Objective To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick’s disease. Methods Detailed neuropathological examination using 70 μm and traditional 6 μm sections was performed using Thioflavin-S staining and immunohistochemistry for phosphorylated-tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n=5) converging evidence was obtained using antemortem neuroimaging measures of grey and white matter integrity. Results Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (Phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus and raphe nuclei (Phase II), followed by primary motor cortex and pre-cerebellar nuclei (Phase III) and finally visual cortex in the most severe (Phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18/21) but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease-duration and inversely correlated with brain-weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. Interpretation Pick’s disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration.

SummaryDigital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick's disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry. We used a color deconvolution process to isolate signal from the chromogen and applied both object detection and intensity thresholding algorithms to quantify pathological burden. We found object-detection algorithms had good agreement with gold-standard manual quantification of tau-and TDP-43-positive inclusions. Our sampling method was reliable across three separate investigators and we obtained similar results in a pilot analysis using open-source software. Regional comparisons using these algorithms finds differences in regional anatomic disease burden between PiD and FTLD-TDP not detected using traditional ordinal scale data, suggesting digital image analysis is a powerful tool for clinicopathological studies in morphologically diverse FTLD syndromes. (J Histochem Cytochem 64:54-66, 2016)

The desmosomal cadherin, desmoglein 2 (Dsg2), is deregulated in a variety of human cancers including those of the skin. When ectopically expressed in the epidermis of transgenic mice, Dsg2 activates multiple mitogenic signaling pathways and increases susceptibility to tumorigenesis. However, the molecular mechanism responsible for Dsg2-mediated cellular signaling is poorly understood. Here we show overexpression as well as co-localization of Dsg2 and EGFR in cutaneous SCCs in vivo. Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation. To determine whether Dsg2 mediates signaling through lipid microdomains, sucrose density fractionation illustrated that Dsg2 is recruited to and displaces Cav1, EGFR and c-Src from light density lipid raft fractions. STED imaging confirmed that the presence of Dsg2 disperses Cav1 from the cell-cell borders. Perturbation of lipid rafts with the cholesterol-chelating agent MβCD also shifts Cav1, c-Src and EGFR out of the rafts and activates signaling pathways. Functionally, overexpression of Dsg2 in human SCC A431 cells enhances EGFR activation and increases cell proliferation and migration through a c-Src and EGFR dependent manner. In summary, our data suggest that Dsg2 stimulates cell growth and migration by positively regulating EGFR level and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms.

Susceptibility MRI measurements capture nigral pathologies associated with parkinsonian syndromes. Whereas quantitative susceptibility mapping is more sensitive to iron, R2* may reflect pathological aspects of the disorders beyond iron such as α-synuclein. They may be invaluable tools in diagnosing differential parkinsonian syndromes, and tracking in living patients the dynamic changes associated with the pathological progression of these disorders. © 2018 International Parkinson and Movement Disorder Society.