Impaired White Matter Research Articles

A novel Lgi1 mutation causes white matter abnormalities and impairs motor coordination in mice.

Leucine-rich glioma-inactivated protein 1 (LGI1) is known to play a key role in autosomal dominant lateral temporal lobe epilepsy (ADLTE). The ADLTE is an inherited disease characterized by focal seizures with distinctive auditory or aphasic symptoms. A large number of mutations on the Lgi1gene have been reported and are believed to be the genetic cause for ADLTE. We identified a novel missense mutation, c.152A>G (p.Asp51Gly), on Lgi1 from a Chinese ADLTE patient who manifests locomotor imbalance and white matter reduction. However, it remains unknown how mutant LGI1 causes white matter abnormalities at molecular and cellular levels. Here, we generated a knock-in mouse bearing this Lgi1mutation. We found that Lgi1D51G/D51G mice exhibited impaired defective white matter and motor coordination. We observed that Lgi1D51G/D51G mice displayed a reduced number of mature oligodendrocytes (OLs) and deficient OL differentiation in the white matter. However, the population of oligodendrocyte precursor cells was not affected in Lgi1D51G/D51G mice. Mechanistically, we showed that the Lgi1D51G mutation resulted in altered mTOR signaling and led to decreased levels of Sox10. Given that Sox10 is a key transcriptional factor to control OL differentiation, our results strongly suggest that the Lgi1D51G mutation may cause white matter abnormalities via inhibiting Sox10-dependent OL differentiation and myelination in the central nervous system.

Effects of enriched environment on microglia and functional white matter recovery in rats with post stroke cognitive impairment

BackgroundWhite matter damage is an important contributor to cognitive impairment after stroke. This study was designed to explore the beneficial effects of enriched environment (EE) on white matter recovery and cognitive dysfunction after stroke, and further explore the potential mechanism of EE on white matter recovery from the perspective of microglia and microglia-mediated neuroinflammation. MethodsMale SD rats underwent middle cerebral artery occlusion (MCAO) or sham surgery. During the MCAO operation, a laser Doppler blood flow meter was used to monitor the blood flow to ensure the success of the model. At 72 h after the operation, 3 rats were selected for TTC staining to identify the infarct size. One week after surgery, the rats were randomly assigned into four different groups—MCAO+standard environment (SE), MCAO+enriched environment (EE), Sham+SE and Sham+EE for 4 weeks. At four weeks after MCAO surgery, neurological function deficiency condition and cognitive function were assessed using Longa score and Morris Water Maze prior to euthanasia. The loss or regeneration of myelin was stained with LFB, the expression of myelin regeneration-related protein and microglia protein was quantified by western blot and immunofluorescence, and the level of inflammatory factors was measured by ELISA. ResultsEE treatment remarkably decreased the neurological deficit score, ameliorated the cognitive functional deficit in MCAO rats. Furthermore, EE alleviated white matter lesions and demyelination, increased myelin basic protein expression and decreased the number of activated microglia in the hippocampus of MCAO rats. In addition, ELISA analysis indicated that EE decreased the level of IL-1β, IL-6, which further suggests that EE may reduce the level of pro-inflammatory factors by affecting the expression of microglia marker, IBA1, provide a benefit physiological environment for myelin recovery, and improve post stroke cognitive impairment. ConclusionsOur results suggest that exposure to EE substantially reduced the damage to brain tissue caused by activation of microglia activation, decreased the level of pro-inflammatory cytokins, which may induced by microglia, protected and promote white matter recovery to improve cognitive function after stroke. Our findings also indicate exposure to EE is beneficial for patients with white matter impairment characterised by white matter disease-related inflammation.

Венозна дисциркуляція та когнітивні порушення

У цій статті розглянутий вплив старіння на функціональну та структурну цілісність венозного кровообігу мозку з точки зору потенційних механізмів, що беруть участь у патогенезі нейродегенерації та когнітивного спаду. Повідомлялося про збільшення венозного колагенозу в мозку з явним лейкоареозом, що свідчить про те, що патологічна перебудова венозної стінки може сприяти ураженню білої речовини як при нормальному старінні, так і при хворобі Альцгеймера. Імовірно, що через вікове зниження розтяжності внутрішня яремна вена втрачає компенсаторну здатність збільшувати трансмуральний тиск і тим самим спричинює у венозній системі мозку венозну гіпертензію. Діосмін підвищує тонус венозних і лімфатичних судин, зменшує венозний і лімфатичний застій, зміцнює стінки капілярів і знижує їх проникність, виявляє протизапальний, протинабряковий і анальгезивний ефекти, покращує мікроциркуляцію і трофіку тканин, перешкоджає тромбоутворенню. Гесперидин сприяє зміцненню стінок дрібних судин, завдяки чому знижується їх проникність, що зумовлює зменшення набряків.

Effects of polygenic risk of schizophrenia on interhemispheric callosal white matter integrity and frontotemporal functional connectivity in first-episode schizophrenia.

Schizophrenia is a severely debilitating psychiatric disorder with high heritability and polygenic architecture. A higher polygenic risk score for schizophrenia (SzPRS) has been associated with smaller gray matter volume, lower activation, and decreased functional connectivity (FC). However, the effect of polygenic inheritance on the brain white matter microstructure has only been sparsely reported. Eighty-four patients with first-episode schizophrenia (FES) patients and ninety-three healthy controls (HC) with genetics, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI) data were included in our study. We investigated impaired white matter integrity as measured by fractional anisotropy (FA) in the FES group, further examined the effect of SzPRS on white matter FA and FC in the regions connected by SzPRS-related white matter tracts. Decreased FA was observed in FES in many commonly identified regions. Among these regions, we observed that in the FES group, but not the HC group, SzPRS was negatively associated with the mean FA in the genu and body of corpus callosum, right anterior corona radiata, and right superior corona radiata. Higher SzPRS was also associated with lower FCs between the left inferior frontal gyrus (IFG)-left inferior temporal gyrus (ITG), right IFG-left ITG, right IFG-left middle frontal gyrus (MFG), and right IFG-right MFG in the FES group. Higher polygenic risks are linked with disrupted white matter integrity and FC in patients with schizophrenia. These correlations are strongly driven by the interhemispheric callosal fibers and the connections between frontotemporal regions.

A tractometry principal component analysis of white matter tract network structure and relationships with cognitive function in relapsing-remitting multiple sclerosis

Understanding the brain changes underlying cognitive dysfunction is a key priority in multiple sclerosis (MS) to improve monitoring and treatment of this debilitating symptom. Functional connectivity network changes are associated with cognitive dysfunction, but it is less well understood how changes in normal appearing white matter relate to cognitive symptoms. If white matter tracts have network structure it would be expected that tracts within a network share susceptibility to MS pathology. In the present study, we used a tractometry approach to explore patterns of variance in white matter metrics across white matter (WM) tracts, and assessed how such patterns relate to neuropsychological test performance across cognitive domains. A sample of 102 relapsing-remitting MS patients and 27 healthy controls underwent MRI and neuropsychological testing. Tractography was performed on diffusion MRI data to extract 40 WM tracts and microstructural measures were extracted from each tract. Principal component analysis (PCA) was used to decompose metrics from all tracts to assess the presence of any co-variance structure among the tracts. Similarly, PCA was applied to cognitive test scores to identify the main cognitive domains. Finally, we assessed the ability of tract co-variance patterns to predict test performance across cognitive domains. We found that a single co-variance pattern which captured microstructure across all tracts explained the most variance (65% variance explained) and that there was little evidence for separate, smaller network patterns of pathology. Variance in this pattern was explained by effects related to lesions, but one main co-variance pattern persisted after this effect was regressed out. This main WM tract co-variance pattern contributed to explaining a modest degree of variance in one of our four cognitive domains in MS. These findings highlight the need to investigate the relationship between the normal appearing white matter and cognitive impairment further and on a more granular level, to improve the understanding of the network structure of the brain in MS.

The Role Of Osteopontin In Patients With Type 2 Diabetes And Cognitive Impairment

Background — type 2 diabetes is associated with obesity and cardiovascular disease; in combination with dysmetabolic and proinflammatory pathophysiological mechanisms, it leads to cognitive impairment. Objective — analysis of the osteopontin role in formation of cognitive disorders in patients with type 2 diabetes. Material and Methods — the study complies with generally accepted ethical rules; it was approved by the Ethics Committee of Siberian State Medical University. It involved 50 patients with type 2 diabetes, who were divided into groups depending on the presence of cognitive impairment; the control group consisted of 25 subjects. All patients underwent general clinical examination, blood sampling for biochemical parameters, and plasma osteopontin content assessment. Magnetic resonance imaging (MRI) was performed on SIGNA Creator E magnetic resonance imaging system, GE Healthcare, 1.5 T, China. The employed techniques included dynamic contrast and arterial spin labeling, proton spectroscopy, tractography. SPSS Statistics software was used for statistical analysis. Results — osteopontin levels were higher in patients with excess weight, hyperglycemia, hyperuricemia, dyslipidemia, and cognitive impairment; and in neuroimaging studies with microangiopathy, based on perfusion MRI, with impaired white matter integration, as well as with neurometabolism of choline, creatine and phosphocreatine metabolites in the hippocampus, as well as their NAA/Cr, NAA/Cho, Cho/Cr ratios (p≤0.05). Conclusion — patients with type 2 diabetes, along with cognitive and metabolic disorders, exhibited elevated levels of osteopontin, which was also associated with impaired cerebral vascularization in general, and white matter organization, as well as neurometabolism in the hippocampus.

Association Between Functional and Structural Brain Connectivity of the Default Mode Network in Non-treatment Seeking Individuals With Alcohol Use Disorder.

Alcohol use disorder (AUD) is associated with alterations within the default mode network (DMN) at rest. Also, impaired white matter structures have been observed in individuals with AUD. This study developed a workflow for examining the relation between functional and structural connectivity, exemplary for nodes of the DMN within a sample of non-treatment seeking individuals with AUD. Furthermore, AUD severity was correlated with both measures independently. The functional magnetic resonance imaging (fMRI) protocol included anatomical, resting state and diffusion weighted imaging measurements. Independent component analyses and deterministic fiber tracking as well as correlation analyses, including the severity of AUD, were performed. N = 18 out of 23 adult study participants took part in the fMRI examination, and N = 15 were included in the final analyses. Established resting-state networks were reliably identified in our sample. Structural connections were found between several nodes of the DMN, whereas only fibers between the medial prefrontal cortex and the posterior cingulate cortex were reliably detected in all individuals. A negative correlation was observed between brain activation during rest and AUD severity in left parietal and temporal regions and the putamen. A more severe AUD predicted impairments in white matter integrity of the cingulum. In AUD, information obtained from a combination of resting-state, diffusion weighted data and clinical information has great potential to provide a more profound understanding of the disorder since alterations may already become apparent at earlier stages of the disorder, e.g. in non-treatment seeking individuals. Alcohol use disorder leads to alterations in the default mode network of the resting brain that is associated with the severity of the disorder. Following our workflow, white matter impairments can be observed between some of the nodes of the default mode network using diffusion tensor imaging. Both, resting-state functional and structural connectivity relate to the severity of alcohol use disorder.

Left Atrial Remodeling and Cerebrovascular Disease Assessed by Magnetic Resonance Imaging in Continuously Monitored Patients

Background: Atrial remodeling is associated with future atrial fibrillation (AF) and stroke. AF has been associated with cognitive impairment and cerebral white matter lesions. We wished to investigate the possible direct association between atrial remodeling and cerebrovascular disease in patients with and without AF documented by implantable loop recorder (ILR). Methods: Cardiac and cerebral magnetic resonance imaging were acquired in a cross-sectional study, including participants ≥70 years of age with stroke risk factors without known AF. Cerebrovascular disease was visually rated using the Fazekas scale and number of lacunar strokes. Left atrial (LA) and ventricular volumes and function were analyzed. Associations between atrial remodeling and cerebrovascular disease were assessed with logistic regression models. The analyses were stratified according to sinus rhythm or any AF during 3 months of continuous ILR monitoring to account for subclinical AF. Results: Of 200 participants investigated, 87% had a Fazekas score ≥1 and 45% had ≥1 lacunar infarct. Within 3 months of ILR monitoring, AF was detected in 28 (14%) participants. For participants with sinus rhythm (n = 172), lower LA passive emptying fraction was associated with Fazekas score after multivariable adjustment (OR [95% CI]: 0.51 [0.27; 0.86] p = 0.02), and increased LA maximum (OR [95% CI]: 1.38 [1.07; 1.82] p = 0.01) and minimum volumes (OR [95% CI]: 1.48 [1.03; 2.17] p = 0.04) were associated with lacunar infarcts. There were no significant associations in patients with AF. Conclusion: In AF-free patients, as documented by ILR monitoring, we found an independent association between LA passive emptying fraction and Fazekas score and between atrial volumes and lacunar infarcts.

The Impacts of Obstructive Sleep Apnea Severity on Brain White Matter Integrity and Cognitive Functions in Children: A Diffusion Tensor Imaging Study.

ObjectiveTo investigate the impacts of obstructive sleep apnea (OSA) on white matter (WM) integrity and cognitive functions of pediatric patients with different levels of OSA severity.MethodsFifty-eight children with OSA and thirty-four healthy controls (HC) were recruited. All participants underwent diffusion tensor imaging (DTI) examination, polysomnography (PSG), and neurocognitive assessments. Patients were divided into mild OSA (MG) and moderate-severe OSA (SG) groups. WM integrity, PSG data, and neurocognitive assessment scores were compared among those groups.ResultsFor apnea hypopnea index (AHI), obstructive apnea hypopnea index (OAHI), arousal index, SpO2 nadir, and attention, SG was worse than both MG and HC with MG worse than HC. For baseline SpO2 and intelligence, SG was worse than both MG and HC with no significant difference between MG and HC. Impaired WM integrity was observed in bilateral anterior thalamic radiation, bilateral inferior fronto-occipital fasciculus, bilateral inferior longitudinal fasciculus, right superior longitudinal fasciculus, right hippocampus, left cingulate gyrus, right uncinate fasciculus, callosum forceps major, and callosum forceps minor only for SG than for HC. WM integrity was significantly correlated with OSA severity and neurocognitive assessment scores only for SG, but not for MG.ConclusionDecreased baseline SpO2, WM impairment, and intelligence decline were all observed only for SG, but not for MG, implying an associated relationship among decreased SpO2, WM impairment and WM impairment. Thus, for SG, additional assessments of brain damage and cognitive function decline are needed for prognostic evaluation of OSA.

Disintegration of anterior thalamic radiation fibers in cerebrovascular disease subjects with periventricular white matter hyperintensities leads to lower executive function performance

AbstractBackgroundWhite matter hyperintensities (WMH) are more prevalent in elder adults and those typically located in periventricular areas are known as periventricular WMHs (pWMH). Recent studies link WMHs to hypoperfusion and ischemic injuries arising from diverse cerebrovascular diseases (CVDs). Previous studies have reported strong associations between WMH burden and disintegration of normal‐appearing white matter (WM) and WM pathways evaluated using diffusion tensor imaging (DTI). This WM deterioration may be the underlying cause of cognitive dysfunction in people with WMHs. The purpose of this study is to identify major WM tracts in which there is evidence of microstructure damage associated with pWMH severity to determine whether this damage is associated with cognitive decline.MethodAssociation between pWMH volume and fractional anisotropy (FA) in 18 major WM tracts in 100 CVD subjects (aged 55‐84 years, 29% female, evidenced by an ischemic stroke event documented by MRI or CT, with a modified Rankin score 0‐3) from the Ontario Neurodegenerative Disease Research Initiative was examined using linear regression. DTI (30 directions, b=1000 s/mm2) was acquired on eight 3T MRI scanners. Mean FA in 18 WM tracts was quantified using TRACULA in FreeSurfer in each subject. Volumes of pWMHs were obtained by semi‐automated segmentation of T1‐weighted images in each subject. Cognitive assessments were completed as part of ONDRI. Associations between cognitive scores and FA in tracts that significantly correlated with pWMH severity were also examined.ResultLinear regression (adjusted by age and sex) detected significant correlation between FA in right anterior thalamic radiation (ATR) (Fig. 1) and pWMH volume after Bonferroni correction (p‐value=0.002, r=‐0.356) (Fig. 2). No other significant associations were identified. Since right ATR is part of fronto‐striato‐thalamic circuit contributing to executive function, FA in ATR predicted association with Trail Making Test‐Part B (adjusted by age, sex, and education) and a signhificant correlation was identified (p‐value=0.006, r=‐0.256) (Fig. 3).ConclusionATR disintegration was associated with pWMH severity in participants with CVD and with executive function. This study suggests that tissue microstructure deterioration in ATR measured by DTI may contribute to decline in executive function in CVD patients with pWMHs.

Impairment and Plasticity of Language-Related White Matter in Patients With Brain Arteriovenous Malformations

Language dysfunction is rarely seen in patients with unruptured brain arteriovenous malformation (AVM) albeit the AVM nidus involving language areas, which provides a unique disease model to study language reorganization. The objective of this study was to investigate the impairment and reorganization patterns and characteristics of language-related white matter in AVMs located at different brain areas. Thirty-three patients with AVMs involving language areas were prospectively enrolled. Patients were categorized into 3 groups according to the lesion locations: the frontal (14 patients), temporal (15 patients), and parietal groups (4 patients). Thirty age- and sex-matched healthy controls were enrolled as comparison. All participants underwent diffusion tensor imaging scans, and automated fiber quantification method was applied to quantitatively study the difference of segmented language-related white matter connectivity between 3 AVM groups and control group. Language functions were normal in all subjects according to Western Aphasia Battery test. In the frontal group, fractional anisotropy (FA) value decreased in the left arcuate fascicle and increased in left superior longitudinal fasciculus and uncinate fascicle; in the temporal group, FA values decreased in left inferior fronto-occipital fascicle and inferior longitudinal fascicle and increased in right anterior thalamic radiation and uncinate fascicle; in the parietal group, FA values decreased in left arcuate fascicle and inferior longitudinal fascicle and increased in bilateral anterior thalamic radiations and uncinate fascicles and right inferior fronto-occipital fascicle. In fascicles with decreased FA values, the increase of radial diffusivity was common, and fascicles with increased FA values usually presented along with increased axial diffusivity values. Remodeling of language-related white matter occurs when traditional language areas are involved by AVM nidus, and its reorganization patterns vary with locations of AVM nidus. Fascicle impairment is mainly caused by the myelin deficits, and its plasticity may be dominated by the axon remodeling procedure.

Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration

Neurologic disorders often disproportionately affect specific brain regions, and different apoptotic mechanisms may contribute to white matter pathology in leukodystrophies or gray matter pathology in poliodystrophies. We previously showed that neural progenitors that generate cerebellar gray matter depend on the anti-apoptotic protein BCL-xL. Conditional deletion of Bcl-xL in these progenitors produces spontaneous apoptosis and cerebellar hypoplasia, while similar conditional deletion of Mcl-1 produces no phenotype. Here we show that, in contrast, postnatal oligodendrocytes depend on MCL-1. We found that brain-wide Mcl-1 deletion caused apoptosis specifically in mature oligodendrocytes while sparing astrocytes and oligodendrocyte precursors, resulting in impaired myelination and progressive white matter degeneration. Disabling apoptosis through co-deletion of Bax or Bak rescued white matter degeneration, implicating the intrinsic apoptotic pathway in Mcl-1-dependence. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mouse model of the leukodystrophy vanishing white matter disease (VWMD), suggesting the potential for MCL-1 deficiency to contribute to clinical neurologic disease. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 deficiency in white matter pathology, and suggest apoptosis inhibition as a leukodystrophy therapy.

Neuroanatomical substrates of attention processing speed in early dementia with Lewy bodies (DLB): A white‐matter voxel‐based morphometry and diffusion tensor imaging study

AbstractBackgroundBased on a previous study (Botzung et al., 2019) that revealed the importance of grey matter (GM) integrity in the striatum for attention processing speed, the purpose of this study was now to examine, in early DLB patients, the relationship between impaired attentional speed performances and white matter changes.MethodWe administered the Trail Making Test A (TMTA) to 73 prodromal to moderate DLB patients (mean MMSE = 26.4) and 30 control subjects (mean MMSE = 28.9) to assess attention processing speed. Three‐dimensional (3D) MRI and Diffusion‐weighted images (DTI) were acquired for all participants and correlational analyses were performed in the patient group using WM‐VBM, fractional anisotropy (FA) and mean diffusivity (MD).ResultBehavioral results showed significantly impaired performances in patients in comparison to control subjects (p = .004). In addition, correlational analyses using WM‐VBM revealed negative WM correlations in the anterior corpus callosum and in the anterior cingulum (p < .05 FDR). Using DTI (p < .05 FDR), correlated with TMTA scores, we found reduced FA in bilateral frontal and posterior regions, and increased MD in bilateral anterior and posterior networks.ConclusionWM‐VBM analysis revealed the involvement of anterior corpus callosum and cingulum, which could indicate a disruption of the loops connecting striatal regions and the prefrontal cortex. Changes in both FA and MD also correlate with impaired attentional speed: further DTI analyses are still ongoing to question the degree of which white matter tracts are disrupted between the striatum and cortical anterior and posterior networks, respectively.

Grey and white matter correlates of behavioural disinhibition assessed under semi-ecological conditions in behavioural variant frontotemporal dementia.

Behavioural variant frontotemporal dementia (bvFTD) is partly characterised by inhibition disorders. Neural correlates of disinhibition being poorly known, we aim to identify grey and white matter impairments associated to behavioural disinhibition. We assess behavioural disinhibition in a semi-ecological setting, noting occurrences of 16 behaviours - derived from clinical criteria of bvFTD - related to compulsivity, impulsivity or social disinhibition, in a population of 20 bvFTD and 20 healthy controls (HC). Subjects also undergo an MRI. In this study, voxel-based morphometry and diffusion tensor tractography (DTI) are used to investigate grey and white matter changes in bvFTD patients compared to HC. Grey matter atrophy and DTI metrics - fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) - are then correlated to behavioural disinhibition scores. Grey matter analysis was conducted on 15 bvFTD and 18 HC. Results mainly show an alteration of frontal and anterior temporal regions as well as subcortical regions (e.g., thalamus) in bvFTD patients compared to HC. Social disinhibition is correlated with a huge atrophy of the frontotemporal regions and of the cingulate cortex, while compulsivity and impulsivity are associated to smaller areas of the orbitofrontal and temporal regions. Based on these results, white matter analysis was conducted on 10 bvFTD patients and 11 HC. Results show a significant decrease of FA and increase of RD in the cingulum, the forceps minor (FM) and the uncinate fasciculus (UF) in bvFTD patients. In addition, patients show a significant increase of MD in the FM and the UF, as well as a significant increase of AD in the FM and right UF. Among bvFTD patients, compulsivity is associated to a weaker integrity of the cingulum while social disinhibition is correlated to alterations of the left UF. On the contrary, impulsivity is correlated with greater integrity of the bilateral uncinate. The cingulum is already known to be impaired in obsessive-compulsive disorder and UF impairments are related to behavioural and social disinhibition. Furthermore, positive correlation between impulsive behaviours and UF integrity are already reported, which is consistent with our findings based on a semi-ecological assessment of behavioural disinhibition.

White matter diffusion abnormalities observed in cognitively normal elderly before conversion to mild cognitive impairment

AbstractBackgroundDifferences in white matter (WM) microstructure, as measured with diffusion tensor imaging (DTI), have been observed between cognitively normal, mild cognitively impaired (MCI), and Alzheimer’s disease (AD) patient groups. With increased focus on early intervention for AD, detection of preclinical changes is paramount; however, due to difficulties in predicting future conversion, few studies have investigated WM deterioration prior to symptom onset. Using DTI data from the Vallecas project (an 8‐year longitudinal study of healthy elderly individuals), we determine if WM changes can be found in cognitively normal individuals before conversion to MCI.MethodsFrom a baseline cohort of 824 cognitively normal 70‐85 year olds, 65 individuals converted to MCI over the study duration (mean age 77.0±4.29 years, 58% female). 65 non‐converters were matched by age, sex, and years of education to act as controls. DTI scans from one year before conversion were analysed using tract‐based spatial statistics implemented in FSL. Fractional anisotropy (FA), mean diffusivity (MD), and mode of anisotropy (MO) were compared between groups using non‐parametric permutation tests. A second comparison between future converters and all 759 non‐converters (mean age 74.0±3.92 years, 65% female) was also conducted, using age, sex, and years of education as covariates.ResultsIn the unmatched comparisons, controls had higher FA in the left forceps minor (ForMin) and anterior corona radiata (CR) (p<0.05), and higher MO along the corpus callosum (CC) and ForMin (p<0.01). Future converters had higher FA in the left posterior CR and corticospinal tract (p<0.05), higher MD in the left anterior CR (p<0.05), and higher MO along the bilateral projection fibres (p<0.01). In the matched comparison, only MO differences were observed, with higher MO in controls along the body of the CC (p<0.05), and higher MO in future converters in the left projection fibres and the splenium of the CC (p<0.01). All significant results were FWE‐corrected.ConclusionsOur results suggest that frontal commissural fibres begin to deteriorate in cognitively normal subjects destined to convert to MCI, whilst also demonstrating selective preservation of projection fibres. We also find that MO is a sensitive measure of white matter microstructural changes presaging cognitive decline, even in preclinical populations.

Associations between mean apparent propagator MRI and cerebrospinal fluid markers of AD pathology, neurodegeneration, and glial activation, in cognitively unimpaired adults

AbstractBackgroundNumerous studies have reported correlations between diffusion tensor imaging (DTI) metrics and cerebrospinal (CSF) biomarkers of Alzheimer’s disease (AD) pathology. However, the assumption of Gaussian diffusion in DTI limits the ability to characterize white matter (WM) microstructural changes. Mean apparent propagator (MAP) MRI is a model that attempts to overcome this limitation by allowing for the estimation of parameters that convey more precise information about WM microstructure.To investigate MAP MRI’s sensitivity to early WM degeneration associated with preclinical, asymptomatic AD pathology, we examined the relationship between CSF biomarkers and MAP MRI microstructural parameters in 92 cognitively unimpaired adults.Method92 cognitively unimpaired controls from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center were imaged with multi‐shell diffusion‐weighted MRI. DTI metrics (FA, MD, RD, AxD) were computed and the MAP MRI model was employed to calculate various microstructural parameters: Return to origin probability (RTOP), return to axis probability (RTAP), return to plane probability (RTPP), mean squared displacement (MSD), Non‐Gaussianity (NG), and q‐space inverse variance (QIV). DTI and MAP parameter values were extracted from the cingulum and correlated to Aβ42, P‐Tau, P‐Tau/Aβ42, YKL‐40, and neurofilament light chain (NFL) levels in lumbar cerebrospinal fluid samples.ResultMAP parameters were moderately and significantly correlated to most CSF measures. RTPP was significantly correlated to all 5 CSF measures, while MSD, NG, and QIV were significantly correlated to 4 of 5 CSF measures. NFL, a known marker for axonal degeneration, was significantly related to 5 of the 6 MAP parameters assessed. Meanwhile, correlations between DTI and CSF measures were weak and non‐significant.ConclusionThese preliminary results highlight the potential of MAP MRI to detect early WM deterioration indicative of preclinical, asymptomatic AD and associated neurodegeneration. MAP metrics extracted from a commonly affected WM tract in AD were more strongly and significantly correlated with CSF measures than DTI metrics were, suggesting that MAP MRI may be more useful than DTI for identifying the earliest WM microstructural changes associated with AD. Future work will incorporate longitudinal data and assess the effects of CSF and molecular imaging markers on MAP age trajectories.

The Relationship Between Renal Function and Imaging Markers and Total Burden of Cerebral Small Vessel Disease.

Previous studies demonstrating the association between renal functions and cerebral small vessel diseases have usually focused on white matter hyperintensity in the general population or lacunar stroke patients. This study aimed to investigate the effects of renal function on imaging markers of cerebral small vessel disease and etiologic subtypes of stroke in patients with acute ischemic stroke or transient ischemic attack. A total of 356 consecutive patients with acute ischemic stroke or transient ischemic attack who were admitted to the Stroke Unit and underwent brain magnetic resonance imaging were evaluated. Demographic data, vascular risk factors, stroke etiology, estimated glomerular filtration rate and severity of cerebral small vessel disease markers, and total cerebral small vessel disease burden were evaluated. There was a significant inverse correlation between estimated glomerular filtration rate and total number of lacunes, periventricular and deep subcortical Fazekas scores, grade of enlarged perivascular spaces in the centrum semiovale, lobar and total cerebral microbleeds, and total cerebral small vessel disease burden. Impaired renal function was an independent risk factor for the presence of lacunes, deep cerebral microbleeds, and increased total burden. Renal function impairment and periventricular white matter hyperintensities were significantly associated with the etiologic subgroup of small vessel occlusion. The results were still significant after the exclusion of patients below 50 years of age. Our results indicate that there is a relationship between renal function impairment and increased total burden, as well as acute ischemic stroke/transient ischemic attack due to small vessel occlusion.

Study of white matter integrity in fathers of children with attention deficit hyperactivity disorder

BackgroundAttention deficit hyperactivity disorder (ADHD) is an early-onset neurodevelopmental disorder that can extend into adulthood with multiple reported neuroimaging abnormalities. The focus of this research was to assess white matter impairments in ADHD children’s fathers with and without potential adult ADHD to see if these differences are connected with the persistence of ADHD into adulthood.ResultsThe occurrence rate of the potential adult ADHD diagnosis among fathers of children with ADHD was 60%. There were statistically significant differences between fathers with ADHD and the non-ADHD population, due to the fact that the mean FA of the left superior corona radiata and the right posterior corona radiata were lower in the ADHD group than in the non-ADHD group, while the FA of the ADHD group was significantly greater than that of the non-ADHD group in terms of the left and right anterior thalamic radiations, the right superior longitudinal fasciculus and the left anterior corona radiata.ConclusionsWe observed an increased prevalence of ADHD in fathers of children diagnosed with ADHD. Fathers with potential adult ADHD have a variety of white matter abnormalities that reflect the neurobiological basis of ADHD, even in sub-threshold cases. This may provide insight into the neuroanatomical locations associated with the maintenance of ADHD throughout adulthood.

Low-grade IVH in preterm infants causes cerebellar damage, motor, and cognitive impairment.

Few studies have examined the effect of low-grade intraventricular hemorrhage (IVH) on the white matter in the cerebellum and its association with neurodevelopment. We evaluated cerebellar white matter at term-equivalent age (TEA) in preterm infants with low-grade IVH. Furthermore, we assessed neurodevelopmental outcomes at 3 years of age to examine the influence of low-grade IVH on neurodevelopment. Thirteen infants with low-grade IVH and 26 without IVH, born at <30 weeks' postmenstrual age (PMA), were enrolled in this study. Diffusion tensor imaging (DTI) parameters, including fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the middle and superior cerebellar peduncles (SCP), were measured. Neurodevelopmental outcomes at three years of age were assessed and the correlation between DTI parameters and developmental quotient (DQ) was analyzed. Preterm infants with IVH showed lower FA values (P < 0.01) and higher ADC values (P < 0.05) in the SCP at TEA than the no-IVH group. Lower Postural-Motor and Cognitive-Adaptive DQ at 3 years of age were observed in the IVH compared to the no-IVH group. A significant correlation between the FA values in the SCP at TEA and the Posture-Motor DQ was observed at three years of age (P = 0.043, r = 0.50). These data suggest that low-grade IVH in preterm infants affects the SCP at TEA and that impaired cerebellar white matter correlates with poor motor development at three years of age.

Disrupted functional connectivity in white matter resting-state networks in unilateral temporal lobe epilepsy.

Unilateral temporal lobe epilepsy (TLE) is the most common type of focal epilepsy characterized by foci in the unilateral temporal lobe grey matters of regions such as the hippocampus. However, it remains unclear how the functional features of white matter are altered in TLE. In the current study, resting-state functional magnetic resonance imaging (fMRI) was performed on 71 left TLE (LTLE) patients, 79 right TLE (RTLE) patients and 47 healthy controls (HC). Clustering analysis was used to identify fourteen white matter networks (WMN). The functional connectivity (FC) was calculated among WMNs and between WMNs and grey matter. Furthermore, the FC laterality of hemispheric WMNs was assessed. First, both patient groups showed decreased FCs among WMNs. Specifically, cerebellar white matter illustrated decreased FCs with the cerebral superficial WMNs, implying a dysfunctional interaction between the cerebellum and the cerebral cortex in TLE. Second, the FCs between WMNs and the ipsilateral hippocampus (grey matter foci) were also reduced in patient groups, which may suggest insufficient functional integration in unilateral TLE. Interestingly, RTLE showed more severe abnormalities of white matter FCs, including links to the bilateral hippocampi and temporal white matter, than LTLE. Taken together, these findings provide functional evidence of white matter abnormalities, extending the understanding of the pathological mechanism of white matter impairments in unilateral TLE.