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Beta amyloid is a protein fragment snipped from the amyloid precursor protein (APP). Aggregation of these peptides into amyloid plaques is one of the hallmarks of Alzheimer's disease. MR imaging of beta amyloid plaques has been attempted using various techniques, notably with T2* contrast. The non-invasive detectability of beta amyloid plaques in MR images has so far been largely attributed to focal iron deposition accompanying the plaques. It is believed that the T2* shortening effects of paramagnetic iron are the primary source of contrast between plaques and surrounding tissue. Amyloid plaque itself has been reported to induce no magnetic susceptibility effect. We hypothesized that aggregations of beta amyloid would increase electron density and induce notable changes in local susceptibility value, large enough to generate contrast relative to surrounding normal tissues that can be visualized by quantitative susceptibility mapping (QSM) MR imaging. To test this hypothesis, we first demonstrated in a phantom that beta amyloid is diamagnetic and can generate strong contrast on susceptibility maps. We then conducted experiments on a transgenic mouse model of Alzheimer's disease that is known to mimic the formation of human beta amyloid but without neurofibrillary tangles or neuronal death. Over a period of 18 months, we showed that QSM can be used to longitudinally monitor beta amyloid accumulation and accompanied iron deposition in vivo. Individual beta amyloid plaque can also be visualized ex vivo in high resolution susceptibility maps. Moreover, the measured negative susceptibility map and positive susceptibility map could provide histology-like image contrast for identifying deposition of beta amyloid plaques and iron. Finally, we demonstrated that the diamagnetic susceptibility of beta amyloid can also be observed in brain specimens of AD patients. The ability to assess beta amyloid aggregation non-invasively with QSM MR imaging may aid the diagnosis of Alzheimer's disease. •We demonstrated in a phantom experiment that beta amyloid has diamagnetic susceptibility contrary to previous hypothesis.•This diamagnetic susceptibility can be measured and used to monitor longitudinal accumulation of beta amyloid in a mouse model and even visualize individual plaques.•The diamagnetic susceptibility map provided image contrast for identifying dominating magnetic sources of beta amyloid plaques, which were validated by histology.•The ability to image and quantify beta amyloid aggregation non-invasively with MRI may aid the diagnosis of Alzheimer’s disease.

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.

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque’s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-positive cases ( n  = 74), including non-demented cases ( n  = 15), early-onset (EO)AD ( n  = 38), and late-onset (LO)AD cases ( n  = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque’s neuritic component (pTau, APP, PrP C ), Aβ isoform composition (Aβ 40 , Aβ 42 , Aβ N3pE , pSer8Aβ), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aβ 40 . Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aβ 40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

•Compartment and cell-specific microscopic anisotropy are measured with DDES.•The intracellular space is highly anisotropic in white (WM) and gray matter (GM).•The extracellular space in GM is isotropic, while that of WM is highly anisotropic.•Water and metabolites intracellular mean diffusivities are lower in GM than in WM.•Intracellular tortuosity derived from water and tNAA is higher in GM than WM. Double diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic orientational distribution of cells. However, the specificity in detected microscopic anisotropy is limited as the signal is averaged over different cell types and across tissue compartments. Performing side-by-side water and metabolite DDE spectroscopic (DDES) experiments provides complementary measures from which intracellular and extracellular microscopic fractional anisotropies (μFA) and diffusivities can be estimated. Metabolites are largely confined to the intracellular space and therefore provide a benchmark for intracellular μFA and diffusivities of specific cell types. By contrast, water DDES measurements allow examination of the separate contributions to water μFA and diffusivity from the intra- and extracellular spaces, by using a wide range of b values to gradually eliminate the extracellular contribution. Here, we aimed to estimate tissue and compartment specific human brain microstructure by combining water and metabolites DDES experiments. We performed our DDES measurements in two brain regions that contain widely different amounts of white matter (WM) and gray matter (GM): parietal white matter (PWM) and occipital gray matter (OGM) in a total of 20 healthy volunteers at 7 Tesla. Metabolite DDES measurements were performed at b = 7199 s/mm2, while water DDES measurements were performed with a range of b values from 918 to 7199 s/mm2. The experimental framework we employed here resulted in a set of insights pertaining to the morphology of the intracellular and extracellular spaces in both gray and white matter. Results of the metabolite DDES experiments in both PWM and OGM suggest a highly anisotropic intracellular space within neurons and glia, with the possible exception of gray matter glia. The water μFA obtained from the DDES results at high b values in both regions converged with that of the metabolite DDES, suggesting that the signal from the extracellular space is indeed effectively suppressed at the highest b value. The μFA measured in the OGM significantly decreased at lower b values, suggesting a considerably lower anisotropy of the extracellular space in GM compared to WM. In PWM, the water μFA remained high even at the lowest b value, indicating a high degree of organization in the interstitial space in WM. Tortuosity values in the cytoplasm for water and tNAA, obtained with correlation analysis of microscopic parallel diffusivity with respect to GM/WM tissue fraction in the volume of interest, are remarkably similar for both molecules, while exhibiting a clear difference between gray and white matter, suggesting a more crowded cytoplasm and more complex cytomorphology of neuronal cell bodies and dendrites in GM than those found in long-range axons in WM. [Display omitted]

We present a quantitative study of different molecular iron forms found in the temporal cortex of Alzheimer (AD) patients. Applying the methodology we developed in our previous work, we quantify the concentrations of non-heme Fe(III) by Electron Paramagnetic Resonance (EPR), magnetite/maghemite and ferrihydrite by SQUID magnetometry, together with the MRI transverse relaxation rate ( R 2 ⁎ ) , to obtain a systematic view of molecular iron in the temporal cortex. Significantly higher values of R 2 ⁎ , a larger concentration of ferrihydrite, and a larger magnetic moment of magnetite/maghemite particles are found in the brain of AD patients. Moreover, we found correlations between the concentration of the iron detected by EPR, the concentration of the ferrihydrite mineral and the average iron loading of ferritin. We discuss these findings in the framework of iron dis-homeostasis, which has been proposed to occur in the brain of AD patients.

We propose a novel combination of methods to study the physical properties of ferric ions and iron-oxide nanoparticles in post-mortem human brain, based on the combination of Electron Paramagnetic Resonance (EPR) and SQUID magnetometry. By means of EPR, we derive the concentration of the low molecular weight iron pool, as well as the product of its electron spin relaxation times. Additionally, by SQUID magnetometry we identify iron mineralization products ascribable to a magnetite/maghemite phase and a ferrihydrite (ferritin) phase. We further derive the concentration of magnetite/maghemite and of ferritin nanoparticles. To test out the new combined methodology, we studied brain tissue of an Alzheimer’s patient and a healthy control. Finally, we estimate that the size of the magnetite/maghemite nanoparticles, whose magnetic moments are blocked at room temperature, exceeds 40–50 nm, which is not compatible with the ferritin protein, the core of which is typically 6–8 nm. We believe that this methodology could be beneficial in the study of neurodegenerative diseases such as Alzheimer’s Disease which are characterized by abnormal iron accumulation in the brain.

Neuroinflammation has been implicated in frontotemporal lobar degeneration (FTLD) pathophysiology, including in genetic forms with microtubule‐associated protein tau (MAPT) mutations (FTLD‐MAPT) or chromosome 9 open reading frame 72 (C9orf72) repeat expansions (FTLD‐C9orf72). Iron accumulation as a marker of neuroinflammation has, however, been understudied in genetic FTLD to date. To investigate the occurrence of cortical iron accumulation in FTLD‐MAPT and FTLD‐C9orf72, iron histopathology was performed on the frontal and temporal cortex of 22 cases (11 FTLD‐MAPT and 11 FTLD‐C9orf72). We studied patterns of cortical iron accumulation and its colocalization with the corresponding underlying pathologies (tau and TDP‐43), brain cells (microglia and astrocytes), and myelination. Further, with ultrahigh field ex vivo MRI on a subset (four FTLD‐MAPT and two FTLD‐C9orf72), we examined the sensitivity of T2*‐weighted MRI for iron in FTLD. Histopathology showed that cortical iron accumulation occurs in both FTLD‐MAPT and FTLD‐C9orf72 in frontal and temporal cortices, characterized by a diffuse mid‐cortical iron‐rich band, and by a superficial cortical iron band in some cases. Cortical iron accumulation was associated with the severity of proteinopathy (tau or TDP‐43) and neuronal degeneration, in part with clinical severity, and with the presence of activated microglia, reactive astrocytes and myelin loss. Ultra‐high field T2*‐weighted MRI showed a good correspondence between hypointense changes on MRI and cortical iron observed on histology. We conclude that iron accumulation is a feature of both FTLD‐MAPT and FTLD‐C9orf72 and is associated with pathological severity. Therefore, in vivo iron imaging using T2*‐weighted MRI or quantitative susceptibility mapping may potentially be used as a noninvasive imaging marker to localize pathology in FTLD.

Animal studies suggest the involvement of natriuretic peptides (NP) in several brain functions that are known to be disturbed during Alzheimer's disease (AD). However, it remains unclear whether such findings extend to humans. In this study, we aimed to: (1) map the gene expression and localization of NP and their receptors (NPR) in human post-mortem brain tissue; (2) compare the relative amounts of NP and NPR between the brain tissue of AD patients and non-demented controls, and (3) compare the relative amounts of NP between the cerebrospinal fluid (CSF) of AD patients and non-demented controls. Using the publicly available Allen Human Brain Atlas dataset, we mapped the gene expression of NP and NPR in healthy humans. Using immunohistochemistry, we visualized the localization of NP and NPR in the frontal cortex of AD patients ( = 10, mean age 85.8 ± 6.2 years) and non-demented controls (mean age = 80.2 ± 9.1 years). Using Western blotting and ELISA, we quantified the relative amounts of NP and NPR in the brain tissue and CSF of these AD patients and non-demented controls. Our results showed that NP and NPR genes were ubiquitously expressed throughout the brain in healthy humans. NP and NPR were present in various cellular structures including in neurons, astrocyte-like structures, and cerebral vessels in both AD patients and non-demented controls. Furthermore, we found higher amounts of NPR type-A in the brain of AD patients ( = 0.045) and lower amounts of NP type-B in the CSF of AD patients ( = 0.029). In conclusion, this study shows the abundance of NP and NPR in the brain of humans suggesting involvement of NP in various brain functions. In addition, our findings suggest alterations of NP levels in the brain of AD patients. The role of NP in the development and progression of AD remains to be elucidated.

Alzheimer's disease (AD) is characterized by amyloid-beta (A[beta]) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical A[beta] deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø [almost equal to] 80 [micro]m) deposit, characterized as having multiple cores and A[beta]-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of A[beta]-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE [epsilon]4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrP.sup.C), A[beta] isoform composition (A[beta].sub.40, A[beta].sub.42, A[beta].sub.N3pE, pSer8A[beta]), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of A[beta].sub.40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular A[beta].sub.40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent A[beta] plaque-type associated with EOAD. Differences in A[beta] processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other A[beta] deposits. Disentangling specific A[beta] deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

Double diffusion encoding (DDE) magnetic resonance measurements of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic orientational distribution of cells. However, the specificity in detected microscopic anisotropy is limited as the signal is averaged over different cell types and across tissue compartments. Performing side-by-side metabolite DDE spectroscopy (DDES) and water DDES in which a wide range of b-values is used to gradually eliminate the extracellular contribution provides complementary measures from which intracellular and extracellular microscopic fractional anisotropies (\\(\\)FA) and diffusivities can be estimated. Metabolites are largely confined to the intracellular space and therefore provide a benchmark for intracellular diffusivity of specific cell types. Here, we aimed to estimate tissue- and compartment-specific human brain microstructure by combining water and metabolites DDES experiments. We performed DDES in human subjects in two brain regions that contain widely different amounts of white matter (WM) and gray matter (GM): parietal white matter (PWM) and occipital gray matter (OGM) on a 7 T MRI scanner. Results of the metabolite DDES experiments in both PWM and OGM suggest a highly anisotropic intracellular space within neurons and glia, with the possible exception of gray matter glia. Tortuosity values in the cytoplasm for water and tNAA, obtained with correlation analysis of microscopic parallel diffusivity with respect to GM/WM tissue fraction in the volume of interest, are remarkably similar for both molecules, while exhibiting a clear difference between gray and white matter, suggesting a more crowded cytoplasm and more complex cytomorphology of neuronal cell bodies and dendrites in GM than those found in long-range axons in WM.