Journal of Neuropathology and Experimental Neurology最新文献

As Alzheimer disease (AD) progresses, pathological tau spreads by cell-to-cell propagation of tau. This study aims to elucidate the impact of AD-associated post-translational modifications of tau-on-tau propagation. Tau propagation reporter constructs distinguishing donor cells from recipient cells were developed, and additional constructs were made with tau residues mutated from serine or threonine to aspartate to mimic the negative charge of a phosphorylation and/or from lysine to glutamine to mimic the charge-neutralizing effect of acetylation. Flow cytometry was used to quantify donor and recipient cells. This revealed that the mutations generally tended to reduce tau propagation compared to wildtype tau. Recombinant tau containing either wildtype or posttranslational modification mimicking mutations were used to treat Chinese hamster ovary cells or human induced pluripotent stem cell-derived neurons to quantify tau uptake, revealing that the mutations generally resulted in reduced uptake compared to wildtype tau. Surface plasmon resonance revealed that the mutations had a reduced affinity for lipoprotein receptor-related protein 1 (LRP1), a tau uptake receptor, compared to wildtype tau. Overall, these results suggest that AD-associated posttranslational modification mimicking mutations reduce the cell-to-cell propagation of tau by reducing tau uptake by recipient cells, which may be in part due to reduced binding affinity to LRP1.

Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimer's disease in which amyloid-β (Aβ) deposits in cerebral and leptomeningeal vessel walls, predisposing vessels to micro- and macro-hemorrhages. The vessel walls contain distinct proteins and heparan sulfate (HS), yet how vascular proteins and HS jointly associate with Aβ is unknown. We conducted the first multi-omics study to systematically characterize the proteins as well as the HS abundance, sulfation level, and disaccharide composition of leptomeninges from 23 moderate to severe CAA cases and controls. We then analyzed the associations between Aβ and other proteins, HS, and apolipoprotein E genotype. We found an increase in a minor HS disaccharide containing unsubstituted glucosamine, as well as 6-O sulfated disaccharides; Aβ40 levels positively correlated with unsubstituted glucosamine. There was also an increase in extracellular proteins derived from brain parenchyma or plasma, including olfactomedin-like protein 3, fibrinogen, serum amyloid protein, apolipoprotein E, and secreted frizzled related protein-3. Our findings of vascular HS and protein alterations specific to CAA-affected leptomeningeal vessels provide molecular insight into the extracellular remodeling that co-occurs with Aβ deposits and may indicate a basis for antemortem diagnostic assay development and therapeutic strategies to impede Aβ-HS interactions.

Solitary fibrous tumors (SFTs) are fibroblastic mesenchymal neoplasms defined by the presence of a NAB2::STAT6 fusion and exhibit a broad range of behaviors. SFTs in the pineal region are poorly understood due to the limited number of reported cases. Here, we report a 48-year-old woman with a pineal region SFT who subsequently developed metastatic left para-falcine parieto-occipital and right lung upper lobe SFTs over the next 12 years. This was the only pineal SFT identified in an institutional cohort of 34 resected pineal region lesions. Review of another, much larger institutional cohort of pineal region lesions revealed 4 additional patients with SFT but none with extracranial metastasis. We present descriptions of their clinical presentations, treatments, histopathologic findings, available genomic alterations, and longitudinal outcomes. Finally, we performed a comprehensive literature search and identified 19 individual patients with pineal region SFTs. None of these reported neoplasms had an extracranial metastasis. Taken together, this work contributes to the growing body of data characterizing this rare tumor with aggressive potential and reinforces SFTs as a possible differential diagnosis for pineal region tumors.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), is common in elderly brains and often seen in conjunction with Alzheimer's disease neuropathologic change (ADNC). LATE-NC typically begins in the amygdala and spreads to the hippocampus and neocortex. Whether it contributes to hippocampal and amygdala atrophy in Down syndrome (DS) remains unexplored. We analyzed amygdala and hippocampal volumes and neuropathological burden in 12 DS cases and 54 non-DS cases with AD and related neurodegenerative pathologies (ADRNP) using 7 Tesla (7T) postmortem ex vivo MRI. Postmortem and antemortem hippocampal volumes were significantly correlated in a subset of 17 cases with available antemortem MRI scans. DS cases had smaller hippocampal and amygdala volumes than ADRNP cases; these correlated with more severe Braak stage but not with Thal phase. LATE-NC and hippocampal sclerosis (HS) were uncommon in DS cases. In ADRNP cases, lower hippocampal volumes associated with dementia duration, advanced Thal phase, Braak NFT stage, C score, LATE-NC stage, HS and arteriolosclerosis severity; reduced amygdala volumes correlated with severe LATE-NC stage, HS, and arteriolosclerosis severity, but not with Thal phase or Braak NFT stage. Lewy body pathology did not affect hippocampal or amygdala volume in either cohort. Thus, hippocampal volumes in ADRNP were influenced by both ADNC and LATE-NC, and amygdala volumes were primarily influenced by LATE-NC. In DS, hippocampal and amygdala volumes were primarily influenced by tau pathology.

Maximum intensity projection is a simple post-hoc dimension reduction approach that yields sharp 2-dimensional images from image stacks but is limited by low signal or high background. Herein, we demonstrated improvement in image contrast using maximum contrast versus maximum intensity projection in 3-dimensional phase-contrast and quantitative phase imaging of frozen cross-sections of murine peripheral nerve. Fresh frozen murine sciatic nerve sections were imaged using 3-dimensional fluorescence, phase-contrast, and quantitative phase microscopy. Images were processed using maximum intensity and maximum contrast projection. Higher image contrast of nerve morphology was obtained when the images were processed with maximum contrast projection. Enhanced image contrast in quantitative phase imaging facilitated label-free multicolor imaging of murine peripheral nerves. Herein, we demonstrate the utility of maximum contrast projection in enhancing image contrast over intensity projection approaches in fluorescence phase-contrast and quantitative phase imaging of nerve histological samples. A user-friendly, open-source Python-based maximum contrast projection algorithm to facilitate the adoption of this technique is provided.

White matter (WM) disruption and atrophy is a consequence of traumatic brain injury (TBI) and contributes to persisting cognitive impairment. An increased expression of the myelin-associated axonal outgrowth inhibitor Nogo-A and oligodendrocyte pathology might be negatively associated with postinjury WM changes. Here, we analyzed brain tissue from severe TBI patients, obtained by surgical decompression in the early postinjury phase and postmortem brain tissue of long-term TBI survivors and observed an increased number of Nogo-A+ cells in WM tracts such as the corpus callosum (CC). Likewise, the number of Nogo-A+ cells in the CC was increased from day 7 postinjury to 6 months postinjury (mpi) following central fluid percussion injury (cFPI) in mice. In addition, the number of Olig2+ cells in the CC and capsula externa remained constant, while the numbers of Olig2+/CC1+ and GST-π+ mature oligodendrocytes declined throughout the observation time of 18 months. A significantly lower number of Olig2+/CC1+ cells was found in cFPI mice compared to controls at 18 mpi. Persistent vulnerability of oligodendrocytes in combination with dynamic alterations of Nogo-A expression may have implications for the WM atrophy and insufficient recovery observed after TBI.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of liver failure. Previous studies described astroglia alterations in HE, but regional changes have not been well investigated. This study addresses regional astroglial response by exploring glial fibrillary acidic protein (GFAP) immunoreactivity in cortical structures including somatosensory (S1Tr and S1BF), piriform (Pir), and perirhinal (PRh) cortices, and subcortical regions including corpus callosum (CC), ventromedial thalamus (VMT), mammillothalamic tract (MTT), and dorsomedial hypothalamic nucleus (DHN) in rats with acute liver failure (ALF) sacrificed at coma stage. Our data showed decreased numbers of astrocytes in S1Tr, Pir, and CC in ALF rats. GFAP-immunoreactive cells were increased within other regions including PRh, VMT, MTT, and DHN. Cell morphometric analysis showed significant increase in GFAP-immunoreactive astrocyte processes and cell bodies in cortical and subcortical regions but not in CC and DHN. However, astrocyte perimeters were increased, particularly in S1Tr and VMT. Our study demonstrates regional specificity including (1) regions with astrocyte activation associated with an increase of GFAP-immunostaining and astrocyte cell counts, together with (2) unaltered GFAP components, and (3) regions characterized by presumably inactive astrocyte with a reduced GFAP-immunostaining. These findings may reflect either different regional alterations in HE, or stages of an alteration progressing differently in different regions.