pydesigner-v10-pythonic-implementation-designer-pipeline-for

PyDesigner v1.0: A Pythonic Implementation of the DESIGNER Pipeline for Diffusion Magnetic Resonance Imaging

PyDesigner is a Python-based software package based on the original Diffusion parameter EStImation with Gibbs and NoisE Removal (DESIGNER) pipeline (Dv1) ...

Medical University of South Carolina

The 3×Tg-AD mouse is one of the most studied animal models of Alzheimer's disease (AD), and develops both amyloid beta deposits and neurofibrillary tangles in a temporal and spatial pattern that is similar to human AD pathology. Additionally, abnormal myelination patterns with changes in oligodendrocyte and myelin marker expression are reported to be an early pathological feature in this model. Only few diffusion MRI (dMRI) studies have investigated white matter abnormalities in 3×Tg-AD mice, with inconsistent results. Thus, the goal of this study was to investigate the sensitivity of dMRI to capture brain microstructural alterations in 2-month-old 3×Tg-AD mice. In the fimbria, the fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), and radial kurtosis (K ) were found to be significantly lower in 3×Tg-AD mice than in controls, while the mean diffusivity (MD) and radial diffusivity (D ) were found to be elevated. In the fornix, K was lower for 3×Tg-AD mice; in the dorsal hippocampus MD and D were elevated, as were FA, MD, and D in the ventral hippocampus. These results indicate, for the first time, dMRI changes associated with myelin abnormalities in young 3×Tg-AD mice, before they develop AD pathology. Morphological quantification of myelin basic protein immunoreactivity in the fimbria was significantly lower in the 3×Tg-AD mice compared with the age-matched controls. Our results demonstrate that dMRI is able to detect widespread, significant early brain morphological abnormalities in 2-month-old 3×Tg-AD mice.

Diffusion MRI detects early brain microstructure abnormalities in 2-month-old 3×Tg-AD mice.

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

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

The Alzheimer's continuum is biologically defined by beta-amyloid deposition, which at the earliest stages is superimposed upon white matter degeneration in aging. However, the extent to which these co-occurring changes is characterized is relatively underexplored. The goal of this study was to use diffusional kurtosis imaging (DKI) and biophysical modeling to detect and describe amyloid-related white matter changes in preclinical Alzheimer disease.

Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease.

Two distinct types of microscopic diffusion anisotropy (MA) are compared in brain for both normal control and transgenic (3xTg-AD) mice, which develop Alzheimer's disease pathology. The first type of MA is the commonly used microscopic fractional anisotropy (μFA), and the second is a new MA measure referred to as μFA'. These two MA parameters have different symmetry properties that are central to their physical interpretations. Specifically, μFA is invariant with respect to local rotations of compartmental diffusion tensors while μFA' is invariant with respect to global diffusion tensor deformations. A key distinction between μFA and μFA' is that μFA is affected by the same type of orientationally coherent diffusion anisotropy as the conventional fractional anisotropy (FA) while μFA' is not. Furthermore, μFA can be viewed as having independent contributions from FA and μFA', as is quantified by an equation relating all three anisotropies. The normal control and transgenic mice are studied at ages ranging from 2 to 15 months, with double diffusion encoding MRI being used to estimate μFA and μFA'. μFA and μFA' are nearly identical in low FA brain regions, but they show notable differences when FA is large. In particular, μFA and FA are found to be strongly correlated in the fimbria, but μFA' and FA are not. In addition, both μFA and μFA' are seen to increase with age in the corpus callosum and external capsule, and modest differences between normal control and transgenic mice are observed for μFA and μFA' in the corpus callosum and for μFA in the fimbria. The triad of FA, μFA, and μFA' is proposed as a useful combination of parameters for assessing diffusion anisotropy in brain.

Comparison of two types of microscopic diffusion anisotropy in mouse brain.

The widely studied triple transgenic (3xTg-AD) mouse provides a robust model of Alzheimer's disease (AD) with region dependent patterns of progressive amyloid-β (Aß) and tau pathology. Using diffusion MRI (dMRI), we investigated the sensitivity of dMRI measures in capturing AD pathology associated microstructure alterations in older 3xTg-AD mice, and the degree to which dMRI changes correlate with measurements of Aβ and tau pathology. 3xTg-AD and normal control (NC) mice, 15 to 21 months of age, were used in this study. In vivo dMRI data were acquired for the generation of diffusion tensor (DT) and diffusional kurtosis (DK) measures within the hippocampus and fimbria (Fi). For these same brain regions, Aβ and tau pathology were quantified by morphological analysis of Aß1-42 and AT8 immunoreactivity. Two-tailed, two-sample t-tests were performed to assess group differences in each brain region of interest (ROI), with the Benjamini-Hochberg false discovery rate (FDR) method being applied to adjust for multiple comparisons. Spearman correlation coefficients were calculated to investigate associations between diffusion and morphological measures. Our results revealed, depending on the brain region, DT and DK measures were able to detect group differences. In the dorsal hippocampus (HD), fractional anisotropy (FA) was significantly higher in the 3xTg-AD mice compared with NC mice. In the subiculum (SUB), FA, axial diffusivity (D) and radial kurtosis (K) were significantly higher in 3xTg-AD mice compared with NC mice. Morphological quantification of Aß1-42 and AT8 immunoreactivity showed elevated Aß and tau in the Fi, ventral hippocampus (HV) and SUB of 3xTg-AD mice. The presence of Aβ and tau was significantly correlated with several DT and DK measures, particularly in the SUB, where an increase in tau correlated with an increase in mean kurtosis (MK) and K. This work demonstrates significant dMRI differences between older 3xTg-AD and NC mice in the hippocampus and Fi. Significant correlations were found between dMRI and morphological measures of Aβ and tau pathology. These results support the potential of dMRI-derived parameters as biomarkers of AD pathology. Since the imaging methods employed here are easily translatable to clinical MRI, our results are also relevant for human AD patients.

Brain microstructure abnormalities in the 3xTg-AD mouse - A diffusion MRI and morphology correlation study.

Age-related white matter degeneration is characterized by myelin breakdown and neuronal fiber loss that preferentially occur in regions that myelinate later in development. Conventional diffusion MRI (dMRI) has demonstrated age-related increases in diffusivity but provide limited information regarding the tissue-specific changes driving these effects. A recently developed dMRI biophysical modeling technique, Fiber Ball White Matter (FBWM) modeling, offers enhanced biological interpretability by estimating microstructural properties specific to the intra-axonal and extra-axonal spaces. We used FBWM to illustrate the biological mechanisms underlying changes throughout white matter in healthy aging using data from 63 cognitively unimpaired adults ages 45-85 with no radiological evidence of neurodegeneration or incipient Alzheimer's disease. Conventional dMRI and FBWM metrics were computed for two late-myelinating (genu of the corpus callosum and association tracts) and two early-myelinating regions (splenium of the corpus callosum and projection tracts). We examined the associations between age and these metrics in each region and tested whether age was differentially associated with these metrics in late- vs. early-myelinating regions. We found that conventional metrics replicated patterns of age-related increases in diffusivity in late-myelinating regions. FBWM additionally revealed specific intra- and extra-axonal changes suggestive of myelin breakdown and preferential loss of smaller-diameter axons, yielding  corroboration of findings from histopathological studies of aged brains. These results demonstrate that advanced biophysical modeling approaches, such as FBWM, offer novel information about the microstructure-specific alterations contributing to white matter changes in healthy aging. These tools hold promise as sensitive indicators of early pathological changes related to neurodegenerative disease.

Fiber Ball White Matter Modeling Reveals Microstructural Alterations in Healthy Brain Aging.

Microglia (MØ) morphologies are closely related to their functional state and have a central role in the maintenance of brain homeostasis. It is well known that inflammation contributes to neurodegeneration at later stages of Alzheimer's Disease, but it is not clear which role MØ-mediated inflammation may play earlier in the disease pathogenesis. We have previously reported that diffusion MRI (dMRI) is able to detect early myelin abnormalities present in 2-month-old 3xTg-AD (TG) mice; since MØ actively participate in regulating myelination, the goal of this study was to assess quantitatively MØ morphological characteristics and its association with dMRI metrics patterns in 2-month-old 3xTg-AD mice. Our results show that, even at this young age (2-month-old), TG mice have statistically significantly more MØ cells, which are overall smaller and more complex, compared with age-matched normal control mice (NC). Our results also confirm that myelin basic protein is reduced in TG mice, particularly in fimbria (Fi) and cortex. Additionally, MØ morphological characteristics, in both groups, correlate with several dMRI metrics, depending on the brain region examined. For example, the increase in MØ number correlated with higher radial diffusivity (r = 0.59, p = 0.008), lower fractional anisotropy (FA) (r = -0.47, p = 0.03), and lower kurtosis fractional anisotropy (KFA) (r = -0.55, p = 0.01) in the CC. Furthermore, smaller MØ cells correlate with higher axial diffusivity) in the HV (r = 0.49, p = 0.03) and Sub (r = 0.57, p = 0.01). Our findings demonstrate, for the first time, that MØ proliferation/activation are a common and widespread feature in 2-month-old 3xTg-AD mice and suggest that dMRI measures are sensitive to these MØ alterations, which are associated in this model with myelin dysfunction and microstructural integrity abnormalities.

Article	Year
Diffusion MRI detects early brain microstructure abnormalities in 2-month-old 3×Tg-AD mice. NMR in biomedicine\| PubMed ID: 32557874	2020
Diffusion MRI detects basal forebrain cholinergic abnormalities in the 3xTg-AD mouse model of Alzheimer's disease. Magnetic resonance imaging\| PubMed ID: 34229088	2021
Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease. Annals of neurology\| PubMed ID: 35285067	2022
Comparison of two types of microscopic diffusion anisotropy in mouse brain. NMR in biomedicine\| PubMed ID: 35994169	2023
Brain microstructure abnormalities in the 3xTg-AD mouse - A diffusion MRI and morphology correlation study. Magnetic resonance imaging\| PubMed ID: 36116712	2022
Fiber Ball White Matter Modeling Reveals Microstructural Alterations in Healthy Brain Aging. Aging brain\| PubMed ID: 36324695	2022
Quantitative microglia morphological features correlate with diffusion MRI in 2-month-old 3xTg-AD mice. Magnetic resonance imaging\| PubMed ID: 37392805	2023

Siddhartha Dhiman

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