Neurite Orientation Dispersion And Density Imaging Research Articles

Sex-related variability of white matter tracts in the whole HCP cohort.

Behavioral differences between men and women have been studied extensively, as have differences in brain anatomy. However, most studies have focused on differences in gray matter, while white matter has been much less studied. We conducted a comprehensive study of 77 deep white matter tracts to analyze their volumetric and microstructural variability between men and women in the full Human Connectome Project (HCP) cohort of 1065 healthy individuals aged 22-35years. We found a significant difference in total brain volume between men and women (+ 12.6% in men), consistent with the literature. 16 tracts showed significant volumetric differences between men and women, one of which stood out due to a larger effect size: the corpus callosum genu, which was larger in women (+ 7.3% in women, p = 5.76 × 10-19). In addition, we found several differences in microstructural parameters between men and women, both using standard Diffusion Tensor Imaging (DTI) parameters and more complex microstructural parameters from the Neurite Orientation Dispersion and Density Imaging (NODDI) model, with the tracts showing the greatest differences belonging to motor (cortico-spinal tracts, cortico-cerebellar tracts) or limbic (cingulum, fornix, thalamo-temporal radiations) systems. These microstructural differences may be related to known behavioral differences between the sexes in timed motor performance, aggressiveness/impulsivity, and social cognition.

Combined MR quantitative susceptibility mapping and multi-shell diffusion in Parkinson's disease.

Quantitative susceptibility mapping (QSM), neurite orientation dispersion and density imaging (NODDI), and the g-ratio have separately shown differences between Parkinson's disease (PD) and healthy controls. The g-ratio has, however, not been studied in PD in the substantia nigra (SN) and the putamen. A combination of these methods could also potentially be a complementary imaging biomarker for PD. This study aimed to assess the diagnostic performance of QSM, NODDI, the g-ratio, and a combined QSM-NODDI imaging marker in the SN and putamen of PD patients. In this prospective study, the diagnostic performance of median region of interest values was compared in a cohort of 15 participants with PD and 14 healthy controls after manual segmentation. The diagnostic performance was assessed using the area under curve (AUC) for the receiving operator characteristic. Median QSM in the contralateral SN identified PD with AUC 0.77, and median isotropic volume fraction identified PD in the ipsilateral SN with AUC 0.68. A combined NODDI-QSM marker improved diagnostic performance (AUC 0.80). No significant differences were found in the g-ratio. A combination of median QSM and median isotropic volume fraction improves the differentiation of PD from healthy controls and is a potential biomarker in the diagnostics of PD. This confirms previously reported results indicating that combining QSM and NODDI modestly improves differentiation of PD.

White matter and cortical gray matter microstructural abnormalities in new daily persistent headache: a NODDI study.

New daily persistent headache (NDPH) is a rare primary headache with unclear pathogenesis. Neuroimaging studies of NDPH are limited, and controversy still exists. Diffusion tensor imaging (DTI) is commonly used to study the white matter. However, lacking specificity, the potential pathological mechanisms of white matter microstructural changes remain poorly understood. In addition, the intricacy of gray matter structures impedes the application of the DTI model. Here, we applied an advanced diffusion model of neurite orientation dispersion and density imaging (NODDI) to study the white matter and cortical gray matter microstructure in patients with NDPH. This study assessed brain microstructure, including 27 patients with NDPH, and matched 28 healthy controls (HCs) by NODDI. The differences between the two groups were assessed by tract-based spatial statistics (TBSS) and surface-based analysis (SBA), focusing on the NODDI metrics (neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF)). Furthermore, we performed Pearson's correlation analysis between the NODDI indicators and clinical characteristics. Compared to HCs, patients with NDPH had a reduction of density and complexity in several fiber tracts. For robust results, the fiber tracts were defined as comprising more than 100 voxels, including bilateral inferior fronto-occipital fasciculus (IFOF), left superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF), as well as right corticospinal tract (CST). Moreover, the reduction of neurite density was uncovered in the left superior and middle frontal cortex, left precentral cortex, and right lateral orbitofrontal cortex and insula. There was no correlation between the NODDI metrics of these brain regions and clinical variables or scales of relevance after the Bonferroni correction. Our research indicated that neurite loss was detected in both white matter and cortical gray matter of patients with NDPH.

White matter and cortical gray matter microstructural abnormalities in new daily persistent headache: a NODDI study.

New daily persistent headache (NDPH) is a rare primary headache with unclear pathogenesis. Neuroimaging studies of NDPH are limited, and controversy still exists. Diffusion tensor imaging (DTI) is commonly used to study the white matter. However, lacking specificity, the potential pathological mechanisms of white matter microstructural changes remain poorly understood. In addition, the intricacy of gray matter structures impedes the application of the DTI model. Here, we applied an advanced diffusion model of neurite orientation dispersion and density imaging (NODDI) to study the white matter and cortical gray matter microstructure in patients with NDPH. This study assessed brain microstructure, including 27 patients with NDPH, and matched 28 healthy controls (HCs) by NODDI. The differences between the two groups were assessed by tract-based spatial statistics (TBSS) and surface-based analysis (SBA), focusing on the NODDI metrics (neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF)). Furthermore, we performed Pearson's correlation analysis between the NODDI indicators and clinical characteristics. Compared to HCs, patients with NDPH had a reduction of density and complexity in several fiber tracts. For robust results, the fiber tracts were defined as comprising more than 100 voxels, including bilateral inferior fronto-occipital fasciculus (IFOF), left superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF), as well as right corticospinal tract (CST). Moreover, the reduction of neurite density was uncovered in the left superior and middle frontal cortex, left precentral cortex, and right lateral orbitofrontal cortex and insula. There was no correlation between the NODDI metrics of these brain regions and clinical variables or scales of relevance after the Bonferroni correction. Our research indicated that neurite loss was detected in both white matter and cortical gray matter of patients with NDPH.

White matter microstructure alterations of the posterior limb of internal capsule in first-episode drug naive schizophrenia patients

ObjectivesPrevious studies have shown that microstructural alterations in white matter (WM) could contribute to the symptom manifestation and support the dysconnectivity hypothesis in schizophrenia patients. These alterations were pervasive, non-specific, and reported inconsistently across the literature. This study aimed to specifically investigate the microstructure alterations of the posterior limb of the internal capsule (PLIC) in first-episode, drug-naive schizophrenia patients. Utilizing a multicompartmental biophysical model, we further explored the correlation between these alterations and syndrome scale scores. MethodsThirty-two individuals with first-episode, drug-naive schizophrenia (FES) and thirty demographically matched healthy controls were enrolled. High-resolution multi-shell diffusion MRI data were collected, followed by the application of a three-compartment Neurite Orientation Dispersion and Density Imaging (NODDI) model to scrutinize the alterations in white matter microstructure. Changes in sensory and motor fibers within the PLIC were specifically focused on. Additionally, the correlation between these pathological changes and scores on the Positive and Negative Syndrome Scale (PANSS) was investigated. ResultsThe Neurite density index (NDI) in the left PLIC was significantly lower in FES patients compared to healthy individuals, and positively correlated with PANSS positive syndrome scores (r = 0.0379, p = 0.046). In the sensory component (left superior thalamic radiation within PLIC, STR_P), the NDI was significantly elevated (p < 0.0001). Conversely, the NDI in the motor component (left corticospinal tract within PLIC, CST_P) was reduced (p = 0.007) in FES patients compared to healthy individuals, and strongly correlated with PANSS positive syndrome scores (p < 0.020) and PANSS total scores (p < 0.045). Moreover, the NDI deviation of STR from total PLIC (fSTR_P) and NDI deviation in STR_P and CST_P compared to PLIC region (fPLIC) were significantly higher in FES patients than in healthy controls (p < 0.00001), with an area under the curve (AUC) of fPLIC reaching 0.872. ConclusionThe study’s findings provided new insights into the discrepancy of white matter microstructure changes associated with the sensory and motor fibers in the PLIC region in FES patients. These results contribute to the growing body of evidence suggesting that WM microstructural alterations play a critical role in schizophrenia pathophysiology.

Quantitative cellular pathology of the amygdala in temporal lobe epilepsy and correlation with magnetic resonance imaging volumetry, tissue microstructure, and sudden unexpected death in epilepsy risk factors.

Amygdala enlargement can occur in temporal lobe epilepsy, and increased amygdala volume is also reported in sudden unexpected death in epilepsy (SUDEP). Apnea can be induced by amygdala stimulation, and postconvulsive central apnea (PCCA) and generalized seizures are both known SUDEP risk factors. Neurite orientation dispersion and density imaging (NODDI) has recently provided additional information on altered amygdala microstructure in SUDEP. In a series of 24 surgical temporal lobe epilepsy cases, our aim was to quantify amygdala cellular pathology parameters that could predict enlargement, NODDI changes, and ictal respiratory dysfunction. Using whole slide scanning automated quantitative image analysis methods, parallel evaluation of myelin, axons, dendrites, oligodendroglia, microglia, astroglia, neurons, serotonergic networks, mTOR-pathway activation (pS6) and phosphorylated tau (pTau; AT8, AT100, PHF) in amygdala, periamygdala cortex, and white matter regions of interest were compared with preoperative magnetic resonance imaging data on amygdala size, and in 13 cases with NODDI and evidence of ictal-associated apnea. We observed significantly higher glial labeling (Iba1, glial fibrillary acidic protein, Olig2) in amygdala regions compared to cortex and a strong positive correlation between Olig2 and Iba1 in the amygdala. Larger amygdala volumes correlated with lower microtubule-associated protein (MAP2), whereas higher NODDI orientation dispersion index correlated with lower Olig2 cell densities. In the three cases with recorded PCCA, higher MAP2 and pS6-235 expression was noted than in those without. pTau did not correlate with SUDEP risk factors, including seizure frequency. Histological quantitation of amygdala microstructure can shed light on enlargement and diffusion imaging alterations in epilepsy to explore possible mechanisms of amygdala dysfunction, including mTOR pathway activation, that in turn may increase the risk for SUDEP.

Antidepressant-related microstructural changes in the external capsule.

Several magnetic resonance imaging (MRI) studies have reported that antidepressant medications are strongly linked to brain microstructural alterations. Notably, external capsule alterations have been reported to be a biological marker for therapeutic response. However, prior studies did not investigate whether a change in the neurite density or directional coherence of white matter (WM) fibers underlies the observed microstructural alterations. This MRI-based case-control study examined the relationship between patients' current use of antidepressant medications and advanced measurements of external capsule WM microstructure derived from multishell diffusion imaging using neurite orientation dispersion and density imaging (NODDI). The study compared a group of thirty-five participants who were taking antidepressant medications comprising selective serotonin reuptake inhibitors (SSRIs) (n = 25) and serotonin and norepinephrine reuptake inhibitors (SNRIs) with a control group of thirty-five individuals matched in terms of age, sex, race, and atherosclerotic cardiovascular risk factors. All participants were selected from the Dallas Heart Study phase 2, a multi-ethnic, population-based cohort study. A series of multiple linear regression analyses were conducted to predict microstructural characteristics of the bilateral external capsule using age, sex, and antidepressant medications as predictor variables. There was significantly reduced neurite density in the bilateral external capsules of patients taking SSRIs. Increased orientation dispersion in the external capsule was predominantly seen in patients taking SNRIs. Our findings suggest an association between specific external capsule microstructural changes and antidepressant medications, including reduced neurite density for SSRIs and increased orientation dispersion for SNRIs.

Diffusion imaging genomics provides novel insight into early mechanisms of cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.

Microstructural changes of the white matter in systemic lupus erythematosus patients without neuropsychiatric symptoms: a multi-shell diffusion imaging study

BackgroundDiffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) provide more comprehensive and informative perspective on microstructural alterations of cerebral white matter (WM) than single-shell diffusion tensor imaging (DTI), especially in the detection of crossing fiber. However, studies on systemic lupus erythematosus patients without neuropsychiatric symptoms (non-NPSLE patients) using multi-shell diffusion imaging remain scarce.MethodsTotally 49 non-NPSLE patients and 41 age-, sex-, and education-matched healthy controls underwent multi-shell diffusion magnetic resonance imaging. Totally 10 diffusion metrics based on DKI (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, mean kurtosis, axial kurtosis and radial kurtosis) and NODDI (neurite density index, orientation dispersion index and volume fraction of the isotropic diffusion compartment) were evaluated. Tract-based spatial statistics (TBSS) and atlas-based region-of-interest (ROI) analyses were performed to determine group differences in brain WM microstructure. The associations of multi-shell diffusion metrics with clinical indicators were determined for further investigation.ResultsTBSS analysis revealed reduced FA, AD and RK and increased ODI in the WM of non-NPSLE patients (P < 0.05, family-wise error corrected), and ODI showed the best discriminative ability. Atlas-based ROI analysis found increased ODI values in anterior thalamic radiation (ATR), inferior frontal-occipital fasciculus (IFOF), forceps major (F_major), forceps minor (F_minor) and uncinate fasciculus (UF) in non-NPSLE patients, and the right ATR showed the best discriminative ability. ODI in the F_major was positively correlated to C3.ConclusionThis study suggested that DKI and NODDI metrics can complementarily detect WM abnormalities in non-NPSLE patients and revealed ODI as a more sensitive and specific biomarker than DKI, guiding further understanding of the pathophysiological mechanism of normal-appearing WM injury in SLE.

Relationship between sleep, physical fitness, brain microstructure, and cognition in healthy older adults: A pilot study

BackgroundThere is a critical need for neuroimaging markers of brain integrity to monitor effects of modifiable lifestyle factors on brain health. This observational, cross-sectional study assessed relationships between brain microstructure and sleep, physical fitness, and cognition in healthy older adults. MethodsTwenty-three adults aged 60 and older underwent whole-brain multi-shell diffusion imaging, comprehensive cognitive testing, polysomnography, and exercise testing. Neurite Orientation Dispersion and Density Imaging (NODDI) was used to quantify neurite density (NDI) and orientation dispersion (ODI). Diffusion tensor imaging (DTI) was used to quantify axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Relationships between sleep efficiency (SE), time and percent in N3 sleep, cognitive function, physical fitness (VO2 peak) and the diffusion metrics in regions of interest and the whole brain were evaluated. ResultsHigher NDI in bilateral white and gray matter was associated with better executive functioning. NDI in the right anterior cingulate and adjacent white matter was positively associated with language skills. Higher NDI in the left posterior corona radiata was associated with faster processing speed. Physical fitness was positively associated with NDI in the left precentral gyrus and corticospinal tract. N3 % was positively associated with NDI in the left caudate and right pre- and postcentral gyri. Higher ODI in the left putamen and adjacent white matter was associated with better executive function. ConclusionNDI and ODI derived from NODDI are potential neuroimaging markers for associations between brain microstructure and modifiable risk factors in aging. If these associations are observable in clinical samples, NODDI could be incorporated into clinical trials assessing the effects of modifiable risk factors on brain integrity in aging and neurodegenerative diseases.

White Matter Microstructure of the Genu of the Corpus Callosum Measured Using Neurite Orientation Dispersion and Density Imaging (NODDI) Is Associated with Cardiorespiratory Fitness in Older Adults

Changes in white matter microstructure of the genu of the corpus callosum are predictive of cognitive decline in patients with mild cognitive impairment. Cardiorespiratory fitness (CRF) is positively associated with brain health; however, the relationship between cardiorespiratory fitness and white matter microstructure of the genu of the corpus callosum is unknown. Further, a novel diffusion method for assessing white matter microstructure, neurite orientation dispersion and density imaging (NODDI), can detect specific microstructural features that are not observed with conventional diffusion tensor imaging (DTI). Young (n=27, age=25±5, m=12, f=15) and older (n=23, age=64±5, m=12, f=11) adults free of underlying disease participated in this study. CRF was assessed using an incremental maximal exercise test on a cycle ergometer. On a separate visit, white matter microstructure of the genu of the corpus callosum was measured using both DTI and NODDI MRI scans. In young adults, there were no associations between CRF and white matter microstructure of the genu of the corpus callosum measured using either DTI or NODDI (p&gt;0.05). In older adults, there were no associations between CRF and white matter microstructure of the genu of the corpus callosum measured with DTI. However, in older adults, there was a positive association between CRF and orientation dispersion index of the genu of the corpus callosum measured with NODDI (r=0.47, p=0.02). In conclusion, using conventional DTI, no associations between CRF and white matter microstructure of the genu of the corpus callosum were observed. However, using NODDI, which can detect specific microstructural features, our results suggest that older adults with higher CRF demonstrated enhanced white matter microstructure, specifically orientation dispersion index, of the genu of the corpus callosum. Conventional DTI may underestimate the impact of CRF on age-related changes in white matter microstructure. National Institutes of Health - HL118154 (JNB), HL007936 (KBM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Assessment of white matter microstructure integrity in subacute postconcussive vestibular dysfunction using NODDI

Abstract Vestibular symptoms, such as dizziness and balance impairment, are frequently reported following mild traumatic brain injury (mTBI) and are associated with a protracted recovery, yet the underlying neuroanatomical substrates remain unclear. The present study utilized advanced diffusion MRI (dMRI) techniques including both conventional diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate microstructural white matter integrity in individuals with postconcussive vestibular dysfunction (PCVD) within the subacute injury period (median of 35 days from injury; IQR of 23). Study participants included 23 individuals with subacute PCVD and 37 healthy control subjects who underwent imaging and comprehensive clinical vestibular testing. Between-group voxelwise analysis of differences in white matter revealed areas of higher intra-neurite volume fraction (VIn) and isotropic volume fraction (VIso) within PCVD subjects compared to controls, which involved overlapping regions within the left hemisphere of the brain. Affected areas of higher VIn and VIso included the superior longitudinal fasciculus (SLF) and superior and posterior corona radiata (SCR and PCR, respectively). We examined the relationship between clinical vestibular measures and diffusion metrics including DTI (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD] and axial diffusivity [AD]) and NODDI (intraneurite volume fraction [VIn], isotropic volume fraction [VIso], dispersion anisotropy [DA], orientation dispersion indexTotal/Primary/Secondary [ODIT/P/S]) within 32 regions-of-interest. Clinical vestibular measures included self-reported measures, including the Dizziness Handicap Inventory, Visual Vertigo Analog Scale, and Vestibular/Ocular-Motor Screening, as well as objective vestibular testing using the sensory organization test. Significant correlations were found with clinical measures across all diffusion maps (except DA), within various regions of interest (ROIs), including SLF, SCR, and PCR. These results implicate several important association bundles that may potentiate sensory processing dysfunction related to PCVD. Whether these neuroanatomical differences found within the subacute phase of PCVD are in response to injury or represent preexisting structural variations that increase vulnerability to sensory processing dysfunction is unclear and remains an active area of study.

Neurite orientation dispersion and density imaging reveals abnormal white matter and glymphatic function in active young boxers.

The neurological effects and underlying pathophysiological mechanisms of sports-related concussion (SRC) in active young boxers remain poorly understood. This study aims to investigate the impairment of white matter microstructure and assess changes in glymphatic function following SRC by utilizing neurite orientation dispersion and density imaging (NODDI) on young boxers who have sustained SRC. A total of 60 young participants were recruited, including 30 boxers diagnosed with SRC and 30 healthy individuals engaging in regular exercise. The assessment of whole-brain white matter damage was conducted using diffusion metrics, while the evaluation of glymphatic function was performed through diffusion tensor imaging (DTI) analysis along the perivascular space (DTI-ALPS) index. A two-sample t-test was utilized to examine group differences in DTI and NODDI metrics. Spearman correlation and generalized linear mixed models were employed to investigate the relationship between clinical assessments of SRC and NODDI measurements. Significant alterations were observed in DTI and NODDI metrics among young boxers with SRC. Additionally, the DTI-ALPS index in the SRC group exhibited a significantly higher value than that of the control group (left side: 1.58 vs. 1.48, PFDR=0.009; right side: 1.61 vs. 1.51, PFDR=0.02). Moreover, it was observed that the DTI-ALPS index correlated with poorer cognitive test results among boxers in this study population. Repetitive SRC in active young boxers is associated with diffuse white matter injury and glymphatic dysfunction, highlighting the detrimental impact on brain health. These findings highlight the importance of long-term monitoring of the neurological health of boxers.

Multimodal 7T imaging reveals enhanced functional coupling between salience and frontoparietal networks in young adult tobacco cigarette smokers.

Tobacco cigarette smoking is associated with disrupted brain network dynamics in resting brain networks including the Salience (SN) and Fronto parietal (FPN). Unified multimodal methods [Resting state connectivity analysis, Diffusion Tensor Imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and cortical thickness analysis] were employed to test the hypothesis that the impact of cigarette smoking on the balance among these networks is due to alterations in white matter connectivity, microstructural architecture, functional connectivity and cortical thickness (CT) and that these metrics define fundamental differences between people who smoke and nonsmokers. Multimodal analyses of previously collected 7 Tesla MRI data via the Human Connectome Project were performed on 22 people who smoke (average number of daily cigarettes was 10 ± 5) and 22 age- and sex-matched nonsmoking controls. First, functional connectivity analysis was used to examine SN-FPN-DMN interactions between people who smoke and nonsmokers. The anatomy of these networks was then assessed using DTI and CT analyses while microstructural architecture of WM was analyzed using the NODDI toolbox. Seed-based connectivity analysis revealed significantly enhanced within network [p = 0.001 FDR corrected] and between network functional coupling of the salience and R-frontoparietal networks in people who smoke [p = 0.004 FDR corrected]. The network connectivity was lateralized to the right hemisphere. Whole brain diffusion analysis revealed no significant differences between people who smoke and nonsmokers in Fractional Anisotropy, Mean diffusivity and in neurite orienting and density. There were also no significant differences in CT in the hubs of these networks. Our results demonstrate that tobacco cigarette smoking is associated with enhanced functional connectivity, but anatomy is largely intact in young adults. Whether this enhanced connectivity is pre-existing, transient or permanent is not known. The observed enhanced connectivity in resting state networks may contribute to the maintenance of smoking frequency.

Influences of amyloid-β and tau on white matter neurite alterations in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer’s disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB.

White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis. To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age. Remote history of mTBI. White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed. A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (β = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (β = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (β = 0.013, Cohen d = 0.61; P < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (β = 5.4 × 10-3; P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (β = 4.3 × 10-4; P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (β = 1.2 × 10-3; P = .02). In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.

101 Glymphatic System Impairment Associated With Neurocognitive Dysfunction and Alzheimers Biomarkers in Moyamoya Disease

INTRODUCTION: Glymphatic system alterations have been proved to be associated with cognitive dysfunction in Alzheimer’s Disease (AD). The glymphatic pathway has not been elucidated in moyamoya disease (MMD), which was recognized as a chronic hypoperfusion model for AD. METHODS: We prospectively recruited 30 MMD patients and 30 matched healthy controls (HC) from October 2022 to March 2023. Participants underwent neurocognition evaluation, and multimodal magnetic resonance imaging (MRI). AD-related serum biomarkers, as well as correlations among these variables were examined. The glymphatic function was assessed by diffusion tensor image analysis along perivascular space (DTI-ALPS). Whole-brain (white matter and grey matter) volumes were calculated by using 3D T1-weighted MRI. Microstructural changes of white matter (intracellular volume fraction, Vic; orientation dispersion index, OD) were evaluated by neurite orientation dispersion and density imaging (NODDI). RESULTS: Serum Alzheimer’s biomarkers (ApoE, Aβ40, Aβ42, and tau) were significantly elevated and associated with neurocognitive dysfunction in MMD. Lower periventricular ALPS-index was identified in patients with MMD (P &lt; 0.001). The decreased ALPS-index correlated with declined neurocognitive performance of intelligence quotient, attention, and memory, increased levels of serum ApoE, Aβ40, Aβ42, as well as higher periventricular white matter volume and lower periventricular grey matter volume (P &lt; 0.001). Moreover, MMD patients had significantly lower Vic in the white matter and a lower OD in the cortex than HC. CONCLUSIONS: We firstly demonstrated the impaired glymphatic system as assessed by lower ALPS-index in patients with MMD. Glymphatic impairment was associated with AD-related biomarkers and cognitive dysfunction in MMD. These findings suggested that glymphatic disorder may interact with MMD-related pathophysiological processes.

Early Infant Prefrontal Cortical Microstructure Predicts Present and Future Emotionality

BackgroundHigh levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite orientation dispersion and density imaging estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality. MethodsWe modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n = 61) and at 9 months (n = 50), using multivariable and subsequent bivariate regression models. ResultsThe most robust statistically significant findings were positive associations among 3-month rostral anterior cingulate cortex (ACC) ODI and caudal ACC NDI and concurrent NE, a positive association between 3-month lateral orbitofrontal cortex ODI and prospective NE, and a negative association between 3-month dorsolateral PFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, as well as infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE. ConclusionsGreater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rostral ACC), decision making (lateral orbitofrontal cortex), action selection (caudal ACC), and attentional processes (dorsolateral PFC) might result in greater integration of these subregions with other neural networks and greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk.

Down-sampling in diffusion MRI: a bundle-specific DTI and NODDI study.

Multi-shell diffusion Magnetic Resonance Imaging (dMRI) data has been widely used to characterise white matter microstructure in several neurodegenerative diseases. The lack of standardised dMRI protocols often implies the acquisition of redundant measurements, resulting in prolonged acquisition times. In this study, we investigate the impact of the number of gradient directions on Diffusion Tensor Imaging (DTI) and on Neurite Orientation Dispersion and Density Imaging (NODDI) metrics. Data from 124 healthy controls collected in three different longitudinal studies were included. Using an in-house algorithm, we reduced the number of gradient directions in each data shell. We estimated DTI and NODDI measures on six white matter bundles clinically relevant for neurodegenerative diseases. Fractional Anisotropy (FA) measures on bundles where data were sampled at the 30% rate, showed a median L1 distance of up to 3.92% and a 95% CI of (1.74, 8.97)% when compared to those obtained at reference sampling. Mean Diffusivity (MD) reached up to 4.31% and a 95% CI of (1.60, 16.98)% on the same premises. At a sampling rate of 50%, we obtained a median of 3.90% and a 95% CI of (1.99, 16.65)% in FA, and 5.49% with a 95% CI of (2.14, 21.68)% in MD. The Intra-Cellular volume fraction (ICvf) median L1 distance was up to 2.83% with a 95% CI of (1.98, 4.82)% at a 30% sampling rate and 3.95% with a 95% CI of (2.39, 7.81)% at a 50% sampling rate. The volume difference of the reconstructed white matter at reference and 50% sampling reached a maximum of (2.09 ± 0.81)%. In conclusion, DTI and NODDI measures reported at reference sampling were comparable to those obtained when the number of dMRI volumes was reduced by up to 30%. Close to reference DTI and NODDI metrics were estimated with a significant reduction in acquisition time using three shells, respectively with: 4 directions at a b value of 700 s/mm2, 14 at 1000 s/mm2, and 32 at 2000 s/mm2. The study revealed aspects that can be important for large-scale clinical studies on bundle-specific diffusion MRI.

Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease

Background and purposeA substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid. The purpose of this work is to leverage multi-shell dMRI to correct for PVA and to evaluate PVA-corrected dMRI measures in fornix as a biomarker for cognition in AD. MethodsThirty-three participants in the Cleveland Alzheimer's Disease Research Center (CADRC) (19 with normal cognition (NC), 10 with mild cognitive impairment (MCI), 4 with dementia due to AD) were enrolled in this study. Multi-shell dMRI was acquired, and voxelwise fits were performed with two models: 1) diffusion tensor imaging (DTI) that was corrected for PVA and 2) neurite orientation dispersion and density imaging (NODDI). Values of tissue integrity in fornix were correlated with neuropsychological scores taken from the Uniform Data Set (UDS), including the UDS Global Composite 5 score (UDSGC5). ResultsStatistically significant correlations were found between the UDSGC5 and PVA-corrected measure of mean diffusivity (MDc, r = −0.35, p < 0.05) from DTI and the intracelluar volume fraction (ficvf, r = 0.37, p < 0.04) from NODDI. A sensitivity analysis showed that the relationship to MDc was driven by episodic memory, which is often affected early in AD, and language. ConclusionThis cross-sectional study suggests that multi-shell dMRI of the fornix that has been corrected for PVA is a potential biomarker for early cognitive domain changes in AD. A longitudinal study will be necessary to determine if the imaging measure can predict cognitive decline.