Integrity Of White Matter Tracts Research Articles

Investigating white matter changes in auditory cortex and association fibres related to speech processing in noise-induced hearing loss: a diffusion tensor imaging study

BackgroundThis study explores the impact of noise-induced hearing loss (NIHL) on the microstructural integrity of white matter tracts in the brain, focusing on areas involved in speech processing. While the primary impact of hearing loss occurs in the inner ear, these changes can extend to the central auditory pathways and have broader effects on brain function. Our research aimed to uncover the neural mechanisms underlying hearing loss-related deficits in speech perception and cognition among NIHL patients.MethodsThe study included two groups: nine bilateral NIHL patients and nine individuals with normal hearing. Advanced diffusion tensor imaging techniques were employed to assess changes in the white matter tracts. Regions of interest (ROIs), including the auditory cortex, cingulum, arcuate fasciculus, and longitudinal fasciculus, were examined. Fractional anisotropy (FA) values from these ROIs were extracted for analysis.ResultsOur findings indicated significant reductions in FA values in NIHL patients, particularly in the left cingulum, right cingulum, and left inferior longitudinal fasciculus. Notably, no significant changes were observed in the auditory cortex, arcuate fasciculus, superior longitudinal fasciculus, middle longitudinal fasciculus, and right inferior longitudinal fasciculus, suggesting differential impacts of NIHL on various white matter tracts.ConclusionsThe study's findings highlight the importance of considering association fibres related to speech processing in treating NIHL, as the broader neural network beyond primary auditory structures is significantly impacted. This research contributes to understanding the neurological impact of NIHL and underscores the need for comprehensive approaches in addressing this condition.

Structural Changes in Brain White Matter Tracts Associated with Overactive Bladder Revealed by Diffusion Tensor MRI: Findings from a LURN Cross-Sectional Case-Control Study.

To investigate structural changes in brain white matter tracts using diffusion tensor magnetic resonance imaging (DTI) in patients with overactive bladder (OAB). Treatment-seeking OAB patients and matched controls enrolled in the cross-sectional case-control Symptoms of Lower Urinary Tract Dysfunction Research Network Neuroimaging Study received a brain DTI scan. Microstructural integrity of brain white matter was assessed using fractional anisotropy (FA) and mean diffusivity (MD). OAB and urgency urinary incontinence (UUI) symptoms were assessed using the OAB Questionnaire Short-Form (OAB-q) and International Consultation on Incontinence Questionnaire-UI. The Lower Urinary Tract Symptoms (LUTS) Tool UUI questions and responses were correlated with FA values. Among 221 participants with evaluable DTI data, 146 had OAB (66 urinary urgency [UU]-only without UUI, 80 with UUI); 75 were controls. Compared with controls, participants with OAB showed decreased FA and increased MD, representing greater microstructural abnormalities of brain white matter tracts among OAB participants. These abnormalities occurred in the corpus callosum, bilateral anterior thalamic radiation and superior longitudinal fasciculus tracts, and bilateral insula and para-hippocampal region. Among participants with OAB, higher OAB-q scores were associated with decreased FA in the left inferior fronto-occipital fasciculus, P < .0001. DTI differences between OAB and controls were driven by the UU-only (OAB-dry) but not the UUI (OAB-wet) subgroup. Abnormalities in microstructural integrity in specific brain white matter tracts were more frequent in OAB patients. More severe OAB symptoms were correlated with greater degree of microstructural abnormalities in brain white matter tracts in patients with OAB.

485 Investigating the Impact of Inflammation on White Matter Tracts using Diffusion Tensor Imaging that may Contribute to Motivational Deficits and Negative Symptoms in Patients with Schizophrenia

OBJECTIVES/GOALS: Previous research has linked inflammation to changes in brain reward circuitry and subsequent negative symptoms in patients with schizophrenia. This project aims to understand brain-immune interactions using diffusion tensor imaging (DTI) to investigate the impact of inflammatory markers on white matter (WM) tracts. METHODS/STUDY POPULATION: Patients with schizophrenia, ages 18 to 45, were recruited at Grady Hospital in Atlanta, GA. All subjects were stable outpatients and underwent extensive medical screening to rule out medical causes of acute inflammation. DTI data was collected from 39 participants on a 3-Tesla Siemens scanner. Blood was collected between 9-11AM for later assay of serum inflammatory markers. Negative symptoms were assessed using the Brief Negative Symptom Scale (BNSS). A diffusion tensor imaging model will be fitted with the data to generate well-known diffusion tensor measures (fractional anisotropy and mean diffusivity). Linear regression will be used to analyze the relationship between DTI measures and inflammation (C-Reactive Protein, CRP), controlling for possible confounders. RESULTS/ANTICIPATED RESULTS: The hypothesis of this proposal is that decreased microstructural integrity in WM tracts between the nucleus accumbens (NAc) and insula will be associated with increased inflammation, which in turn are associated with increased negative symptoms. Negative symptoms include deficits in motivation/pleasure as well as diminished expressivity, and are strongly associated with poor functional outcomes. Based on previous data from this sample demonstrating relationships between CRP and negative symptoms as well as CRP and fMRI functional connectivity between the NAc and insula, we anticipate results that demonstrate similar relationships with WM microstructural integrity, such as functional anisotropy and mean diffusivity. DISCUSSION/SIGNIFICANCE: Given the lack of treatment options for negative symptoms, this research will provide key data to further our understanding of the potential role of inflammation on neural circuits that underlie these symptoms, including WM integrity. This research also has the potential to inform future anti-inflammatory therapies for patients with schizophrenia.

White matter tract integrity in isolated oral clefts: relationship to cognition and reading skills

ABSTRACT Children with isolated cleft of the lip and/or palate (iCL/P) have been shown to be at risk for impaired reading ability. Structural and functional neuroimaging studies have revealed subtle morphological and functional abnormalities correlated to cognition and reading ability. However, the integrity of white matter tracts and their potential relationship to reading performance in iCL/P is under-studied. The purpose of the present study was to evaluate white matter integrity related to cognition and reading skills among participants with and without iCL/P. Data from two cross-sectional, case/control studies with similar neuropsychological batteries and diffusion tensor imaging (DTI) protocols were combined. The final sample included 210 participants (ages 7 to 27 years). Group and sex differences in fractional anisotropy (FA) values were examined between participants with (n = 105) and without (n = 105) iCL/P. Potential associations between FA values and age, cognition, and reading skills were also evaluated separately by group and sex. Sex effects were prominent in association and projection fibers, and effects of cleft status were found in association fibers and cerebellar regions, with isolated associations to reading skills. Findings provide preliminary understanding of microstructural associations to cognitive and reading performance among children, adolescents, and young adults with iCL/P.

Integration of whole-exome sequencing and structural neuroimaging analysis in major depressive disorder: a joint study

Major depressive disorder (MDD) is a common mental illness worldwide and is triggered by an intricate interplay between environmental and genetic factors. Although there are several studies on common variants in MDD, studies on rare variants are relatively limited. In addition, few studies have examined the genetic contributions to neurostructural alterations in MDD using whole-exome sequencing (WES). We performed WES in 367 patients with MDD and 161 healthy controls (HCs) to detect germline and copy number variations in the Korean population. Gene-based rare variants were analyzed to investigate the association between the genes and individuals, followed by neuroimaging-genetic analysis to explore the neural mechanisms underlying the genetic impact in 234 patients with MDD and 135 HCs using diffusion tensor imaging data. We identified 40 MDD-related genes and observed 95 recurrent regions of copy number variations. We also discovered a novel gene, FRMPD3, carrying rare variants that influence MDD. In addition, the single nucleotide polymorphism rs771995197 in the MUC6 gene was significantly associated with the integrity of widespread white matter tracts. Moreover, we identified 918 rare exonic missense variants in genes associated with MDD susceptibility. We postulate that rare variants of FRMPD3 may contribute significantly to MDD, with a mild penetration effect.

Analysis of white matter tract integrity using diffusion kurtosis imaging reveals the correlation of white matter microstructural abnormalities with cognitive impairment in type 2 diabetes mellitus.

This study aimed to identify disruptions in white matter integrity in type 2 diabetes mellitus (T2DM) patients by utilizing the white matter tract integrity (WMTI) model, which describes compartment-specific diffusivities in the intra- and extra-axonal spaces, and to investigate the relationship between WMTI metrics and clinical and cognitive measurements. A total of 73 patients with T2DM and 57 healthy controls (HCs) matched for age, sex, and education level were enrolled and underwent diffusional kurtosis imaging and cognitive assessments. Tract-based spatial statistics (TBSS) and atlas-based region of interest (ROI) analysis were performed to compare group differences in diffusional metrics, including fractional anisotropy (FA), mean diffusivity (MD), axonal water fraction (AWF), intra-axonal diffusivity (Daxon), axial extra-axonal space diffusivity (De,//), and radial extra-axonal space diffusivity (De,⊥) in multiple white matter (WM) regions. Relationships between diffusional metrics and clinical and cognitive functions were characterized. In the TBSS analysis, the T2DM group exhibited decreased FA and AWF and increased MD, De,∥, and De,⊥ in widespread WM regions in comparison with the HC group, which involved 56.28%, 32.07%, 73.77%, 50.47%, and 75.96% of the mean WM skeleton, respectively (P < 0.05, TFCE-corrected). De,⊥ detected most of the WM changes, which were mainly located in the corpus callosum, internal capsule, external capsule, corona radiata, posterior thalamic radiations, sagittal stratum, cingulum (cingulate gyrus), fornix (stria terminalis), superior longitudinal fasciculus, and uniform fasciculus. Additionally, De,⊥ in the genu of the corpus callosum was significantly correlated with worse performance in TMT-A (β = 0.433, P < 0.001) and a longer disease duration (β = 0.438, P < 0.001). WMTI is more sensitive than diffusion tensor imaging in detecting T2DM-related WM microstructure abnormalities and can provide novel insights into the possible pathological changes underlying WM degeneration in T2DM. De,⊥ could be a potential imaging marker in monitoring disease progression in the brain and early intervention treatment for the cognitive impairment in T2DM.

Qualitative and Visual Along-Tract Analysis of Diffusion-Based Parameters in Patients with Diffuse Gliomas.

Grade 2-3 diffuse gliomas (DGs) show extensive infiltration through white matter (WM) tracts. Along-tract analysis of WM tracts based on diffusion tensor tractography (DTI) can been performed to assess the microstructural integrity of WM tracts. The clinical implication of these DTI-related findings is still under debate, especially in tumor patients. The aim of this study was to analyze and compare diffusion-based parameters along WM tracts and variables specific to WM -tumor interactions in DGs and correlate them with preoperative neuropsychological assessment. Fourteen patients with IDH-mutated grade 2-3 DGs were included. Tumor volumes were manually segmented on 3D-FLAIR images after spatial normalisation to MNI space. DTI was acquired using a single-shot echo-planar sequence on a 3T with 48 sampling directions. DTI data were reconstructed within the MNI space using q-space diffeomorphic reconstruction (QSDR) in DSI studio. Five bilateral sets of WM tracts were reconstructed based on the HCP-1065 template. All WM tracts were stretched to the same length of 100 indices, and for each index diffusion-based parameters fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), mean diffusivity (MD) and quantitative anisotropy (QA) were sampled. Tumor-related parameters (TRP); tumor volume (Tv), maximum tumor presence (MTP) and the number of sequential indices in which a tumor is present (Te) were derived based on the along-tract analysis. Normal data were constructed by calculating the average and standard deviations of contralateral and not-affected WM tracts for each diffusion-based parameter, respectively. Affected WM tracts were individually compared to normal data using a z-test. Preoperative neuropsychological assessment was performed in all subjects and correlated to results from the along-tract analysis using correlation and logistic regression models. Abnormalities in diffusion-based parameters were detected in WM tracts. Topographical and quantitative information were presented within the same graph. AD and MD displayed the highest linear correlation with the TRPs. Abnormal QA showed a linear correlation with Tv per WM tract. Neuropsychological impairment was correlated with all the TRPs and with abnormal FA (p < 0.05) and abnormal QA (p < 0.01). Abnormal QA was the only independent variable able to predict the presence of neuropsychological impairment in the patients based on the linear regression analysis. Graphical presentation of the along-tract analysis presented in this study shows that it may be a sensitive and robust method to acquire and display topographical and qualitative information regarding WM tracts in close proximity to DGs. Further studies and refinements to the methods presented herein may advance current clinical methods for evaluating displacement and infiltrations and further aid the efforts of pre-planning surgical interventions with the goal to maximise EOR and tailor oncological treatment.

Association Between White Matter Tract Integrity and Frontal-Executive Function in Non-Geriatric Adult Patients With Major Depressive Disorder.

This study investigated the association between white matter tract integrity and frontal executive function in adult non-geriatric patients with major depressive disorder (MDD) and healthy controls (HCs) using diffusion tensor imaging (DTI). In total, 57 patients with MDD and 115 HCs participated in this study. We calculated the integrity of the white matter tracts using the Tracts Constrained by Underlying Anatomy tool (TRACULA) from FreeSurfer. We performed cognitive function tests. Oneway analysis of covariance was used to investigate the DTI parameters as dependent variables; diagnosis of MDD as an independent variable; and age, sex, and education level as covariates. For correlation analysis between the DTI parameters and cognitive function tests, Pearson's partial correlation analyses were performed in the MDD and HC groups. The patients with MDD showed significantly decreased axial diffusivity (AD) in forceps major (FMajor), left corticospinal tract (CST), left superior longitudinal fasciculus-parietal bundle (SLFP), right anterior thalamic radiation (ATR), right CST, right inferior longitudinal fasciculus (ILF) and right superior longitudinal fasciculus-temporal bundle (SLFT) and mean diffusivity (MD) in the left CST, right CST, and right SLFT compared to HCs. We found that non-geriatric patients with MDD showed a significant negative correlation between the response time in the Stroop task and the AD value of the FMajor. Our findings suggest that impaired structural connectivity in the FMajor may be associated with cognitive dysfunction in non-geriatric patients with MDD.

Tract-based analyses of white matter in schizophrenia, bipolar disorder, aging, and dementia using high spatial and directional resolution diffusion imaging: a pilot study.

Structural brain connectivity abnormalities have been associated with several psychiatric disorders. Schizophrenia (SCZ) is a chronic disabling disorder associated with accelerated aging and increased risk of dementia, though brain findings in the disorder have rarely been directly compared to those that occur with aging. We used an automated approach to reconstruct key white matter tracts and assessed tract integrity in five participant groups. We acquired one-hour-long high-directional diffusion MRI data from young control (CON, n =28), bipolar disorder (BPD, n =21), and SCZ (n =22) participants aged 18-30, and healthy elderly (ELD, n =15) and dementia (DEM, n =9) participants. Volume, fractional (FA), radial diffusivity (RD) and axial diffusivity (AD) of seven key white matter tracts (anterior thalamic radiation, ATR; dorsal and ventral cingulum bundle, CBD and CBV; corticospinal tract, CST; and the three superior longitudinal fasciculi: SLF-1, SLF-2 and SLF-3) were analyzed with TRACULA. Group comparisons in tract metrics were performed using multivariate and univariate analyses. Clinical relationships of tract metrics with recent and chronic symptoms were assessed in SCZ and BPD participants. A MANOVA showed group differences in FA (λ=0.5; p=0.0002) and RD (λ=0.35; p<0.0001) across the seven tracts, but no significant differences in tract AD and volume. Post-hoc analyses indicated lower tract FA and higher RD in ELD and DEM groups compared to CON, BPD and SCZ groups. Lower FA and higher RD in SCZ compared to CON did not meet statistical significance. In SCZ participants, a significant negative correlation was found between chronic psychosis severity and FA in the SLF-1 (r= -0.45; p=0.035), SLF-2 (r= -0.49; p=0.02) and SLF-3 (r= -0.44; p=0.042). Our results indicate impaired white matter tract integrity in elderly populations consistent with myelin damage. Impaired tract integrity in SCZ is most prominent in patients with advanced illness.

Exploring White Matter Abnormalities in Young Children with Autism Spectrum Disorder: Integrating Multi-shell Diffusion Data and Machine Learning Analysis

This study employed tract-based spatial statistics (TBSS) to investigate abnormalities in the white matter microstructure among children with autism spectrum disorder (ASD). Additionally, an eXtreme Gradient Boosting (XGBoost) model was developed to effectively classify individuals with ASD and typical developing children (TDC). Multi-shell diffusion weighted images were acquired from 62 children with ASD and 44 TDC. Using the Pydesigner procedure, diffusion tensor (DT), diffusion kurtosis (DK), and white matter tract integrity (WMTI) metrics were computed. Subsequently, TBSS analysis was applied to discern differences in these diffusion parameters between ASD and TDC groups. The XGBoost model was then trained using metrics showing significant differences, and Shapley Additive explanations (SHAP) values were computed to assess the feature importance in the model's predictions. TBSS analysis revealed a significant reduction in axonal diffusivity (AD) in the left posterior corona radiata and the right superior corona radiata. Among the DK indicators, mean kurtosis, axial kurtosis, and kurtosis fractional anisotropywere notably increased in children with ASD, with no significant difference in radial kurtosis. WMTI metrics such as axonal water fraction, axonal diffusivity of the extra-axonal space (EAS_AD), tortuosity of the extra-axonal space (EAS_TORT), and diffusivity of intra-axonal space (IAS_Da) were significantly increased, primarily in the corpus callosum and fornix. Notably, there was no significant difference in radial diffusivity of the extra-axial space (EAS_RD). The XGBoost model demonstrated excellent classification ability, and the SHAP analysis identified EAS_TORT as the feature with the highest importance in the model's predictions. This study utilized TBSS analyses with multi-shell diffusion data to examine white matter abnormalities in pediatric autism. Additionally, the developed XGBoost model showed outstanding performance in classifying ASD and TDC. The ranking of SHAP values based on the XGBoost model underscored the significance of features in influencing model predictions.

Diffusion tensor imaging of the brain in children with sensory processing disorder: A review.

Sensory processing disorder (SPD) is a clinical condition characterized by difficulties in the neurological processes of registering, discriminating, organizing, and responding to various sensory sensations. This study aimed to review the association between impaired white matter (WM) tract structure and neurofunctional deficits in children with SPD using diffusion tensor imaging (DTI). A comprehensive literature search was conducted using the online databases Google Scholar and PubMed (from 2010 to July 2023), resulting in the selection of nine relevant studies. Findings revealed that the splenium of the corpus callosum (SCC), superior longitudinal fasciculus (SLF), posterior corona radiata (PCR), and posterior thalamic radiation (PTR) exhibited reduced microstructural integrity, strongly associated with SPD. Specifically, auditory over-responsivity, a subtype of SPD, was linked to impaired integrity of the PCR, PTR, anterior corona radiata, and SLF. Tactile over-responsivity (TOR) was correlated with markers of decreased integrity in the SCC, superior corona radiata, and left PTR. Among the DTI parameters, decreased fractional anisotropy (FA) emerged as the most reliable factor for identifying SPD, followed by increased radial diffusivity (RD) and mean diffusivity (MD). Notably, significant correlations were observed between with auditory over-responsivity and TOR with the DTI parameters (positive for FA and negative for RD and MD). Overall, this review confirms the impaired integrity of specific WM tracts in children with SPD and establishes correlations between DTI parameters and neurobehavioral deficits associated with the disorder. The insights gained from this review contribute to a better understanding of SPD and hold clinical implications for its diagnosis and treatment.

Insights and improvements in correspondence between axonal volume fraction measured with diffusion-weighted MRI and electron microscopy.

Biophysical diffusion-weighted imaging (DWI) models are increasingly used in neuroscience to estimate the axonal water fraction ( ), which in turn is key for noninvasive estimation of the axonal volume fraction ( ). These models require thorough validation by comparison with a reference method, for example, electron microscopy (EM). While EM studies often neglect the unmyelinated axons and solely report the fraction of myelinated axons, in DWI both myelinated and unmyelinated axons contribute to the DWI signal. However, DWI models often include simplifications, for example, the neglect of differences in the compartmental relaxation times or fixed diffusivities, which in turn might affect the estimation of . We investigate whether linear calibration parameters (scaling and offset) can improve the comparability between EM- and DWI-based metrics of . To this end, we (a) used six DWI models based on the so-called standard model of white matter (WM), including two models with fixed compartmental diffusivities (e.g., neurite orientation dispersion and density imaging, NODDI) and four models that fitted the compartmental diffusivities (e.g., white matter tract integrity, WMTI), and (b) used a multimodal data set including ex vivo diffusion DWI and EM data in mice with a broad dynamic range of fibre volume metrics. We demonstrated that the offset is associated with the volume fraction of unmyelinated axons and the scaling factor is associated with different compartmental and can substantially enhance the comparability between EM- and DWI-based metrics of . We found that DWI models that fitted compartmental diffusivities provided the most accurate estimates of the EM-based . Finally, we introduced a more efficient hybrid calibration approach, where only the offset is estimated but the scaling is fixed to a theoretically predicted value. Using this approach, a similar one-to-one correspondence to EM was achieved for WMTI. The method presented can pave the way for use of validated DWI-based models in clinical research and neuroscience.

Relationship between disproportionately enlarged subarachnoid-space hydrocephalus and white matter tract integrity in normal pressure hydrocephalus

Normal pressure hydrocephalus (NPH) patients had altered white matter tract integrities on diffusion tensor imaging (DTI). Previous studies suggested disproportionately enlarged subarachnoid space hydrocephalus (DESH) as a prognostic sign of NPH. We examined DTI indices in NPH subgroups by DESH severity and clinical symptoms. This retrospective case–control study included 33 NPH patients and 33 age-, sex-, and education-matched controls. The NPH grading scales (0–12) were used to rate neurological symptoms. Patients with NPH were categorized into two subgroups, high-DESH and low-DESH groups, by the average value of the DESH scale. DTI indices, including fractional anisotropy, were compared across 14 regions of interest (ROIs). The high-DESH group had increased axial diffusivity in the lateral side of corona radiata (1.43 ± 0.25 vs. 1.72 ± 0.25, p = 0.04), and showed decreased fractional anisotropy and increased mean, and radial diffusivity in the anterior and lateral sides of corona radiata and the periventricular white matter surrounding the anterior horn of lateral ventricle. In patients with a high NPH grading scale, fractional anisotropy in the white matter surrounding the anterior horn of the lateral ventricle was significantly reduced (0.36 ± 0.08 vs. 0.26 ± 0.06, p = 0.03). These data show that DESH may be a biomarker for DTI-detected microstructural alterations and clinical symptom severity.

Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology

AbstractBackgroundThe association between hearing impairment and Alzheimer’s disease (AD) and the mechanisms involved remain unclear.MethodsSurvival analyses were performed in 66,577 participants from the UK Biobank to investigate whether hearing impairment is associated with an increased risk of AD. The association of hearing status with cognitive function, brain structure and CSF proteins were explored in cross‐sectional, longitudinal, and mediation analyses across the UK Biobank (n = 165,550), Chinese Alzheimer’s Biomarker and Lifestyle (CABLE, n = 867), and Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 802).ResultsHearing impairment was associated with an increased risk of AD over 11 years of follow‐up (HR 1.80, 95%CI 1.50‐2.15). Poor hearing status was associated with worse cognitive function in cross‐sectional and longitudinal studies. Moreover, hearing impairment was significantly related to lower volume of the temporal cortex, hippocampus, amygdala, inferior parietal lobe, precuneus and orbitofrontal cortex, to lower integrity of white matter tracts, and to a higher level of CSF tau protein. Mediation analyses showed that brain structure and CSF tau partly mediated the association between hearing impairment and cognitive decline.ConclusionHearing impairment is a risk factor for AD, and is associated with brain structure, tau pathology, and cognitive decline.

White Matter Tract Integrity Is Reduced in Depression and in Individuals With Genetic Liability to Depression

BackgroundWhile major depression has been linked to changes in white matter architecture, it remains unclear whether risk factors for depression are directly associated with these alterations. We reexamined white matter fiber tracts in individuals with depressive symptoms and investigated the connection between genetic and environmental risk for depression and structural changes in the brain. MethodsWe included 19,183 participants from the UK Biobank imaging cohort, with depression status and adverse life experience based on questionnaire data and genetic liability for depression quantified by polygenic scores. The integrity of 27 white matter tracts was assessed using mean fractional anisotropy derived from diffusion magnetic resonance imaging. ResultsWhite matter integrity was reduced, particularly in thalamic and intracortical fiber tracts, in individuals with depressive symptoms, independent of current symptom status. In a group of healthy individuals without depression, increasing genetic risk and increasing environmental risk were associated with reduced integrity in relevant fiber tracts, particularly in thalamic radiations. This association was stronger than expected based on statistical dependencies between samples, as confirmed by subsequent in silico simulations and permutation tests. ConclusionsWhite matter alterations in thalamic and association tracts are associated with depressive symptoms and genetic risk for depression in unaffected individuals, suggesting an intermediate phenotype at the brain level.

Higher baseline cerebrospinal fluid platelet‐derived growth factor receptor‐β levels are associated with slower reductions in longitudinal cerebral blood flow among cognitively unimpaired individuals

AbstractBackgroundCerebrospinal fluid (CSF) platelet‐derived growth factor receptor‐β (PDGFR‐β) is an emerging biomarker hypothesized to reflect pericyte damage. CSF PDGFR‐β levels are increased in Alzheimer’s disease (AD), but it is unknown if pericyte injury contributes to cerebrovascular changes common in AD. We examined if PDGFR‐β relates to changes in cerebral blood flow (CBF) and white matter injury in older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 43% mild cognitive impairment [MCI]) underwent baseline lumbar puncture and serial brain MRI over a 7‐year (5.5±2.3) follow‐up period. CSF PDGFR‐β concentrated was measured by immunoassay. MRI included pseudo‐continuous arterial spin‐labeling to quantify CBF, T2‐FLAIR to quantify white matter hyperintensities (WMHs), and diffusion tensor imaging (DTI) to quantify white matter microstructural integrity. Ordinary least squares regression and linear mixed‐effects models related baseline CSF PDGFR‐β to baseline and longitudinal whole brain and regional CBF, WMH, and DTI metrics, adjusting for baseline demographic variables, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐ε4 status, and regional tissue volume. Longitudinal models adjusted for follow‐up time. Follow‐up models tested a CSF PDGFR‐β x cognitive status interaction.ResultIn main models, higher CSF PDGFR‐β levels were cross‐sectionally associated with lower mean diffusivity (indicating better microstructural integrity) in white matter tracts in the frontal, temporal, parietal, and occipital lobes (p‐values&lt;0.03) but were unrelated to WMHs (p‐values&gt;0.18). Models investigating associations with longitudinal white matter variables were null (p‐values&gt;0.35). CSF PDGFR‐β cross‐sectionally interacted with diagnosis on temporal lobe CBF, such that higher CSF PDGFR‐β related to higher CBF in MCI participants (p = 0.01). In longitudinal models, baseline CSF PDGFR‐β interacted with cognitive status on whole brain and occipital lobe CBF (p‐values&lt;0.04). Stratified models showed higher baseline CSF PDGFR‐β related slower reductions in longitudinal CBF in whole brain (p = 0.02), frontal (p = 0.04), temporal (p = 0.02), parietal (p = 0.01), and occipital lobes (p = 0.008) in cognitively unimpaired participants only.ConclusionAmong older adults, higher CSF PDGFR‐β levels are associated with better white matter integrity at study entry and predict slower reductions in longitudinal CBF among cognitively unimpaired individuals. Results suggest that higher PDGFR‐β levels may reflect subclinical vascular remodeling that provides protection to future cerebrovascular compromise.

Brain connectivity underlying apathy in Alzheimer’s and Parkinson’s diseases

AbstractBackgroundApathy, defined as a lack of motivation towards goal‐directed behavior, is a common neuropsychiatric symptom in Alzheimer’s (AD) and Parkinson’s (PD) disease. However, the mechanism underlying apathy is still unclear. Studies have postulated that the degeneration of frontal cortical and subcortical structures may play a major role in the mechanism of apathy. This study investigates whether associations between degeneration in structural and functional connectivity between frontal and subcortical regions contributes to the development of apathetic behavior and whether these associations differ by diseases.MethodForty‐four patients, 8 with AD, 14 amnestic mild cognitive impairment (aMCI), and 22 PD, received MRI brain scans, a decision‐making behavioral task, cognitive and psychosocial assessments including the dimensional apathy scale (DAS). We quantified functional connectivity and white matter tract integrity for a set of frontal and subcortical regions of interest, and examined the associations among fronto‐subcortical connectivity, behavioral measures, and the DAS. These associations were tested for patient group interactions.ResultCombining AD and aMCI into one patient group, the AD/aMCI group showed worse apathy than PD in terms of the total, the executive, and the behavioral/cognitive subscores (see Table 1), while the DAS emotional subscore was not different between the two groups. For the decision‐making task, the proportion of trial acceptance was similar between the groups, but AD/aMCI had slower decision latency than PD. Group interaction with brain measures was observed in the association between DAS total score and the functional connectivity between the right pars triangularis in the inferior frontal gyrus and the caudate (See Figure 1; interaction effect: beta = ‐.367, p = .0422 FDR corrected). The white matter tract connecting the right pars triangularis to subcortical regions also showed a group interaction with DAS total score but at an uncorrected statistical level (Figure 2; beta = 3.61, p = .0454, uncorrected).ConclusionOur preliminary analyses exposed phenotypic differences in apathy profiles and decision‐making behavior between AD and PD. Furthermore, the observed functional and structural neurodegenerative changes associated with higher apathy severity may also differ between the two diseases. Future analyses in a larger cohort will examine distinct neurodegeneration patterns between the two diseases.

Medial Temporal Lobe White Matter Integrity is Related to Memory and Amyloid‐Beta Pathology in Aging

AbstractBackgroundDamage to white matter (WM) within the medial temporal lobe (MTL) may underlie memory decline in aging and Alzheimer’s disease (AD). We measured MTL WM tract integrity through diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging (NODDI). We tested WM integrity associations with memory performance and amyloid‐ß pathology in cognitively normal older adults.Method105 cognitively normal older adults (70.8 years old, 65% female) with diffusion MRI were processed with MRtrix3. Standard diffusion metrics of fractional anisotropy (FA) and mean diffusivity (MD) were calculated. NODDI MDT was used to generate the neurite density index (NDI), representing number of voxels with unhindered diffusion, and the orientation dispersion index (ODI), representing the variability of neurite orientation. We calculated these measures for MTL tracts from the JHU WM Atlas: cingulum‐hippocampus, fornix column/body, and fornix/stria terminalis. Participants received 18F‐florbetapir (FBP) to measure Aß pathology (n = 94), and global FBP SUVR was calculated. Memory was measured with the Rey Auditory Verbal Learning Test delayed recall score (RAVLT, n = 81). Analyses covaried for age and/or education.ResultBetter memory was associated with lower ODI in the fornix column/body (r = ‐0.27, p = 0.018), with trends for higher FA (r = 0.021, p = 0.06) and lower NDI (r = ‐0.19, p = 0.09). Better memory was also associated with higher MD in the cingulum‐hippocampus (right: r = 0.23, p = 0.04; left: r = 0.25, p = 0.03), with trends for lower ODI (right: r = ‐.20, p = 0.08; left: r = ‐0.20, p = 0.09). Higher FBP SUVR was associated with increased FA in the fornix column/body (r = 0.31, p = 0.003) and a trend in the left cingulum hippocampus (r = 0.20, p = 0.054). Memory or FBP SUVR was not significantly related to integrity of the fornix/stria terminalis.ConclusionIntegrity of fornix column/body and cingulum‐hippocampus were related to both memory performance and Aß pathology. Our results suggest that using a combination of NODDI as well as diffusion tensor metrics provided a more robust understanding of memory impacts in aging.

Abstract 13302: Associations of Allostatic Load With Brain Macro-Morphology, Subclinical Cerebrovascular Disease, and Microstructural Integrity of White Matter Pathways: The Boston Puerto Rican Health Study

Introduction: Allostatic load (AL), a measure of overall body wear and tear, has been associated with structural and functional alterations of the brain, but the evidence remains scarce. We aimed to evaluate the prospective associations of AL with brain MRI measures in the Boston Puerto Rican Health Study (BPRHS). Research Questions: Whether AL is associated with 1) brain macro-morphology: brain age and volumes, 2) subclinical cerebrovascular disease: white matter hyperintensity (WMH) and brain infarcts, and 3) microstructural integrity of white matter (WM) pathways in Puerto Rican adults. Methods: Adults from the BPRHS cohort who provided blood and urine samples at baseline, 2-y, and 6-y visits and underwent MRI scans at 13-y visit were included in analyses (n=226). AL was evaluated as a composite score (0-11) of 11 physiological parameters in five body systems. An overall AL score was calculated by averaging the scores of the baseline, 2-y, and 6-y visits, with higher scores indicating greater dysregulation. We evaluated brain age and volumes using T1-weighted MRI, WMH and brain infarcts using T2-weighted MRI, and microstructural integrity of WM pathways using diffusion tensor imaging. Multivariable logistic regression models were used to examine the associations between AL and brain infarcts, and linear regression models were used for other MRI outcomes. Results: Mean age at baseline was 54.6 ± 6.6 y, with 79.2% female. Higher AL was associated with higher brain age z scores (β = 0.129, P = 0.031) and lower volumes of total WM, cerebral WM (especially parietal and temporal lobes), cerebellum, and brain stem. Higher AL was also associated with higher grades of WMH (β = 0.207, P = 0.024) and higher odds of small vessel infarcts [OR (95% CI) = 3.50 (1.56-7.87), P = 0.002], but not large vessel infarcts [OR (95% CI) = 1.33 (0.73-2.40), P = 0.348]. Diffusion tensor imaging parameters showed that participants with higher AL had more microstructural deterioration patterns in major WM pathways. Conclusions: Higher AL score was associated with brain macro- and microstructural disruptions and a higher risk of subclinical cerebrovascular disease, suggesting that AL may be a potential indicator of the need for early intervention in preventing neuronal damage in older adults.

42 White matter injury is driven by HIV duration, immune and vascular factors in virally suppressed people living with HIV: a longitudinal diffusion imaging study

Objective:The aim of the current longitudinal study was to use improved brain white matter integrity outcomes (better at resolving white matter complexity, hence with improved biological significance compared to traditional diffusion tensor imaging - DTI outcomes) while considering baseline age, cardiovascular diseases (CVD), and HIV disease markers impacts on the health of major white matter tracts in virally suppressed people Living with HIV infection (PLHIV) versus demographically, geographically, and life-style comparable HIVnegative controls. Furthermore, white-matter hyperintensity (WMH) and normal-appearing white matter (NAWM) volumes and microstructure were considered.Participants and Methods:At baseline 48 HIV-controls and 84 virally suppressed PLHIV (mean age 55), and at 24-month follow-up, 40 HIV-controls and 75 virally suppressed PLHIV underwent an MRI scan (3T Phillips) collecting a high-resolution anatomical MRI, FLAIR, and a 32-direction diffusion imaging. The diffusion data were processed using mrtrix and intra-cranial volume-corrected outcomes included fibre density (FD), fibre cross-section (log was used; logFC) and a composite fibre density and cross-section (FDC). The volumetric data was first processed in Freesurfer 6.0, and WMH were segmented using the “pgs” U-Net neural network. Using mixed models, we examine the longitudinal mrtrix outcomes across major white matter tracts by HIV status, and associations with CVD (sum of the scaled scores of total cholesterol, HDL, Systolic BP, current smoking, and diabetes) and HIV disease (HIV duration, historical AIDS, nadir CD4, baseline CD4) markers. Additionally, we assessed the volume, and FDC in the periventricular and deep WMH, as well as NAWM, and the associations with CVD and HIV disease markers. We used FDR control procedure (alpha = 0.05), and all p-values reported are FDR adjusted.Results:Relative to controls, PLHIV showed significant reductions (p&lt;.05 - p&lt;.01) of FC, and FDC to a lesser extent, in multiple long cortical association tracts, and within striatal- and thalamic-frontoparietal connections. A small HIV by age interaction was only detected for FC of inferior longitudinal fasciculus (Beta = -0.004, SE = 0.002 p&lt;.04). However, HIV duration (corrected for baseline age) was associated with worse FDC across multiple tracts (p&lt;03 -p&lt;.001). Baseline CD4 counts associated with lower FD in frontal association tracts (p&lt;.05 -p&lt;.005). Furthermore, WMH increased in size with time, age, and higher CVD risk factors, but not HIV status. In PLHIV, deep WMH and NAWM microstructure were both associated with worse CVD but not HIV disease markers.Conclusions:The fine integrity of major white matter tracts is impacted by HIV status, HIV duration and baseline CD4, whereas WMH and NAWM volumes and microstructure are affected by CVD. Our study provides further evidence of the immuno-vascular underpinning of HIV neuropathogenesis in virally suppressed PLHIV. The convergence of these effects in aging PLHIV may lead to early neurodegeneration. Hence, improving CVD health and maintaining high CD4 is critical.