The impact of antidepressants on human neurodevelopment: Brain organoids as experimental tools.

The use of antidepressants during pregnancy benefits the mother's well-being, but the effects of such substances on neurodevelopment remain poorly understood. Moreover, the consequences of early exposure to antidepressants may not be immediately apparent at birth. In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been related to developmental abnormalities, including a reduced white matter volume. Several reports have observed an increased incidence of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) after prenatal exposure to SSRIs such as sertraline, the most widely prescribed SSRI. The advent of human-induced pluripotent stem cell (hiPSC) methods and assays now offers appropriate tools to test the consequences of such compounds for neurodevelopment in vitro. In particular, hiPSCs can be used to generate cerebral organoids - self-organized structures that recapitulate the morphology and complex physiology of the developing human brain, overcoming the limitations found in 2D cell culture and experimental animal models for testing drug efficacy and side effects. For example, single-cell RNA sequencing (scRNA-seq) and electrophysiological measurements on organoids can be used to evaluate the impact of antidepressants on the transcriptome and neuronal activity signatures in developing neurons. While the analysis of large-scale transcriptomic data depends on dimensionality reduction methods, electrophysiological recordings rely on temporal data series to discriminate statistical characteristics of neuronal activity, allowing for the rigorous analysis of the effects of antidepressants and other molecules that affect the developing nervous system, especially when applied in combination with relevant human cellular models such as brain organoids.

Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association.

Lacunar infarcts and vascular dementia are important phenotypic characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the most common inherited cerebral small vessel disease. Individuals with the disease show variability in the nature and onset of symptoms and rates of progression, which are only partially explained by differences in pathogenic mutations in the NOTCH3 gene. Recognizing the disease early in its course and securing a molecular diagnosis are important clinical goals, despite the lack of proven disease-modifying treatments. The purposes of this scientific statement are to review the clinical, genetic, and imaging aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, contrasting it with other inherited small vessel diseases, and to provide key prevention, management, and therapeutic considerations with the intent of reducing practice variability and encouraging production of high-quality evidence to support future treatment recommendations.

Age-related white matter hyperintensities and overactive bladder: A systematic review.

INTRODUCTION: Age-related white matter hyperintensities (ARWMHs) on brain magnetic resonance imaging have been associated with lower urinary tract symptoms/dysfunction (LUTS/LUTD), namely overactive bladder (OAB) and detrusor overactivity. We aimed to systematically review existing data on the association between ARWMH and LUTS and which clinical tools have been used for this assessment. MATERIALS AND METHODS: We searched PubMed/MEDLINE, Cochrane Library, and clinicaltrials.gov (from 1980 to November 2021) and considered original studies reporting data on ARWMH and LUTS/LUTD in patients of both sexes aged 50 or above. The primary outcome was OAB. We calculated the unadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the outcomes of interest using random-effects models. RESULTS: Fourteen studies were included. LUTS assessment was heterogeneous and mainly based on the use of nonvalidated questionnaires. Urodynamics assessment was reported in five studies. ARWMHs were graded using visual scales in eight studies. Patients with moderate-to-severe ARWMHs were more likely to present with OAB and urgency urinary incontinence (UUI; OR = 1.61; 95% CI: 1.05-2.49, p = 0.03), I2 = 21.3%) when compared to patients with similar age and absent or mild ARWMH. DISCUSSION AND CONCLUSIONS: High-quality data on the association between ARWMH and OAB is scarce. Patients with moderate to severe ARWMH showed higher levels of OAB symptoms, including UUI, when compared to patients with absent or mild ARWMH. The use of standardized tools to assess both ARWMH and OAB in these patients should be encouraged in future research.

Association of white matter lesions and brain atrophy with the development of dementia in a community: the Hisayama Study.

AIM: To investigate the association of white matter lesions volume (WMLV) levels with dementia risk and the association between dementia risk and the combined measures of WMLV and either total brain atrophy or dementia-related gray matter atrophy in a general older population. METHODS: One thousand one hundred fifty-eight Japanese dementia-free community-residents aged ≥65 years who underwent brain magnetic resonance imaging were followed for 5.0 years. WMLV were segmented using the Lesion Segmentation Toolbox. Total brain volume (TBV) and regional gray matter volume were estimated by voxel-based morphometry. The WMLV-to-intracranial brain volume ratio (WMLV/ICV) was calculated, and its association with dementia risk was estimated using Cox proportional hazard models. Total brain atrophy, defined as the TBV-to-ICV ratio (TBV/ICV), and dementia-related regional brain atrophy defined based on our previous report were calculated. The association between dementia risk and the combined measures of WMLV/ICV and either total brain atrophy or the number of atrophied regions was also tested. RESULTS: During the follow-up, 113 participants developed dementia. The risks of dementia increased significantly with higher WMLV/ICV levels. In addition, dementia risk increased additively both in participants with higher WMLV/ICV levels and lower TBV/ICV levels and in those with higher WMLV/ICV levels and a higher number of dementia-related brain regional atrophy. CONCLUSION: The risk of dementia increased significantly with higher WMLV/ICV levels. An additive increment in dementia risk was observed with higher WMLV/ICV levels and lower TBV/ICV levels or a higher number of dementia-related brain regional atrophy, suggesting the importance of prevention or control of cardiovascular risk factors.

Elevated Aortic Pulse Wave Velocity Relates to Longitudinal Gray and White Matter Changes.

OBJECTIVE: To determine whether baseline aortic stiffness, measured by aortic pulse wave velocity (PWV), relates to longitudinal cerebral gray or white matter changes among older adults. Baseline cardiac magnetic resonance imaging will be used to assess aortic PWV while brain magnetic resonance imaging will be used to assess gray matter and white matter hyperintensity (WMH) volumes at baseline, 18 months, 3 years, 5 years, and 7 years. Approach and Results: Aortic PWV (m/s) was quantified from cardiac magnetic resonance. Multimodal 3T brain magnetic resonance imaging included T1-weighted imaging for quantifying gray matter volumes and T2-weighted fluid-attenuated inversion recovery imaging for quantifying WMHs. Mixed-effects regression models related baseline aortic PWV to longitudinal gray matter volumes (total, frontal, parietal, temporal, occipital, hippocampal, and inferior lateral ventricle) and WMH volumes (total, frontal, parietal, temporal, and occipital) adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham stroke risk profile, APOE (apolipoprotein E)-ε4 carrier status, and intracranial volume. Two hundred seventy-eight participants (73±7 years, 58% male, 87% self-identified as non-Hispanic White, 159 with normal cognition, and 119 with mild cognitive impairment) from the Vanderbilt Memory & Aging Project (n=335) were followed on average for 4.9±1.6 years with PWV measurements occurring from September 2012 to November 2014 and longitudinal brain magnetic resonance imaging measurements occurring from September 2012 to June 2021. Higher baseline aortic PWV was related to greater decrease in hippocampal (ß=-3.6 [mm3/y]/[m/s]; [95% CI, -7.2 to -0.02] P=0.049) and occipital lobe (ß=-34.2 [mm3/y]/[m/s]; [95% CI, -67.8 to -0.55] P=0.046) gray matter volume over time. Higher baseline aortic PWV was related to greater increase in WMH volume over time in the temporal lobe (ß=17.0 [mm3/y]/[m/s]; [95% CI, 7.2-26.9] P<0.001). All associations may be driven by outliers. CONCLUSIONS: In older adults, higher baseline aortic PWV related to greater decrease in gray matter volume and greater increase in WMHs over time. Because of unmet cerebral metabolic demands and microvascular remodeling, arterial stiffening may preferentially affect certain highly active brain regions like the temporal lobes. These same regions are affected early in the course of Alzheimer disease.

Moderate-Severe White Matter Lesion Predicts Delayed Intraventricular Hemorrhage in Intracerebral Hemorrhage.

BACKGROUND: Most existing studies have focused on the correlation between white matter lesion (WML) and baseline intraventricular hemorrhage (IVH) in patients with intracerebral hemorrhage (ICH), whereas few studies have investigated the relationship between WML severity and delayed IVH after admission. This study aimed to investigate the correlation between WML severity and delayed IVH and to verify the association between WML and baseline IVH. METHODS: A total of 480 patients with spontaneous ICH from February 2018 to October 2020 were selected. WML was scored using the Van Swieten Scale, with scores of 0-2 representing nonslight WML and scores of 3-4 representing moderate-severe WML. We determined the presence of IVH on baseline (< 6 h) and follow-up computed tomography (< 72 h) images. Univariate analysis and multiple logistic regression were used to analyze the influencing factors of baseline and delayed IVH. RESULTS: Among 480 patients with ICH, 172 (35.8%) had baseline IVH, and there was a higher proportion of moderate-severe WML in patients with baseline IVH (20.3%) than in those without baseline IVH (12.7%) (P = 0.025). Among 308 patients without baseline IVH, delayed IVH was found in 40 patients (12.9%), whose proportion of moderate-severe WML (25.0%) was higher than that in patients without delayed IVH (10.8%) (P = 0.012). Multiple logistic regression results showed that moderate-severe WML was independently correlated with baseline IVH (P = 0.006, odds ratio = 2.266, 95% confidence interval = 1.270-4.042) and delayed IVH (P = 0.002, odds ratio = 7.009, 95% confidence interval = 12.086-23.552). CONCLUSIONS: Moderate-severe WML was an independent risk factor for delayed IVH as well as baseline IVH.

Genetic disorders with central nervous system white matter abnormalities: An update.

Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.

Hypomyelinating leukodystrophies in adults: Clinical and genetic features.

BACKGROUND AND PURPOSE: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood. METHODS: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel. RESULTS: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination. CONCLUSIONS: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.

Adult Hereditary White Matter Diseases With Psychiatric Presentation: Clinical Pointers and MRI Algorithm to Guide the Diagnostic Process.

OBJECTIVE: The investigators aimed to provide clinical and MRI guidelines for determining when genetic workup should be considered in order to exclude hereditary leukoencephalopathies in affected patients with a psychiatric presentation. METHODS: A systematic literature review was conducted, and clinical cases are provided. Given the central role of MRI pattern recognition in the diagnosis of white matter disorders, the investigators adapted an MRI algorithm that guides the interpretation of MRI findings and thus directs further investigations, such as genetic testing. RESULTS: Twelve genetic leukoencephalopathies that can present with psychiatric symptoms were identified. As examples of presentations that can occur in clinical practice, five clinical vignettes from patients assessed at a referral center for adult genetic leukoencephalopathies are provided. CONCLUSIONS: Features such as drug-resistant symptoms, presence of long-standing somatic features, trigger events, consanguinity, and positive family history should orient the clinician toward diagnostic workup to exclude the presence of a genetic white matter disorder. The identification of MRI white matter abnormalities, especially when presenting a specific pattern of involvement, should prompt genetic testing for known forms of genetic leukoencephalopathies.

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years.

INTRODUCTION AND OBJECTIVES: Leukodystrophies and genetic leukoencephalopathies constitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques. MATERIALS AND METHODS: A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones. RESULTS: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease. CONCLUSIONS: Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase.

Relationship of White Matter Lesions with Intracerebral Hemorrhage Expansion and Functional Outcome: MISTIE II and CLEAR III.

BACKGROUND/OBJECTIVE: Intracerebral hemorrhage (ICH) patients commonly have concomitant white matter lesions (WML) which may be associated with poor outcome. We studied if WML affects hematoma expansion (HE) and post-stroke functional outcome in a post hoc analysis of patients from randomized controlled trials. METHODS: In ICH patients from the clinical trials MISTIE II and CLEAR III, WML grade on diagnostic computed tomography (dCT) scan (dCT, < 24 h after ictus) was assessed using the van Swieten scale (vSS, range 0-4). The primary outcome for HE was > 33% or > 6 mL ICH volume increase from dCT to the last pre-randomization CT (< 72 h of dCT). Secondary HE outcomes were: absolute ICH expansion, > 10.4 mL total clot volume increase, and a subgroup analysis including patients with dCT < 6 h after ictus using the primary HE definition of > 33% or > 6 mL ICH volume increase. Poor functional outcome was assessed at 180 days and defined as modified Rankin Scale (mRS) ≥ 4, with ordinal mRS as a secondary endpoint. RESULTS: Of 635 patients, 55% had WML grade 1-4 at dCT (median 2.2 h from ictus) and 13% had subsequent HE. WML at dCT did not increase the odds for primary or secondary HE endpoints (P ≥ 0.05) after adjustment for ICH volume, intraventricular hemorrhage volume, warfarin/INR > 1.5, ictus to dCT time in hours, age, diabetes mellitus, and thalamic ICH location. WML increased the odds for having poor functional outcome (mRS ≥ 4) in univariate analyses (vSS 4; OR 4.16; 95% CI 2.54-6.83; P < 0.001) which persisted in multivariable analyses after adjustment for HE and other outcome risk factors. CONCLUSIONS: Concomitant WML does not increase the odds for HE in patients with ICH but increases the odds for poor functional outcome. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov trial-identifiers: NCT00224770 and NCT00784134.

Leukodystrophies and genetic leukoencephalopathies in children.

Leukodystrophies and genetic leukoencephalopathies are a large group of genetic disorders affecting central nervous system white matter. They can begin at any age, however this study focuses on disorders beginning in childhood and adolescence. We discuss the recent definitions, classifications, and classic syndromes, as well as genetic progress in the field through the identification of new genes and several new genetic syndromes.

[Study on the white matter neuronal integrity in amnestic mild cognitive impairment based on automating fiber-tract quantification].

Objective: To analyze the pattern of the change in cerebral white matter tract in amnestic mild cognitive impairment (aMCI) patients based on the automating fiber-tract quantification (AFQ). Methods: A total of 20 aMCI patients,9 males,11 females, the mean age was (67±9) years, and 22 patients with naMCI, 8 males,14 females, the mean age was (64±10) years, and 23 normal control subjects, 10 males, 13 females, with a mean age of (65±9) years were enrolled from the Affiliated Drum Tower Hospital of Nanjing University Medical School from January 2018 to March 2019. All of them underwent 3.0 T MRI scan, which include DTI and 3D T(1)WI sequence.Two tract profiles, fractional anisotropy (FA) and mean diffusivity (MD), were extracted to evaluate the white matter integrity at 100 locations along each of 20 fiber tracts based on the AFQ. Results: In a pointwise comparison of FA profiles,the aMCI patients showed FA reduction in the middle part of right corticospinal tract (t=-4.023, P<0.01, FWE corrected) relative to the naMCI patients. There was a positive correlation between the decreased FA value and the auditory verbal learning test score (P=0.039). In a pointwise comparison of MD profiles, the aMCI patients showed extensive MD elevation in the middle part of the left cingulum hippocampus (t=2.408,P=0.037,FWE corrected) relative to the naMCI patients. The aMCI patients showed MD elevation in the posterior part of the left inferior longitudinal fasciculus (t=-2.919, P=0.006, FWE corrected) and the middle part of the left cingulum hippocampus (t=-3.878, P=0.002, FWE corrected) relative to the NC subjects. And the elevated MD in left inferior longitudinal fasciculus showed negative correlation with MoCA (P=0.039) and auditory verbal learning test score (P=0.015). There was also a negative correlation between the elevated MD value in the left cingulum hippocampus and the auditory verbal learning test score (P=0.033). Conclusions: Disruption is found in specific part along the white matter tract in the aMCI group. Furthermore, the pattern of white matter abnormalities is different across neuronal fiber tracts. These findings will have an impact on the further specific study of the white matter tract in aMCI patients.

Cervical Spinal Involvement in a Chinese Pedigree With Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy Caused by a 3' Untranslated Region Mutation of COL4A1 Gene.

Background and Purpose- Pontine autosomal dominant microangiopathy and leukoencephalopathy, a recently defined subtype of cerebral small vessel disease, is associated with mutations in COL4A1 (collagen type IV alpha 1 chain) 3' untranslated region. We here describe a pontine autosomal dominant microangiopathy and leukoencephalopathy pedigree with COL4A1 mutation presenting both pontine and cervical spinal cord involvement. Methods- For the diagnostic purpose, brain and spinal magnetic resonance imaging scanning, skin biopsy, and whole-exome sequencing were performed on the patients in the pedigree. Suspected pathogenic variants were further confirmed by cosegregation analysis using Sanger sequencing in the family members. Results- We identified a mutation located at the binding site of miR-29 (microRNA-29) in 3' untranslated region of COL4A1(c.*32G>A). The pontine autosomal dominant microangiopathy and leukoencephalopathy patients in this pedigree carried this variant, whereas other healthy family members but one did not. Magnetic resonance imaging showed lesions in the pons, white matter, and cervical spinal cord. Skin biopsy revealed thickened basal lamina in vessels. Conclusions- For the first time, we reported cervical spinal involvement in pontine autosomal dominant microangiopathy and leukoencephalopathy and expanded the clinical spectrum of this disease.

Telemedicine for Follow-Up of Rare Neurological Disease.

Background and Purpose- Providing ongoing care for rare neurological conditions is challenging. Telemedicine can reduce patient travel. We set up and evaluated a telemedicine service for patients with a genetic form of stroke and dementia cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Methods- One hundred fourteen patients with mutation-positive cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (64 telemedicine and 50 face-to-face) were recruited. Patient and clinician satisfaction questionnaires rated the service to create a mean satisfaction score for both face-to-face and telemedicine follow-up appointments. Results- There was no difference in mean (SD) patient or clinician satisfaction scores between telemedicine and face-to-face appointments (patient: 4.57 [0.56] and 4.69 [0.42]; P=0.99; clinician: 4.55 [0.49] and 4.60 [0.43]; P=0.44). Conclusions- Telemedicine follow-up was suited to patients with stroke and dementia and offered satisfaction levels similar to that for face-to-face consultations.

Association of Atrial Fibrillation With White Matter Disease.

Background and Purpose- Evidence suggests that atrial fibrillation (AF) is associated with increased risk of cognitive decline and dementia, even in the absence of stroke. White matter disease (WMD) is a potential mechanism linking AF to cognitive impairment. In this study, we explored the association between prevalent AF and WMD. Methods- We performed a cross-sectional analysis of participants attending the ARIC-NCS (Atherosclerosis Risk in Communities-Neurocognitive Study) in 2011 to 2013 who underwent brain magnetic resonance imaging. AF was ascertained from study visit electrocardiograms or prior hospitalization codes. Extent of WMD was defined by measures of white matter (WM) microstructural integrity and WM hyperintensity volume. Multivariable linear regression models were used to assess the association between AF and WMD. Results- Among 1899 participants (mean age, 76 years; 28% black; 60% women), 133 (7%) had prevalent AF. After multivariable adjustment, differences between participants with and without AF were -0.001 (95% CI, -0.006 to 0.004) for global WM fractional anisotropy, 0.031×10-4 mm2/s (95% CI, -0.075 to 0.137) for global WM mean diffusivity, and 0.08 mm3 (95% CI, -0.14 to 0.30) for WM hyperintensity volume. Conclusions- The results suggest that there is no association between prevalent AF and WMD.

CLCN2-related leukoencephalopathy: a case report and review of the literature.

BACKGROUND: Loss-of-function mutations in the CLCN2 gene were recently discovered to be a cause of a type of leukodystrophy named CLCN2-related leukoencephalopathy (CC2L), which is characterized by intramyelinic edema. Herein, we report a novel mutation in CLCN2 in an individual with leukodystrophy. CASE PRESENTATION: A 38-year-old woman presented with mild hand tremor, scanning speech, nystagmus, cerebellar ataxia in the upper limbs, memory decline, tinnitus, and dizziness. An ophthalmologic examination indicated macular atrophy, pigment epithelium atrophy and choroidal capillary atrophy. Brain magnetic resonance imaging (MRI) showed the diffuse white matter involvement of specific white matter tracts. Decreased diffusion anisotropy was detected in various brain regions of the patient. Diffusion tensor tractography (DTT) showed obviously thinner tracts of interest than in the controls, with a decreased fiber number (FN), increased radial diffusivity (RD) and unchanged axial diffusivity (AD). A novel homozygous c.2257C > T (p.Arg753Ter) mutation in exon 20 of the CLCN2 gene was identified. CONCLUSION: CC2L is a rare condition characterized by diffuse edema involving specific fiber tracts that pass through the brainstem. The distinct MRI patterns could be a strong indication for CLCN2 gene analysis. The findings of our study may facilitate the understanding of the pathophysiology and clinical symptoms of this disease.

[Value of intravoxel incoherent motion diffusion weighted imaging in evaluating the microstructure changes in white matter hyperintensities].

Objective: To investigate the value of intravoxel incoherent motion diffusion weighted imaging (IVIM DWI) in evaluating microstructure changes in elderly white matter hyperintensities (WMH) patients and to analyze the correlation between IVIM parameters and severity grading and cognitive scores. Methods: Sixty-two WMH patients in Zhejiang Hospital were collected from December 2014 to March 2018 and underwent conventional magnetic resonance (MR) plain scan and diffusion weighted imaging with different b values. The age was 60-92(74±10) years with 37 males, 25 females. The severity of WMH was assessed by T(2) fluid attenuated inversion recovery (FLAIR) sequence and Fazekas score,which were divided into two subgroups. Slow diffusion coefficient (D), fast diffusion coefficient (D(*)) and perfusion fraction (f) from IVIM parameters of double exponential model were compared between regions of WMH (deep WMH (DWMH) and periventricular WMH (PWMH)) and surrounding normal white matter (NWM).The Shapiro-Wilk test was used for normality tests, Kruskal-Wallis tests and Dwass-Steel-Critchlow-Fligner (DSCF) procedure were used for the comparison among these parameters. Furthermore, Wilcoxon two-sample test was used for the comparisons between different severity. Pearson correlation analysis was performed to determine whether these D, D(*), f values were correlated with the mini mental state examination (MMSE) scores. Results: D(D)WMH (0.83(0.72,0.99)×10(-3) mm(2)/s), D(PWMH)((1.13±0.25)×10(-3) mm(2)/s) were significantly higher than D(NWM) ((0.71±0.05)×10(-3) mm(2)/s)(P<0.01). f (DWMH) ((8.94%(7.46%,11.67%)), f (PWMH)(8.34%(6.73%,9.96%)) were significantly higher than f (NWM)(6.71%±1.72%)(P<0.01).D in DWMH were significantly lower than that in PWMH(P<0.01), there's no statistically difference between other groups. D in severe WMH (both DWMH and PWMH) were significantly higher than that in mild WMH (P=0.000 1, P=0.04). Only f in PWMH were positively associated with the MMSE scores (r=0.326 5,P<0.05). Conclusions: IVIM DWI can noninvasively assess the variation of microstructure diffusion and perfusion in WMH in one sequence,which may objectively reflect the severity of these lesions. This method has important clinical significance for better assessment and management of this disease.