Hemispheric White Matter Research Articles

Cerebral Oxygen Metabolic Stress in Children and Adults With Large Vessel Vasculopathy Due to Sickle Cell Disease.

Large vessel vasculopathy (LVV), or moyamoya syndrome, increases the risk of stroke in patients with sickle cell disease (SCD), yet effective treatments are lacking. In atherosclerotic carotid disease, previous studies demonstrated elevated oxygen extraction fraction (OEF) as a predictor of ipsilateral stroke. In a SCD cohort, we examined hemispheric hemodynamic and oxygen metabolic dysfunction as tissue-based biomarkers of cerebral ischemic risk in patients with LVV. Children and adults with SCD were recruited from a SCD clinic associated with a tertiary medical center and underwent prospective brain MRI and MR angiography. LVV was defined as ≥75% stenosis in a major anterior circulation artery, excluding occlusion or previous revascularization surgery. Baseline characteristics, cerebral blood flow (CBF), normalized OEF (nOEF), infarct volume, white matter microstructure, and brain volume were compared in hemispheres with vs without LVV. In a cross-sectional analysis, mixed-effects linear multivariable models examined the effect of LVV on: (1) CBF and nOEF, as tissue markers of hemodynamic and oxygen metabolic stress, respectively, and (2) endpoints of cerebral ischemic injury including infarct volume, white matter microstructure, and brain volume. Of 155 patients (22 [12-31] years, 57% female), 33 (21%) had ≥25% stenosis, 22 (14%) had ≥50% stenosis, 14 (9%) had 75%-99% stenosis, and 5 (3%) had 100% occlusion. After excluding hemispheres with previous revascularization surgery, LVV was present in 16 hemispheres from 11 patients. Hemispheres with (N = 16) vs without (N = 283) LVV had lower CBF (25.2 vs 32.1 mL/100 g/min, p = 0.01) and higher nOEF (0.99 vs 0.95, p = 0.02). On multivariable analysis, CBF was nonsignificantly lower (β = -0.16, p = 0.07) while nOEF remained higher in hemispheres with LVV (β = 0.04, p = 0.03). Moreover, LVV was associated with greater hemispheric infarct volume, microstructural disruption, and atrophy. Beyond greater infarct burden, LVV was associated with hemispheric atrophy and white matter microstructural injury. As an indicator of active hypoxia, elevated nOEF likely represents a compensatory response to flow-limiting stenosis in hemispheres with LVV. The study is limited by a small number of patients with severe stenosis. Future studies are needed to evaluate the potential of tissue-based CBF and nOEF in assessing stroke risk and guide timely treatment of vasculopathy in SCD.

Plastic reorganization of the topological asymmetry of hemispheric white matter networks induced by congenital visual experience deprivation

Congenital blindness offers a unique opportunity to investigate human brain plasticity. The influence of congenital visual loss on the asymmetry of the structural network remains poorly understood. To address this question, we recruited 21 participants with congenital blindness (CB) and 21 age-matched sighted controls (SCs). Employing diffusion and structural magnetic resonance imaging, we constructed hemispheric white matter (WM) networks using deterministic fiber tractography and applied graph theory methodologies to assess topological efficiency (i.e., network global efficiency, network local efficiency, and nodal local efficiency) within these networks. Statistical analyses revealed a consistent leftward asymmetry in global efficiency across both groups. However, a different pattern emerged in network local efficiency, with the CB group exhibiting a symmetric state, while the SC group showed a leftward asymmetry. Specifically, compared to the SC group, the CB group exhibited a decrease in local efficiency in the left hemisphere, which was caused by a reduction in the nodal properties of some key regions mainly distributed in the left occipital lobe. Furthermore, interhemispheric tracts connecting these key regions exhibited significant structural changes primarily in the splenium of the corpus callosum. This result confirms the initial observation that the reorganization in asymmetry of the WM network following congenital visual loss is associated with structural changes in the corpus callosum. These findings provide novel insights into the neuroplasticity and adaptability of the brain, particularly at the network level.

Clinical and magnetic resonance imaging features of unilateral thalamic porencephaly in a dog

AbstractA 1‐year‐3‐month‐old, female, neutered labrador retriever was presented with a history of circling behaviour since 2 months of age and a recently detected blindness affecting its right eye. Neurological examination revealed a left‐sided head tilt, compulsive tight circling towards the left, postural reaction deficits in the right thoracic and pelvic limbs, absent menace response in the right eye and ventral positional strabismus of the left eye. The neurological examination findings were localised to the left thalamus. Magnetic resonance imaging of the head revealed porencephaly involving the left dorsal aspect of the thalamus. Furthermore, reduced volume of the left rostral colliculus, crus cerebri and optic chiasm, alongside marked thinning of the left cerebral hemispheric white matter tracts with associated left lateral ventriculomegaly, were present. Based on magnetic resonance imaging features and clinical history, a congenital or perinatal encephaloclastic porencephaly with secondary hypoplasia or atrophy of the associated thalamic projection pathways was prioritised.

Is Broca's area critical for speech and language? Evidence from lesion-symptom mapping in chronic aphasia

IntroductionThe specific role that Broca's area plays in speech and language has been hotly debated in the literature. Some research has pointed to a specific role in particular aspects of speech production, while other findings have suggested additional roles in aspects of language comprehension. In the current study, we had the opportunity to take a broad approach by analyzing lesion and behavioral data from a large cohort of left hemisphere stroke patients. In this brief report, our objective was to identify which speech-language measures show a significant association with Broca's area, specifically pars opercularis and pars triangularis.MethodsLesion site and neuropsychological data from 173 chronic left hemisphere stroke patients were analyzed in the current study. Univariate lesion-symptom mapping (LSM) with rigorous correction was used to identify brain regions associated with individual test performance on a large battery of speech and language tasks. Multivariate LSM analyses were conducted in subsequent runs to confirm findings.ResultsThe LSM results identified many predictable left hemisphere gray and white matter regions significantly associated with the speech-language data, but Broca's area was not implicated in performance on any speech or language measure. Regions adjacent to Broca's area, however, in left central opercular, precentral, and insular cortices were associated with speech production and motor speech performance.DiscussionThe current study failed to identify a single speech or language measure in our comprehensive test battery that was dependent on Broca's area. This finding could not be attributed to a lack of power, as Broca's area had among the highest power values and substantial lesion coverage. Interrogation of data at the individual patient level revealed the likely source of this null finding: Patients with lesions involving Broca's area varied widely in their speech-language performance, with profiles ranging from non-aphasic to Broca's to global aphasia. Given previous studies in acute stroke patients and healthy participants implicating Broca's area in speech-language, the current findings suggest that Broca's area plays a more supplementary than critical role and can be compensated by surrounding brain regions in chronic stroke.

Differentiation of hemispheric white matter lesions in migraine and multiple sclerosis with similar radiological features using advanced MRI.

White matter hyperintensities (WMHs), presented on T2-weighted or fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequences, are lesions in the human brain that can be observed in both migraine and multiple sclerosis (MS). Seventeen migraine patients and 15 patients with relapsing-remitting multiple sclerosis with WMHs, and 17 healthy subjects age-and sex-matched to the migraine group were prospectively enrolled and underwent conventional and advanced MRI studies with diffusion-and perfusion-weighted imaging and single voxel proton magnetic resonance spectroscopy. In both disease groups, elevated T2 relaxation time, apparent diffusion coefficient (ADC) values, and decreased N-acetyl-aspartate levels were found in the intralesional white matter compared to the contralateral normal-appearing white matter (NAWM), while there was no difference between the hemispheres of the control subjects. Migraine patients had the lowest intralesional creatine + phosphocreatine and myo-inositol (mI) values among the three groups, while patients with MS showed the highest intralesional T1 and T2 relaxation times, ADC, and mI values. In the contralateral NAWM, the same trend with mI changes was observed in migraineurs and MS patients. No differences in perfusion variables were observed in any groups. Our multimodal study showed that tissue damage is detectable in both diseases. Despite the differences in various advanced MRI measures, with more severe injury detected in MS lesions, we could not clearly differentiate the two white matter lesion types.

Partial volume correction in longitudinal tau PET studies: is it really needed?

Background[18F]flortaucipir (FTP) tau PET quantification is known to be affected by non-specific binding in off-target regions. Although partial volume correction (PVC) techniques partially account for this effect, their inclusion may also introduce noise and variability into the quantification process. While the impact of these effects has been studied in cross-sectional designs, the benefits and drawbacks of PVC on longitudinal FTP studies is still under scrutiny. The aim of this work was to study the performance of the most common PVC techniques for longitudinal FTP imaging. MethodsA cohort of 247 individuals from the Alzheimer's Disease Neuroimaging Initiative with concurrent baseline FTP-PET, amyloid-beta (Aβ) PET and structural MRI, as well as with follow-up FTP-PET and MRI were included in the study. FTP-PET scans were corrected for partial volume effects using Meltzer's, a simple and popular analytical PVC, and both the region-based voxel-wise (RBV) and the iterative Yang (iY) corrections. FTP SUVR values and their longitudinal rates of change were calculated for regions of interest (ROI) corresponding to Braak Areas I-VI, for a temporal meta-ROI and for regions typically displaying off-target FTP binding (caudate, putamen, pallidum, thalamus, choroid plexus, hemispheric white matter, cerebellar white matter, and cerebrospinal fluid). The longitudinal correlation between binding in off-target and target ROIs was analysed for the different PVCs. Additionally, group differences in longitudinal FTP SUVR rates of change between Aβ-negative (A-) and Aβ-positive (A+), and between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, were studied. Finally, we compared the ability of different partial-volume-corrected baseline FTP SUVRs to predict longitudinal brain atrophy and cognitive decline. ResultsAmong off-target ROIs, hemispheric white matter showed the highest correlation with longitudinal FTP SUVR rates from cortical target ROIs (R2=0.28–0.82), with CSF coming in second (R2=0.28–0.42). Application of voxel-wise PVC techniques minimized this correlation, with RBV performing best (R2=0.00–0.07 for hemispheric white matter). PVC also increased group differences between CU and CI individuals in FTP SUVR rates of change across all target regions, with RBV again performing best (No PVC: Cohen's d = 0.26–0.66; RBV: Cohen's d = 0.43–0.74). These improvements were not observed for differentiating A- from A+ groups. Additionally, voxel-wise PVC techniques strengthened the correlation between baseline FTP SUVR and longitudinal grey matter atrophy and cognitive decline. ConclusionQuantification of longitudinal FTP SUVR rates of change is affected by signal from off-target regions, especially the hemispheric white matter and the CSF. Voxel-wise PVC techniques significantly reduce this effect. PVC provided a significant but modest benefit for tasks involving the measurement of group-level longitudinal differences. These findings are particularly relevant for the estimations of sample sizes and analysis methodologies of longitudinal group studies.

Intragenic homozygous duplication in HEPACAM is associated with megalencephalic leukoencephalopathy with subcortical cysts type 2A.

Disease-causing variants in HEPACAM are associated with megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A, MIM# 613,925, autosomal recessive), and megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development (MLC2B, MIM# 613,926, autosomal dominant). These disorders are characterised by macrocephaly, seizures, motor delay, cognitive impairment, ataxia, and spasticity. Brain magnetic resonance imaging (MRI) in these individuals shows swollen cerebral hemispheric white matter and subcortical cysts, mainly in the frontal and temporal regions. To date, 45 individuals from 39 families are reported with biallelic and heterozygous variants in HEPACAM, causing MLC2A and MLC2B, respectively. A 9-year-old male presented with developmental delay, gait abnormalities, seizures, macrocephaly, dysarthria, spasticity, and hyperreflexia. MRI revealed subcortical cysts with diffuse cerebral white matter involvement. Whole-exome sequencing (WES) in the proband did not reveal any clinically relevant single nucleotide variants. However, copy number variation analysis from the WES data of the proband revealed a copy number of 4 for exons 3 and 4 of HEPACAM. Validation and segregation were done by quantitative PCR which confirmed the homozygous duplication of these exons in the proband and carrier status in both parents. To the best of our knowledge, this is the first report of an intragenic duplication in HEPACAM causing MLC2A.

Intrascopic predictors of favorable outcomes after ventriculoperitoneal shunting in Hakim-Adams syndrome: a single-center retrospective non-randomized study

To identify intrascopic predictors of favorable outcomes after ventriculoperitoneal shunting in Hakim-Adams syndrome; to present a model for evaluating MRI data and selecting candidates for surgery. A single-center retrospective non-randomized study enrolled head MRI data in patients with idiopathic normal-pressure hydrocephalus who underwent ventriculoperitoneal shunting between September 2020 and March 2022. There were 34 patients including 15 ones in the main group (significant improvement after surgery) and 19 ones in the control group. We analyzed quantitative neuroimaging features: ventriculocranial indices, DESH syndrome (DESH score), angle of corpus callosum at the level of anterior and posterior commissures, dimensions of temporal horns of lateral ventricles, the number of lacunar infarcts in basal ganglia and white matter of hemispheres. We identified the most significant predictors of favorable outcomes after ventriculoperitoneal shunting: Evans index, indexed longitudinal size of lateral ventricles, angle of corpus callosum (at the level of anterior and posterior commissures) and DESH score. We created a classification model using discriminant analysis. This model allows us to predict the outcomes after ventriculoperitoneal shunting. A comprehensive assessment of intrascopic symptoms allows us to predict the outcomes after ventriculoperitoneal shunting in patients with Hakim-Adams syndrome. In the future, we can avoid invasive diagnostic manipulations in some patients.

Mapping sentence comprehension and syntactic complexity: evidence from 131 stroke survivors.

Understanding and interpreting how words are organized in a sentence to convey distinct meanings is a cornerstone of human communication. The neural underpinnings of this ability, known as syntactic comprehension, are far from agreed upon in current neurocognitive models of language comprehension. Traditionally, left frontal regions (e.g. left posterior inferior frontal gyrus) were considered critical, while more recently, left temporal regions (most prominently, left posterior middle temporal gyrus) have been identified as more indispensable to syntactic comprehension. Syntactic processing has been investigated by using different types of non-canonical sentences i.e. those that do not follow prototypical word order and are considered more syntactically complex. However, non-canonical sentences can be complex for different linguistic reasons, and thus, their comprehension might rely on different neural underpinnings. In this cross-sectional study, we explored the neural correlates of syntactic comprehension by investigating the roles of left hemisphere brain regions and white matter pathways in processing sentences with different levels of syntactic complexity. Participants were assessed at a single point in time using structural MRI and behavioural tests. Employing lesion-symptom mapping and indirect structural disconnection mapping in a cohort of 131 left hemisphere stroke survivors, our analysis revealed the following left temporal regions and underlying white matter pathways as crucial for general sentence comprehension: the left mid-posterior superior temporal gyrus, middle temporal gyrus and superior temporal sulcus and the inferior longitudinal fasciculus, the inferior fronto-occipital fasciculus, the middle longitudinal fasciculus, the uncinate fasciculus and the tracts crossing the most posterior part of the corpus callosum. We further found significant involvement of different white matter tracts connecting the left temporal and frontal lobes for different sentence types. Spared connections between the left temporal and frontal regions were critical for the comprehension of non-canonical sentences requiring long-distance retrieval (spared superior longitudinal fasciculus for both subject and object extraction and spared arcuate fasciculus for object extraction) but not for comprehension of non-canonical passive sentences and canonical declarative sentences. Our results challenge traditional language models that emphasize the primary role of the left frontal regions, such as Broca's area, in basic sentence structure comprehension. Our findings suggest a gradient of syntactic complexity, rather than a clear-cut dichotomy between canonical and non-canonical sentence structures. Our findings contribute to a more nuanced understanding of the neural architecture of language comprehension and highlight potential directions for future research.

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities

AbstractBackgroundWhite matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer’s disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aβ) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury.MethodA total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aβ or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables.ResultBaseline Aβ deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (β = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aβ deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female (β = 0.427, p = 0.001), but not in male.ConclusionOur findings suggest that Aβ deposition, but not tau, accelerates cerebral white matter injury, particularly in female.

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities

AbstractBackgroundWhite matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer’s disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aß) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury.MethodA total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aß deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aß or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aß or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables.ResultBaseline Aß deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (ß = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aß deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aß deposition was associated with increase of WMH volume over 2 years in female (ß = 0.427, p = 0.001), but not in male.ConclusionOur findings suggest that Aß deposition, but not tau, accelerates cerebral white matter injury, particularly in female.

Novel Homozygous Variants of SLC13A5 Expand the Functional Heterogeneity of a Homogeneous Syndrome of Early Infantile Epileptic Encephalopathy

BackgroundEarly infantile epileptic encephalopathy 25 (EIEE25) is a distinct type of neonatal epileptic encephalopathy caused by autosomal recessive mutations in the SLC13A5 gene. SLC13A5 encodes a transmembrane sodium/citrate cotransporter required for regulating citrate entry into cells. MethodsFour families with recessively inherited epileptic encephalopathy were sequenced by clinically accredited laboratories using commercially available epilepsy gene panels. Patients were examined by a neurologist and were clinically diagnosed with infantile epileptic encephalopathy. ResultsWe present four families with global developmental delay, intellectual disability, and defective tooth development with four novel homozygous mutations in SLC13A5. The neurological examination showed spastic quadriplegia with increased deep tendon reflexes. Brain magnetic resonance imaging showed nonspecific signal abnormality of the bilateral hemispheric white matter. Despite similar clinical features, the conditions were based on different molecular mechanisms acting on SLC13A5 (abnormal splicing, large-scale deletions, and tandem-residue insertion). ConclusionsOur results extend the landscape of autosomal recessive inherited homozygous mutations in SLC13A5 that cause a distinctive syndrome of severe neonatal epileptic encephalopathy. Our observations confirm the homogeneity of epileptic encephalopathy and dental abnormalities as a distinct clinical marker for EIEE25 despite the heterogeneous functional and mutational background.

Viral Encephalitis (Human Herpes Virus Type 6) after COVID-19 in a Child: Clinical Case

Background. Immune system disorders early after COVID-19 are associated with high risk of other infections development, including viral ones. Their diagnosis is complicated especially in the absence of clinical symptoms of primary infection and alongside with serious disease course. There are no reports on encephalitis development due to reactivation of latent viral infection.Clinical case description. Girl, 4 years-old, had psycho-neurological symptoms followed by tonic seizures on the next day. The child was hospitalized on the 3rd day after disease onset with preliminary diagnosis of viral encephalitis. The child has contacted with patients with laboratory-confirmed new coronavirus infection 3-4 weeks before the disease onset, later she had signs of mild respiratory infection (no examination of SARS-CoV-2 was carried out). Autoimmune nature of central nervous system injury was suspected after excluding a wide range of infections (negative PCR results for SARS-CoV-2, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, toxoplasma, enterovirus), however it was not confirmed later on. Human herpes virus type 6 was revealed via blood tests and oropharyngeal swаb on the 15th day of disease. High concentration of IgG antibodies to SARS-CoV-2 was found was revealed as well. Treatment (antibacterial, anticonvulsant, anticoagulant, antiviral, immunosupportive, and sedative therapy, glucocorticosteroids) did not achieve significant improvement. Brain MRI (on the 23rd day of the disease) has shown leukoencephalopathy zones in subcortical white matter of convexital surfaces of parietal and occipital lobes, subatrophic changes in white matter of cerebral hemispheres with moderate vicarious enlargement of the subarachnoid spaces. Disease progression led to patient’s death on the 32nd day after first signs appearance.Conclusion. The development of severe viral encephalitis (as a result of primary herpes virus infection or its reactivation) in the early period after mild COVID-19 is shown. Its cause-effect relations require further examination.

Study of the relationship between onset lateralization and hemispheric white matter asymmetry in Parkinson's disease.

Parkinson's disease (PD) is characterized by a lateralized onset, but its cause and mechanism are still unclear. Obtaining diffusion tensor imaging (DTI) data from the Parkinson's Progression Markers Initiative (PPMI). Tract-based spatial statistics analysis and region-of-interest-based analysis were performed to evaluate the white matter (WM) asymmetry using original DTI parameters, Z Score normalized parameters, or the asymmetry index (AI). Hierarchical cluster analysis and least absolute shrinkage and selection operator regression were performed to construct predictive models for predicting the PD onset side. DTI data from The Second Affiliated Hospital of Chongqing Medical University were obtained for external validation of the prediction model. 118 PD patients and 69 healthy controls (HC) from PPMI were included. Right-onset PD patients presented more asymmetric areas than left-onset PD patients. The inferior cerebellar peduncle (ICP), superior cerebellar peduncle (SCP), external capsule (EC), cingulate gyrus (CG), superior fronto-occipital fasciculus (SFO), uncinate fasciculus (UNC), and tapetum (TAP) showed significant asymmetry inleft-onset and right-onset PD patients. An onset-side-specific pattern of WM alterations exists in PD patients, and a prediction model was constructed. The predicting models based on AI and ΔZ Score presented favorable efficacy in predicting PD onset side by external validation in 26 PD patients and 16 HCs from our hospital. Right-onset PD patients may have more severe WM damage than left-onset PD patients. WM asymmetry in ICP, SCP, EC, CG, SFO, UNC, and TAP may predict PD onset side. Imbalances in the WM network may underlie the mechanism of lateralized onset in PD.

Cerebellar axonopathy in Shivers horses identified by spatial transcriptomic and proteomic analyses.

Shivers in horses is characterized by abnormal hindlimb movement when walking backward and is proposed to be caused by a Purkinje cell (PC) axonopathy based on histopathology. Define region-specific differences in gene expression within the lateral cerebellar hemisphere and compare cerebellar protein expression between Shivers horses and controls. Case-control study of 5 Shivers and 4 control geldings ≥16.2 hands in height. Using spatial transcriptomics, gene expression was compared between Shivers and control horses in PC soma and lateral cerebellar hemisphere white matter, consisting primarily of axons. Tandem-mass-tag (TMT-11) proteomic analysis was performed on lateral cerebellar hemisphere homogenates. Differences in gene expression between Shivers and control horses were evident in principal component analysis of axon-containing white matter but not PC soma. In white matter, there were 455/1846 differentially expressed genes (DEG; 350 ↓DEG, 105 ↑DEG) between Shivers and controls, with significant gene set enrichment of the Toll-Like Receptor 4 (TLR4) cascade, highlighting neuroinflammation. There were 50/936 differentially expressed proteins (DEP). The 27 ↓DEP highlighted loss of axonal proteins including intermediate filaments (5), myelin (3), cytoskeleton (2), neurite outgrowth (2), and Na/K ATPase (1). The 23 ↑DEP were involved in the extracellular matrix (7), cytoskeleton (7), redox balance (2), neurite outgrowth (1), signal transduction (1), and others. Our findings support axonal degeneration as a characteristic feature of Shivers. Combined with histopathology, these findings are consistent with the known distinctive response of PC to injury where axonal changes occur without a substantial impact on PC soma.

Brain asymmetry: a novel perspective on hemispheric network

Brain asymmetry, involving structural and functional differences between the two hemispheres, is a major organizational principle of the human brain. The structural and functional connectivity within each hemisphere defines the hemispheric network or connectome. Elucidating left-right differences of the hemispheric network provides opportunities for brain asymmetry exploration. This review examines the asymmetry in the hemispheric white matter and functional network to assess health and brain disorders. In this article, the brain asymmetry in structural and functional connectivity including network topologies of healthy individuals, involving brain cognitive systems and the development trend, is highlighted. Moreover, the abnormal asymmetry of the hemispheric network related to cognition changes in brain disorders, such as Alzheimer’s disease, schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder, and bipolar disorder, is presented. This review suggests that the hemispheric network is highly conserved for measuring human brain asymmetries and has potential in the study of the cognitive system and brain disorders.

Mechanisms of Cognitive Improvement After Carotid Endarterectomy: Results of an Autopsy

To develop a clinically meaningful definition of cognitive change before and after carotid endarterectomy (CEA), we categorized patients with “improved postoperative function” and “non-improved postoperative function” based on subjective assessment and neuropsychological tests. The results showed that 11% of the patients showed an improvement in postoperative function. Through single-photon emission computerized tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), etc., it was found that improvement of cerebral blood flow by carcinoembryonic antigen (CEA) → improvement of cerebral metabolism → improvement of cerebral cortical neuroreceptor function and cerebral white matter microstructure → improvement of cognitive function. The degree of preoperative cerebral hemispheric white matter lesions was the rate-limiting factor for improvement in cognitive function.

Perifocal Zone of Brain Gliomas: Application of Diffusion Kurtosis and Perfusion MRI Values for Tumor Invasion Border Determination.

(1) Purpose: To determine the borders of malignant gliomas with diffusion kurtosis and perfusion MRI biomarkers. (2) Methods: In 50 high-grade glioma patients, diffusion kurtosis and pseudo-continuous arterial spin labeling (pCASL) cerebral blood flow (CBF) values were determined in contrast-enhancing area, in perifocal infiltrative edema zone, in the normal-appearing peritumoral white matter of the affected cerebral hemisphere, and in the unaffected contralateral hemisphere. Neuronavigation-guided biopsy was performed from all affected hemisphere regions. (3) Results: We showed significant differences between the DKI values in normal-appearing peritumoral white matter and unaffected contralateral hemisphere white matter. We also established significant (p < 0.05) correlations of DKI with Ki-67 labeling index and Bcl-2 expression activity in highly perfused enhancing tumor core and in perifocal infiltrative edema zone. CBF correlated with Ki-67 LI in highly perfused enhancing tumor core. One hundred percent of perifocal infiltrative edema tissue samples contained tumor cells. All glioblastoma samples expressed CD133. In the glioblastoma group, several normal-appearing white matter specimens were infiltrated by tumor cells and expressed CD133. (4) Conclusions: DKI parameters reveal changes in brain microstructure invisible on conventional MRI, e.g., possible infiltration of normal-appearing peritumoral white matter by glioma cells. Our results may be useful for plotting individual tumor invasion maps for brain glioma surgery or radiotherapy planning.

Ammonia level and Alzheimer type 2 astrocytes in the brain of deceased patients with liver cirrhosis of the varying degree

The aim of the study – comparative analysis of the ammonia level and Alzheimer type 2 astrocytes in the brain cortex and white matter of cerebral hemispheres, hippocampus, thalamus, striatum and cerebellum in the deceased patients with liver cirrhosis of classes A, B and C according to Child–Pugh. Materials and methods. The study was performed on the brain of deceased 90 patients (65 ± 3 years) suffered from non-alcoholic liver cirrhosis (LC) of classes A (n = 30, group “A”), B (n = 30, group “B”) and C (n = 30, group “C”) according to Child–Pugh score, among which 59 (65.55 %) patients had clinical symptoms of hepatic encephalopathy of I–IV grades. The control group included postmortem brains of 30 patients (59.0 ± 2.5 years) who died from acute cardiovascular insufficiency and did not suffer from liver diseases or intoxication. A retrospective analysis of clinical and laboratory data from case histories was carried out. For histochemical (HC) determination of the ammonia in paraffin sections of the cerebral cortex and white matter, hippocampus, thalamus, striatum and cerebellum we used the protocol with Nessler’s reagent proposed by Gutierrez-de-Juan et al. (2017). In the noted brain regions, the analysis of HC ammonia optical density was performed in five standardized fields of view (×200) of the microscope scope A1 “Carl Zeiss” (Germany) with Jenoptik camera progress Gryphax 60 N-C1ꞌꞌ1.0x426114 (Germany) using ImageJ software; in each noted brain region the number of Alzheimer’s type 2 astrocytes (AA2) was counted per twenty standardized fields of view at magnification ×400. Results. HC method for ammonia detection with Nessler’s reagent according to V. Gutiérrez-de-Juan et al. (2017) reveals region-dependent fine-grained expression of ammonia in the brain neuropil of deceased patients in control and cirrhotic groups. In control patients, a very low HC ammonia expression is observed with higher values in cerebellum, thalamus, and striatum, while still ranked as negative. Increased HC ammonia expression (compared to control) is observed in deceased patients with compensated LC of “A” group in the cortex, thalamus, striatum and cerebellum; in subcompensated LC of “B” group – as well in the white matter and hippocampus. In deceased patients with decompensated LC of “C” group, in cerebellum, thalamus and striatum HC ammonia expression is maximally increased (by 6.18, 5.72, and 5.50 folds, respectively). Significant correlations are present between patients’ postmortem brain HC ammonia expression and the last intravital indicators of the blood total bilirubin, AST, ALT, albumin, leukocytic intoxication index. In compensated cirrhosis, increase in AA2 numbers compared to control is found in thalamus, striatum and cerebellum, which corresponds to AA2-astrocytosis of I degree. In subcompensated cirrhosis, AA2-astrocytosis of moderate II degree is found in the cortex, thalamus and cerebellum; AA2-astrocytosis of I degree – in striatum. In decompensated cirrhosis, pronounced AA2-astrocytosis of III degree is determined in the cortex, thalamus, striatum and cerebellum; moderate AA2-astrocytosis of II degree – in cerebral white matter, and mild AA2-astrocytosis of I degree – in the hippocampus. There is a moderate, strong, and very strong positive relationship between the levels of AA2-astrocytosis and HC ammonia expression in the thalamus, striatum, and cerebellum. Conclusions. In deceased patients with LC, the neuropil HC ammonia expression in cerebellum, thalamus, striatum, and cerebral cortex directly correlates with the severity of LC according to Child–Pugh, reaching a maximum in LC of class C, and has significant correlations with intravital blood levels of total bilirubin, AST, ALT, albumin, leukocytic intoxication index. With LC progression, AA2-astrocytosis increases significantly in thalamus, cerebellum, striatum and cerebral cortex, which positively correlates with HC ammonia expression in these brain regions.

A Caveat in Identifying a Suitable Reference for Quantitative Susceptibility Mapping in Parkinson’s Disease (P4-11.015)

<h3>Objective:</h3> To identify the lowest mean and standard deviation of susceptibility in two reference regions, lateral ventricle (LV) and white matter (WM) and compare them to choroid plexus (CP) and putamen (PUT), two areas of known iron accumulation. <h3>Background:</h3> Quantitative Susceptibility Mapping (QSM) is a promising non-invasive approach for investigating Parkinson9s Disease, as several studies have reported a correlation of magnetic susceptibility with brain iron concentrations <i>in vivo</i>. Since QSM measures susceptibility relative to a reference value, a suitable reference region must be chosen to compare patients and the stages of the disease. Some studies using non-PD patients suggest LV as a reference with a low susceptibility of cerebrospinal fluid (CSF) that is closest to water, while others use white matter. <h3>Design/Methods:</h3> 44 PD patients underwent baseline QSM as part of a phase II mesenchymal stem cell trial assessing a disease-modifying therapy for PD. We compared the regional mean and standard deviation of susceptibility in parts per billion in left (LH) and right hemisphere (RH) LV, WM, CP and PUT after image processing in QSMxT. <h3>Results:</h3> WM had the lowest susceptibility (LH mean −1.044 std 0.939, RH −1.053 std 0.950), followed by LV (LH mean 3.181 std 1.654, RH 3.167 std 1.555). The two iron-accumulating regions had higher susceptibility, with CP (LH mean 5.205 std 4.214, RH mean 6.316 std 4.404) followed by PUT (LH mean 7.069 std 4.068, RH 7.301 std 4.247). Notably, both left, and right LV susceptibility were significantly higher than left and right hemisphere WM (LH LV vs. LH WM t₍₄₃₎=14.44, p&lt;0.001; RH LV vs. RH WM t₍₄₃₎=13.91, p&lt;0.001). <h3>Conclusions:</h3> WM is a more suitable QSM reference region than LV in PD. However, elevated susceptibility of LV CSF may be promising for future QSM analysis in PD as a correlation of iron CSF levels with disease duration has been reported. <b>Disclosure:</b> The institution of Prof. Ellmore has received research support from NIMH. Dr. Suescun has nothing to disclose. The institution of Dr. Shahnawaz has received research support from American Parkinson Disease Association. The institution of Dr. Shahnawaz has received research support from NIH. The institution of Dr. Shahnawaz has received research support from Texas Alzheimer’s Research &amp; Care Consortium . Dr. Shahnawaz has received intellectual property interests from a discovery or technology relating to health care. Dr. Schiess has nothing to disclose.