In vivo 3-photon fluorescence microscopy of white matter in mouse brain excited at the 1700 nm window

White matter,a densely packed collection of myelinated axons,plays an essential part in neural networks.With high spatial resolution and deep penetration,multi-photon microscopy(MPM)is promising for white matter imaging in animal models in vivo.The third harmonic generation(THG)signal can be generated from white matter,but the bottom part of the white matter layer generates weak THG due to its high scattering.Here,we demonstrate an in vivo labeling and imaging technology,capable of visualizing the white matter layer in the mouse brain,combining°uorescence labeling with MitoTracker Red and three-photon°uorescence(3PF)microscopy excited at the 1700 nm window.3PF signals are several times higher than THG signals,resulting in deeper imaging of the white matter layer with the former.Our results indicate that 3PF microscopy is a promising technology for white matter imaging in the deep brain in vivo.

White Matter Lesions in Young-Middle Aged Migraineurs with Patent Foreman Ovale: A Case-Control Study

Background:White matter lesion(WML)is common in aging brain and is associated with cognitive impairment and dementia.However,recent studies reported an association between patent foramen ovale(PFO)and WML in migraineurs,especially in young,middle-aged migraineurs.Our retrospective,case-control study aims to describe the clinical characteristics of WML in this population and to explore potential risk factors.Methods:226 patients with migraine and PFO were consecutively initially screened.Relevant factors were selected by the least absolute shrinkage and selection operator(LASSO)regression and multivariable logistic regression model.A Nomogram was employed to visualize the prediction model conveniently.The discrimination and calibration abilities were evaluated using the Receiver Operating Characteristic(ROC)curve,the Hosmer-Lemeshow test,and calibration curves.Results:One hundred and nineteen participants were ultimately enrolled in our study,with a median age of 36.9±12.7 years and 80.7%of females.Brain magnetic resonance imaging MRI showed 67(56.3%)patients had WML,whereas 52(43.7%)patients were categorized into the non-WML group.LASSO regression screened out potential variables and subsequent multivariate analysisfinally identified age,mean platelet volume,andfibri-nogen(FIB)as independent predictive factors of WML.The area under the ROC curve(AUC)was 0.807.Hos-mer-Lemeshow test and calibration curve verified a consistency between the predicted and actual probability.Conclusion:The predictive nomogram established and validated in our study may assist clinicians in screening WML among young middle-aged migraineurs with PFO and developing individualized preventive and treatment strategies.

Application of proton magnetic resonance spectroscopy in metabolic alterations of prefrontal white and gray matter in depression adolescents

BACKGROUND Cases of depression among adolescents are gradually increasing.The study of the physiological basis of cognitive function from a biochemical perspective has therefore been garnering increasing attention.Depression has been hypothesized to be associated with the brain biochemical metabolism of the anterior cingulate gyrus,frontal lobe white matter,and the thalamus.AIM To explore the application of proton magnetic resonance spectroscopy(1H-MRS)in the metabolic alterations in the prefrontal white matter(PWM)and gray matter(GM)in adolescents with depression.METHODS 1H-MRS was performed for semi-quantitative analysis of the biochemical metabolites N-acetylaspartate(NAA),choline(Cho)complexes,creatine(Cr),and myoinositol(mI)in bilateral PWM,anterior cingulate GM,and thalami of 31 adolescent patients with depression(research group)and 35 healthy adolescents(control group),and the NAA/Cr,Cho/Cr,and mI/Cr ratios were calculated.Meanwhile,Hamilton Depression Scale(HAMD)and Wechsler Memory Scale were used to assess the degree of depression and memory function in all adolescents.The correlation of brain metabolite levels with scale scores was also analyzed.RESULTS The research group had markedly higher HAMD-24 scores and lower memory quotient(MQ)compared with the control group(P<0.05).Adolescents with depression were found to have lower bilateral PWM NAA/Cr and Cho/Cr ratios compared with healthy adolescents(P<0.05).The mI/Cr ratios were found to be similar in both groups(P>0.05).The bilateral anterior cingulate GM NAA/Cr,Cho/Cr,and mI/Cr also did not demonstrate marked differences(P>0.05).No statistical inter-group difference was determined in NAA/Cr of the bilateral thalami(P>0.05),while bilateral thalamic Cho/Cr and mI/Cr were reduced in teenagers with depression compared with healthy adolescents(P<0.05).A significant negative correlation was observed between the HAMD-24 scores in adolescents with depression with bilateral PWM NAA/Cr and Cho/Cr and were inversely linked to bilateral thalamic Cho/Cr and mI/Cr(P<0.05).In adolescents with depressions,MQ positively correlated with right PWH NAA/Cr,left PWH Cho/Cr,and bilateral thalamic Cho/Cr and mI/Cr.CONCLUSION PWM and thalamic metabolic abnormalities might influence teen depression,and the reduction in bilateral PWM NAA/Cr and Cho/Cr could be related to the neuropathology of adolescents with depression suffering from memory impairment.There exists a possibility of dysfunction of nerve cell membrane phospholipids in the thalami of adolescent patients with depression.

Performance of the walking trail making test in older adults with white matter hyperintensities

BACKGROUND Several studies have reported that the walking trail making test(WTMT)completion time is significantly higher in patients with developmental coordination disorders and mild cognitive impairments.We hypothesized that WTMT performance would be altered in older adults with white matter hyperintensities(WMH).AIM To explore the performance in the WTMT in older people with WMH.METHODS In this single-center,observational study,25 elderly WMH patients admitted to our hospital from June 2019 to June 2020 served as the WMH group and 20 participants matched for age,gender,and educational level who were undergoing physical examination in our hospital during the same period served as the control group.The participants completed the WTMT-A and WTMT-B to obtain their gait parameters,including WTMT-A completion time,WTMT-B completion time,speed,step length,cadence,and stance phase percent.White matter lesions were scored according to the Fazekas scale.Multiple neuropsychological assessments were carried out to assess cognitive function.The relationships between WTMT performance and cognition and motion in elderly patients with WMH were analyzed by partial Pearson correlation analysis.RESULTS Patients with WMH performed significantly worse on the choice reaction test(CRT)(0.51±0.09 s vs 0.44±0.06 s,P=0.007),verbal fluency test(VFT,14.2±2.75 vs 16.65±3.54,P=0.012),and digit symbol substitution test(16.00±2.75 vs 18.40±3.27,P=0.010)than participants in the control group.The WMH group also required significantly more time to complete the WTMT-A(93.00±10.76 s vs 70.55±11.28 s,P<0.001)and WTMT-B(109.72±12.26 s vs 82.85±7.90 s,P<0.001).WTMT-A completion time was positively correlated with CRT time(r=0.460,P=0.001),while WTMT-B completion time was negatively correlated with VFT(r=-0.391,P=0.008).On the WTMT-A,only speed was found to statistically differ between the WMH and control groups(0.803±0.096 vs 0.975±0.050 m/s,P<0.001),whereas on the WTMT-B,the WMH group exhibited a significantly lower speed(0.778±0.111 vs 0.970±0.053 m/s,P<0.001)and cadence(82.600±4.140 vs 85.500±5.020 steps/m,P=0.039),as well as a higher stance phase percentage(65.061±1.813%vs 63.513±2.465%,P=0.019)relative to controls.CONCLUSION Older adults with WMH showed obviously poorer WTMT performance.WTMT could be a potential indicator for cognitive and motor deficits in patients with WMH.

Neuropathological characteristics of abnormal white matter functional signaling in adolescents with major depression

BACKGROUND Major depression disorder(MDD)constitutes a significant mental health concern.Epidemiological surveys indicate that the lifetime prevalence of depression in adolescents is much higher than that in adults,with a corresponding increased risk of suicide.In studying brain dysfunction associated with MDD in adolescents,research on brain white matter(WM)is sparse.Some researchers even mistakenly regard the signals generated by the WM as noise points.In fact,studies have shown that WM exhibits similar blood oxygen level-dependent signal fluctuations.The alterations in WM signals and their relationship with disease severity in adolescents with MDD remain unclear.AIM To explore potential abnormalities in WM functional signals in adolescents with MDD.METHODS This study involved 48 adolescent patients with MDD and 31 healthy controls(HC).All participants were assessed using the Patient Health Questionnaire-9 Scale and the mini international neuropsychiatric interview(MINI)suicide inventory.In addition,a Siemens Skyra 3.0T magnetic resonance scanner was used to obtain the subjects'image data.The DPABI software was utilized to calculate the WM signal of the fractional amplitude of low frequency fluctuations(fALFF)and regional homogeneity,followed by a two-sample t-test between the MDD and HC groups.Independent component analysis(ICA)was also used to evaluate the WM functional signal.Pearson’s correlation was performed to assess the relationship between statistical test results and clinical scales.RESULTS Compared to HC,individuals with MDD demonstrated a decrease in the fALFF of WM in the corpus callosum body,left posterior limb of the internal capsule,right superior corona radiata,and bilateral posterior corona radiata[P<0.001,family-wise error(FWE)voxel correction].The regional homogeneity of WM increased in the right posterior limb of internal capsule and left superior corona radiata,and decreased in the left superior longitudinal fasciculus(P<0.001,FWE voxel correction).The ICA results of WM overlapped with those of regional homogeneity.The fALFF of WM signal in the left posterior limb of the internal capsule was negatively correlated with the MINI suicide scale(P=0.026,r=-0.32),and the right posterior corona radiata was also negatively correlated with the MINI suicide scale(P=0.047,r=-0.288).CONCLUSION Adolescents with MDD involves changes in WM functional signals,and these differences in brain regions may increase the risk of suicide.

Differential neuronal reprogramming induced by NeuroD1 from astrocytes in grey matter versus white matter

A new technology called in vivo glia-to-neuron conversion has emerged in recent years as a promising next generation therapy for neural regeneration and repair. This is achieved through reprogramming endogenous glial cells into neurons in the central nervous system through ectopically expressing neural transcriptional factors in glial cells. Previous studies have been focusing on glial cells in the grey matter such as the cortex and striatum, but whether glial cells in the white matter can be reprogrammed or not is unknown. To address this fundamental question, we express NeuroD1 in the astrocytes of both grey matter(cortex and striatum) and white matter(corpus callosum) to investigate the conversion efficiency, neuronal subtypes, and electrophysiological features of the converted neurons. We discover that NeuroD1 can efficiently reprogram the astrocytes in the grey matter into functional neurons, but the astrocytes in the white matter are much resistant to neuronal reprogramming. The converted neurons from cortical and striatal astrocytes are composed of both glutamatergic and GABAergic neurons, capable of firing action potentials and having spontaneous synaptic activities. In contrast, the few astrocyte-converted neurons in the white matter are rather immature with rare synaptic events. These results provide novel insights into the differential reprogramming capability between the astrocytes in the grey matter versus the white matter, and highlight the impact of regional astrocytes as well as microenvironment on the outcome of glia-toneuron conversion. Since human brain has large volume of white matter, this study will provide important guidance for future development of in vivo glia-to-neuron conversion technology into potential clinical therapies. Experimental protocols in this study were approved by the Laboratory Animal Ethics Committee of Jinan University(approval No. IACUC-20180321-03) on March 21, 2018.

Prevalence of white matter hyperintensities increases with age

White matter hyperintensities（WMHs） that arise with age and/or atherosclerosis constitute a heterogeneous disorder in the white matter of the brain. However, the relationship between age-related risk factors and the prevalence of WMHs is still obscure. More clinical data is needed to confirm the relationship between age and the prevalence of WMHs. We collected 836 patients, who were treated in the Renmin Hospital, Hubei University of Medicine, China from January 2015 to February 2016, for a case-controlled retrospective analysis. According to T2-weighted magnetic resonance imaging results, all patients were divided into a WMHs group（n = 333） and a non-WMHs group（n = 503）. The WMHs group contained 159 males and 174 females. The prevalence of WMHs increased with age and was associated with age-related risk factors, such as cardiovascular diseases, smoking, drinking, diabetes, hypertension and history of cerebral infarction. There was no significant difference in sex, education level, hyperlipidemia and hyperhomocysteinemia among the different age ranges. These findings confirm that age is an independent risk factor for the prevalence and severity of WMHs. The age-related risk factors enhance the occurrence of WMHs.

Diffusion tensor imaging assesses white matter injury in neonates with hypoxic-ischemic encephalopathy

With improvements in care of at-risk neonates, more and more children survive. This makes it increasingly important to assess, soon after birth, the prognosis of children with hypoxic-ischemic encephalopathy. Computed tomography, ultrasound, and conventional magnetic resonance imaging are helpful to diagnose brain injury, but cannot quantify white matter damage. In this study, ten full-term infants without brain injury and twenty-two full-term neonates with hypoxic-ischemic encephalopathy （14 moderate cases and 8 severe cases） underwent diffusion tensor imaging to assess its feasibility in evaluating white matter damage in this condition. Results demonstrated that fractional anisotropy, voxel volume, and number of fiber bundles were different in some brain areas between infants with brain injury and those without brain injury. The correlation between fractional anisotropy values and neonatal behavioral neurological assessment scores was closest in the posterior limbs of the internal capsule. We conclude that diffusion tensor imaging can quantify white matter injury in neonates with hypoxic-ischemic encephalopathy.

Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion

Carnosine is a dipeptide that scavenges free radicals, inhibits infammation in the central nervous system, and protects against ischemic and hypoxic brain damage through its anti-oxidative and anti-apoptotic actions. Therefore, we hypothesized that carnosine would also protect against white matter damage caused by subcortical ischemic injury. White matter damage was induced by right unilateral common carotid artery occlusion in mice. The animals were treated with 200, 500 or 750 mg/kg carnosine by intraperitoneal injection 30 minutes before injury and every other day after injury. Then, 37 days later, Klfiver-Barrera staining, toluidine blue staining and immunofluorescence stain- ing were performed. Carnosine （200, 500 mg/kg） substantially reduced damage to the white matter in the corpus callosum, internal capsule and optic tract, and it rescued expression of myelin basic protein, and alleviated the loss of oligodendrocytes. However, carnosine at the higher dose of 750 mg/kg did not have the same effects as the 200 and 500 mg/kg doses. These findings show that carnosine, at a particular dose range, protects against white matter damage caused by chronic cerebral ischemia in mice, likely by reducing oligodendroglial cell loss.

Protective Effects of Activated Protein C on Neurovascular Unit in a Rat Model of Intrauterine Infection-Induced Neonatal White Matter Injury

Summary： Activated protein C （APC）, a natural anticoagulant, has been reported to exert direct vascu- loprotective, neural protective, anti-inflammatory, and proneurogenic activities in the central nervous system. This study was aimed to explore the neuroprotective effects and potential mechanisms of APC on the neurovascular unit of neonatal rats with intrauterine infection-induced white matter injury. In- traperitoneal injection of 300 ~tg/kg lipopolysaccharide （LPS） was administered consecutively to preg- nant Sprague-Dawley rats at embryonic days 19 and 20 to establish the rat model of intrauterine infec- tion-induced white matter injury. Control rats were injected with an equivalent amount of sterile saline on the same time. APC at the dosage of 0.2 mg/kg was intraperitoneally injected to neonatal rats imme- diately after birth. Brain tissues were collected at postnatal day 7 and stained with hematoxylin and eo- sin （H＆E）. Immunohistochemistry was used to evaluate myelin basic protein （MBP） expression in the periventricular white matter region. Blood-brain barrier （BBB） permeability and brain water content ~were measured using Evens Blue dye and wet/dry weight method. Double immunofluorescence staining and real-time quantitative PCR were performed to detect microglial activation and the expression of protease activated receptor 1 （PAR1）. Typical pathological changes of white matter injury were ob- served in rat brains exposed to LPS, and MBP expression in the periventricular region was significantly decreased. BBB was disrupted and the brain water content was increased. Microglia were largely acti- vated and the mRNA and protein levels of PAR1 were elevated. APC administration ameliorated the pathological lesions of the white matter and increased MBP expression. BBB permeability and brain water content were reduced. Microglia activation was inhibited and the PAR1 mRNA and protein ex- pression levels were both down-regulated. Our results suggested that APC exerted neuroprotective ef- fects on multiple components of the neurovascular unit in neonatal rats with intrauterine infec- tion-induced white matter injury, and the underlying mechanisms might involve decreased expression of PAR1.

Correlation between white matter damage and gray matter lesions in multiple sclerosis patients

We observed the characteristics of white matter fibers and gray matter in multiple sclerosis patients, to identify changes in diffusion tensor imaging fractional anisotropy values following white matter fiber injury. We analyzed the correlation between fractional anisotropy values and changes in whole-brain gray matter volume. The participants included 20 patients with relapsing-remitting multiple sclerosis and 20 healthy volunteers as controls. All subjects underwent head magnetic resonance imaging and diffusion tensor imaging. Our results revealed that fractional anisotropy values decreased and gray matter volumes were reduced in the genu and splenium of corpus callosum, left anterior thalamic radiation, hippocampus, uncinate fasciculus, right corticospinal tract, bilateral cingulate gyri, and inferior longitudinal fasciculus in multiple sclerosis patients. Gray matter volumes were significantly different between the two groups in the right frontal lobe（superior frontal, middle frontal, precentral, and orbital gyri）, right parietal lobe（postcentral and inferior parietal gyri）, right temporal lobe（caudate nucleus）, right occipital lobe（middle occipital gyrus）, right insula, right parahippocampal gyrus, and left cingulate gyrus. The voxel sizes of atrophic gray matter positively correlated with fractional anisotropy values in white matter association fibers in the patient group. These findings suggest that white matter fiber bundles are extensively injured in multiple sclerosis patients. The main areas of gray matter atrophy in multiple sclerosis are the frontal lobe, parietal lobe, caudate nucleus, parahippocampal gyrus, and cingulate gyrus. Gray matter atrophy is strongly associated with white matter injury in multiple sclerosis patients, particularly with injury to association fibers.

Modeling subcortical ischemic white matter injury in rodents:unmet need for a breakthrough in translational research

Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.

Mechanism underlying the protective effect of Kaixin Jieyu Fang on vascular depression following cerebral white matter damage

The Chinese compound Kaixin fieyu Fang can be used to treat vascular depression; however, the underlying mechanism remains unclear. This study established a rat model of chronic cerebral ischemia-caused white matter damage by ligation of the bilateral common carotid arteries. Rats received daily intragastric administration of a suspension of Kaixin ]ieyu Fang powder. After 3, 7 and 21 days of treatment, the degree of white matter damage in the cerebral ischemia rat model was alleviated, Bcl-2 protein and mRNA expression in brain tissue increased, and Bax protein and mRNA expression decreased. These results indicate that Kaixin Jieyu Fang can alleviate cere- bral white matter damage, and the underlying mechanism is associated with regulation of Bcl-2/ Bax protein and mRNA expression, which is one of possible mechanism behind the protective effect of Kaixin Jieyu Fang against vascular depression.

Decellularized optic nerve functional scaffold transplant facilitates directional axon regeneration and remyelination in the injured white matter of the rat spinal cord

Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury.However,achieving good outcome remains difficult.Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites.However,it has not been reported whether this material promotes axonal regeneration in vivo.In the present study,a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells.This functional scaffold promoted the directional growth and remyelination of regenerating axons.In vitro,the porcine decellularized optic nerve contained many straight,longitudinal channels with a uniform distribution,and microscopic pores were present in the channel wall.The spatial micro topological structure and extracellular matrix were conducive to the adhesion,survival and migration of neural stem cells.The scaffold promoted the directional growth of dorsal root ganglion neurites,and showed strong potential for myelin regeneration.Furthermore,we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo.Four weeks later,the regenerating axons grew straight,the myelin sheath in the injured/transplanted area recovered its structure,and simultaneously,the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced.Together,these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration.All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University(approval No.SYSU-IACUC-2019-B034)on February 28,2019.

Compression analysis of the gray and white matter of the spinal cord

The spinal cord is composed of gray matter and white matter.It is well known that the properties of these two tissues differ considerably.Spinal diseases often present with symptoms that are caused by spinal cord compression.Understanding the mechanical properties of gray and white matter would allow us to gain a deep understanding of the injuries caused to the spinal cord and provide information on the pathological changes to these distinct tissues in several disorders.Previous studies have reported on the physical properties of gray and white matter,however,these were focused on longitudinal tension tests.Little is known about the differences between gray and white matter in terms of their response to compression.We therefore performed mechanical compression test of the gray and white matter of spinal cords harvested from cows and analyzed the differences between them in response to compression.We conducted compression testing of gray matter and white matter to detect possible differences in the collapse rate.We found that increased compression(especially more than 50%compression)resulted in more severe injuries to both the gray and white matter.The present results on the mechanical differences between gray and white matter in response to compression will be useful when interpreting findings from medical imaging in patients with spinal conditions.

White matter abnormalities in young males with antisocial personality disorder Evidence from voxel-based morphometry-diffeomorphic anatomical registration using exponentiated lie algebra analysis

Voxel-based morphometry-diffeomorphic anatomical registration using exponentiated lie algebra analysis was used to investigate the structural characteristics of white matter in young males with antisocial personality disorder （APD） and healthy controls without APD. The results revealed that APD subjects, relative to healthy subjects, exhibited increased white matter volume in the bilateral prefrontal lobe, right insula, precentral gyrus, bilateral superior temporal gyrus, right postcentral gyrus, right inferior parietal Iobule, right precuneus, right middle occipital lobe, right parahippocampal gyrus and bilateral cingulate, and decreased volume in the middle temporal cortex and right cerebellum. The white matter volume in the medial frontal gyrus was significantly correlated with antisocial type scores on the Personality Diagnostic Questionnaire in APD subjects. These experimental findings indicate that white matter abnormalities in several brain areas may contribute to antisocial behaviors in APD subjects.

Significance of Increased CIMT with Coexisting Carotid Plaques in Cerebral White Matter Lesions in Elders

It is very common that increased carotid intima media thickness （CIMT） and carotid plaque coexist in a single subject in elderly patients with white matter lesions （WMLs）. In this study we inves- tigated whether the coexistence of increased CIMT and carotid plaque is more strongly associated with the presence and extent of WMLs than either alone. All patients were classified into 1 of the following 4 groups： without either increased CIMT （I） or carotid plaque （P）： I（-）P（-）; with only increased CIMT： I（＋）P（-）; with only carotid plaque： I（-）P（＋）; and with both increased CIMT and carotid plaque： I（＋）P（＋） The presence and severity of periventricular WMLs （PWMLs） and deep WMLs （DWMLs） were as- sessed and the prevalence of MRI findings by the Cochran-Armitage trend test was calculated. The characteristics of subjects showed that the percentages of patients with increased CIMT and carotid plaque in the DWMLs group and the PWMLs group were significantly higher than those without WMLs group. Both DWMLs and PWMLs were strongly associated with age, carotid plaque and CIMT. Furthermore, the Cochran-Armitage trend test indicated that the prevalence of MRI findings of PWMLs and DWMLs increased in the order of I（-）P（-）〈 I（＋）P（-）〈 I（-）P（＋）〈 I（＋）P（＋） （P〈0.0001）. For the pa- tients with DWMLs, the grades of both I（＋）P（-） and I（＋）P（＋） were increased significantly compared to I（-）P（-） （P〈0.0025, P〈0.05, respectively） without such a difference found in patients with PWMLs. Our results suggested that the coexistence of increased CIMT and carotid plaque is most closely associated with WMLs, and that increased CIMT is associated with the severity of DWMLs, whereas carotid plaque is related to the presence of WMLs.

Diffusion tensor imaging pipeline measures of cerebral white matter integrity: An overview of recent advances and prospects

Cerebral small vessel disease(CSVD)is a leading cause of age-related microvascular cognitive decline,resulting in significant morbidity and decreased quality of life.Despite a progress on its key pathophysiological bases and general acceptance of key terms from neuroimaging findings as observed on the magnetic resonance imaging(MRI),key questions on CSVD remain elusive.Enhanced relationships and reliable lesion studies,such as white matter tractography using diffusion-based MRI(dMRI)are necessary in order to improve the assessment of white matter architecture and connectivity in CSVD.Diffusion tensor imaging(DTI)and tractography is an application of dMRI that provides data that can be used to non-invasively appraise the brain white matter connections via fiber tracking and enable visualization of individual patient-specific white matter fiber tracts to reflect the extent of CSVD-associated white matter damage.However,due to a lack of standardization on various sets of software or image pipeline processing utilized in this technique that driven mostly from research setting,interpreting the findings remain contentious,especially to inform an improved diagnosis and/or prognosis of CSVD for routine clinical use.In this minireview,we highlight the advances in DTI pipeline processing and the prospect of this DTI metrics as potential imaging biomarker for CSVD,even for subclinical CSVD in at-risk individuals.

Multifractal analysis of white matter structural changes on 3D magnetic resonance imaging between normal aging and early Alzheimer's disease

Applications of multifractal analysis to white matter structure changes on magnetic resonance imaging（MRI） have recently received increasing attentions. Although some progresses have been made, there is no evident study on applying multifractal analysis to evaluate the white matter structural changes on MRI for Alzheimer＇s disease（AD） research. In this paper, to explore multifractal analysis of white matter structural changes on 3D MRI volumes between normal aging and early AD, we not only extend the traditional box-counting multifractal analysis（BCMA） into the 3D case, but also propose a modified integer ratio based BCMA（IRBCMA） algorithm to compensate for the rigid division rule in BCMA. We verify multifractal characteristics in 3D white matter MRI volumes. In addition to the previously well studied multifractal feature,△α, we also demonstrated △ f as an alternative and effective multifractal feature to distinguish NC from AD subjects.Both △α and △ f are found to have strong positive correlation with the clinical MMSE scores with statistical significance.Moreover, the proposed IRBCMA can be an alternative and more accurate algorithm for 3D volume analysis. Our findings highlight the potential usefulness of multifractal analysis, which may contribute to clarify some aspects of the etiology of AD through detection of structural changes in white matter.

Neuroprotection and neuroregeneration:roles for the white matter

Efficient strategies for neuroprotection and repair are still an unmet medical need for neurodegenerative diseases and lesions of the central nervous system.Over the last few decades,a great deal of attention has been focused on white matter as a potential therapeutic target,mainly due to the discovery of the oligodendrocyte precursor cells in the adult central nervous system,a cell type able to fully repair myelin damage,and to the development of advanced imaging techniques to visualize and measure white matter lesions.The combination of these two events has greatly increased the body of research into white matter alte rations in central nervous system lesions and neurodegenerative diseases and has identified the oligodendrocyte precursor cell as a putative target for white matter lesion repair,thus indirectly contributing to neuroprotection.This review aims to discuss the potential of white matter as a therapeutic target for neuroprotection in lesions and diseases of the central nervous system.Pivot conditions are discussed,specifically multiple scle rosis as a white matter disease;spinal cord injury,the acute lesion of a central nervous system component where white matter prevails over the gray matte r,and Alzheimer's disease,where the white matter was considered an ancilla ry component until recently.We first describe oligodendrocyte precursor cell biology and developmental myelination,and its regulation by thyroid hormones,then briefly describe white matter imaging techniques,which are providing information on white matter involvement in central nervous system lesions and degenerative diseases.Finally,we discuss pathological mechanisms which interfere with myelin repair in adulthood.