25 research outputs found
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Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants.
Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick's disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied
Dynamic Interpretation of Hedgehog Signaling in the Drosophila Wing Disc
Morphogens are classically defined as molecules that control patterning by acting at a distance to regulate gene expression in a concentration-dependent manner. In the Drosophila wing imaginal disc, secreted Hedgehog (Hh) forms an extracellular gradient that organizes patterning along the anterior–posterior axis and specifies at least three different domains of gene expression. Although the prevailing view is that Hh functions in the Drosophila wing disc as a classical morphogen, a direct correspondence between the borders of these patterns and Hh concentration thresholds has not been demonstrated. Here, we provide evidence that the interpretation of Hh signaling depends on the history of exposure to Hh and propose that a single concentration threshold is sufficient to support multiple outputs. Using mathematical modeling, we predict that at steady state, only two domains can be defined in response to Hh, suggesting that the boundaries of two or more gene expression patterns cannot be specified by a static Hh gradient. Computer simulations suggest that a spatial “overshoot” of the Hh gradient occurs, i.e., a transient state in which the Hh profile is expanded compared to the Hh steady-state gradient. Through a temporal examination of Hh target gene expression, we observe that the patterns initially expand anteriorly and then refine, providing in vivo evidence for the overshoot. The Hh gene network architecture suggests this overshoot results from the Hh-dependent up-regulation of the receptor, Patched (Ptc). In fact, when the network structure was altered such that the ptc gene is no longer up-regulated in response to Hh-signaling activation, we found that the patterns of gene expression, which have distinct borders in wild-type discs, now overlap. Our results support a model in which Hh gradient dynamics, resulting from Ptc up-regulation, play an instructional role in the establishment of patterns of gene expression
Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution
Teachers’ Experiences with Literacy Instruction for Dual-Media Students who Use Print and Braille
Adult learners and traditional age freshmen: Comparing the ?new? pool with the ?old? pool of students
Signaling cascade coordinating growth of dorsal and ventral tissues of the vertebrate brain, with special reference to the involvement of Sonic hedgehog signaling
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Comorbid neuropathological diagnoses in early versus late-onset Alzheimer’s disease
Co-pathologies play an important role in the expression of the Alzheimer's disease clinical phenotype and may influence treatment efficacy. Early-onset Alzheimer's disease, defined as manifesting before age 65, is viewed as a relatively pure form of Alzheimer's disease with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with early-onset Alzheimer's disease (median age of onset = 55 years, 44 females) and 48 with late-onset Alzheimer's disease (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of Alzheimer's disease. Prevalence and stage of Lewy body disease, limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and vascular brain injury were compared between the two cohorts. We found at least one non-Alzheimer's disease pathological diagnosis in 98% of patients with early-onset Alzheimer's disease (versus 100% of late onset), and the number of comorbid diagnoses per patient was lower in early-onset than in late-onset Alzheimer's disease (median = 2 versus 3, Mann-Whitney Z = 3.00, P = 0.002). Lewy body disease and cerebral amyloid angiopathy were common in both early and late onset Alzheimer's disease (cerebral amyloid angiopathy: 86% versus 79%, Fisher exact P = 0.33; Lewy body disease: 49% versus 42%, P = 0.48, respectively), although amygdala-predominant Lewy body disease was more common in early than late onset Alzheimer's disease (22% versus 6%, P = 0.02). In contrast, LATE (35% versus 8%, P < 0.001), hippocampal sclerosis (15% versus 3%, P = 0.02), argyrophilic grain disease (58% versus 41%, P = 0.052), and vascular brain injury (65% versus 39%, P = 0.004) were more common in late than in early onset Alzheimer's disease, respectively. The number of co-pathologies predicted worse cognitive performance at the time of death on Mini-Mental State Examination [1.4 points/pathology (95% confidence interval, CI -2.5 to -0.2) and Clinical Dementia Rating-Sum of Boxes (1.15 point/pathology, 95% CI 0.45 to 1.84)], across early and late onset cohorts. The effect of sex on the number of co-pathologies was not significant (P = 0.17). Prevalence of at least one APOE ε4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of co-pathologies (+0.40, 95% CI 0.01 to 0.79, P = 0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to males, controlling for age of onset, APOE ε4, and disease duration. Our findings suggest that non-Alzheimer's disease pathological diagnoses play an important role in the clinical phenotype of early onset Alzheimer's disease with potentially significant implications for clinical practice and clinical trials design
Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein
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Diagnostic Accuracy of Amyloid versus 18 F-Fluorodeoxyglucose Positron Emission Tomography in Autopsy-Confirmed Dementia.
ObjectiveThe purpose of this study was to compare the diagnostic accuracy of antemortem 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients.MethodsOne hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC).ResultsOne hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies.InterpretationIn our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401