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Accumulation of iron within the cortex of Alzheimer’s disease (AD) patients has been reported by numerous MRI studies using iron-sensitive methods. Validation of iron-sensitive MRI is important for the interpretation of in vivo findings. In this study, the relation between the spatial iron distribution and T2∗-weighted MRI in the human brain was investigated using a direct comparison of spatial maps of iron as detected by T2∗-weighted MRI, iron histochemistry and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), in postmortem brain tissue of the medial frontal gyrus of three control subjects and six AD patients. In addition, iron levels measured by LA-ICP-MS and three quantitative MRI methods, namely R2∗ (=1/T2∗), image phase and quantitative susceptibility mapping (QSM), were compared between 19 AD and 11 controls. Histochemistry results we obtained with the modified Meguro staining were highly correlated with iron levels as detected by LA-ICP-MS (r2 ​= ​0.82, P ​< ​0.0001). Significant positive correlations were also found between LA-ICP-MS and the three quantitative MRI measurements: R2∗ (r2 ​= ​0.63), image phase (r2 ​= ​0.70) and QSM (r2 ​= ​0.74 (all p ​< ​0.0001)). R2∗ and QSM showed the strongest correlation with iron content; the correlation of phase with iron clearly showed increased variation, probably due to its high orientation dependence. Despite the obvious differences in iron distribution patterns within the cortex between AD patients and controls, no overall significant differences were found in iron as measured by LA-ICP-MS, nor in R2∗, phase or susceptibility. In conclusion, our results show that histochemistry as well as quantitative MRI methods such as R2∗ mapping and QSM provide reliable measures of iron distribution in the cortex. These results support the use of MRI studies focusing on iron distribution in both the healthy and the diseased brain. •Alzheimer patients have a different cortical appearance on T2∗-weighted MRI.•Cortical iron can be accurately measured using QSM and R2∗ mapping.•Iron histochemistry is a reliable measure of iron content within the cortex.•LA-ICP-MS confirms iron as the substrate of cortical contrast on MRI and histology.

The major vascular cause of dementia is cerebral small vessel disease (SVD), including white matter hyperintensities (WMH) amongst others. While the underlying pathology of SVD remains unclear, chronic hypertension and neuroinflammation are recognized as important risk factors for SVD and for the conversion of normal-appearing white matter (NAWM) to WMH. Unfortunately, most studies investigating the role of neuroinflammation in WMH relied on peripheral blood markers, e.g., markers for systemic or vascular inflammation, as a proxy for inflammation in the brain itself. However, it is unknown whether such markers accurately capture inflammatory changes within the cerebral white matter. Therefore, we aimed to comprehensively investigate the impact of hypertension on perivascular- and neuroinflammation in both WMH and NAWM. We conducted high field brain magnetic resonance imaging (MRI), followed by (immuno-)histopathological staining of neuroinflammatory markers on human post-mortem brains of elderly people with a history of hypertension (n = 17) and age-matched normotensive individuals (n = 5). MRI images were co-registered to (immuno-)histopathological data including stainings for microglia and astroglia to assess changes in MRI-based WMH at microscopic resolution. Perivascular inflammation was carefully assessed based on the severity of perivascular astrogliosis of the smallest vessels throughout white matter regions. Hypertension was associated with a larger inflammatory response in both WMH and NAWM. Notably, the presence of close-range perivascular inflammation was twice as common among those with hypertension than in controls both in WMH and NAWM, suggesting that neurovascular inflammation is critical in the etiology of WMH. Moreover, a higher degree of microglial activation was related to a higher burden of WMH. Our results indicate that neuro(vascular)inflammation at the level of the brain itself is involved in the etiology of WMH. Future therapeutic strategies focusing on multitarget interventions including antihypertensive treatment as well as neuroinflammation may ameliorate WMH progression.

Background Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. Discussion Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer’s disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer’s disease, vascular dementia and mixed Alzheimer’s disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. Conclusion Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.

Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI—ex vivo MRI—histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI−/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls ( p  = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of microinfarcts.

Objective To prospectively compare diagnostic accuracy of fetal post-mortem whole-body MRI at 3-T vs. 1.5-T. Methods Between 2012 and 2015, post-mortem MRI at 1.5-T and 3-T was performed in fetuses after miscarriage/stillbirth or termination. Clinical MRI diagnoses were assessed using a confidence diagnostic score and compared with classical autopsy to derive a diagnostic error score. The relation of diagnostic error for each organ group with gestational age was calculated and 1.5-T with 3-T was compared with accuracy analysis. Results 135 fetuses at 12–41 weeks underwent post-mortem MRI (followed by conventional autopsy in 92 fetuses). For all organ groups except the brain, and for both modalities, the diagnostic error decreased with gestation ( P  < 0.0001). 3-T MRI diagnostic error was significantly lower than that of 1.5-T for all anatomic structures and organ groups, except the orbits and brain. This difference was maintained for fetuses <20 weeks gestation. Moreover, 3-T was associated with fewer non-diagnostic scans and greater concordance with classical autopsy than 1.5-T MRI, especially for the thorax, heart and abdomen in fetuses <20 weeks. Conclusion Post-mortem fetal 3-T MRI improves confidence scores and overall accuracy compared with 1.5-T, mainly for the thorax, heart and abdomen of fetuses <20 weeks of gestation. Key Points • In PM-MRI, diagnostic error using 3-T is lower than that with 1.5-T. • In PM-MRI, diagnostic scan rate is higher using 3-T than 1.5-T. • In PM-MRI, concordance with classical autopsy increases with 3-T. • PM-MRI using 3-T is particularly interesting for thoracic and abdominal organs. • PM-MRI using 3-T is particularly interesting for fetuses < 20 weeks’ gestation.

Quantitative proton density (PD) maps measure the amount of free water, which is important for non-invasive tissue characterization in pathology and across lifespan. PD mapping requires the estimation and subsequent removal of factors influencing the signal intensity other than PD. These factors include the T1, T2* relaxation effects, transmit field inhomogeneities, receiver coil sensitivity profile (RP) and the spatially invariant factor that is required to scale the data. While the transmit field can be reliably measured, the RP estimation is usually based on image post-processing techniques due to limitations of its measurement at magnetic fields higher than 1.5 T. The post-processing methods are based on unified bias-field/tissue segmentation, fitting the sensitivity profile from images obtained with different coils, or on the linear relationship between T1 and PD. The scaling factor is derived from the signal within a specific tissue compartment or reference object. However, these approaches for calculating the RP and scaling factor have limitations particularly in severe pathology or over a wide age range, restricting their application. We propose a new approach for PD mapping based on a multi-contrast variable flip angle acquisition protocol and a data-driven estimation method for the RP correction and map scaling. By combining all the multi-contrast data acquired at different echo times, we are able to fully correct the MRI signal for T2* relaxation effects and to decrease the variance and the entropy of PD values within tissue class of the final map. The RP is determined from the corrected data applying a non-parametric bias estimation, and the scaling factor is based on the median intensity of an external calibration object. Finally, we compare the signal intensity and homogeneity of the multi-contrast PD map with the well-established effective PD (PD*) mapping, for which the RP is based on concurrent bias field estimation and tissue classification, and the scaling factor is estimated from the mean white matter signal. The multi-contrast PD values homogeneity and accuracy within the cerebrospinal fluid (CSF) and deep brain structures are increased beyond that obtained using PD* maps. We demonstrate that the multi-contrast RP approach is insensitive to anatomical or a priori tissue information by applying it in a patient with extensive brain abnormalities and for whole body PD mapping in post-mortem foetal imaging. •PD measures free water content, crucial for non-invasive tissue characterization.•We achieve high quality PD mapping using data-driven methods.•Our new method does not rely on prior anatomical or tissue information.•PD mapping is demonstrated in highly abnormal brain and post-mortem.

Background The hippocampus is highly affected in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The relationship between neuropathology and atrophy in hippocampal subfields is complex due to differences in the selective neuronal vulnerability to distinct protein aggregates that underlie cognitive impairment. The aim of the current study was to investigate the relation between hippocampal subfield volumes, neuropathological burden (amyloid-β, p-tau and α-synuclein) and cognitive performance in AD, PD and control brain donors, using a cross-disease and within-subject post-mortem in situ MRI and neuropathology approach. Methods A total of 60 brain donors, including 14 non-neurological controls, 27 AD and 19 PD, underwent post-mortem in situ MRI. From 3D-T1 images hippocampal subfield and entorhinal cortex volumes were derived using FreeSurfer-based subfield segmentation. Hippocampal tissue was obtained at subsequent autopsy, fixed and immunostained for amyloid-β, p-tau and pSer129-αSyn. Immunoreactivity in hippocampal subfields was quantified as area% load using QuPath. Clinical Dementia Rating scores were extracted from the clinical files when available. Results AD showed atrophy and increased p-tau, but not amyloid-β, burden in the CA1, subiculum and entorhinal cortex compared to controls, however MRI and neuropathology did not correlate. Controls and PD had similar hippocampal subfield volumes and pathology load. In PD, p-tau pathology, rather than pSer129-αSyn, was associated with lower total hippocampal volume ( r =-0.68, p  = 0.045), predominantly in PD with dementia (PDD) ( r =-0.99, p  = 0.013). Cross-disease, volume loss of the subiculum ( r=- 0.68, p =  0.001) and entorhinal cortex ( r=- 0.73, p =  0.004) strongly associated with cognitive impairment. Moreover, p-tau pathology had the strongest effect on subfield atrophy, most pronounced in the subiculum ( β=-0.570 , p  < 0.001), but could only explain 22–44% of the volumetric variance. Conclusions Even though p-tau was the strongest predictor of hippocampal subfield atrophy, AD-pathology (p-tau and amyloid-β) only partially accounted for volumetric differences in hippocampal subfields, highlighting the significance of other pathologies or mechanisms. The increased sensitivity of subicular and entorhinal cortical atrophy compared to total hippocampal atrophy highlights the potential clinical value of incorporating hippocampal subfield atrophy in monitoring disease progression.

With the increasing use of medical imaging in forensics, as well as the technological advances in rapid prototyping, we suggest combining these techniques to generate displays of forensic findings. We used computed tomography (CT), CT angiography, magnetic resonance imaging (MRI) and surface scanning with photogrammetry in conjunction with segmentation techniques to generate 3D polygon meshes. Based on these data sets, a 3D printer created colored models of the anatomical structures. Using this technique, we could create models of bone fractures, vessels, cardiac infarctions, ruptured organs as well as bitemark wounds. The final models are anatomically accurate, fully colored representations of bones, vessels and soft tissue, and they demonstrate radiologically visible pathologies. The models are more easily understood by laypersons than volume rendering or 2D reconstructions. Therefore, they are suitable for presentations in courtrooms and for educational purposes.

Cortical microinfarcts (CMI) are increasingly recognized in the neurological community as a biomarker related to cognitive impairment and dementia. If their radiological depiction has been largely described in experimental settings using ultra-high-field magnetic resonance imaging (MRI), less is known about their visibility on routinely used 3-T MRI. In this radiologic-pathologic correlation study, using 3-T post-mortem MRI, we searched for hippocampal CMI, in a double-blinded fashion, and found that only 4/36, or 11%, were clearly demonstrated on both radiological and histopathological exams.

Iron plays an important role in many neurobiological processes, especially in the basal ganglia, the brain structures with the highest concentration. Composed of the pallidum and putamen, the lentiform nucleus plays a key role in the basal ganglia circuitry. With MRI advances, iron-based sequences such as R2* and quantitative susceptibility mapping (QSM) are now available for detecting and quantifying iron in different brain structures. Since their validation using classic iron detection techniques (histology or physical techniques), these sequences have attracted growing clinical attention, especially in the field of extrapyramidal syndromes that particularly affect the basal nuclei. Accurate mapping of iron in these nuclei and their connections is needed to gain a better understanding of this specific anatomy, before considering its involvement in the physiopathological processes. We performed R2* and QSM along with Perls histology, to gain new insights into the distribution of iron in the lentiform nucleus and its surrounding structures, based on four specimens obtained from voluntary donors. We found that iron is preferentially distributed in the anterior part of the globus pallidus externus and the posterior part of the putamen. The lateral wall of the putamen is iron-poor, compared with the lateral medullary lamina and intraputaminal fibers. The relevance of perivascular iron concentration, along with pallido- and putaminofugal iron-rich fibers, is discussed.