach could be an initial step toward the successful clinical evaluation of the neonatal brain.
Magnetic resonance imaging clinics of North America 02/2012; 20(1):81-91.
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ABSTRACT: The arcuate fasciculus (AF) is believed to be fundamental to the neural circuitry behind many important cognitive processes. Connecting Wernicke's and Broca's area, these fibers are thought to be especially important for repetition. In this case study we present evidence from a patient that set doubt on these assumptions. We present structural imaging, diffusion tensor imaging, and language data on a patient with a large left-sided stroke and severely damaged left AF who showed intact word repetition and relatively intact sentence repetition performance. Specifically, his sentence repetition is more fluent and grammatical, with less hesitation than spontaneous speech, and with rare omissions only during the longest sentences. These results challenge classical theories that maintain the left AF is the dominant language processing pathway or mechanism for repetition.
Neurocase 01/2012; · 1.11 Impact Factor
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Elaine Waldron-Roby,
Tamara Ratovitski,
XiaoFang Wang,
Mali Jiang,
Erin Watkin,
Nikolas Arbez,
Rona K Graham,
Michael R Hayden,
Zhipeng Hou, Susumu Mori,
Deborah Swing,
Mikhail Pletnikov,
Wenzhen Duan,
Lino Tessarollo,
Christopher A Ross
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ABSTRACT: Huntington's disease (HD) is caused by a polyglutamine expansion in the Huntingtin (Htt) protein. Proteolytic cleavage of Htt into toxic N-terminal fragments is believed to be a key aspect of pathogenesis. The best characterized putative cleavage event is at amino acid 586, hypothesized to be mediated by caspase 6. A corollary of the caspase 6 cleavage hypothesis is that the caspase 6 fragment should be a toxic fragment. To test this hypothesis, and further characterize the role of this fragment, we have generated transgenic mice expressing the N-terminal 586 aa of Htt with a polyglutamine repeat length of 82 (N586-82Q), under the control of the prion promoter. N586-82Q mice show a clear progressive rotarod deficit by 4 months of age, and are hyperactive starting at 5 months, later changing to hypoactivity before early mortality. MRI studies reveal widespread brain atrophy, and histologic studies demonstrate an abundance of Htt aggregates, mostly cytoplasmic, which are predominantly composed of the N586-82Q polypeptide. Smaller soluble N-terminal fragments appear to accumulate over time, peaking at 4 months, and are predominantly found in the nuclear fraction. This model appears to have a phenotype more severe than current full-length Htt models, but less severe than HD mouse models expressing shorter Htt fragments. These studies suggest that the caspase 6 fragment may be a transient intermediate, that fragment size is a factor contributing to the rate of disease progression, and that short soluble nuclear fragments may be most relevant to pathogenesis.
Journal of Neuroscience 01/2012; 32(1):183-93. · 7.11 Impact Factor
