Edward S. Hui

LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis

Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain–containing, Nogo receptor–interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.

Does diffusion kurtosis imaging lead to better neural tissue characterization? A rodent brain maturation study

Diffusion kurtosis imaging (DKI) can be used to estimate excess kurtosis, which is a dimensionless measure for the deviation of water diffusion profile from Gaussian distribution. Several recent studies have applied DKI to probe the restricted water diffusion in biological tissues. The directional analysis has also been developed to obtain the directionally specific kurtosis. However, these studies could not directly evaluate the sensitivity of DKI in detecting subtle neural tissue alterations. Brain maturation is known to involve various biological events that can affect water diffusion properties, thus providing a sensitive platform to evaluate the efficacy of DKI. In this study, in vivo DKI experiments were performed in normal Sprague-Dawley rats of 3 different ages: postnatal days 13, 31 and 120 (N=6 for each group). Regional analysis was then performed for 4 white matter (WM) and 3 gray matter (GM) structures. Diffusivity and kurtosis estimates derived from DKI were shown to be highly sensitive to the developmental changes in these chosen structures. Conventional diffusion tensor imaging (DTI) parameters were also computed using monoexponential model, yielding reduced sensitivity and directional specificity in monitoring the brain maturation changes. These results demonstrated that, by measuring directionally specific diffusivity and kurtosis, DKI offers a more comprehensive and sensitive detection of tissue microstructural changes. Such imaging advance can provide a better MR diffusion characterization of neural tissues, both WM and GM, in normal, developmental and pathological states.

Towards better MR characterization of neural tissues using directional diffusion kurtosis analysis

MR diffusion kurtosis imaging (DKI) was proposed recently to study the deviation of water diffusion from Gaussian distribution. Mean kurtosis, the directionally averaged kurtosis, has been shown to be useful in assessing pathophysiological changes, thus yielding another dimension of information to characterize water diffusion in biological tissues. In this study, orthogonal transformation of the 4th order diffusion kurtosis tensor was introduced to compute the diffusion kurtoses along the three eigenvector directions of the 2nd order diffusion tensor. Such axial (K(//)) and radial (K( upper left and right quadrants)) kurtoses measured the kurtoses along the directions parallel and perpendicular, respectively, to the principal diffusion direction. DKI experiments were performed in normal adult (N=7) and formalin-fixed rat brains (N=5). DKI estimates were documented for various white matter (WM) and gray matter (GM) tissues, and compared with the conventional diffusion tensor estimates. The results showed that kurtosis estimates revealed different information for tissue characterization. For example, K(//) and K( upper left and right quadrants) under formalin fixation condition exhibited large and moderate increases in WM while they showed little change in GM despite the overall dramatic decrease of axial and radial diffusivities in both WM and GM. These findings indicate that directional kurtosis analysis can provide additional microstructural information in characterizing neural tissues.

Stroke Assessment With Diffusional Kurtosis Imaging

Background and Purpose— Despite being the gold standard technique for stroke assessment, conventional diffusion MRI provides only partial information about tissue microstructure. Diffusional kurtosis imaging is an advanced diffusion MRI method that yields, in addition to conventional diffusion information, the diffusional kurtosis, which may help improve characterization of tissue microstructure. In particular, this additional information permits the description of white matter (WM) in terms of WM-specific diffusion metrics. The goal of this study is to elucidate possible biophysical mechanisms underlying ischemia using these new WM metrics. Methods— We performed a retrospective review of clinical and diffusional kurtosis imaging data of 44 patients with acute/subacute ischemic stroke. Patients with a history of brain neoplasm or intracranial hemorrhages were excluded from this study. Region of interest analysis was performed to measure percent change of diffusion metrics in ischemic WM lesions compared with the contralateral hemisphere. Results— Kurtosis maps exhibit distinct ischemic lesion heterogeneity that is not apparent on apparent diffusion coefficient maps. Kurtosis metrics also have significantly higher absolute percent change than complementary conventional diffusion metrics. Our WM metrics reveal an increase in axonal density and a larger decrease in the intra-axonal (Da) compared with extra-axonal diffusion microenvironment of the ischemic WM lesion. Conclusions— The well-known decrease in the apparent diffusion coefficient of WM after ischemia is found to be mainly driven by a significant drop in the intra-axonal diffusion microenvironment. Our results suggest that ischemia preferentially alters intra-axonal environment, consistent with a proposed mechanism of focal enlargement of axons known as axonal swelling or beading.

Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

Objectives Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood. Method We used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities. Results PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating. Conclusions Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.

B-value dependence of DTI quantitation and sensitivity in detecting neural tissue changes

Recently, remarkable success has been demonstrated in using MR diffusion tensor imaging (DTI) to characterize white matter. Water diffusion in complex biological tissue microstructure is not a free or Gaussian process but is hindered and restricted, thus contradicting the basic assumption in conventional DTI that diffusion weighted signal decays with b-value in a monoexponential manner. Nevertheless, DTI by far is still the fastest and most robust protocol in routine research and clinical settings. To assess the b-value dependence of DTI indices and evaluate their sensitivities in detecting neural tissues changes, in vivo DTI data acquired from rat brains at postnatal day 13, 21 and 120 with different b-values (0.5-2.5 ms/microm(2)) and 30 gradient directions were analyzed. Results showed that the mean and directional diffusivities consistently decreased with b-value in both white and gray matters. The sensitivity of axial diffusivity (lambda(//)) in monitoring brain maturation generally decreased with b-value whereas that of radial diffusivity (lambda( perpendicular)) increased. FA generally varied less with b-value but in a manner dependent of the age and tissue type. Analysis also revealed that the FA sensitivity in detecting specific tissue changes was affected by b-value. These experimental findings confirmed the crucial effect of b-value on quantitative DTI in monitoring neural tissue alterations. They suggested that the choice of b-value in conventional DTI acquisition can be optimized for detecting neural tissue changes but shall depend on the specific tissue type and its changes or pathologies targeted, and caution must be taken in interpreting DTI indices.

Evaluation of the retina and optic nerve in a rat model of chronic glaucoma using in vivo manganese-enhanced magnetic resonance imaging

Glaucoma is a neurodegenerative disease of the visual system. While elevated intraocular pressure is considered to be a major risk factor, the primary cause and pathogenesis of the disease are still unclear. This study aims to employ in vivo manganese-enhanced magnetic resonance imaging (MEMRI) to evaluate dynamically the Mn(2+) enhancements in the visual components following an induction of ocular hypertension in a rat model of chronic glaucoma. The episcleral and limbal veins were photocoagulated unilaterally in the right eye using an argon laser to maintain a consistent elevation of intraocular pressure by about 1.6 times above the normal level. Two and six weeks after glaucoma induction, MnCl(2) solution (50 mM, 3 microL) was injected intravitreally into both eyes, and MEMRI was performed 2 to 5 h after injection. Results showed a delayed increase in T1-weighted signal intensity in the glaucomatous optic nerve at 6 weeks but not 2 weeks after glaucoma induction. In addition, there was an accumulation of Mn(2+) ions in the vitreous humour of the glaucomatous eye, with a high concentration of Mn(2+) ions at the optic nerve head and the retina. These MEMRI findings may help understand the disease mechanisms, monitor the effect of drug interventions in glaucoma models and complement the conventional techniques in examining the glaucomatous visual components.

Spatiotemporal dynamics of diffusional kurtosis, mean diffusivity and perfusion changes in experimental stroke

Diffusional kurtosis imaging (DKI), which measures the non-Gaussianity of water diffusion, has been demonstrated to be a sensitive biomarker in many neuropathologies. The goal of this study was to longitudinally examine the spatiotemporal dynamics of DKI in cerebral ischemia in an animal model of permanent and transient (45 min) middle cerebral artery occlusion (MCAO) during the hyperacute, acute and chronic phases. Diffusional kurtosis showed different spatiotemporal dynamics. In particular, mean kurtosis (MK) was sensitive to hyperacute and acute stroke changes, and exhibited different contrast than mean diffusivity (MD) and higher contrast than fractional anisotropy (FA) and T2. MK contrast persisted 1 to 7 days post-occlusion, whereas MD showed renormalization at day 1-2 and reversed contrast at day 7. The current study showed that DKI has the potential to complement existing stroke imaging techniques, particularly in the assessment of subacute to early chronic stroke evolution.

Diffusion Tensor MR Study of Optic Nerve Degeneration in Glaucoma

Axonal degeneration has been known to occur in the optic nerve (ON) of rat glaucoma model. Recently, quantitative diffusion tensor imaging (DTI) has been developed to investigate various white matter diseases in vivo. In this study, longitudinal DTI was thus employed to study such animal model in the present study. The results showed that radial diffusivity (lambdaperp) and fractional anisotropy (FA) of the glaucomatous ON (gON) was increasing and decreasing respectively with time after glaucoma induction, whereas there was no significant change in the axial diffusivity (lambda//). Supported by the histological staining of the ON, such changes in the two DTI-derived parameters were attributed to the 10% decrease in the axonal density of the gON as compared to nON. It was shown for the first time that DTI can be sensitive enough to detect axonal degeneration in rat glaucoma model. DTI therefore holds promise for reliable diagnoses and assessment of the glaucoma disease in human upon careful interpretation of the DTI-derived directional diffusivities.

Histological correlation of diffusional kurtosis and white matter modeling metrics in cuprizone-induced corpus callosum demyelination.

The cuprizone mouse model is well established for studying the processes of both demyelination and remyelination in the corpus callosum, and it has been utilized together with diffusion tensor imaging (DTI) to investigate myelin and axonal pathology. Although some underlying morphological mechanisms contributing to the changes in diffusion tensor (DT) metrics have been identified, the understanding of specific associations between histology and diffusion measures remains limited. Diffusional kurtosis imaging (DKI) is an extension of DTI that provides metrics of diffusional non‐Gaussianity, for which an associated white matter modeling (WMM) method has been developed. The main goal of the present study was to quantitatively assess the relationships between diffusion measures and histological measures in the mouse model of cuprizone‐induced corpus callosum demyelination. The diffusional kurtosis (DK) and WMM metrics were found to provide additional information that enhances the sensitivity to detect the morphological heterogeneity in the chronic phase of the disease process in the rostral segment of the corpus callosum. Specifically, in the rostral segment, axonal water fraction (d = 2.6; p < 0.0001), radial kurtosis (d = 2.0; p = 0.001) and mean kurtosis (d = 1.5; p = 0.005) showed the most sensitivity between groups with respect to yielding statistically significant p values and high Cohens d values. These results demonstrate the ability of DK and WMM metrics to detect white mater changes and inflammatory processes associated with cuprizone‐induced demyelination. They also validate, in part, the application of these new WMM metrics for studying neurological diseases, as well as helping to elucidate their biophysical meaning. Copyright