Posterior Periventricular White Matter Research Articles

Expanding the neuroimaging findings of guanidinoacetate methyltransferase deficiency in an Iranian girl with a homozygous frameshift variant in the GAMT.

Guanidinoacetate methyltransferase deficiency (GAMTD) is a treatable neurodevelopmental disorder with normal or nonspecific imaging findings. Here, we reported a 14-month-old girl with GAMTD and novel findings on brain magnetic resonance imaging (MRI).A 14-‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍month-old female patient was referred to Myelin Disorders Clinic due to onset of seizures and developmental regression following routine vaccination at 4months of age. Brain MRI, prior to initiation of treatment, showed high signal intensity in T2-weighted imaging in bilateral thalami, globus pallidus, subthalamic nuclei, substantia nigra, dentate nuclei, central tegmental tracts in the brainstem, and posterior periventricular white matter which was masquerading for mitochondrial leukodystrophy. Basic metabolic tests were normal except for low urine creatinine; however, exome sequencing identified a homozygous frameshift deletion variant [NM_000156: c.491del; (p.Gly164AlafsTer14)] in the GAMT. Biallelic pathogenic or likely pathogenic variants cause GAMTD. We confirmed the homozygous state for this variant in the proband, as well as the heterozygote state in the parents by Sanger sequencing.MRI features in GAMTD can mimic mitochondrial leukodystrophy. Pediatric neurologists should be aware of variable MRI findings in GAMTD since they would be misleading to other diagnoses.

Varicella-Zoster Virus Meningoencephalitis in a Lung Transplant Recipient

Introduction Solid organ transplant (SOT) recipients are susceptible to an array of infections and atypical clinical presentations. Varicella-zoster virus (VZV) becomes latent in dorsal root ganglia after the initial infection, and reinfection commonly presents with a painful rash. In SOT recipients, VZV can present as meningoencephalitis without an associated rash and is associated with high morbidity and mortality. We present a rare case of VZV meningoencephalitis in a lung transplant recipient. Case Report A 71-year-old woman with a history of bilateral lung transplant in 2014 and rheumatoid arthritis presented to an outside hospital with one week of fever and confusion. She was subsequently intubated after suffering a generalized tonic-clonic seizure. Upon transfer to our facility she had an unremarkable exam including skin exam. She was started on vancomycin, ceftriaxone, ampicillin, acyclovir, and fluconazole for presumed meningoencephalitis. Lumbar puncture revealed 100 WBC/mm3, with 93% lymphocytes. The cerebrospinal fluid (CSF) glucose was 125 mg/dL, protein was 233 mg/dL, cultures were negative but qualitative polymerase chain reaction (PCR) was positive for VZV. Electroencephalogram (EEG) revealed status epilepticus and magnetic resonance imaging (MRI) showed a T1 and T2 hypointensity in the right posterior periventricular white matter and scattered foci in bilateral cerebral white matter. Her status epilepticus was treated with antiepileptics and resolved by hospital day eight. She received 14 days of intravenous (IV) acyclovir 10mg/kg every 8 hours and was transitioned to oral valacyclovir for suppression for two months. On discharge her mental status had significantly improved but had not fully returned to her baseline. Summary Zoster is a common, benign disease caused by VZV and associated with painful cutaneous lesions. However, neurological manifestations without a rash are possible in SOT patients. Lumbar puncture and CSF analysis are crucial for diagnosis and typically shows lymphocytosis with viral culture, antibody, or PCR positive for VZV. Treatment of choice for VZV encephalitis is IV acyclovir for 7 days in the immunocompetent patient and 14 days in the immunosuppressed patient. This case demonstrates how prompt recognition and treatment of VZV meningoencephalitis can decrease mortality and neurologic disease in the immunocompromised patient. Solid organ transplant (SOT) recipients are susceptible to an array of infections and atypical clinical presentations. Varicella-zoster virus (VZV) becomes latent in dorsal root ganglia after the initial infection, and reinfection commonly presents with a painful rash. In SOT recipients, VZV can present as meningoencephalitis without an associated rash and is associated with high morbidity and mortality. We present a rare case of VZV meningoencephalitis in a lung transplant recipient. A 71-year-old woman with a history of bilateral lung transplant in 2014 and rheumatoid arthritis presented to an outside hospital with one week of fever and confusion. She was subsequently intubated after suffering a generalized tonic-clonic seizure. Upon transfer to our facility she had an unremarkable exam including skin exam. She was started on vancomycin, ceftriaxone, ampicillin, acyclovir, and fluconazole for presumed meningoencephalitis. Lumbar puncture revealed 100 WBC/mm3, with 93% lymphocytes. The cerebrospinal fluid (CSF) glucose was 125 mg/dL, protein was 233 mg/dL, cultures were negative but qualitative polymerase chain reaction (PCR) was positive for VZV. Electroencephalogram (EEG) revealed status epilepticus and magnetic resonance imaging (MRI) showed a T1 and T2 hypointensity in the right posterior periventricular white matter and scattered foci in bilateral cerebral white matter. Her status epilepticus was treated with antiepileptics and resolved by hospital day eight. She received 14 days of intravenous (IV) acyclovir 10mg/kg every 8 hours and was transitioned to oral valacyclovir for suppression for two months. On discharge her mental status had significantly improved but had not fully returned to her baseline. Zoster is a common, benign disease caused by VZV and associated with painful cutaneous lesions. However, neurological manifestations without a rash are possible in SOT patients. Lumbar puncture and CSF analysis are crucial for diagnosis and typically shows lymphocytosis with viral culture, antibody, or PCR positive for VZV. Treatment of choice for VZV encephalitis is IV acyclovir for 7 days in the immunocompetent patient and 14 days in the immunosuppressed patient. This case demonstrates how prompt recognition and treatment of VZV meningoencephalitis can decrease mortality and neurologic disease in the immunocompromised patient.

Predictors and integrative index of severity of cognitive disorders in cerebral microangiopathy

To search for sensitive predictors of cognitive impairment (CI) and an integrative index of their severity. We assessed CI and diffusion-tensor MRI (DT-MRI) in the regions of interest (ROI) significant for CI in 74 patients (48 women, mean age 60.6±6.9 years) with cerebral small vessel disease (CSVD). The results of DT-MRI were used to construct a predictive model of CI using binary logistic regression and to calculate an integrative index of CI severity. According to the constructed model, the predictors of CI were axial diffusivity (AD) of posterior frontal periventricular normal-appearing white matter (pvNAWM), right middle cingulum bundle (CB) and mid-posterior corpus callosum (CC). ROC analysis showed strong model predictive power for CI in cSVD (AUC (95% CI): 0.845 (0.740-0.950)). The threshold value of the AD predictors model for CI in cSVD was 0.53 (sensitivity 84%, specificity 76%). AD predictors of CI showed significant correlations with white matter hyperintensities volume and MoCA scores. The presence of CI as measured by neuropsychological testing and regression equation solution was corresponded to individual AD predictors of patients exceeding the CI model's threshold. Disturbances in the AD of pvNAWM, right middle CB and mid-posterior CC associated with axonal damage are a predominant factor in the development of CI in CSVD. The predictors of CI and the integrative index of CI severity calculated on their basis can potentially be used as a tool for assessing the severity of CI and the effectiveness of treatment, as well as in clarifying the interaction between vascular and degenerative pathology and in developing measures for the prevention of CI in patients with MRI signs of cSVD.

Microstructural Predictors of Cognitive Impairment in Cerebral Small Vessel Disease and the Conditions of Their Formation.

Introduction: Cerebral small vessel disease (CSVD) is the leading cause of vascular and mixed degenerative cognitive impairment (CI). The variability in the rate of progression of CSVD justifies the search for sensitive predictors of CI. Materials: A total of 74 patients (48 women, average age 60.6 ± 6.9 years) with CSVD and CI of varying severity were examined using 3T MRI. The results of diffusion tensor imaging with a region of interest (ROI) analysis were used to construct a predictive model of CI using binary logistic regression, while phase-contrast magnetic resonance imaging and voxel-based morphometry were used to clarify the conditions for the formation of CI predictors. Results: According to the constructed model, the predictors of CI are axial diffusivity (AD) of the posterior frontal periventricular normal-appearing white matter (pvNAWM), right middle cingulum bundle (CB), and mid-posterior corpus callosum (CC). These predictors showed a significant correlation with the volume of white matter hyperintensity; arterial and venous blood flow, pulsatility index, and aqueduct cerebrospinal fluid (CSF) flow; and surface area of the aqueduct, volume of the lateral ventricles and CSF, and gray matter volume. Conclusion: Disturbances in the AD of pvNAWM, CB, and CC, associated with axonal damage, are a predominant factor in the development of CI in CSVD. The relationship between AD predictors and both blood flow and CSF flow indicates a disturbance in their relationship, while their location near the floor of the lateral ventricle and their link with indicators of internal atrophy, CSF volume, and aqueduct CSF flow suggest the importance of transependymal CSF transudation when these regions are damaged.

Post-traumatic stress disorder in convalescent patients of severe acute respiratory syndrome: (1)H-MRS study

To ascertain the metabolic changes in patients of severe acute respiratory syndrome (SARS) and SARS-related post-traumatic stress disorder (PTSD) and elucidate the relationship between PTSD, SARS and brain metabolism. A total of 58 convalescent SARS patients were evaluated by the scores of impact of event scale (IES), self-rating anxiety scale (SAS) and self-rating depression scale (SDS), etc. And 44 of them participated in (1)H-MRS study. There were 18 patients (M:F = 6:12) with SARS-related PTSD and 26 convalescent SARS patients without PTSD. And the procedures were repeated in 18 age, gender and education-matched normal control subjects. In all patients and controls, the regions of interest on magnetic resonance spectroscopy (MRS) were anterior cingulate gyrus (ACG), posterior cingulate gyrus (PCG), left anterior periventricular white matter (LAPWM) and left posterior periventricular white matter (LPPWM). And the correlations between MRS findings and the scores of SAS, SDS and IES were evaluated. In comparisons with the control subjects (n = 18) and convalescent SARS patients without PTSD (n = 26), the SARS-related PTSD group (n = 18) had significantly lower N-acetylaspartate/creatine (NAA/Cr) in 4 regions of interest while the NAA/Cr of the convalescent SARS patients was significantly lower than controls in 3 regions of interest (ACG, PCG and LAPWM). The ratios of NAA/Cr showed no close correlation with the scores of IES, SAS and SDS in convalescent SARS patients. The changes of brain metabolism in PTSD are caused by SARS. But their exact relationship awaits further explorations. SARS may also lead to the changes of brain metabolism.

Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta.

Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

Brain MRI features and scoring of leukodystrophy in adult-onset Krabbe disease.

To perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease. We retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center. The corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1). We specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.

Revisiting magnetic resonance imaging pattern of Krabbe disease - Lessons from an Indian cohort.

Context:Krabbe disease shows considerable heterogeneity in clinical features and disease progression. Imaging phenotypes are equally heterogeneous but show distinct age-based patterns. It is important for radiologists to be familiar with the imaging spectrum to substantially contribute toward early diagnosis, prognostication, and therapeutic decisions.Aims:The study aims to describe different magnetic resonance imaging (MRI) patterns observed in a cohort of children with Krabbe disease and to assess correlation with age-based clinical phenotypes.Materials and Methods:This is a retrospective descriptive study done at the Departments of Radiodiagnosis and Neurological Sciences of our institution, a tertiary care hospital in Southern India. Imaging features of children diagnosed with Krabbe disease over a 10-year period (2009–2018) were collected and analyzed.Results:A total of 38 MRI brain studies from 27 patients were analyzed. Four distinct MRI patterns were recognizable among the different clinical subtypes. All patients from the early and late infantile group showed deep cerebral and cerebellar white matter and dentate hilum involvement. Optic nerve thickening was, however, more common in the former group. Adult-onset subtype showed isolated involvement of corticospinal tract, posterior periventricular white matter, and callosal splenium with the absence of other supra- and infra-tentorial findings. Juvenile subgroup showed heterogeneous mixed pattern with 78% showing adult subtype pattern and 22% showing patchy involvement of deep cerebral white matter with dentate hilum signal changes.Conclusion:Krabbe disease shows distinct imaging features which correspond to different clinical age-based subtypes. This article reemphasizes these distinct imaging phenotypes, highlights a novel imaging appearance in juvenile Krabbe, and also alludes to the rare variant of saposin deficiency. Awareness of these patterns is essential in suggesting the appropriate diagnosis and guiding conclusive diagnostic workup. Large multicenter longitudinal studies are needed to further define the role of imaging in predicting the clinical course and thus to guide therapeutic options.

Reduced cerebrovascular reactivity among adolescents with bipolar disorder

Cardiovascular disease (CVD) is excessive and premature among individuals with bipolar disorder (BD). Cerebrovascular reactivity (CVR), reflecting vasodilatory capacity of cerebral blood vessels in response to vasoactive substances, is a marker of cerebrovascular health. Despite informative findings in other diseases, CVR has not previously been examined in BD. Twenty-five adolescents with BD and 25 age and sex-matched psychiatrically healthy controls (HCs) completed six 15-second breath-holds (BHs) during functional magnetic resonance imaging (fMRI) at 3-Tesla. CVR was determined by comparing blood-oxygenation-level dependent (BOLD) signal changes. Voxel-wise contrasts were analyzed. Body mass index (BMI) was examined as a potential confound. CVR in the posterior cingulate gyrus and periventricular white matter was lower in BD vs HC. After controlling for differences in BMI, additional between-group CVR differences were observed in the temporal poles, supramarginal gyrus, and lingual gyrus. There were no regions in which CVR was significantly greater in BD vs HC. CVR was not associated with mood symptoms. This preliminary study provides evidence of cerebrovascular dysfunction in BD, including regions known to be susceptible to cerebrovascular dysfunction and/or disease. These findings warrant additional research on the causes and consequences of cerebrovascular dysfunction in early-onset BD.

Neuroanatomical correlates of sensory deficits in children with neonatal arterial ischemic stroke.

Our aim was to characterize the sensory processing outcome following neonatal arterial ischemic stroke (NAIS) and identify neuroanatomical correlates of abnormal sensory processing. We evaluated children with NAIS longitudinally at 12 months, 18 months, and/or 30 months in areas of cognitive, motor, and language development. We gathered sensory processing data using the Sensory Profile-2 Caregiver Questionnaire. These data were analyzed against early magnetic resonance imaging using a voxel-based approach. Eighteen children (10 males, 8 females) with NAIS were evaluated longitudinally, of which six exhibited atypical sensory processing. Children with sensory processing deficits had lower overall developmental scores in motor, cognitive, and language domains. Neuroanatomical correlates were identified in the posterior periventricular white matter extending superiorly into the supramarginal gyrus, and inferiorly into the fusiform and inferior temporal gyri. Our results provide new evidence that children with NAIS may experience difficulty processing sensory information, which is most likely associated with injuries in the posterior periventricular white matter, supramarginal gyrus, fusiform gyrus, and posterior thalamic radiation. Atypical sensory processing is common in children with neonatal arterial ischemic stroke (NAIS). NAIS territories in sensory areas were correlated with atypical sensory processing behaviors. Children with NAIS may benefit from early interventions targeted toward sensory processing. Future research mapping NAIS injuries using early magnetic resonance imaging may predict long-term outcomes.

Lesion correlates of secondary paroxysmal dyskinesia in multiple sclerosis.

Secondary paroxysmal dyskinesia is a rare but life-quality-compromising symptom in multiple sclerosis (MS) and might be associated with particular MS lesions. The present study intended to determine associations between paroxysmal dyskinesia and the MS-associated lesion site using a voxelwise lesion analysis. We conducted a retrospective study and sought MS patients with documented paroxysmal dyskinesia and controls without paroxysmal dyskinesia matched for age, disease severity, and disease duration in a local database. The MS lesions were analysed on T2-weighted magnetic resonance imaging scans (1.5 or 3T), manually outlined, and transformed into stereotaxic space. We determined the lesion overlap and compared the absence or presence of paroxysmal dyskinesia voxelwise between patients with and without lesions in a given voxel using the Liebermeister test with 4000 permutations. From 15,869 MS patient records screened, we identified 25 patients with paroxysmal dyskinesia. The voxelwise analysis in 22 subjects yielded associations between paroxysmal dyskinesia and MS lesions in the internal capsule, the basal ganglia, and another prominent lesion cluster in the posterior periventricular white matter. Our voxelwise analysis shows associations between paroxysmal dyskinesia and MS lesions in the internal capsule and basal ganglia, areas contributing to motor sequence programming. This association in another lesion site located in the posterior thalamic radiation suggests that lesions in subcortical sensory pathways may also contribute to paroxysmal dyskinesia in MS.

Periventricular White Matter Hyperintensities and Functional Decline.

We previously showed that global brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. The objective of the current study was to determine whether WMHV in particular brain regions is more predictive of functional decline. Prospective population-based study. Northern Manhattan magnetic resonance imaging (MRI) study. Individuals free of stroke at baseline (N = 1,195; mean age 71 ± 9; n = 460 (39%) male). Participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences. Volumetric WMHV distribution across 14 brain regions (brainstem; cerebellum; bilateral frontal, occipital, temporal, and parietal lobes; and bilateral anterior and posterior periventricular white matter (PVWM)) was determined using a combination of bimodal image intensity distribution and atlas-based methods. Participants had annual functional assessments using the Barthel Index (BI) (range 0-100) over a mean of 7.3 years and were followed for stroke, myocardial infarction (MI), and mortality. Because there were multiple collinear variables, least absolute shrinkage and selection operator (LASSO) regression-selected regional WMHV variables most associated with outcomes and adjusted generalized estimating equations models were used to estimate associations with baseline BI and change over time. Using LASSO regularization, only right anterior PVWM was found to meet criteria for selection, and each standard deviation greater WMHV was associated with accelerated functional decline of 0.95 additional BI points per year (95% confidence interval (CI) = -1.20 to -0.70) in an unadjusted model, -0.92 points per year (95% CI = -1.18 to -0.67) with baseline covariate adjustment, and -0.87 points per year (95% CI = -1.12 to -0.62) after adjusting for incident stroke and MI. In this large population-based study with long-term repeated measures of function, periventricular WMHV was particularly associated with accelerated functional decline.

Disconnections of Cortico-Subcortical Pathways Related to Cognitive Impairment in Patients with Leukoaraiosis: A Preliminary Diffusion Tensor Imaging Study

Background: We aimed to explore the relation between the microstructural integrity of white matter using the technique of diffusion tensor imaging (DTI) and changes of cognition in leukoaraiosis (LA). Methods: Fifty patients with LA and 50 age- and gender-matched controls were recruited consecutively. The average values of mean diffusivity (MD) and fractional anisotropy (FA) were quantified both within white matter lesions (WMLs) and normal-appearing white matter (NAWM) from the regions of interest (ROIs). Results: We found significantly decreased FA and increased MD in WMLs at the 5 ROIs than that in NAWM and controls (p < 0.05). The values of FA in NAWM were significantly lower at centrum semiovale and posterior periventricular white matter than those of controls (p < 0.05). The values of MD in NAWM were significantly higher at the anterior periventricular white matter and corpus callosum than those of controls (p < 0.05). The values of FA in NAWM located at anterior periventricular white matter correlated inversely with the Z scores of executive function (r = -0.420, p = 0.028). Conclusions: DTI may provide some important information about the cognitive dysfunction in patients with LA, which may largely attribute to the “disconnection” of cortico-subcortical pathways, with the evidence of reduced FA and increased MD.

Correlation between prefrontal-striatal pathway impairment and cognitive impairment in patients with leukoaraiosis

Our study aimed to investigate the changes of white matter microstructure of cortico-subcortical pathways using diffusion tensor imaging (DTI), and to explore the relationship between abnormal parameters of DTI and cognitive function underlying in patients with leukoaraiosis (LA).A total of 42 patients with LA and 42 age- and sex-matched healthy controls were recruited from Beijing Chaoyang Hospital, Capital Medical University between January 2012 and December 2012. All the subjects underwent scans of conventional magnetic resonance imaging and DTI, and a comprehensive neuropsychological battery was utilized. The regions of interest (ROIs) were located at the white matter of centrum semiovale, anterior and posterior periventricular white matter, basal ganglia, corpus callosum. The averaged values of mean diffusivity (MD) and fractional anisotropy (FA) were quantified both within white matter lesions (WMLs) and normal appearing white matter (NAWM). A linear regression analysis was performed to assess the association between diffusion parameters and decline in cognitive domains.Patients with LA were associated with comprehensive cognitive function deficits. We found that significantly decreased FA and increased MD in WMLs at the 5 ROIs than that of NAWM and controls (P < .05). The values of FA in NAWM were significantly lower and MD in NAWM were significantly higher at centrum semiovale and posterior periventricular white matter than that of controls (P < .05). The values of FA in WMLs at anterior periventricular white matter were positively related to the performances of cognition in patients with LA (P < .05). The values of FA in NAWM located at anterior periventricular white matter were positively related to the score of Digit-symbol test (r = 0.446, P = .002). The values of FA in NAWM located at anterior periventricular white matter correlated inversely with the Z scores of executive function (r = −0.418, P = .03).In our study, patients with LA exhibited significant cognitive impairment especially in the domains of executive function. The technique of DTI revealed that the reduced FA and increased MD at the corresponding regions of cortico-subcortical pathways in patients with LA. DTI may be of great help for an early pathology of white matter microstructure underlying in patients with LA.

Abstract MP057: Subclinical Cerebrovascular Disease is Associated with Worsening Gait and Balance in an Elderly Multi-Ethnic Population: The Northern Manhattan Study (NOMAS)

Introduction: Age-related decline in gait and balance is a contributor to morbidity in the elderly. Subclinical cerebrovascular disease, seen on magnetic resonance imaging (MRI) as white matter hyperintensities (WMH) and silent brain infarcts (SBI), is associated with impaired mobility. Less is known about the association of WMH in specific brain regions and mobility impairment. We hypothesized that anterior WMH volume would be associated with lower scores on the Short Physical Performance Battery (SPPB), a well-validated mobility scale associated with falls and mortality in the elderly. Methods: Participants in the Northern Manhattan Study MRI cohort had the SPPB measured a median of 5 years after enrollment. The SPPB has three domains with a maximum total score of 12: gait speed, chair stands, standing balance. Volumetric distributions for WMH volume across 14 brain regions (brainstem, cerebellum, and bilateral frontal, occipital, temporal, and parietal lobes, and bilateral anterior and posterior periventricular white matter) were determined separately for each hemisphere by combining bimodal image intensity distribution and atlas based methods. Multi-variable linear regression was performed to examine the association between SBI and total and regional (frontal, parietal, occipital, temporal, anterior, posterior, and brainstem) head size-corrected WMH volumes, with the total SPPB score; models were adjusted for cardiovascular disease risk factors, osteo-arthritis, and grip strength. Results: Among 668 stroke-free participants with the SPPB available, mean age at the time of assessment was 74 ±9 years, 37% were male and 70% Hispanic; the mean SPPB score was 8.2 ± 2.9, interquartile range 7-10. Mean total WMHV was 0.55±0.75cc, mean anterior WMH volume 0.18±0.24cc, and 12% of participants had SBI. In multi-variable models, total WMHV was associated with a lower SPPB (beta = -0.3 per SD of logWMH, p=0.004), while SBI was not (beta= -0.12, p=0.7). For regional WMH volumes, only greater anterior periventricular WMHV was associated with SPPB (beta= -0.29 per SD, p=0.009). Conclusions: White matter hyperintensities, especially in the anterior cerebral regions, are associated with a lower SPPB. Prevention of subclinical cerebrovascular disease is a potential target to prevent physical aging in the elderly.

Abstract WP192: Periventricular White Matter Hyperintensities Are Associated With Functional Decline: The Northern Manhattan Study

Background: We previously showed that overall brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. However, it was unclear whether WMHV in particular brain regions was more predictive of decline. We hypothesized that WMHV in particular brain regions would be more predictive of functional decline. Methods: In the Northern Manhattan MRI study, participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences, with baseline interview and examination. Volumetric WMHV distribution across 14 brain regions (brainstem, cerebellum, and bilateral frontal, occipital, temporal, and parietal lobes, and bilateral anterior and posterior periventricular white matter [PVWM]) was determined separately by combining bimodal image intensity distribution and atlas based methods. Participants had annual functional assessments with the Barthel index (BI, range 0-100) over a mean of 7.3 years and were followed for stroke and myocardial infarction (MI). Due to multiple collinear variables, lasso regression was used to select regional WMHV variables, and adjusted generalized estimating equations models estimated associations with baseline BI and change over time. Results: Among 1195 participants, mean age was 71 (SD 9) years, 460 (39%) were male, 802 (67%) had hypertension and 224 (19%) diabetes. Using lasso regularization, only right anterior PVWM was selected, and each SD increase was associated with accelerated functional decline, of -0.95 additional BI points per year (95% CI -1.20, -0.70) in an unadjusted model, -0.92 points per year (95% CI -1.18, -0.67) with baseline covariate adjustment, and -0.87 points per year (95% CI -1.12, -0.62) after adjusting for stroke and MI. This decline was in addition to a mean decline of -1.13 (95% CI -1.29, -0.97), -1.19 (95% CI -1.36, -1.01), and -1.04 (95% CI -1.21, -0.88) BI points per year, respectively. Conclusions: In this large population-based study with long-term repeated measures of function, periventricular WMHV was particularly associated with accelerated functional decline. Periventricular WMHV may have a greater effect on mobility due to dysfunction in descending leg motor tracts.

Abstract TMP56: Differential Effect of Left versus Right White Matter Hyperintensity Burden on Functional Decline: The Northern Manhattan Study

Background: We previously showed that overall brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. Asymmetry of brain dysfunction may disrupt brain network efficiency. We hypothesized that greater left-right WMHV asymmetry was associated with functional trajectories. Methods: In the Northern Manhattan MRI study, participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences, with baseline interview and examination. Volumetric WMHV distribution across 14 brain regions (brainstem, cerebellum, and bilateral frontal, occipital, temporal, and parietal lobes, and bilateral anterior and posterior periventricular white matter) was determined separately by combining bimodal image intensity distribution and atlas based methods.. Participants had annual functional assessments with the Barthel index (BI, range 0-100) over a mean of 7.3 years. Generalized estimating equations models estimated associations of regional WMHV and regional left-right asymmetry with baseline BI and change over time, adjusted for baseline medical risk factors, sociodemographics, and cognition, and stroke and myocardial infarction during follow-up. Results: Among 1195 participants, mean age was 71 (SD 9) years, 39% were male, 67% had hypertension and 19% diabetes. Greater WMHV asymmetry in the frontal lobes (-3.53 BI points per unit greater WMHV on the right compared to left, 95% CI -0.18, -6.88) and whole brain (-7.23 BI points, 95% CI 0.07, -14.54) was associated with lower overall function. Greater WMHV asymmetry in the frontal lobes (-0.74 additional BI points per year per unit greater WMHV on the right compared to left, 95% CI 0.05, -1.54) and parietal lobes (1.11 additional BI points per year, 95% CI 0.30, 1.93) was independently associated with accelerated functional decline. Periventricular WMHV asymmetry was not associated with function. Conclusions: In this large population-based study with long-term repeated measures of function, greater regional WMHV asymmetry was associated with lower function and functional decline, especially with greater WMHV on the right. In addition to global WMHV, WHMV asymmetry may be an important predictor of long-term functional decline.

Periventricular White Matter Is a Nexus for Network Connectivity in the Human Brain.

The edges of the structural connectome traverse the white matter to connect cortical and subcortical nodes, although the anatomic embedding of these edges is generally overlooked in the literature. Characterization of the geometry of the structural connectome could provide an improved understanding of the relative importance of various white matter regions to the network architecture of the human brain in normal development and aging, as well as in white matter diseases with regionally specific patterns of vulnerability. Edge density imaging (EDI) has previously been used to show that the posterior periventricular white matter contains a disproportionately large number of connectome edges. In this study, the regional distribution of connectome edges within cerebral white matter, including the importance of posterior periventricular white matter, is further investigated and demonstrated to be invariant to different gray matter parcellations and different diffusion MRI acquisition and postprocessing/tractography methods. An examination of the highest k-core edges and a virtual lesion analysis illuminate hemispheric asymmetries (left>right) in the embedding of connectome edges. Therefore, EDI reveals specific areas of vulnerability within the white matter connectivity of the human brain, especially in the periventricular white matter. The idea of a periventricular nexus fits with the known neurobiology of brain development and may result from simple geometrical considerations in minimizing wiring cost in structural brain connectivity.

Intervention versus Aggressive Medical Therapy for Cognition in Severe Asymptomatic Carotid Stenosis.

Asymptomatic carotid stenosis of ≥70% increases the incidence of microembolism and/or chronic hypoperfusion, which may consequently impair neurocognition and brain connections. We sought controlled evidence for any cognitive benefit of aggressive medical therapy and combined carotid revascularization. Patients with asymptomatic, unilateral, ≧70% stenosis of the extracranial ICA chose either aggressive medical therapy alone or in combination with carotid artery stent placement in this nonrandomized controlled study. They were examined with a battery of neuropsychological tests, structural MR imaging, DTI, and resting-state fMRI before and 3 months after treatment. Forty patients were included with 15 in the medical group and 25 in the stent-placement group. Among them, 13 and 21 in the respective groups completed neuroimaging follow-up. The baseline characteristics and the changes in cognitive performance during 3 months showed no differences between treatment groups. Nevertheless, compared with the medical group, the stent-placement group showed subjective dizziness alleviation (P = .045) and a small increase in fractional anisotropy at the splenium of the corpus callosum and the posterior periventricular white matter ipsilateral to carotid artery stent placement. Moreover, only the stent-placement group showed interval improvement in immediate memory and visuospatial performance, which was accompanied by an increase of functional connectivity at the insular cortex of the dorsal attention network and the medial prefrontal cortex of the default mode network. Both aggressive medical therapy alone and combined carotid revascularization in ≧70% asymptomatic carotid stenosis similarly preserved cognition during 3-month follow-up, though the latter had the potential for dizziness alleviation and cognitive and connectivity enhancement.

Electroclinical phenotype in Rubinstein–Taybi syndrome

ObjectiveRubinstein–Taybi syndrome (RSTS) is a rare congenital disorder (1:125.000) characterized by growth retardation, psychomotor developmental delay, microcephaly and dysmorphic features. In 25% of patients seizures have been described, and in about 66% a wide range of EEG abnormalities, but studies on neurological features are scant and dated.The aim of this study is to describe the electroclinical phenotype of twenty-three patients with RSTS, and to try to correlate electroclinical features with neuroradiological, cognitive and genetic features. Patients and methodsElectroclinical features of twenty-three patients with RSTS (age between18months and 20years) were analyzed. Sleep and awake EEG was performed in twenty-one patients, and brain MRI in nineteen patients. All subjects received cognitive evaluation. ResultsEEG abnormalities were observed in 76% (16/21) of patients. A peculiar pattern prevalent in sleep, characterized by slow monomorphic activity on posterior regions was also observed in 33% (7/21) of patients. Almost no patient presented seizures. Eighty-four percentage of patients had brain MRI abnormalities, involving corpus callosum and/or posterior periventricular white matter. Average General Quotient (GQ) was 52, while average IQ was 55, corresponding to mild Intellectual Disability. The homogeneous electroclinical pattern was observed mainly in patients with more severe neuroradiologic findings and moderate Intellectual Disability/Developmental Disability (ID/DD). No genotype-phenotype correlations were found. ConclusionThe specific electroclinical and neuroradiological features described may be part of a characteristic RSTS phenotype. Wider and longitudinal studies are needed to verify its significance and impact on diagnosis, prognosis and clinical management of RSTS patients.