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INTRODUCTION We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle‐aged adults. METHODS We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB‐R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme‐linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS Higher sOB‐R was associated with lower fractional anisotropy (FA, β = −0.114 ± 0.02, p < 0.001), and higher free water (FW, β = 0.091 ± 0.022, p < 0.001) and peak‐width skeletonized mean diffusivity (PSMD, β = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (β = 0.115 ± 0.027, p < 0.001) and lower FW (β = ‐0.096 ± 0.029, p = 0.001) and PSMD (β = ‐0.085 ± 0.028, p = 0.002). DISCUSSION Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle‐aged adults, supporting the putative neuroprotective role of leptin in late‐life dementia risk. Highlights Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Introduction To describe the protocol and findings of the instrumental validation of three imaging‐based biomarker kits selected by the MarkVCID consortium: free water (FW) and peak width of skeletonized mean diffusivity (PSMD), both derived from diffusion tensor imaging (DTI), and white matter hyperintensity (WMH) volume derived from fluid attenuation inversion recovery and T1‐weighted imaging. Methods The instrumental validation of imaging‐based biomarker kits included inter‐rater reliability among participating sites, test–retest repeatability, and inter‐scanner reproducibility across three types of magnetic resonance imaging (MRI) scanners using intra‐class correlation coefficients (ICC). Results The three biomarkers demonstrated excellent inter‐rater reliability (ICC >0.94, P‐values < .001), very high agreement between test and retest sessions (ICC >0.98, P‐values < .001), and were extremely consistent across the three scanners (ICC >0.98, P‐values < .001). Discussion The three biomarker kits demonstrated very high inter‐rater reliability, test–retest repeatability, and inter‐scanner reproducibility, offering robust biomarkers suitable for future multi‐site observational studies and clinical trials in the context of vascular cognitive impairment and dementia (VCID).

We measure spectra of water mobilities (i.e., mean diffusivities) from intravoxel pools in brain tissues of healthy subjects with a non-parametric approach. Using a single-shot isotropic diffusion encoding (IDE) preparation, we eliminate signal confounds caused by anisotropic diffusion, including microscopic anisotropy, and acquire in vivo diffusion-weighted images (DWIs) over a wide range of diffusion sensitizations. We analyze the measured IDE signal decays using a regularized inverse laplace transform (ILT) to derive a probability distribution of mean diffusivities of tissue water in each voxel. Based on numerical simulations we assess the sensitivity and accuracy of our ILT analysis and optimize an experimental protocol for use with clinical MRI scanners. In vivo spectra of intravoxel mean diffusivities measured in healthy subjects generally show single-peak distributions throughout the brain parenchyma, with small differences in peak location and shape among white matter, cortical and subcortical gray matter, and cerebrospinal fluid. Mean diffusivity distributions (MDDs) with multiple peaks are observed primarily in voxels at tissue interfaces and are likely due to partial volume contributions. To quantify tissue-specific MDDs with improved statistical power, we average voxel-wise normalized MDDs in corresponding regions-of-interest (ROIs). This non-parametric, rotation-invariant assessment of isotropic diffusivities of tissue water may reflect important microstructural information, such as cell packing and cell size, and active physiological processes, such as water transport and exchange, which may enhance biological specificity in the clinical diagnosis and characterization of ischemic stroke, cancer, neuroinflammation, and neurodegenerative disorders and diseases. •We optimize a clinical protocol to measure isotropic diffusion encoded brain images.•We derive rotation-invariant distributions of intravoxel mean diffusivities in vivo.•We assess the uncertainty of measuring intravoxel mean diffusivity distributions.•Mean diffusivities distributions show mostly single peaks in healthy brain voxels.

BACKGROUND Peak‐width of skeletonized mean diffusivity (PSMD), a neuroimaging marker of cerebral small vessel disease (SVD), has shown excellent instrumental properties. Here, we extend our work to perform a biological validation of PSMD. METHODS We included 396 participants from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID‐1) Consortium and three replication samples (Cohorts for Heart and Aging Research in Genomic Epidemiology = 6172, Rush University Medical Center = 287, University of California Davis Alzheimer's Disease Research Center = 567). PSMD was derived from diffusion tensor imaging using an automated algorithm. We related PSMD to a composite measure of general cognitive function using linear regression models adjusting for confounders. RESULTS Higher PSMD was associated with lower general cognition in MarkVCID‐1 independent of age, sex, education, and intracranial volume (Beta [95% confidence interval], −0.8 [−1.2, −0.4], P < 0.001). These findings were replicated in independent samples. Furthermore, PSMD explained cognitive status above and beyond white matter hyperintensities. DISCUSSION Our biological validation work supports the pursuit of larger clinical validation studies evaluating PSMD as a susceptibility/risk biomarker of small vessel disease contributing to cognitive impairment and dementia. Highlights Peak‐width of skeletonized mean diffusivity (PSMD) is a novel small vessel disease neuroimaging biomarker. A prior instrumental validation study demonstrated that PSMD is a robust biomarker. This biological validation study shows that high PSMD relates to worse cognition. PSMD explains cognitive function above and beyond white matter hyperintensities. Future clinical validation will assess PSMD as a vascular contribution to cognitive impairment and dementia biomarker in clinical trials.

The aim of this study was to investigate the fractional anisotropy (FA) and mean diffusivity (MD) using a diffusion tensor imaging technique and whole-brain voxel-based analysis in patients with comitant strabismus. A total of 19 (nine males and ten females) patients with comitant strabismus and 19 age-, sex-, and education-matched healthy controls (HCs) underwent magnetic resonance imaging examination. Imaging data were analyzed using two-sample t-tests to identify group differences in FA and MD values. Patients with comitant strabismus were distinguishable from HCs by receiver operating characteristic curves. Compared with HCs, patients with comitant strabismus exhibited significantly decreased FA values in the brain regions of the left superior temporal gyrus and increased values in the bilateral medial frontal gyrus, right globus pallidus/brainstem, and bilateral precuneus. Meanwhile, MD value was significantly reduced in the brain regions of the bilateral cerebellum posterior lobe and left middle frontal gyrus but increased in the brain regions of the right middle frontal gyrus and left anterior cingulate. These results suggest significant brain abnormalities in comitant strabismus, which may underlie the pathologic mechanisms of fusion defects and ocular motility disorders in patients with comitant strabismus.

Dopamine content in the basal ganglia is strongly associated with the degree of dopaminergic neuron loss in the substantia nigra pars compacta. Symptoms of Parkinson's disease might not arise until more than 50% of the substantia nigra pars compacta is lost and the dopamine content in the basal ganglia is reduced by more than 80%. Greater diagnostic sensitivity and specificity would allow earlier detection of Parkinson's disease. Diffusion tensor imaging is a recently developed magnetic resonance imaging technique that measures mean diffusivity and fractional anisotropy, and responds to changes in brain microstructure. When the microscopic barrier (including cell membranes, microtubules and other structures that interfere with the free diffusion of water) is destroyed and extracellular fluid volume accumulates, the mean diffusivity value increases; when the integrity of the microstructure (such as myelin) is destroyed, fractional anisotropy value decreases. However, there is no consensus as to whether these changes can reflect the early pathological alterations in Parkinson's disease. Here, we established a rat model of Parkinson's disease by injecting rotenone (or sunflower oil in controls) into the right substantia nigra. Diffusion tensor imaging results revealed that in the stages of disease, at 1, 2, 4, and 6 weeks after rotenone injection, fractional anisotropy value decreased, but mean diffusivity values increased in the right substantia nigra in the experimental group. Fractional anisotropy values were lower at 4 weeks than at 6 weeks in the right substantia nigra of rats from the experimental group. Mean diffusivity values were markedly greater at 1 week than at 6 weeks in the right corpus striatum of rats from the experimental group. These findings suggest that mean diffusivity and fractional anisotropy values in the brain of rat models of Parkinson's disease 4 weeks after model establishment can reflect early degeneration of dopaminergic neurons. The change in fractional anisotropy values after destruction of myelin integrity is likely to be of greater early diagnostic significance than the change in mean diffusivity values.

We collected MRI diffusion tensor imaging data from 80 younger (20–32 years) and 63 older (60–71 years) healthy adults. Tract-based spatial statistics (TBSS) analysis revealed that white matter integrity, as indicated by decreased fractional anisotropy (FA), was disrupted in numerous structures in older compared to younger adults. These regions displayed five distinct region-specific patterns of age-related differences in other diffusivity properties: (1) increases in both radial and mean diffusivity; (2) increases in radial diffusivity; (3) no differences in parameters other than FA; (4) a decrease in axial and an increase in radial diffusivity; and (5) a decrease in axial and mean diffusivity. These patterns suggest different biological underpinnings of age-related decline in FA, such as demyelination, Wallerian degeneration, gliosis, and severe fiber loss, and may represent stages in a cascade of age-related degeneration in white matter microstructure. This first simultaneous description of age-related differences in FA, mean, axial, and radial diffusivity requires histological and functional validation as well as analyses of intermediate age groups and longitudinal samples.

INTRODUCTION The spatial and temporal patterns of cortical mean diffusivity (cMD), as well as its association with Alzheimer's disease (AD) and suspected non‐Alzheimer's pathophysiology (SNAP), are not yet fully understood. METHODS We compared baseline (n = 617) and longitudinal changes (n = 421) of cMD, cortical thickness, and gray matter volume and their relations to vascular risk factors, amyloid beta (Aβ), and tau positron emission tomography (PET), and longitudinal cognitive decline in Aβ PET negative and positive older adults. RESULTS cMD increases were more sensitive to detecting brain structural alterations than cortical thinning and gray matter atrophy. Tau‐related cMD increases partially mediated Aβ‐related cognitive decline in AD, whereas vascular disease‐related increased cMD levels substantially mediated age‐related cognitive decline in SNAP. DISCUSSION These findings revealed the dynamic changes of microstructural and macrostructural indicators and their associations with AD and SNAP, providing novel insights into understanding upstream and downstream events of cMD in neurodegenerative disease. Highlights Cortical mean diffusivity (cMD) was more sensitive to detecting structural changes than macrostructural factors. Tau‐related cMD increases partially mediated amyloid beta–related cognitive decline in Alzheimer's disease (AD). White matter hyperintensity–related higher cMD mainly explained the age‐related cognitive decline in suspected non‐Alzheimer's pathophysiology (SNAP). cMD may assist in tracking earlier neurodegenerative signs in AD and SNAP.

In the developmental field, sex differences can alter brain growth and development. Across the literature, sex differences have been reported in overall brain volume, white matter, gray matter and numerous other regions and tracts captured through non-invasive neuroimaging. Growing evidence suggests that sex differences appear at birth and continue through childhood. However, limited work has been completed in translational animal models, such as the domestic pig. Additionally, when using neuroimaging, uncertainties remain about which method best depicts microstructural changes, such as myelination. To address this gap, the present study utilized a total of 24 pigs (11 intact males or boars; 13 females or gilts) that underwent neuroimaging at postnatal day (PND) 29 or 30 to assess overall brain structural anatomy (MPRAGE), microstructural differences using diffusion (DTI), and an estimation of myelin content via myelin water fraction (MWF). On PND 32, brains were collected from all pigs, with the left hippocampus isolated, sectioned, and stained using the Gallyas silver impregnation method to quantify myelin density. Minimal sex differences were observed across neuroimaging modalities, with only myelin content exhibiting sex differences in the hippocampus ( = 0.022). In the left hippocampus ( = 0.038), females had a higher MWF value compared with males. This was supported by histologically derived myelin density as assessed by positive pixel percentage, but differences were isolated to one anatomical plane of the hippocampus ( = 0.024) and not the combined mean value ( = 0.333). Further regression analysis determined that axial ( = 0.01) and mean ( = 0.048) diffusivity measures, but not fractional anisotropy or MWF, were positively correlated with histologically derived myelin density in the left hippocampus, independent of sex. These findings suggest that at 4 weeks of age, axial and mean diffusivity may better reflect myelin density. Further investigation is required to confirm underlying mechanisms. Overall, minimal sex differences were observed in 4-week-old domestic pigs, indicating similar brain structure at this early stage of development.

Diffusion-weighted (DW) magnetic resonance imaging (MRI) is a unique method to investigate microstructural tissue properties noninvasively and is one of the most popular methods for studying the brain white matter in vivo. To obtain reliable statistical inferences with diffusion MRI, however, there are still many challenges, such as acquiring high-quality DW-MRI data (e.g., high SNR and high resolution), careful data preprocessing (e.g., correcting for subject motion and eddy current induced geometric distortions), choosing the appropriate diffusion approach (e.g., diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), or diffusion spectrum MRI), and applying a robust analysis strategy (e.g., tractography based or voxel based analysis). Notwithstanding the numerous efforts to optimize many steps in this complex and lengthy diffusion analysis pipeline, to date, a well-known artifact in MRI – i.e., Gibbs ringing (GR) – has largely gone unnoticed or deemed insignificant as a potential confound in quantitative DW-MRI analysis. Considering the recent explosion of diffusion MRI applications in biomedical and clinical applications, a systematic and comprehensive investigation is necessary to understand the influence of GR on the estimation of diffusion measures. In this work, we demonstrate with simulations and experimental DW-MRI data that diffusion estimates are significantly affected by GR artifacts and we show that an off-the-shelf GR correction procedure based on total variation already can alleviate this issue substantially. [Display omitted] •We propose a method to identify Gibbs Ringing (GR) artifacts in diffusion MRI data.•We quantify the error introduced by GR artifacts in diffusion estimates.•We optimize a standard GR correction procedure to deal with GR artifacts in real data.