Cognitive impairment in cerebral small vessel disease induced by hypertension

Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular disease.Howeve r,the causal relationship between hypertension and cerebral small vessel disease remains unclear.Hypertension has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular disease.Chronic hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and stroke.Hypertension is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of hypertension.This review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive ability.We also discuss drugs to treat cerebral small vessel disease and cognitive impairment.

Effects of Progressive Muscle Relaxation Training on Anxiety, Depression, and Quality of Life in Patients with Cerebral Small Vessel Disease

Objective:To explore the effects of progressive muscle relaxation training on anxiety,depression,and quality of life in patients with cerebral small vessel disease(CSVD).Methods:Sixty-one patients with CSVD in the Department of Neurology of a tertiary hospital were divided into an observation group(28 patients)and a control group(33 patients)by lottery method.The control group received conventional nursing care,while the observation group received progressive muscle relaxation training interventions in addition to the conventional care.The Hamilton Anxiety Scale(HAMA),the Hamilton Depression Scale(HAMD),and the Stroke-Specific Quality of Life Scale(SS-QOL)were used to compare the effects before the intervention,7 days after the intervention,and 30 days after the intervention.Results:Over time,at different time points after the intervention,the anxiety and depression scores of patients with CSVD in the observation group were significantly lower than those in the control group(P<0.05).The quality of life scores were significantly higher in the observation group compared to the control group(P<0.05),and these differences were statistically significant.Conclusion:Progressive muscle relaxation training can improve anxiety and depression in patients with cerebral small vessel disease and can effectively enhance their quality of life.

Exosomal miR-320e through wnt2targeted inhibition of the Wnt/β-catenin pathway allevisate cerebral small vessel disease and cognitive impairment

BACKGROUND Exosomal miRNAs play crucial roles in many central nervous system diseases.Cerebral small vessel disease(CVSD)is a small vessel disease that is affected by various factors.This study aimed to investigate the role of exosomal miR-320e in the Wnt/β-catenin pathway stimulated by oxidative stress and assess its clinical correlation with psychiatric symptoms in patients with CVSD.AIM To explore whether exosomal miR-320e could suppress the Wnt/β-catenin pathway and play a protective role in CVSD progression,as well as examine its potential correlation with cognitive impairment and depression in patients with CVSD.METHODS Differentially expressed exosomal miRNAs were filtered by sequencing plasma exosomes from patients with CVSD and healthy controls.Bioinformatics and dual luciferase analyses were used to confirm the binding of miR-320e to Wnt2,and the mRNA and protein levels of downstream components in the Wnt/β-catenin pathway were evaluated when overexpressed or with knockdown of miR-320e under H2O2-induced oxidative stress.In addition,Wnt2-targeting siRNA was used to confirm the role of miR-320e in the Wnt2-mediated inhibition of the Wnt/β-catenin pathway.A retrospective analysis was conducted among patients with CVSD to confirm the correlation between miR-320e expression and the severity of cognitive impairment and depression,which were quantified using the Montreal Cognitive Assessment(MoCA)/Executive Function Assessment(EFA),and the Hamilton Depression Scale(HAMD)/Beck Depression Inventory(BDI),respectively.RESULTS High-throughput sequencing revealed that exosomal miR-320e was downregulated in patients with CVSD.Bioinformatics analysis and dual-luciferase reporter gene experiments showed that exosomal miR-320e inhibited the Wnt/β-catenin pathway in response to oxidative stress by targeting the 3'noncoding region of Wnt2.Uptake of exosomes carrying miR-320e into endothelial cells could also target Wnt2 and inhibit the Wnt2/β-catenin pathway.Elevated miR-320e expression may protect patients with CVSD from relatively severe cognitive impairment and depression,as it was found to have a positive correlation with the MoCA/EFA and HAMD/BDI scores.CONCLUSION Our results suggest that exosomal miR-320e suppresses the Wnt/β-catenin pathway and may play a protective role in CVSD progression.

The role of small vessel disease in development of Alzheimer's disease

Classically Alzheimer＇s disease and vascular dementia have been considered as two different entities, with their own clinical criteria, but relatively recent epidemiological and clinicopathological studies suggest an overlap between them sharing not only most of the risk factors and some clinical aspects but also pathophysiological mechanisms. Cerebrovascular lesions, especially small vessel disease （lacunar infarcts, white matter hyperintensities and microbleeds）, may magnify the effects of mild Alzheimer＇s disease pathology and promote the progression of cognitive decline and may also be a precursor of neuronal damage and dementia. ＂Vascular hypothesis＂ of Alzheimer＇s disease would open a window for new approaches and treatments.

Roles of NG2 Glia in Cerebral Small Vessel Disease

Cerebral small vessel disease(CSVD)is one of the most prevalent pathologic processes affecting 5%of people over 50 years of age and contributing to 45%of dementia cases.Increasing evidence has demonstrated the pathological roles of chronic hypoperfusion,impaired cerebral vascular reactivity,and leakage of the blood–brain barrier in CSVD.However,the pathogenesis of CSVD remains elusive thus far,and no radical treatment has been developed.NG2 glia,also known as oligodendrocyte precursor cells,are the fourth type of glial cell in addition to astrocytes,microglia,and oligodendrocytes in the mammalian central nervous system.Many novel functions for NG2 glia in physiological and pathological states have recently been revealed.In this review,we discuss the role of NG2 glia in CSVD and the underlying mechanisms.

Hypertension-Induced Cerebral Small Vessel Disease Leading to Cognitive Impairment

Objective： Alzheimer＇s disease and vascular dementia are responsible for more than 80% of dementia cases. These two conditions share common risk factors including hypertension. Cerebral small vessel disease （CSVD） is strongly associated with both hypertension and cognitive impairment. In this review, we identify the pathophysiological changes in CSVD that are caused by hypertension and further explore the relationship between CSVD and cognitive impairment. Data Sources： We searched and scanned the PubMed database for recently published literatures up to December 2017. We used the keywords of＂hypertension＂, ＂cerebral small vessel disease＂, ＂＇white matter lesions＂, ＂enlarged perivascular spaces＂, ＂lacunar infarcts＂, ＂cerebral microbleeds＂, and ＂cognitive impairment＂ in the database of PubMed. Study Selection： Articles were obtained and reviewed to analyze the hypertension-induced pathophysiological changes that occur in CSVD and the correlation between CSVD and cognitive impairment. Results： In recent years, studies have demonstrated that hypertension-related changes （e.g., small vascular lesions, inflarnmator3, reactions, hypoperfusion, oxidative stress, damage to autoregulatory processes and the blood-brain barrier, and cerebral amyloid angiopathy） can occur over time in cerebral small vessels, potentially leading to lower cognitive function when blood pressure （BP） control is poor or lacking. Both isolated and co-occurrent CSVD can lead to cognitive deterioration, and this effect may be attributable to a dysfunction in either the cholinergic system or the functionality of cortical and subcortical tracts. Conclusions： We explore the currently available evidence about the hypertensive vasculopathy and inflammatory changes that occur in CSVD. Both are vital prognostic indicators of the development of cognitive impairment. Future studies should be performed to validate the relationship between BP levels and CSVD progression and between the nunabers, volumes, and anatomical locations of CSVD and cognitive impairment.

Association between large artery stenosis,cerebral small vessel disease and risk of ischemic stroke

We aimed to assess the associations of large artery stenosis(LAS)and cerebral small vessel disease(CSVD)with the risk of ischemic stroke and to investigate their respective and combined contributions.In the prospective population-based Shunyi Study,1,082 stroke-free participants aged 55.9±9.1 years were included.Participants were followed for incident stroke throughout the study period(2013-2019).Total small vessel disease score was used to measure CSVD burden.Cervico-cerebral large artery stenosis was evaluated via brain magnetic resonance angiography and carotid ultrasound.We estimated the risk of ischemic stroke in relation to LAS and CSVD with Cox regression models.During a mean follow-up of 4.2 years,34 participants(3.1%)experienced at least one ischemic stroke.Severe LAS(≥50% stenosis versus no stenosis:HR=3.27(95%CI:1.31-8.18))and high CSVD burden(total small vessel disease score 2-4 versus 0 point:HR=12.73(4.83-33.53))were associated with increased stroke risk independently.In multivariate models,CSVD burden(7.72%)explained a larger portion of the variation in stroke risk than severity of LAS(3.49%).Our findings identified that both LAS and CSVD were associated with future ischemic stroke in asymptomatic subjects,while those with high CSVD burden deserve more attention in primary prevention of stroke.

Magnetic resonance imaging manifestations of cerebral small vessel disease:automated quantification and clinical application

The common cerebral small vessel disease(CSVD)neuroimaging features visible on conventional structural magnetic resonance imaging include recent small subcortical infarcts,lacunes,white matter hyperintensities,perivascular spaces,microbleeds,and brain atrophy.The CSVD neuroimaging features have shared and distinct clinical consequences,and the automatic quantification methods for these features are increasingly used in research and clinical settings.This review article explores the recent progress in CSVD neuroimaging feature quantification and provides an overview of the clinical consequences of these CSVD features as well as the possibilities of using these features as endpoints in clinical trials.The added value of CSVD neuroimaging quantification is also discussed for researches focused on the mechanism of CSVD and the prognosis in subjects with CSVD.

Pandemic of the aging society—sporadic cerebral small vessel disease

Age-related sporadic cerebral small vessel disease(CSVD)has gained increasing attention over the past decades because of its increasing prevalence associated with an aging population.The widespread application of and advances in brain magnetic resonance imaging in recent decades have significantly increased researchers’understanding in the in vivo evolution of CSVD,its impact upon the brain,its risk factors,and the mechanisms that explain the various clinical manifestation associated with sporadic CSVD.In this review,we aimed to provide an update on the pathophysiology,risk factors,biomarkers,and the determinants and spectrum of the clinical manifestation of sporadic CSVD.

Clinical management of cerebral small vessel disease:a call for a holistic approach

Cerebral small vessel disease(SVD)is a common global brain disease that causes cognitive impairment,ischemic or hemorrhagic stroke,problems with mobility,and neuropsychiatric symptoms.The brain damage,seen as focal white and deep grey matter lesions on brain magnetic resonance imaging(MRI)or computed tomography(CT),typically accumulates"covertly"and may reach an advanced state before being detected incidentally on brain scanning or causing symptoms.Patients have typically presented to different clinical services or been recruited into research focused on one clinical manifestation,perhaps explaining a lack of awareness,until recently,of the full range and complexity of SVD.In this review,we discuss the varied clinical presentations,established and emerging risk factors,relationship to SVD features on MRI or CT,and the current state of knowledge on the effectiveness of a wide range of pharmacological and lifestyle interventions.The core message is that effective assessment and clinical management of patients with SVD,as well as future advances in diagnosis,care,and treatment,will require a more"joined-up"’approach.This approach should integrate clinical expertise in stroke neurology,cognitive,and physical dysfunctions.It requires more clinical trials in order to improve pharmacological interventions,lifestyle and dietary modifications.A deeper understanding of the pathophysiology of SVD is required to steer the identification of novel interventions.An essential prerequisite to accelerating clinical trials is to improve the consistency,and standardization of clinical,cognitive and neuroimaging endpoints.

HTRA1-related autosomal dominant cerebral small vessel disease

Background:Homozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1(HTRA1)gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy(CARASIL).Recently,increasing evidence has shown that heterozygous HTRA1 mutations are also associated with cerebral small vessel disease(CSVD)with an autosomal dominant pattern of inheritance.This study was aimed to analyze the genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD.Methods:We presented three new Chinese cases of familial CSVD with heterozygous HTRA1 mutations and reviewed all clinical case reports and articles on HTRA1-related autosomal dominant CSVD included in PUBMED by the end of March 1,2020.CARASIL probands with genetic diagnosis reported to date were also reviewed.The genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD were summarized and analyzed by comparing with CARASIL.Results:Forty-four HTRA1-related autosomal dominant CSVD probands and 22 CARASIL probands were included.Compared with typical CARASIL,HTRA1-related autosomal dominant probands has a higher proportion of vascular risk factors(P<0.001),a later onset age(P<0.001),and a relatively slower clinical progression.Alopecia and spondylosis can be observed,but less than those in the typical CARASIL.Thirty-five heterozygous mutations in HTRA1 were reported,most of which were missense mutations.Amino acids located close to amino acids 250-300 were most frequently affected,followed by these located near 150∼200.While amino acids 250∼300 were also the most frequently affected region in CARASIL patients,fewer mutations precede the 200th amino acids were detected,especially in the Kazal-type serine protease domain.Conclusions:HTRA1-related autosomal dominant CSVD is present as a mild phenotype of CARASIL.The trend of regional concentration of mutation sites may be related to the concentration of key sites in these regions which are responsible for pathogenesis of HTRA1-related autosomal dominant CSVD.

Cerebral small vessel disease caused by PLOD3 mutation:Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency

Introduction:Pathogenic variants inPLOD3,encoding lysyl hydroxylase-3(LH3),can cause a hereditary connective tissue disorder that has rarely been reported.It is a multi-system disease,presenting with craniofacial dysmorphisms,skeletal and eye manifestations,sensorineural hearing loss,and variable skin manifestations.Severe central nervous system involvement has not been reported.Case presentation:A 10-month-old girl was admitted with development delay and clustered epileptic spasms.Hypertelorism,an upturned nose,and low-set ears were noted in physical examination.Cerebral magnetic resonance imaging showed multiple intracranial malacias and bleeding foci,extensive abnormal signals in the white matter,and obvious brain atrophy,which was consistent with cerebral small vessel disease(SVD).Electroencephalography suggested hypsarrhythmia.The vertebrae were flattened.The distal end of the metacarpal bone in the left hand was irregular.She was diagnosed with West syndrome.Whole-exome sequencing revealed a novel homozygous variant of c.12161218delCTC(p.L406del)inPLOD3,which was found to be inherited from her heterozygous parents.Conclusion:We report a patient with pathogenicPLOD3 mutation who presented with cerebral SVD.This report expands the phenotypic spectrum of LH3 deficiency.

Evaluation of Clinical Outcomes of ses Stent in Patients with Coronary Artery Disease After Intracoronary Stenting in Small Vessels

Background:Limited data are available for sirolimus-eluting stent(SES,Cypher)implantation in patients with coronary artery disease in small vessels.The clinical longtermoutcomes of SES in patients with coronary artery disease after intracoronary stenting in small vessels has not been yet evaluated.

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.

Progress on Prevention and Treatment of Cerebral Small Vascular Disease Using Integrative Medicine

Cerebral small vessel disease(CSVD)is a senile brain lesion caused by the abnormal structure and function of arterioles,venules and capillaries in the aging brain.The etiology of CsvD is complex,and disease is often asymptomatic in its early stages.However,as CsvD develops,brain disorders may occur,such as stroke,cognitive dysfunction,dyskinesia and mood disorders,and heart,kidney,eye and systemic disorders.As the population continues to age,the burden of CsvD is increasing.Moreover,there is an urgent need for better screening methods and diagnostic markers for CsvD,in addition to preventive and asymptomatic-and mild-stage treatments.Integrative medicine(IM),which combines the holistic concepts and syndrome differentiations of Chinese medicine with modern medical perspectives,has unique advantages for the prevention and treatment of CsvD.In this review,we summarize the biological markers,ultrasound and imaging features,disease-related genes and risk factors relevant to CsvD diagnosis and screening.Furthermore,we discuss IM-based csvD prevention and treatment strategies to stimulate further research in this field.

Microbleeds in fronto-subcortical circuits are predictive of dementia conversion in patients with vascular cognitive impairment but no dementia

Cerebral small vessel disease（CSVD） is a common etiology of vascular cognitive impairment with no dementia（V-CIND）. Studies have revealed that cerebral microbleeds（CMBs）, a feature of CSVD, contribute to cognitive impairment. However, the association between CMBs and dementia conversion in individuals with V-CIND is still unclear. Here, we analyzed the predictive role of CMBs in the conversion from V-CIND to dementia in CSVD patients. We recruited and prospectively assessed 85 patients with CSVD and V-CIND. V-CIND was evaluated using a series of comprehensive neuropsychological scales, including the Chinese version of the Montreal Cognitive Assessment and the Clinical Dementia Rating. MRI assessments were used to quantify lacunar infarcts, white matter hyperintensities, CMBs, and medial temporal lobe atrophy. Eighty-two of the 85 patients completed the assessment for dementia conversion at a 1-year follow-up assessment. Multivariate logistic regression analyses were conducted to examine independent clinical and MRI variables associated with dementia conversion. Twenty-four patients（29.3%） had converted to dementia at the 1-year follow-up, and these individuals had significantly more CMBs in the fronto-subcortical circuits. Multivariate logistic regression analyses revealed that the patients with CMBs in the fronto-subcortical circuits（odds ratio = 4.4; 95% confidence interval： 1.602-12.081, P = 0.004） and 5 or more CMBs overall（odds ratio = 17.6, 95% confidence interval： 3.23-95.84, P = 0.001） had a significantly increased risk of dementia at the 1-year follow-up. These findings indicate that CMBs in the fronto-subcortical circuits may be predictive of dementia conversion in CSVD patients with V-CIND, and thus extend the clinical significance of CMBs.

Clinical usefulness of ankle brachial index and brachial-ankle pulse wave velocity in patients with ischemic stroke

Ankle brachial index （ABI） and brachial-ankle pulse wave velocity （baPWV） are widely used noninvasive modalities to evaluate atherosclerosis. Recently, evidence has increased supporting the use of ABI and baPWV as markers of cerebrovascular disease. This study sought to examine the relationship between ABI and baPWV with ischemic stroke. This study also aimed to determine which pathogenic mechanism, large artery disease （LAD） or small vessel disease （SVD）, is related to ABI or baPWV. Retrospectively, 121 patients with ischemic stroke and 38 subjects with no obvious ischemic stroke history were recruited. First, ABI and baPWV were compared between the groups. Then, within the stroke group, the relevance of ABI and baPWV with regard to SVD and LAD, which were classified by brain magnetic resonance image （MRI） and magnetic resonance angiography （MRA） or computed tomography angiography （CTA） findings, was assessed. The baPWV was higher in the stroke group than non-stroke group （1,944.18±416.6 cm/s vs. 1,749.76±669.6 crn/s, P 〈 0.01）. Regarding LAD, we found that mean ABI value was lower in the group with extracranial large artery stenosis （P 〈 0.01）, and there was an inverse linear correlation between ABI and the grade of extracranial large artery stenosis （P〈 0.01）. For SVD, there was a significant correlation between SVD and baPWV （2,057.6±456.57 cm/s in the SVD （＋） group vs. 1,491±271.62 cm/s in the SVD （-） group; P 〈 0.01）. However, the grade of abnormalities detected in SVD did not correlate linearly with baPWV. These findings show that baPWV is a reliable surrogate marker ofischemic stroke. Furthermore, baPWVand ABI can be used to indicate the presence of small vessel disease and large arterial disease, respectively.

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.

Effects of different regional cerebral blood flow on white matter hyperintensity in CADASIL patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is an early-onset inherited small vessel disease.Decreased cerebral blood flow(CBF)may contribute to white matter hyperintensity(WMH)severity in CADASIL,but more evidence is needed to support this hypothesis.This study comprised six patients with CADASIL who harbored mutations in the coding sequence of NOTCH3 and twelve age-matched neurologically healthy controls.We collected clinical and imaging data from patients with CADASIL and divided the brain into four regions:WMH,normal-appearing white matter(NAWM),gray matter(GM),and global brain.We analyzed the relationship between CBF of each region and the WMH volume.Compared with the control group,CBF was significantly decreased in all four regions in the CADASIL group.Lower CBF in these regions was correlated with higher WMH volume in CADASIL.CBF in the NAWM,GM and global regions was positively correlated with that in WMH region.However,after correction tests,only CBF in the WMH region but not in NAWM,GM and global regions was associated with WMH volume.Our findings suggest that CBF in the WMH region is an influencing factor of the WMH severity in CADASIL.

Using multimodal MRI to investigate alterations in brain structure and function in the BBZDR/Wor rat model of type 2 diabetes

Background:This is an exploratory study using multimodal magnetic resonance imaging(MRI)to interrogate the brain of rats with type 2 diabetes(T2DM)as compared to controls.It was hypothesized there would be changes in brain structure and function that reflected the human disorder,thus providing a model system by which to follow disease progression with noninvasive MRI.Methods:The transgenic BBZDR/Wor rat,an animal model of T2MD,and agematched controls were studied for changes in brain structure using voxel-based morphometry,alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy,and functional coupling using restingstate BOLD functional connectivity.Images from each modality were registered to,and analyzed,using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas.Results:There was an overall reduction in brain volume focused primarily on the somatosensory cortex,cerebellum,and white matter tracts.The putative changes in white and gray matter microarchitecture were pervasive affecting much of the brain and not localized to any region.There was a general increase in connectivity in T2DM rats as compared to controls.The cerebellum presented with strong functional coupling to pons and brainstem in T2DM rats but negative connectivity to hippocampus.Conclusion:The neuroradiological measures collected in BBBKZ/Wor rats using multimodal imaging methods did not reflect those reported for T2DB patients in the clinic.The data would suggest the BBBKZ/Wor rat is not an appropriate imaging model for T2DM.