Disruption Of White Matter Tracts Research Articles

Using Neuroimaging to Study Cerebral Amyloid Angiopathy and Its Relationship to Alzheimer's Disease.

Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β aggregation in the media and adventitia of the leptomeningeal and cortical blood vessels. CAA is one of the strongest vascular contributors to Alzheimer's disease (AD). It frequently co-occurs in AD patients, but the relationship between CAA and AD is incompletely understood. CAA may drive AD risk through damage to the neurovascular unit and accelerate parenchymal amyloid and tau deposition. Conversely, early AD may also drive CAA through cerebrovascular remodeling that impairs blood vessels from clearing amyloid-β. Sole reliance on autopsy examination to study CAA limits researchers' ability to investigate CAA's natural disease course and the effect of CAA on cognitive decline. Neuroimaging allows for in vivo assessment of brain function and structure and can be leveraged to investigate CAA staging and explore its associations with AD. In this review, we will discuss neuroimaging modalities that can be used to investigate markers associated with CAA that may impact AD vulnerability including hemorrhages and microbleeds, blood-brain barrier permeability disruption, reduced cerebral blood flow, amyloid and tau accumulation, white matter tract disruption, reduced cerebrovascular reactivity, and lowered brain glucose metabolism. We present possible areas for research inquiry to advance biomarker discovery and improve diagnostics.

Localization of Silent Cerebral Infarcts in Children with Sickle Cell Disease Impacts Structural Disconnection

Silent cerebral infarcts (SCIs) occur in 40% of children with sickle cell disease (SCD) by 18 years of age and are associated with cognitive dysfunction. SCIs localize to the border zone of the brain, but the significance of this localization is unclear. In adults with stroke, an infarct's disruption of white matter (WM) tracts, or structural disconnection, is more strongly associated with the functional impact of the infarct than the size of the lesion. We aim to define the WM tracts disconnected by SCIs and the relationship between structural disconnection and functional connectivity (FC) in SCD. Simulated and real-world data were used to test the hypothesis that specific WM tracts are vulnerable to disconnection if an infarct occurs in the region at highest risk for SCIs, and that FC will decrease with increased structural disconnection in SCD. Utilizing data from the Silent Infarct Transfusion (SITT) trial, the regions at greatest risk for SCIs were defined (risk region, PMID 30061156). A simulated dataset comprised of 1000 infarcts within the risk region and 1000 infarcts within the white matter outside of the risk region was created. The real-world dataset was comprised of 44 participants with SCD and SCIs (median age 13.0 [11.0, 15.8] years, 29 female/15 male). The Human Connectome Project (HCP) 842 atlas contains thousands of streamlines comprising 28 WM tracts (excluding brainstem and cerebellar tracts). The Lesion Connectivity Toolbox defined streamlines within the HCP 842 atlas that intersected with each individual lesion, permitting quantification of two measures of structural disconnection: tract-wise disconnection (the percentage of streamlines within each tract that intersect a lesion) and global disconnection (the average percentage of streamlines connecting each pair of gray matter (GM) parcels in the FC parcellation (PMID 25316338)). Tract density images (TDi) illustrate the number of streamlines impacted by a lesion within each voxel of the brain permitting computation of total lesion impact as the volume of the TDi image associated with each lesion. Resting state functional connectivity MRI was obtained in 27 of the real-world participants for computation of whole brain modularity as a metric of global FC. The WM tracts with the highest mean tract-wise disconnection due to lesions within the risk region were the posterior and mid-anterior corpus callosum, superior longitudinal fasciculus, frontal aslant tract, and middle longitudinal fasciculus while the inferior frontal occipital fasciclus, anterior commissure, inferior longitudinal fasciculus, posterior corpus callosum, and arculate fasciculus were most impacted by lesions outside of the risk region. Numerous tracts showed a significant difference in tract-wise disconnection resulting from lesions in the risk region vs. lesions outside the risk region. The tracts impacted due to real-world lesions were similar to tracts impacted from lesions within the risk region (Table 1). Despite lesioned volume being equivalent (p = 0.31) for simulated data within and outside the risk region, the average volume of lesion impact as measured by volume of the TDi image was significantly larger for lesions occurring inside the risk region (p < 0.001; Fig 1). In the real-world dataset, whole brain modularity, a metric of global FC, decreased as global structural disconnection increased (r = -0.49, p =0.009) Using simulated data that was validated with a real-world dataset, specific WM tracts vulnerable to SCIs were identified. Previous work on cerebral hemodynamics in SCD elucidated the mechanism of injury in the border zone, and these results demonstrate the significance of the localization of this injury to the border zone. SCIs have a far-reaching effect as lesions in the risk region within the border zone were associated with a greater volume of structural disconnection compared to lesions of the same size distributed outside the risk region. These results suggest that the regions in which the SCIs localize represent “high impact” areas of the brain, where a lesion of a given volume may intersect a large number of streamlines. Further, given the correlation between global structural disconnection and whole brain modularity, these data link structural disconnection with function of the brain, suggesting these “high impact” regions may also play a key role in mediating communication between functionally connected GM regions.

White matter tracts contribute selectively to cognitive functioning in patients with glioma.

The functional organization of white matter (WM) tracts is not well characterized, especially in patients with intrinsic brain tumors where complex patterns of tissue injury, compression, and neuroplasticity may be present. This study uses diffusion tensor imaging (DTI) to investigate the relationships between WM tract disruption and cognitive deficits in glioma patients. Seventy-nine patients with glioma underwent preoperative DTI and neuropsychological testing. Thirteen WM tracts were reconstructed bilaterally. Fractional anisotropy and streamline number were obtained for each tract as indices of connectivity. Univariate regression models were used to model the association between WM tract connectivity and neuropsychological outcomes. Glioma patients exhibited variable injury to WM tracts and variable cognitive deficits on validated neuropsychological tests. We identified 16 age-adjusted associations between WM tract integrity and neuropsychological function. The left inferior frontal-occipital fasciculus (IFOF) predicted list learning and dominant-hand fine motor dexterity. The right IFOF predicted non-dominant-hand fine motor dexterity and visuospatial index scores. The left inferior longitudinal fasciculus (ILF) predicted immediate memory list learning and index scores. The right ILF predicted non-dominant-hand fine motor dexterity and backward digit span scores. The left superior longitudinal fasciculus (SLF) I predicted processing speed. The left SLF III predicted list learning, immediate memory index scores, phonemic fluency, and verbal abstract reasoning. The left cingulum predicted processing speed. The right anterior AF predicted verbal abstract reasoning. WM tract disruption predicts cognitive dysfunction in glioma patients. By improving knowledge of WM tract organization, this analysis may guide maximum surgical resection and functional preservation in glioma patients.

Convergence of visual and motor awareness in human parietal cortex.

Brain lesions sometimes induce a failure of recognition of one's own deficits (anosognosia). Lack of deficit awareness may underlie damage of modality-specific systems, e.g., visual cortex for visual anosognosia or motor/premotor cortex for motor anosognosia. However, focal lesions induce widespread remote structural and functional disconnection, and anosognosia, independent of modality, may also involve common neural mechanisms. Here, we study the neural correlates of Anton syndrome (AS), anosognosia of blindness, and compare them with anosognosia for hemiplegia to test if they share different or common mechanisms. We measured both local damage and patterns of structural-functional disconnection as predicted from healthy normative atlases. AS depends on bilateral striate and extra-striate occipital damage, and disconnection of ventral and dorsal frontoparietal regions involved in attention control. Visual and motor anosognosia each share damage of modality-specific regions, but also involve the disruption of white matter tracts leading to functional disconnection within dorsal frontal-parietal regions that play critical roles in motor control, visuospatial attention, and multi-sensory integration. These results reveal the unique shared combination of content-specific and supra-modal mechanisms in anosognosia. This article is protected by copyright. All rights reserved.

P.115 MRI based methodology for assessment of white matter neuroplasticity: preclinical validation using human motor training data

Background: Disruption of white matter (WM) tracts is common in traumatic injury to the brain and spinal cord. However, imaging techniques for prognostication and monitoring of recovery are lacking. Myelin Water Imaging (MWI) is a validated MRI based method of quantifying myelin volume and represents a potential tool for application in a clinical environment. Methods: 12 healthy, right-handed participants completed a two-week visuomotor maze training program with MRI scans at baseline and endpoint. The task was designed to be difficult for the non-dominant hand and easy for the dominant, allowing for an inbuilt control. Diffusion Tensor Imaging (DTI) along with MWI data were collected at both timepoints using a 3T MRI. Results: Performance metrics confirmed task performance increased only in the non-dominant hand, and a corresponding endpoint>baseline comparison showed significant increases in the MWF (p<0.05) and DTI indices (p<0.05) in the right corticospinal tract (CST), and no significant change in the left CST. Conclusions: This preclinical validation shows MWI is capable of quantitatively tracking WM changes over the course of weeks in humans. MWI’s clinical utility lies in its ability to assess WM changes over short time periods, as monitoring changes in tissue integrity will assist in guiding treatment decisions after critical injury.

Apathy in Patients With Cerebral Amyloid Angiopathy: A Multimodal Neuroimaging Study.

To analyze the prevalence and associated clinical characteristics of apathy in sporadic cerebral amyloid angiopathy and investigate whether apathy was associated with disease burden and disconnections of key structures in the reward circuit through a structural and functional multimodal neuroimaging approach. Thirty-seven participants with probable sporadic cerebral amyloid angiopathy without symptomatic intracranial hemorrhage or dementia (mean age, 73.3 ± 7.2 years, % male = 59.5%) underwent a detailed neuropsychological evaluation, including measures of apathy and depression, and a multimodal MR neuroimaging study. A multiple linear regression analysis was used to assess the association of apathy with conventional small vessel disease neuroimaging markers. A voxel-based morphometry with a small volume correction within regions previously associated with apathy and a whole-brain tract-based spatial statistics were performed to identify differences in the gray matter and white matter between the apathetic and nonapathetic groups. Gray matter regions significantly associated with apathy were further evaluated for their functional alterations as seeds in the seed-based resting-state functional connectivity analysis. Potential confounders, namely, age, sex, and measures of depression, were entered as covariates in all analyses. A higher composite small vessel disease marker score (CAA-SVD) was associated with a higher degree of apathy (standardized coefficient = 1.35 (0.07-2.62), adjusted R2 = 27.90, p = 0.04). Lower gray matter volume of the bilateral orbitofrontal cortices was observed in the apathetic group than in the nonapathetic group (F = 13.20, family-wise error-corrected p = 0.028). The apathetic group demonstrated a widespread decrease in white matter microstructural integrity compared with the nonapathetic group. These tracts connect key regions within and between related reward circuits. Finally, there were no significant functional alterations between the apathetic and nonapathetic groups. Our findings revealed the orbitofrontal cortex as a key region in the reward circuit associated with apathy in sporadic cerebral amyloid angiopathy, independent from depression. Apathy was shown to be associated with a higher CAA-SVD score and an extensive disruption of white matter tracts, which suggested that a higher burden of CAA pathology and the disruption in large-scale white matter networks may underlie manifestations of apathy.

High cortical iron is associated with the disruption of white matter tracts supporting cognitive function in healthy older adults.

Aging is associated with brain iron accumulation, which has been linked to cognitive decline. However, how brain iron affects the structure and function of cognitive brain networks remains unclear. Here, we explored the possibility that iron load in gray matter is associated with disruption of white matter (WM) microstructure within a network supporting cognitive function, in a cohort of 95 cognitively normal older adults (age range: 60-86). Functional magnetic resonance imaging was used to localize a set of brain regions involved in working memory and diffusion tensor imaging based probabilistic tractography was used to identify a network of WM tracts connecting the functionally defined regions. Brain iron concentration within these regions was evaluated using quantitative susceptibility mapping and microstructural properties were assessed within the identified tracts using neurite orientation dispersion and density imaging. Results indicated that high brain iron concentration was associated with low neurite density (ND) within the task-relevant WM network. Further, regional associations were observed such that brain iron in cortical regions was linked with lower ND in neighboring but not distant WM tracts. Our results provide novel evidence suggesting that age-related increases in brain iron concentration are associated with the disruption of WM tracts supporting cognitive function in normal aging.

Intracortical myelin in individuals with alcohol use disorder: An initial proof-of-concept study.

IntroductionDisruption of cortical gray matter and white matter tracts are well‐established markers of alcohol use disorder (AUD), but less is known about whether similar differences are present in intracortical myelin (ICM, i.e., highly myelinated gray matter in deeper cortical layers). The goal of this study was to provide initial proof‐of‐concept for using an optimized structural magnetic resonance imaging (MRI) sequence to detect differences in ICM in individuals with AUD compared to control participants reporting drinking within recommended guidelines.MethodsThis study used an optimized 3T MRI sequence for high intracortical contrast to examine ICM‐related MRI signal in 30 individuals with AUD and 33 healthy social drinkers. Surface‐based analytic techniques were used to quantify ICM‐related MRI signal in 20 bilateral a priori regions of interest based on prior cortical thickness studies, and exploratory vertex‐wise analyses were examined using Cohen's d effect size.ResultsThe global distribution of ICM‐related signal was largely comparable between groups. Region of interest analysis indicated that AUD group exhibited greater ICM‐related MRI signal in precuneus, ventromedial prefrontal cortex, posterior cingulate, middle anterior cingulate, middle/posterior insula, and dorsolateral prefrontal cortex (Cohen's ds = 0.50–0.75). Four regions (right precuneus, ventromedial prefrontal cortex, posterior cingulate and left dorsolateral prefrontal cortex) remained significant (p < .05) after covarying for smoking status.ConclusionThese findings provide initial evidence of ICM differences in a moderately sized sample of individuals with AUD compared to controls, although the inflation of type 1 error rate necessitates caution in drawing conclusions. Robustly establishing these differences in larger samples is necessary. The cross‐sectional design cannot address whether the observed differences predate AUD or are consequences of heavy alcohol consumption.

Time course of lesion-induced atrophy in multiple sclerosis.

White matter (WM) tract disruption impacts volume loss in connected deep gray matter (DGM) over 5years in people with multiple sclerosis (PwMS). However, the timeline of this phenomenon remains poorly characterized. Annual serial MRI for 181 PwMS was retrospectively analyzed from a 10-year clinical trial database. Annualized thalamic atrophy, DGM atrophy, and disruption of connected WM tracts were measured. For time series analysis, ~700 epochs were collated using a sliding 5-year window, and regression models predicting 1-year atrophy were applied to characterize the influence of new tract disruption from preceding years, while controlling for whole brain atrophy and other relevant factors. Disruptions of WM tracts connected to the thalamus were significantly associated with thalamic atrophy 1year later (β: 0.048-0.103). This effect was not observed for thalamic tract disruption concurrent with the time of atrophy nor for thalamic tract disruption preceding the atrophy by 2-4years. Similarly, disruptions of white matter tracts connected to the DGM were significantly associated with DGM atrophy 1year later (β: 0.078-0.111), but not for tract disruption concurrent with, nor preceding the atrophy by 2-4years. Increased rates of thalamic and DGM atrophy were restricted to 1year following newly developed disruption in connected WM tracts. In research and clinical settings, additional gray matter atrophy may be expected 1year following new lesion growth in connected white matter.

White matter tract disruption is associated with ipsilateral hand impairment in subacute stroke: a diffusion MRI study.

The ipsilateral hand (ILH) is impaired after unilateral stroke, but the underlying mechanisms remain unresolved. Based on the degeneracy theory of network connectivity that many connectivity patterns are functionally equivalent, we hypothesized that ILH impairment would result from the summation of microstructural white matter (WM) disruption in the motor network, with a task-related profile. We aimed to determine the WM disruption patterns associated with ILH impairment. This was a cross-sectional analysis of patients in the ISIS-HERMES Study with ILH and diffusion-MRI data collected 1month post-stroke. Patients performed three tasks, the Purdue Pegboard Test (PPT), handgrip strength, and movement time. Fractional anisotropy (FA) derived from diffusion MRI was measured in 33 WM regions. We used linear regression models controlling for age, sex, and education to determine WM regions associated with ILH impairment. PPT was impaired in 42%, grip in 59%, and movement time in 24% of 29 included patients (mean age, 51.9 ± 10.5years; 21 men). PPT was predicted by ipsilesional corticospinal tract (i-CST) (B = 17.95; p = 0.002) and superior longitudinal Fasciculus (i-SLF) (B = 20.52; p = 0.008); handgrip by i-CST (B = 109.58; p = 0.016) and contralesional anterior corona radiata (B = 42.69; p = 0.039); and movement time by the corpus callosum (B = - 1810.03; p = 0.003) i-SLF (B = - 917.45; p = 0.015), contralesional pons-CST (B = 1744.31; p = 0.016), and i-corticoreticulospinal pathway (B = - 380.54; p = 0.037). ILH impairment was associated with WM disruption to a combination of ipsilateral and contralesional tracts with a pattern influenced by task-related processes, supporting the degeneracy theory. We propose to integrate ILH assessment in rehabilitation programs and treatment interventions such as neuromodulation.

The association between white matter hyperintensities, cognition and regional neural activity in healthy subjects.

White matter hyperintensities (WMH) are common findings that can be found in physiological ageing. Several studies suggest that the disruption of white matter tracts included in WMH could induce abnormal functioning of the respective linked cortical structures, with consequent repercussion on the cerebral functions, included the cognitive sphere. In this cross-sectional research, we analysed the effects of the total WMH burden (tWMHb) on resting-state functional magnetic resonance imaging (rs-fMRI) and cognition. Functional and structural MR data, as well as the scores of the trail making test subtests A (TMT-A) and B (TMT-B) of 75 healthy patients, were extracted from the public available Leipzig Study for Mind-Body-Emotion Interactions dataset. tWMHb was extracted from structural data. Spearman's correlation analyses were made for investigating correlations between WMHb and the scores of the cognitive tests. The fractional amplitude of low-frequency fluctuations (fALFF) method was applied for analysing the rs-fMRI data, adopting a multiple regression model for studying the effects of tWMHb on brain activity. Three different subanalyses were conducted using different statistical methods. We observed statistically significant correlations between WMHb and the scores of the cognitive tests. The fALFF analysis revealed that tWMHb is associated with the reduction of regional neural activity of several brain areas (in particular the prefrontal cortex, precuneus and cerebellar crus I/II). We conclude that our findings clarify better the relationships between WMH and cognitive impairment, evidencing that tWMHb is associated with impairments of the neurocognitive function in healthy subjects by inducing a diffuse reduction of the neural activity.

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.

Heterogeneity of behavioural and language deficits in FTD-MND.

To comprehensively examine the clinical presentation of patients diagnosed with frontotemporal dementia-motor neuron disease (FTD-MND) compared to FTD subtypes. To clarify the heterogeneity of behavioural and language deficits in FTD-MND using a data-driven approach. Patients with FTD-MND (n = 31), behavioural variant FTD (n = 119), non-fluent variant primary progressive aphasia (n = 47), semantic variant primary progressive aphasia (n = 42), and controls (n = 127) underwent comprehensive clinical, cognitive and behavioural assessments. Two-step cluster analysis examined patterns of behavioural and language impairment. Voxel-based morphometry and tract-based spatial statistics were used to investigate differences across the subgroups that emerged from cluster analysis. More than half of FTD-MND patients initially presented with variable combinations of deficits (e.g., mixed behaviour/cognitive, mixed behaviour/cognitive/motor deficits), with 74% of them meeting criteria for FTD-MND within 24months with a median of 12months. The frequency and severity of behavioural and language abnormalities in FTD-MND lie between that seen in the three FTD phenotypes. Cluster analysis identified three patterns of behavioural and language impairment in FTD-MND. The three FTD-MND subgroups demonstrated different profiles of white matter tract disruption, but did not differ in age at onset, disease duration or patterns of cortical atrophy. While highly heterogeneous, in terms of behavioural and language deficits, and disease severity, the presentation of FTD-MND may be distinct to that of FTD. Distinct white matter degeneration patterns may underpin heterogeneous clinical profiles in FTD-MND. FTD presenting with mixed behavioural-language disturbances should be monitored closely for at least 12-24months for the emergence of MND symptoms/signs.

Mind the gap: from neurons to networks to outcomes in multiple sclerosis.

MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure.

Grey and white matter network disruption is associated with sensory deficits after stroke

Somatosensory deficits after ischaemic stroke are common and can occur in patients with lesions in the anterior parietal cortex and subcortical nuclei. It is less clear to what extent damage to white matter tracts within the somatosensory system may contribute to somatosensory deficits after stroke. We compared the roles of cortical damage and disruption of subcortical white matter tracts as correlates of somatosensory deficit after ischaemic stroke.Clinical and imaging data were assessed in incident stroke patients. Somatosensory deficits were measured using a standardized somatosensory test. Remote effects were quantified by projecting the MRI-based segmented stroke lesions onto a predefined atlas of white matter connectivity. Direct ischaemic damage to grey matter was computed by lesion overlap with grey matter areas. The association between lesion impact scores and sensory deficit was assessed statistically.In 101 patients, median sensory score was 188/193 (97.4%). Lesion volume was associated with somatosensory deficit, explaining 23.3% of variance. Beyond this, the stroke-induced grey and white matter disruption within a subnetwork of the postcentral, supramarginal, and transverse temporal gyri explained an additional 14% of the somatosensory outcome variability. On mutual comparison, white matter network disruption was a stronger predictor than grey matter damage.Ischaemic damage to both grey and white matter are structural correlates of acute somatosensory disturbance after ischaemic stroke. Our data suggest that white matter integrity of a somatosensory network of primary and secondary cortex is a prerequisite for normal processing of somatosensory inputs and might be considered as an additional parameter for stroke outcome prediction in the future.

Diffusion imaging in dementia with Lewy bodies: Associations with amyloid burden, atrophy, vascular factors and clinical features

IntroductionWhite matter disruption in dementia has been linked to a variety of factors including vascular disease and cortical pathology. We aimed to examine the relationship between white matter changes on diffusion tensor imaging (DTI) in DLB and factors including vascular disease, structural atrophy and amyloid burden. MethodsParticipants with DLB (n = 29), Alzheimer's disease (AD, n = 17) and healthy controls (n = 20) had clinical and neuropsychological assessments followed by structural and diffusion tensor 3T MRI and 18F-Florbetapir PET-CT imaging. Voxelwise statistical analysis of white matter fractional anisotropy (FA) and mean diffusivity (MD) was carried out using Tract-Based Spatial Statistics with family-wise error correction (p < 0.05). ResultsDLB and AD groups demonstrated widespread increased MD and decreased FA when compared with controls. There were no differences between the DLB and AD groups. In DLB, increased MD and decreased FA correlated with decreased grey matter and hippocampal volumes as well as vascular disease. There was no correlation with cortical florbetapir SUVR. The relationship between DTI changes and grey matter/hippocampal volumes remained after including Cumulative Illness Rating Scale-Geriatric vascular score as a covariate. ConclusionsWidespread disruption of white matter tracts is present in DLB and is associated with vascular disease, reduced hippocampal volume and reduced grey matter volume, but not with cortical amyloid deposition. The mechanism behind the correlation observed between hippocampal volume and white matter tract disruption should be investigated in future cohorts using tau imaging, as hippocampal atrophy has been shown to correlate with tau deposition in DLB.

Diagnosis of depression in multiple sclerosis is predicted by frontal-parietal white matter tract disruption.

Persons with multiple sclerosis (PwMS) are at an elevated risk of depression. Decreased Conscientiousness may affect patient outcomes in PwMS. Low Conscientiousness has a strong correlation with depression. Previous work has also reported that white matter (WM) tract disruption in frontal-parietal networks explains reduced Conscientiousness in PwMS. We hypothesized that Conscientiousness-associated WM tract disruption predicts new-onset depression over 5years in PwMS and evaluated this by assessing the predictive power of mean Conscientiousness associated frontal-parietal network (CFPN) disruption in PwMS for clinically diagnosed depression over 5years. This longitudinal retrospective analysis included 53 PwMS who were not previously diagnosed as depressed. All participants underwent structural MRI. Medical records were reviewed to evaluate diagnosis of depression for these patients over 5years. WM tract damage between pairs of gray matter regions in the CFPN was measured using diffusion imaging. The relationship between CFPN disruption and depression was analyzed using logistic regression. Participants with MS had a mean age of 46.0years (SD = 11.2). 22.6% (n = 12) acquired a diagnosis of clinical depression over the 5-year period. Baseline disruption in the CFPN was a significant predictor (ROC AUC = 61.8%). of new-onset clinical depression, accounting for age, sex, lateral ventricular volume, disease modifying treatment, and lesion volume. Baseline CFPN disruption is associated with progression to clinical depression over 5years in PwMS. Development of new WM pathology within this network may be a risk factor for depression.

Functional Connectivity and Structural Disruption in the Default-Mode Network Predicts Cognitive Rehabilitation Outcomes in Multiple Sclerosis.

Efficacy of restorative cognitive rehabilitation can be predicted from baseline patient factors. In addition, patient profiles of functional connectivity are associated with cognitive reserve and moderate the structure-cognition relationship in people with multiple sclerosis (PwMS). Such interactions may help predict which PwMS will benefit most from cognitive rehabilitation. Our objective was to determine whether patient response to restorative cognitive rehabilitation is predictable from baseline structural network disruption and whether this relationship is moderated by functional connectivity. For this single-arm repeated measures study, we recruited 25 PwMS for a 12-week program. Following magnetic resonance imaging, participants were tested using the Symbol Digit Modalities Test (SDMT) pre- and postrehabilitation. Baseline patterns of structural and functional connectivity were characterized relative to healthy controls. Lower white matter tract disruption in a network of region-pairs centered on the precuneus and posterior cingulate (default-mode network regions) predicted greater postrehabilitation SDMT improvement (P = .048). This relationship was moderated by profiles of functional connectivity within the network (R2 = .385, P = .017, Interaction β = -.415). Patient response to restorative cognitive rehabilitation is predictable from the interaction between structural network disruption and functional connectivity in the default-mode network. This effect may be related to cognitive reserve.

White Matter Hyperintensities Related to Parkinson's Disease Executive Function.

BackgroundPeople with Parkinson's disease (PD) can develop multidomain cognitive impairments; however, it is unclear whether different pathologies underlie domain‐specific cognitive dysfunction.ObjectivesWe investigated the contribution of vascular copathology severity and location, as measured by MRI white matter hyperintensities (WMHs), to domain‐specific cognitive impairment in PD.MethodsWe studied 85 PD (66.6 ± 9.2 years) and 18 control (65.9 ± 6.6) participants. Using the Fazekas scale for rating the severity of WMH, we subdivided PD into 14 PD–WMH+ and 71 PD–WMH–. Participants underwent global, executive, visuospatial, episodic memory, and language testing. We performed nonparametric permutation testing to create WMH probability maps based on PD‐WMH group and cognitive test performance.ResultsThe PD–WMH+ group showed worse global and executive cognitive performance than the PD–WMH– group. On individual tests, the PD–WMH+ group showed worse Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities Test (SDMT), and Digit Span scores. WMH probability maps showed that in the PD–WMH+ group, worse Stroop was associated with lesions centered around the corticospinal tract (CST), forceps major, inferior‐fronto‐occipital fasciculus, and superior longitudinal fasciculus; worse SDMT with lesions around the CST, forceps major, and posterior corona radiata; worse Digit Span with lesions around the posterior corona radiata; and worse MoCA with lesions around the CST.ConclusionsWe found that WMH severity was associated with PD executive dysfunction, including worse attention, working memory, and processing speed. Disruption of key white matter tracts in proximity to vascular lesions could contribute to these specific cognitive impairments. Early treatment of vascular disease might mitigate some executive dysfunction in a subset of patients with PD.

Preserved network functional connectivity underlies cognitive reserve in multiple sclerosis.

Cognitive reserve is one's mental resilience or resistance to the effects of structural brain damage. Reserve effects are well established in people with multiple sclerosis (PwMS) and Alzheimer's disease, but the neural basis of this phenomenon is unclear. We aimed to investigate whether preservation of functional connectivity explains cognitive reserve. Seventy‐four PwMS and 29 HCs underwent neuropsychological assessment and 3 T MRI. Structural damage measures included gray matter (GM) atrophy and network white matter (WM) tract disruption between pairs of GM regions. Resting‐state functional connectivity was also assessed. PwMS exhibited significantly impaired cognitive processing speed (t = 2.14, p = .037) and visual/spatial memory (t = 2.72, p = .008), and had significantly greater variance in functional connectivity relative to HCs within relevant networks (p < .001, p < .001, p = .016). Higher premorbid verbal intelligence, a proxy for cognitive reserve, predicted relative preservation of functional connectivity despite accumulation of GM atrophy (standardized‐β = .301, p = .021). Furthermore, preservation of functional connectivity attenuated the impact of structural network WM tract disruption on cognition (β = −.513, p = .001, for cognitive processing speed; β = −.209, p = .066, for visual/spatial memory). The data suggests that preserved functional connectivity explains cognitive reserve in PwMS, helping to maintain cognitive capacity despite structural damage.