Journal of Neuropathology and Experimental Neurology最新文献

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.

Human brain tissue studies have used a range of metrics to assess RNA quality but there are few large-scale cross-comparisons of presequencing quality metrics with RNA-seq quality. We analyzed how postmortem interval (PMI) and RNA integrity number (RIN) before RNA-seq relate to RNA quality after sequencing (percent of counts in top 10 genes [PTT], 5' bias, and 3' bias), and with individual gene counts across the transcriptome. We analyzed 4 human cerebrocortical tissue sets (1 surgical, 3 autopsy), sequenced with varying protocols. Postmortem interval and RIN had a low inverse correlation (down to r = -0.258, P < .001 across the autopsy cohorts); both PMI and RIN showed consistent and opposing correlations with PTT (up to r = 0.215, P < .001 for PMI and down to r = -0.677, P < .001 for RIN across the autopsy cohorts). Unlike PMI, RIN showed consistent correlations with measurements of 3' and 5' bias in autopsies (r = -0.366, P < .001 with 3' bias). RNA integrity number correlated with 3933 genes across the 4 datasets vs 138 genes for PMI. Neuronal and immune response genes correlated positively and negatively with RIN, respectively. Thus, different gene sets have divergent relationships with RIN. These analyses suggest that conventional metrics of RNA quality have varying values and that PMI has an overall modest effect on RNA quality.

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.

Mesencephalosynapsis is characterized by a failure of the dorsal brainstem colliculi to separate into distinct lateral masses (non-cleavage, a.k.a. "fusion"). It is linked to ventriculomegaly and aqueductal stenosis but other associations have not been systematically examined. We reviewed a large cohort of fetal hydrocephalus cases to explore associations of aqueductal stenosis, mesencephalosynapsis, and other pathologies. Among 115 cases of fetal obstructive hydrocephalus (15-41 weeks gestation), mesencephalosynapsis was seen in 44 cases (38.3%). We graded the wide range of abnormal aqueductal histology; mesencephalosynapsis was associated with 67% of severe, 35% of mild, and 10% of borderline aqueductal pathologies. In 75% of cases, it was associated with other CNS anomalies, including rhombencephalosynapsis, holoprosencephaly, hemifacial microsomia, and amniotic rupture sequence. We also identified 2 cases of aqueductal stenosis associated with brainstem tegmental injury, probably ischemic in origin, without mesencephalosynapsis. Clinical and genetic associations of mesencephalosynapsis included diabetic embryopathy, amniotic rupture sequence, chromosomal abnormalities, and mutations in TBCD132, FRAS1, and NECTIN1. This is the largest review of the histology of fetal aqueductal stenosis to date. We conclude that mesencephalosynapsis points to a defect in embryonic brainstem patterning and may be isolated, associated with other malformations, and that it is found in heritable and non-heritable conditions.