Diffusion MRI is an exquisitely sensitive probe of tissue microstructure, and is currently the only non-invasive measure of the brain's fibre architecture. As this technique becomes more sophisticated and microstructurally informative, there is increasing value in comparing diffusion MRI with microscopic imaging in the same tissue samples. This study compared estimates of fibre orientation dispersion in white matter derived from diffusion MRI to reference measures of dispersion obtained from polarized light imaging and histology.Three post-mortem brain specimens were scanned with diffusion MRI and analyzed with a two-compartment dispersion model. The specimens were then sectioned for microscopy, including polarized light imaging estimates of fibre orientation and histological quantitative estimates of myelin and astrocytes. Dispersion estimates were correlated on region – and voxel-wise levels in the corpus callosum, the centrum semiovale and the corticospinal tract.The region-wise analysis yielded correlation coefficients of r = 0.79 for the diffusion MRI and histology comparison, while r = 0.60 was reported for the comparison with polarized light imaging. In the corpus callosum, we observed a pattern of higher dispersion at the midline compared to its lateral aspects. This pattern was present in all modalities and the dispersion profiles from microscopy and diffusion MRI were highly correlated. The astrocytes appeared to have minor contribution to dispersion observed with diffusion MRI.These results demonstrate that fibre orientation dispersion estimates from diffusion MRI represents the tissue architecture well. Dispersion models might be improved by more faithfully incorporating an informed mapping based on microscopy data.

BackgroundAmyotrophic lateral sclerosis (ALS) is a clinically and histopathologically heterogeneous neurodegenerative disorder, in which therapy is hindered by the rapid progression of disease and lack of biomarkers. Magnetic resonance imaging (MRI) has demonstrated its potential for detecting the pathological signature and tracking disease progression in ALS. However, the microstructural and molecular pathological substrate is poorly understood and generally defined histologically. One route to understanding and validating the pathophysiological correlates of MRI signal changes in ALS is to directly compare MRI to histology in post mortem human brains.ResultsThe article delineates a universal whole brain sampling strategy of pathologically relevant grey matter (cortical and subcortical) and white matter tracts of interest suitable for histological evaluation and direct correlation with MRI. A standardised systematic sampling strategy that was compatible with co-registration of images across modalities was established for regions representing phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) patterns that were topographically recognisable with defined neuroanatomical landmarks. Moreover, tractography-guided sampling facilitated accurate delineation of white matter tracts of interest. A digital photography pipeline at various stages of sampling and histological processing was established to account for structural deformations that might impact alignment and registration of histological images to MRI volumes. Combined with quantitative digital histology image analysis, the proposed sampling strategy is suitable for routine implementation in a high-throughput manner for acquisition of large-scale histology datasets. Proof of concept was determined in the spinal cord of an ALS patient where multiple MRI modalities (T1, T2, FA and MD) demonstrated sensitivity to axonal degeneration and associated heightened inflammatory changes in the lateral corticospinal tract. Furthermore, qualitative comparison of R2* and susceptibility maps in the motor cortex of 2 ALS patients demonstrated varying degrees of hyperintense signal changes compared to a control. Upon histological evaluation of the same region, intensity of signal changes in both modalities appeared to correspond primarily to the degree of microglial activation.ConclusionThe proposed post mortem whole brain sampling methodology enables the accurate intraindividual study of pathological propagation and comparison with quantitative MRI data, to more fully understand the relationship of imaging signal changes with underlying pathophysiology in ALS.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0416-1) contains supplementary material, which is available to authorized users.

Some dietary fats are a risk factor for Alzheimer's disease (AD) but the mechanisms for this association are presently unknown. In the present study we showed in wild-type mice that chronic ingestion of SFA results in blood -brain barrier (BBB) dysfunction and significant delivery into the brain of plasma proteins, including apo B lipoproteins that are endogenously enriched in amyloid-b (Ab). Conversely, the plasma concentration of S100B was used as a marker of brain-to-blood leakage and was found to be increased two-fold because of SFA feeding. Consistent with a deterioration in BBB integrity in SFA-fed mice was a diminished cerebrovascular expression of occludin, an endothelial tight junction protein. In contrast to SFA-fed mice, chronic ingestion of MUFA or PUFA had no detrimental effect on BBB integrity. Utilising highly sensitive three-dimensional immunomicroscopy, we also showed that the cerebral distribution and co-localisation of Ab with apo B lipoproteins in SFA-fed mice are similar to those found in amyloid precursor protein/presenilin-1 (APP/PS1) amyloid transgenic mice, an established murine model of AD. Moreover, there was a strong positive association of plasma-derived apo B lipoproteins with cerebral Ab deposits. Collectively, the findings of the present study provide a plausible explanation of how dietary fats may influence AD risk. Ingestion of SFA could enhance peripheral delivery to the brain of circulating lipoprotein -Ab and exacerbate the amyloidogenic cascade.Alzheimer's disease: Amyloid-b: Blood-brain barrier: SFA: TAG-rich lipoproteins An accumulating body of evidence is consistent with the concept that the onset and progression of Alzheimer's disease (AD) is influenced by lifestyle factors including nutrition (1) . Several population studies have found that SFA are a positive risk factor for AD (2 -3) and in animal models of AD, SFA or cholesterol feeding markedly exacerbates cerebral pathology (4 -5) . However, the mechanisms that link dietary fat to the pathogenesis of AD are unclear.The cerebrovasculature in subjects with AD shows pathological alterations including vascular endothelial and smooth muscle cell proliferation (6) . Blood plasma proteins have been detected in the parenchyma of AD brains (7 -8) and inflammatory sequalae are commonly reported (9 -10) , observations that are consistent with breakdown of the blood-brain barrier (BBB). Yet despite evidence supportive of AD having an underlying vascular component, most research focuses on damage of neurons (11) .A major neuropathological marker of AD is amyloid-b (Ab) deposition in the cerebrovasculature and in the cerebral parenchyma. Derived from amyloid precursor protein (APP), Ab is the predominant component of amyloid plaque (12) . The source of cerebral Ab deposits in AD is uncertain, though there is little evidence for increased cerebral Ab production in sporadic, late-onset AD which accounts for over 96 % of AD cases. Rather, decreased Ab clearance across the BBB via receptor pathways and/or via the choroid plexus h...

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Background: Disturbances in blood-brain barrier (BBB) integrity contribute to the onset and progression of neurodegenerative diseases including Alzheimer's disease (AD) and vascular dementia (VaD). Aging is positively associated with AD and VaD risk, but this may reflect comorbidities or the effects of other chronic modulators of vascular function such as diet. Objective: To explore putative synergistic effects of aging with diet, in this study genetically unmanipulated mice were maintained on diets enriched in saturated fatty acids (SFA) or cholesterol and compared to mice provided with low-fat (LF) feed formula. Methods: The functional integrity of the BBB was assessed following 3, 6 and 12 months of dietary intervention commenced at 6 weeks of age, by determining the brain parenchymal extravasation of immunoglobulin G (IgG). Results: Mice maintained on the SFA- or cholesterol-enriched diet showed significant parenchymal IgG abundance following 3 months of feeding, concomitant with diminished expression of the tight junction protein occludin. LF control mice had essentially no evidence of BBB disturbances. Six months of SFA feeding exacerbated the difference in IgG abundance compared to the LF mice. At 12 months of feeding, the control LF mice also had significant parenchymal IgG that was comparable to mice fed the SFA- or cholesterol-enriched diet for 3 months. However, there may have been an adaptation to the fat-enriched diets because SFA and cholesterol did not exacerbate IgG parenchymal accumulation beyond 6 months of feeding. Conclusion: Collectively, the study suggests that diets enriched in SFA or cholesterol accelerate the onset of BBB dysfunction that otherwise occurs with aging.