White Matter Disruption Research Articles

White matter disruptions related to inattention and autism spectrum symptoms in tuberous sclerosis complex

Tuberous sclerosis complex is a rare genetic multisystem condition that is associated with a high prevalence of neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder. The underlying neural mechanisms of the emergence of these symptom domains in tuberous sclerosis complex remain unclear.Here, we use fixel-based analysis of diffusion-weighted imaging, which allows for the differentiation between multiple fibre populations within a voxel, to compare white matter properties in 16 participants with tuberous sclerosis complex (aged 11–19) and 12 age and sex matched control participants. We further tested associations between white matter alterations and autism and inattention symptoms as well as cognitive ability in participants with tuberous sclerosis complex.Compared to controls, participants with tuberous sclerosis complex showed reduced fibre density cross-section (FDC) in the dorsal branch of right superior longitudinal fasciculus and bilateral inferior longitudinal fasciculus, reduced fibre density (FD) in bilateral tapetum, and reduced fibre cross-section (FC) in the ventral branch of right superior longitudinal fasciculus. In participants with tuberous sclerosis complex, the extent of FDC reductions in right superior longitudinal fasciculus was significantly associated with autism traits (social communication difficulties and restricted, repetitive behaviours), whereas FDC reductions in right inferior longitudinal fasciculus were associated with inattention. The observed white matter alterations were unrelated to cognitive ability.Our findings shed light on the fibre-specific biophysical properties of white matter alterations in tuberous sclerosis complex and suggest that these regional changes are selectively associated with the severity of neurodevelopmental symptoms.

White Matter Disruptions Related to Inattention and Autism Spectrum Symptoms in Tuberous Sclerosis Complex

White Matter Disruptions Related to Inattention and Autism Spectrum Symptoms in Tuberous Sclerosis Complex

Diffusion Tensor Imaging Correlates of Resilience Following Adolescent Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with considerable mortality and morbidity in adolescents, but positive outcomes are possible. Resilience is the concept that some individuals flourish despite significant adversity. To determine if there is a relationship between resilience-promoting factors that are known to promote resilience and white matter (WM) microstructure 1 year after complicated mild TBI or moderate or severe TBI that is sustained by adolescents. We examined the relationship between performance on a self-report measure of resilience-promoting factors and WM integrity assessed by diffusion tensor imaging in a group of adolescents who had sustained either a TBI (n = 38) or an orthopedic injury (OI) (n = 23). Immediately following injury, the individuals with TBI and the OI controls had comparable levels of resilience-promoting factors; however, at 1 year post injury, the TBI group endorsed fewer resilience-promoting factors and exhibited WM disruption compared with the OI controls. The individuals with TBI who had more resilience-promoting factors at 1 year post injury exhibited increased WM integrity, but the OI controls did not. Findings were particularly strong for the following structures: anterior corona radiata, anterior limb of the internal capsule, and genu of the corpus callosum-structures that are implicated in social cognition and are frequently disrupted after TBI. Relationships were notable for caregiver and community-level resilience-promoting factors. The current findings are some of the first to indicate neurobiological evidence of previously noted buffering effects of resilience-promoting factors in individuals with TBI.

The posterior interhemispheric transparieto-occipital fissure approach to the atrium of the lateral ventricle: a fiber microdissection study with case series.

The surgical approach to the atrium of the lateral ventricle remains a challenge because of its deep location and close relationship to important neurovascular structures. We present an alternative and safer approach to lesions of the atrium using a natural pathway through the parieto-occipital fissure. We demonstrate this approach through cadaveric anatomical microdissection and a case series. Five formalin-fixed brain specimens (10 hemispheres) were dissected with the Klingler technique. Transillumination was used to show the trajectory of the approach in cadaveric specimens. Clinical data from five patients who underwent this approach were reviewed. This data included intraoperative ultrasound images, operative images, pre- and postoperative magnetic resonance imaging, MR tractography, and visual field examination. The parieto-occipital fissure is a constant, uninterrupted fissure that can be easily identified in cadavers. Our anatomical dissection study revealed that the atrium of the lateral ventricle can be approached through the parieto-occipital fissure with minor damage to the short association fibers between the precuneus and cuneus, and a few fibers of the forceps major. In our series, five patients underwent total resection of their atrial lesions via the posterior interhemispheric transparieto-occipital fissure. No morbidity or mortality was observed, and the disruption of white matter was minimal, as indicated on postoperative tractography. The postoperative visual fields were normal. The posterior interhemispheric transparieto-occipital fissure approach is an alternative to remove lesions in the atrium of the lateral ventricle, causing the least damage to white matter tracts and preserving visual cortex and optic radiation.

Frontal white matter lesions in Alzheimer\u2019s disease are associated with both small vessel disease and AD-associated cortical pathology

Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer’s disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms.

White Matter Abnormalities in Patients With Typhoon-Related Posttraumatic Stress Disorder.

Patients with posttraumatic stress disorder (PTSD) might have white matter abnormalities. However, less is known about white matter changes after exposing a specific traumatic event. The purpose of this study was to explore the abnormalities of diffusion in cerebral white matter and its relationship with the clinical symptoms in patients with PTSD by using diffusion tensor imaging (DTI). Diffusion-weighted imaging of the cerebrum was performed in typhoon survivors with (n = 27) and without PTSD (n = 33) and healthy controls (HCs) (n = 30). Differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated among groups using voxel-based analysis of the DTI data. Correlations between diffusion indices and clinical symptoms in patients with PTSD were also assessed. Both patients with PTSD and trauma-exposed control (TEC) group showed increased FA in the anterior limb of the internal capsule, forceps of the corpus callosum, and corona radiata relative to the HC group. Additionally, there was a negative correlation between FA values in the white matter and the clinical symptoms. Trauma exposure may result in disruption of cerebral white matter in individuals with or without PTSD, particularly in the frontal fibers. Aberrant white matter alterations may be associated with the severity of PTSD symptoms.

Widespread White Matter Alterations in Patients With Visual Snow Syndrome.

Background: Visual snow is considered a disorder of central visual processing resulting in a perturbed perception of constant binocular flickering or pixilation of the whole visual field. The underlying neurophysiological and structural alterations remain elusive.Methods: In this study, we included patients (final n = 14, five dropouts; five females, mean age: 32 years) with visual snow syndrome (VSS) and age- and sex-matched controls (final n = 20, 6 dropouts, 13 females, mean age: 28.2 years). We applied diffusion tensor imaging to examine possible white matter (WM) alterations in patients with VSS.Results: The patient group demonstrated higher (p-corrected < 0.05, adjusted for age and sex) fractional anisotropy (FA) and lower mean diffusivity (MD) and radial diffusivity (RD) compared to controls. These changes were seen in the prefrontal WM (including the inferior fronto-occipital fascicle), temporal and occipital WM, superior and middle longitudinal fascicle, and sagittal stratum. When additionally corrected for migraine or tinnitus—dominant comorbidities in VSS—similar group differences were seen for FA and RD, but less pronounced.Conclusions: Our results indicate that patients with VSS present WM alterations in parts of the visual cortex and outside the visual cortex. As parts of the inferior fronto-occipital fascicle and sagittal stratum are associated with visual processing and visual conceptualisation, our results suggest that the WM alterations in these regions may indicate atypical visual processing in patients with VSS. Yet, the frequent presence of migraine and other comorbidities such as tinnitus in VSS makes it difficult to attribute WM disruptions solely to VSS.

Reduced default mode network connectivity relative to white matter integrity is associated with poor cognitive outcomes in patients with idiopathic normal pressure hydrocephalus

BackgroundThe aim of this study was to investigate whether default mode network (DMN) connectivity and brain white matter integrity at baseline were associated with severe cognitive impairments at baseline and poor cognitive outcomes after shunt placement in patients with idiopathic normal pressure hydrocephalus (iNPH).MethodsTwenty consecutive patients with iNPH whose symptoms were followed for 6 months after shunt placement and 10 healthy controls (HCs) were enrolled. DMN connectivity and brain white matter integrity at baseline in the patients with iNPH and HCs were detected by using resting-state functional magnetic resonance imaging (MRI) with independent component analysis and diffusion tensor imaging, respectively, and these MRI indexes were compared between the patients with iNPH and HCs. Performance on neuropsychological tests for memory and executive function and on the gait test was assessed in the patients with iNPH at baseline and 6 months after shunt placement. We divided the patients with iNPH into the relatively preserved and reduced DMN connectivity groups using the MRI indexes for DMN connectivity and brain white matter integrity, and the clinical measures were compared between the relatively preserved and reduced DMN connectivity groups.ResultsMean DMN connectivity in the iNPH group was significantly lower than that in the HC group and was significantly positively correlated with Rey auditory verbal learning test (RAVLT) immediate recall scores and frontal assessment battery (FAB) scores. Mean fractional anisotropy of the whole-brain white matter skeleton in the iNPH group was significantly lower than that in the HC group. The reduced DMN connectivity group showed significantly worse performance on the RAVLT at baseline and significantly worse improvement in the RAVLT immediate recall and recognition scores and the FAB scores than the preserved DMN connectivity group. Moreover, the RAVLT recognition score highly discriminated patients with relatively preserved DMN connectivity from those with relatively reduced DMN connectivity.ConclusionsOur findings indicated that iNPH patients with reduced DMN connectivity relative to the severity of brain white matter disruption have severe memory deficits at baseline and poorer cognitive outcomes after shunt placement. However, further larger-scale studies are needed to confirm these findings.

Neurobiological substrates of major psychiatry disorders: transdiagnostic associations between white matter abnormalities, neuregulin 1 and clinical manifestation.

Background:Schizophrenia, bipolar disorder and major depressive disorder are increasingly being conceptualized as a transdiagnostic continuum. Disruption of white matter is a common alteration in these psychiatric disorders, but the molecular mechanisms underlying the disruption remain unclear. Neuregulin 1 (NRG1) is genetically linked with susceptibility to schizophrenia, bipolar disorder and major depressive disorder, and it is also related to white matter.Methods:Using a transdiagnostic approach, we aimed to identify white matter differences associated with NRG1 and their relationship to transdiagnostic symptoms and cognitive function. We examined the white matter of 1051 participants (318 healthy controls and 733 patients with major psychiatric disorders: 254 with schizophrenia, 212 with bipolar disorder and 267 with major depressive disorder) who underwent diffusion tensor imaging. We measured the plasma NRG1-β1 levels of 331 participants. We also evaluated clinical symptoms and cognitive function.Results:In the patient group, abnormal white matter was negatively associated with NRG1-β1 levels in the genu of the corpus callosum, right uncinate fasciculus, bilateral inferior fronto-occipital fasciculus, right external capsule, fornix, right optic tract, left straight gyrus white matter and left olfactory radiation. These NRG1-associated white matter abnormalities were also associated with depression and anxiety symptoms and executive function in patients with a major psychiatric disorder. Furthermore, across the 3 disorders we observed analogous alterations in white matter, NRG1-β1 levels and clinical manifestations.Limitations:Medication status, the wide age range and our cross-sectional findings were limitations of this study.Conclusion:This study is the first to provide evidence for an association between NRG1, white matter abnormalities, clinical symptoms and cognition in a transdiagnostic psychiatric cohort. These findings provide further support for an understanding of the molecular mechanisms that underlie the neuroimaging substrates of major psychiatric disorders and their clinical implications.

The Associations Between White Matter Disruptions and Cognitive Decline at the Early Stage of Subcortical Vascular Cognitive Impairment: A Case-Control Study.

ObjectiveEmerging evidence suggests that white matter (WM) disruption is associated with the incidence of subcortical vascular cognitive impairment (SVCI). However, our knowledge regarding this relationship in the early stage of SVCI is limited. We aimed to investigate the associations between WM disruptions and cognitive declines at the early stage of SVCI.MethodWe performed a case–control study, involving 22 cases and 19 controls. The cases were patients at the early stage of SVCI, which was defined as subcortical ischemic vascular disease with normal global cognitive measures (pre-SVCI). The controls were healthy people matched by age, sex, and education years. We assessed the differences in a battery of neuropsychological tests between the two groups, investigated the diffusion changes in 40 WM tracts among the participants via an atlas-based segmentation strategy, and compared the differences between the cases and controls by multiple linear regression analysis. We then evaluated the relationships between diffusion indices and cognitive assessment scores by Pearson’s correlation.ResultsThe pre-SVCI group exhibited significant differences in the Montreal cognitive assessment (MoCA), Rey–Osterrieth Complex Figure (R-O)-copy, and Trail Making Test (TMT)-B test compared with the controls. Compared with the controls, some long associative and projective bundles, such as the right anterior corona radiata (ACR), the right inferior fronto-occipital fasciculus (IFOF), and the left external capsule (EC), were extensively damaged in cases after Bonferroni correction (p < 0.05/40). Damages to specific fibers, such as the right ACR, IFOF, and posterior thalamic radiation (PTR), exhibited significant correlations with declines in MoCA, R-O delay, and the Mini-Mental State Examination (MMSE), respectively, after Bonferroni correction (p < 0.05/14).ConclusionLong WM tracts, especially those in the right hemisphere, were extensively damaged in the pre-SVCI patients and correlated with declines in executive functions and spatial processing. Patients of pre-SVCI are likely at an ultra-early stage of SVCI, and there is a very high risk of this condition becoming SVCI.

Multi-Dimensional Diffusion Tensor Imaging Biomarkers for Cognitive Decline From the Preclinical Stage: A Study of Post-stroke Small Vessel Disease.

Objectives: We aim to investigate whether multi-dimensional diffusion tensor imaging (DTI) measures can sensitively identify different cognitive status of cerebral small vessel disease (CSVD) and to explore the underlying pattern of white matter disruption in CSVD.Methods: Two hundred and two participants were recruited, composed of 99 CSVD patients with mild cognitive impairment (VaMCI) and 60 with no cognitive impairment (NCI) and 43 healthy subjects as normal controls (NC). Full domain neuropsychological tests and diffusion-weighted imaging were performed on each subject. DTI metrics such as fractional anisotropy (FA), mean diffusivity (MD), the skeletonized mean diffusivity (PSMD), and structural brain network measures including network strength, global efficiency (EGlobal), and local efficiency (ELocal) were calculated. Region of interest (ROI) analysis of 42 white matter tracts was performed to examine the regional anatomical white matter disruption for each group.Results: Significant differences of multiple cognitive test scores across all cognitive domains especially processing and executive function existed among the three groups. DTI measures (FA, MD, and PSMD) showed significant group difference with the cognitive status changing. FA and EGlobal showed significant correlation with processing speed, executive function, and memory. ROI analysis found that white matter integrity impairment occurred from the preclinical stage of vascular cognitive impairment (VCI) due to CSVD. These lesions in the NCI group mainly involved some longitudinal fibers such as right superior longitudinal fasciculus (SLF-R), right superior fronto-occipital fasciculus (SFO-R), and right uncinate fasciculus (UNC-R), which might be more vulnerable to the cerebrovascular aging and disease process.Conclusions: DTI measures are sensitive neuroimaging markers in detecting the early cognitive impairment and able to differentiate the different cognitive status due to CSVD. Subtle changes of some vulnerable white matter tracts may be observed from the preclinical stage of VCI and have a local to general spreading pattern during the disease progression.

Diffusion MRI detects basal forebrain cholinergic abnormalities in the 3xTg-AD mouse model of Alzheimer's disease

Degeneration of the basal forebrain (BF) is detected early in the course of Alzheimer's disease (AD). Reduction in the number of BF cholinergic (ChAT) neurons associated with age-related hippocampal cholinergic neuritic dystrophy is described in the 3xTg-AD mouse model; however, no prior diffusion MRI (dMRI) study has explored the presence of BF alterations in this model. Here we investigated the ability of diffusion MRI (dMRI) to detect abnormalities in BF microstructure for the 3xTg-AD mouse model, along with related pathology in the hippocampus (HP) and white matter (WM) tracks comprising the septo-hippocampal pathway. 3xTg-AD and normal control (NC) mice were imaged in vivo using the specific dMRI technique known as diffusional kurtosis imaging (DKI) at 2, 8, and 15 months of age, and 8 dMRI parameters were measured at each time point. Our results revealed significant lower dMRI values in the BF of 2 months-old 3xTg-AD mice compared with NC mice, most likely related to the increased number of ChAT neurons seen in this AD mouse model at this age. They also showed significant age-related dMRI changes in the BF of both groups between 2 and 8 months of age, mainly a decrease in fractional anisotropy and axial diffusivity, and an increase in radial kurtosis. These dMRI changes in the BF may be reflecting the complex aging and pathological microstructural changes described in this region. Group differences and age-related changes were also observed in the HP, fimbria (Fi) and fornix (Fx). In the HP, diffusivity values were significantly higher in the 2 months-old 3xTg-AD mice, and the HP of NC mice showed a significant increase in axial kurtosis after 8 months, reflecting a normal pattern of increased fiber density complexity, which was not seen in the 3xTg-AD mice. In the Fi, mean and radial diffusivity values were significantly higher, and fractional anisotropy, radial kurtosis and kurtosis fractional anisotropy were significantly lower in the 2 months-old 3xTg-AD mice. The age trajectories for both NC and TG mice in the Fi and Fx were similar between 2 and 8 months, but after 8 months there was a significant decrease in diffusivity metrics associated with an increase in kurtosis metrics in the 3xTg-AD mice. These later HP, Fi and Fx dMRI changes probably reflect the growing number of dystrophic neurites and AD pathology progression in the HP, accompanied by WM disruption in the septo-hippocampal pathway. Our results demonstrate that dMRI can detect early cytoarchitectural abnormalities in the BF, as well as related aging and neurodegenerative changes in the HP, Fi and Fx of the 3xTg-AD mice. Since DKI is widely available on clinical scanners, these results also support the potential of the considered dMRI parameters as in vivo biomarkers for AD disease progression.

White Matter Survival within and around the Hematoma: Quantification by MRI in Patients with Intracerebral Hemorrhage.

White matter (WM) injury and survival after intracerebral hemorrhage (ICH) has received insufficient attention. WM disruption surrounding the hematoma has been documented in animal models with histology, but rarely in human ICH with noninvasive means, like magnetic resonance imaging (MRI). A few human MRI studies have investigated changes in long WM tracts after ICH remote from the hematoma, like the corticospinal tract, but have not attempted to obtain an unbiased quantification of WM changes within and around the hematoma over time. This study attempts such quantification from 3 to 30 days post ictus. Thirteen patients with mild to moderate ICH underwent diffusion tensor imaging (DTI) MRI at 3, 14, and 30 days. Fractional anisotropy (FA) maps were used to calculate the volume of tissue with FA > 0.5, both within the hematoma (lesion) and in the perilesional tissue. At day 3, the percentages of both lesional and perilesional tissue with an FA > 0.5 were significantly less than contralateral, unaffected, anatomically identical tissue. This perilesional contralateral difference persisted at day 14, but there was no significant difference at day 30. The loss of perilesional tissue with FA > 0.5 increased with increasing hematoma size at day 3 and day 14. All patients had some tissue within the lesion with FA > 0.5 at all time points. This did not decrease with duration after ictus, suggesting the persistence of white matter within the hematoma/lesion. These results outline an approach to quantify WM injury, both within and surrounding the hematoma, after mild to moderate ICH using DTI MRI. This may be important for monitoring treatment strategies, such as hematoma evacuation, and assessing efficacy noninvasively.

Disrupted Structural Brain Connectome Is Related to Cognitive Impairment in Patients With Ischemic Leukoaraiosis.

Ischemic leukoaraiosis (ILA) is related to cognitive impairment and vascular dementia in the elderly. One possible mechanism could be the disruption of white matter (WM) tracts and network function that connect distributed brain regions involved in cognition. The purpose of this study was to investigate the relationship between structural connectome and cognitive functions in ILA patients. A total of 89 patients with ILA (Fazekas score ≥ 3) and 90 healthy controls (HCs) underwent comprehensive neuropsychological examinations and diffusion tensor imaging scans. The tract-based spatial statistics approach was employed to investigate the WM integrity. Graph theoretical analysis was further applied to construct the topological architecture of the structural connectome in ILA patients. Partial correlation analysis was used to investigate the relationships between network measures and cognitive performances in the ILA group. Compared with HCs, the ILA patients showed widespread WM integrity disruptions. The ILA group displayed increased characteristic path length (Lp) and decreased global network efficiency at the level of the whole brain relative to HCs, and reduced nodal efficiencies, predominantly in the frontal–subcortical and limbic system regions. Furthermore, these structural connectomic alterations were associated with cognitive impairment in ILA patients. The association between WM changes (i.e., fractional anisotropy and mean diffusivity measures) and cognitive function was mediated by the structural connectivity measures (i.e., local network efficiency and Lp). In conclusion, cognitive impairment in ILA patients is related to microstructural disruption of multiple WM fibers and topological disorganization of structural networks, which have implications in understanding the relationship between ILA and the possible attendant cognitive impairment.

White Matter Disruption in Pediatric Traumatic Brain Injury: Results From ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury.

Our study addressed aims (1) to test the hypothesis that moderate-severe traumatic brain injury (TBI) in pediatric patients is associated with widespread white matter (WM) disruption, (2) to test the hypothesis that age and sex affect WM organization after injury, and (3) to examine associations between WM organization and neurobehavioral outcomes. Data from 10 previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Pediatric Moderate/Severe TBI (msTBI) working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline. Five hundred seven children and adolescents (244 with complicated msTBI and 263 controls) were included. Patients were clustered into 3 postinjury intervals: acute/subacute, <2 months; postacute, 2 to 6 months; and chronic, ≥6 months. Outcomes were dMRI metrics and postinjury behavioral problems as indexed by the Child Behavior Checklist. Our analyses revealed altered WM diffusion metrics across multiple tracts and all postinjury intervals (effect sizes range d = -0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time after injury. We observed a sex-by-group interaction: female patients with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (β = 0.043), which coincided with more parent-reported behavioral problems (β = -0.0027). WM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically meaningful patient subtypes.

Reader Response: Longitudinal Changes of Brain Microstructure and Function in Nonconcussed Female Rugby Players.

We read the article by Manning et al.1 with interest. Studies of professional contact-sports athletes have made clear that exposures to repetitive head impacts over decades are associated with late-life neurodegenerative dementia.2,3 It is less clear whether participation in contact sports at the amateur level results in comparable risks. The study by Manning et al. found white matter (WM) microstructural disruption—especially in the corpus callosum and impaired functional connectivity in the default mode network over time in concussion-free and asymptomatic female rugby players—using diffusion tensor (DTI) and resting-state connectivity MRI (rsMRI), respectively.1 These WM tracts are known to be disrupted as a consequence of more severe traumatic brain injuries.4 In contrast to the existing studies,5 Manning et al. assessed WM and functional changes in female athletes and noncontact sport athletes longitudinally, which is a novel and strong study design. Although the results of the Manning et al. study are compelling, they should be interpreted with caution. Although DTI and rsMRI are sensitive for identifying WM disruption, it is likely that there is substantial cognitive reserve built into brain and that these elegant imaging techniques may detect small degrees of disruption that are unlikely to result in functional limitations. Future studies with larger sample sizes and longer follow-up will be required to answer this important question. Finally, the DTI and rsMRI methods have several limitations, including limited availability and cumbersome image processing, which limits their usefulness for routine assessment of athletes. Future studies should include blood-based biomarkers, such as neurofilament light and glial fibrillary acidic protein, which are inexpensive and straightforward to interpret, as markers of axonal disruption. How well blood biomarkers correlate with the imaging biomarkers of axonal injury after concussive and subconcussive head impacts is a critical issue which remains to be resolved.

Assessing Behavioral Impairment after Doxorubicin Chemotherapy in Rats

Chemotherapy has been associated with deficits in cognition and memory, delayed processing speed and executive function which may remain in patients as a long-term neurological effects. In addition, it also causes the disruption of hippocampal cell proliferation and neurogenesis, increased oxidative stress, and disruption in white matter. The cellular mechanisms linked with these side effects are poorly understood until now. Doxorubicin is Anthracycline agent that adversely affects the hippocampal neurogenesis and induces apoptosis by increasing oxygen radicals. It is considered first line therapy treatment for the most common cancers like breast, ovarian, and bladder. Young adult female Long Evans Hooded rats were divided into Doxorubicin treated (6mg/kg IP injection; once weekly for 4 weeks) and control groups (IP injection of sterile 0.9% saline on same schedule). We utilized the string pulling task, skilled ladder rung walking task, and other standard cognitive tests. We also performed immunohistochemistry to examine markers of inflammation related to chemotherapy and the extent to which chemotherapy would affect the process of neurogenesis. The results of the experiment we performed will be presented at the meeting and represent preliminary data for future studies.

White matter deficits in cocaine use disorder: convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomic analysis

White matter (WM) abnormalities in patients with cocaine use disorder (CUD) have been studied; however, the reported effects on the human brain are heterogenous and most results have been obtained from male participants. In addition, biological data supporting the imaging findings and revealing possible mechanisms underlying the neurotoxic effects of chronic cocaine use (CU) on WM are largely restricted to animal studies. To evaluate the neurotoxic effects of CU in the WM, we performed an in vivo diffusion tensor imaging assessment of male and female cocaine users (n = 75) and healthy controls (HC) (n = 58). Moreover, we performed an ex vivo large-scale proteomic analysis using liquid chromatography-tandem mass spectrometry in postmortem brains of patients with CUD (n = 8) and HC (n = 12). Compared with the HC, the CUD group showed significant reductions in global fractional anisotropy (FA) (p < 0.001), and an increase in global mean (MD) and radial diffusion (RD) (both p < 0.001). The results revealed that FA, RD, and MD alterations in the CUD group were widespread along the major WM tracts, after analysis using the tract-based special statistics approach. Global FA was negatively associated with years of CU (p = 0.0421) and female sex (p < 0.001), but not with years of alcohol or nicotine use. Concerning the fibers connecting the left to the right prefrontal cortex, Brodmann area 9 (BA9), the CUD group presented lower FA (p = 0.006) and higher RD (p < 0.001) values compared with the HC group. A negative association between the duration of CU in life and FA values in this tract was also observed (p = 0.019). Proteomics analyses in BA9 found 11 proteins differentially expressed between cocaine users and controls. Among these, were proteins related to myelination and neuroinflammation. In summary, we demonstrate convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomics analysis of WM disruption in CUD.

Diffusion Imaging Reveals Sex Differences in the White Matter Following Sports-Related Concussion.

Sports-related concussion (SRC) is a serious health concern. However, the temporal profile of neuropathophysiological changes after SRC and how these relate to biological sex are still poorly understood. This preliminary study investigated whether diffusion-weighted magnetic resonance imaging (dMRI) was sensitive to neuropathophysiological changes following SRC; whether these changes were sex-specific; and whether they persisted beyond the resolution of self-reported symptoms. Recently concussed athletes (n = 14), and age- and education-matched nonconcussed control athletes (n = 16), underwent MRI 24-48-h postinjury and again at 2-week postinjury (i.e., when cleared to return-to-play). Male athletes reported more symptoms and greater symptom severity compared with females. dMRI revealed white matter differences between athletes with SRC and their nonconcussed counterparts at 48-h postinjury. These differences were still present at 2-week postinjury, despite SRC athletes being cleared to return to play and may indicate increased cerebral vulnerability beyond the resolution of subjective symptoms. Furthermore, we identified sex-specific differences, with male SRC athletes having significantly greater white matter disruption compared with female SRC athletes. These results have important implications for the management of concussion, including guiding return-to-play decisions, and further improve our understanding regarding the role of sex in SRC outcomes.

Abstract 9: Peak Width of Skeletonized Mean Diffusivity and Cognition in Cerebral Amyloid Angiopathy

Background: We hypothesized that Peak Width of Skeletonized Mean Diffusivity (PSMD), an automated marker of cerebral microangiopathy representing microstructural disruption of white matter (WM), would be increased in patients with cerebral amyloid angiopathy (CAA) compared to healthy controls (HCs) and increased PSMD would be associated with lower processing speed scores (PSSs) in patients with CAA. Methods: Seventy-two nondemented probable CAA patients and 23 HCs prospectively underwent high-resolution brain MRIs and cognitive tests. PSMD scores were quantified from a probabilistic skeleton of the WM tracts as previously validated (http://www.psmd-marker.com). In subjects with intracerebral hemorrhage (ICH, n=27), ICH regions were masked and removed from the PSMD pipeline. The analyses were repeated in the non-ICH hemisphere. Raw scores of Trail Making Test-B and Symbol Substitution Test were transformed into standardized z -scores and averaged to obtain PSSs. Results: The mean age (p=0.366) and sex (p=0.811) were similar between CAA patients and HCs. PSMD was higher in the CAA group [(3.95±0.9) х 10 –4 mm 2 /s] compared to HCs [(3.32±0.6) х 10 –4 mm 2 /s] (p=0.003). This association remained significant in a linear regression model corrected for age and sex (β=0.700, 95%CI 0.3-1, p=0.001). Within the CAA cohort, higher PSMD was associated with higher WM hyperintensity volume in a multiple regression model adjusted for all relevant variables (β=0.890, 95%CI 0.7-1, p&lt;0.001). In a regression model corrected for age, sex, years of education and presence of ICH, a lower PSS was independently associated with increased PSMD (β=-0.405, 95%CI {-0.6}-{-0.2}, p&lt;0.001). These results did not change when the non-ICH hemisphere was used for PSMD processing. Conclusion: PSMD is increased in CAA and is associated with worse PSSs supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA.