The human olfactory system in two proteinopathies: Alzheimer's and Parkinson's diseases.

Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative disorders. Their etiologies are idiopathic, and treatments are symptomatic and orientated towards cognitive or motor deficits. Neuropathologically, both are proteinopathies with pathological aggregates (plaques of amyloid-ß peptide and neurofibrillary tangles of tau protein in Alzheimer's disease, and Lewy bodies mostly composed of α-synuclein in Parkinson's disease). These deposits appear in the nervous system in a predictable and accumulative sequence with six neuropathological stages. Both disorders present a long prodromal period, characterized by preclinical signs including hyposmia. Interestingly, the olfactory system, particularly the anterior olfactory nucleus, is initially and preferentially affected by the pathology. Cerebral atrophy revealed by magnetic resonance imaging must be complemented by histological analyses to ascertain whether neuronal and/or glial loss or neuropil remodeling are responsible for volumetric changes. It has been proposed that these proteinopathies could act in a prion-like manner in which a misfolded protein would be able to force native proteins into pathogenic folding (seeding), which then propagates through neurons and glia (spreading). Existing data have been examined to establish why some neuronal populations are vulnerable while others are resistant to pathology and to what extent glia prevent and/or facilitate proteinopathy spreading. Connectomic approaches reveal a number of hubs in the olfactory system (anterior olfactory nucleus, olfactory entorhinal cortex and cortical amygdala) that are key interconnectors with the main hubs (the entorhinal-hippocampal-cortical and amygdala-dorsal motor vagal nucleus) of network dysfunction in Alzheimer's and Parkinson's diseases.

Cranial Pair 0: The Nervus Terminalis.

Originally discovered in elasmobranchs by Fritsh in 1878, the nervus terminalis has been found in virtually all species, including humans. After more than one-century debate on its nomenclature, it is nowadays recognized as cranial pair zero. The nerve mostly originates in the olfactory placode, although neural crest contribution has been also proposed. Developmentally, the nervus terminalis is clearly observed in human embryos; subsequently, during the fetal period loses some of its ganglion cells, and it is less recognizable in adults. Fibers originating in the nasal cavity passes into the cranium through the middle area of the cribiform plate of the ethmoid bone. Intracranially, fibers joint the telencephalon at several sites including the olfactory trigone and the primordium of the hippocampus to reach preoptic and precommissural regions. The nervus terminalis shows ganglion cells, that sometimes form clusters, normally one or two located at the base of the crista galli, the so-called ganglion of the nervus terminalis. Its function is uncertain. It has been described that its fibers facilitates migration of luteinizing hormone-releasing hormone cells to the hypothalamus thus participating in the development of the hypothalamic-gonadal axis, which alteration may provoke Kallmann's syndrome in humans. This review summarizes current knowledge on this structure, incorporating original illustrations of the nerve at different developmental stages, and focuses on its anatomical and clinical relevance. Anat Rec, 302:394-404, 2019. © 2018 Wiley Periodicals, Inc.

Prognostic Role of Early and End-of-Neoadjuvant Treatment 18F-FDG PET/CT in Patients With Breast Cancer.

AIM: To determine the use of early and final treatment F-FDG PET/CT in the prediction of response to neoadjuvant chemotherapy (NAC) and its role in the prognosis of patients with locally advanced breast cancer (LABC). METHODS: One hundred thirty-two patients underwent a baseline FDG PET/CT (PET-1) after the second course of chemotherapy (PET-2) and after the last course (PET-3). Breast tumors were categorized into molecular phenotypes and risk categories according to the biological prognostic factors obtained by immunohistochemistry. PET/CT scans were semiquantitatively evaluated, obtaining the Δ% SUV1-2 and SUV1-3 in primary tumor and axillary lymph nodes to establish response groups attending to EORTC criteria. Moreover, a binary assessment was obtained classifying the studies as positive or negative. Histopathological response was obtained in breast and lymph node specimens. Overall survival (OS) and disease-free survival (DFS) were obtained after the follow-up. ROC analysis was performed to determine a cutoff value of Δ% SUV1-2 and SUV1-3 for the prediction of response and prognosis. Relations between phenotypes, metabolic behavior, final histopathological response, OS, and DFS were evaluated. RESULTS: In binary analysis, only PET-3 was able to predict histopathological response in lymph nodes. The cutoff values of %Δ SUV1-2 and %Δ SUV1-3 with the best sensitivity and specificity in the prediction of response in breast tumor were 62% (Se: 70% and Sp: 69%) and 84% (Se: 70% and Sp: 88%). A %ΔSUV1-3 of 74% in breast tumor was a predictor of DFS (AUC = 0.647; P = 0.037, Se: 52% and Sp: 66%). Kaplan-Meier analysis revealed significant relations between the binary lymph node assessment of PET-3 with OS (P = 0.016, χ = 5.78) and DFS (P = 0.003, χ = 9.10). CONCLUSIONS: End-of-treatment F-FDG PET/CT was a predictor of lymph node response and prognosis. Most of metabolic response variables related to histopathological response showed association with the prognosis.

Glycolytic activity with 18F-FDG PET/CT predicts final neoadjuvant chemotherapy response in breast cancer.

The purpose of the present study is to explore the relation between glycolytic metabolism assessed by (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and final neoadjuvant chemotherapy (NC) response in locally advanced breast tumors. Of women with breast cancer, 126 were prospectively evaluated. All patients underwent (18)F-FDG PET/CT previous to NC. Standard uptake value (SUV) max was calculated in the primary tumor. After NC, residual primary tumor specimen was histopathologically classified according to Miller and Payne tumor regression grades (TRG), from G1 to G5 and in response groups as good responders (G4 or G5), partial responders (G2 or G3), and non-responders (G1). Furthermore, residual lesions were classified following a binary assessment as responders (G4 or G5) and non-responders (the rest of cases). The relationship between SUV max with TRG and response groups was evaluated. Of tumors, 127 were assessed (a patient had bilateral breast lesions). TRG were as follows: G1 (27), G2 (27), G3 (32), G4 (11), and G5 (30). Forty-one were classified as good responders, 59 as partial responders, and 27 as non-responders. For the binary assessment, 41 lesions were classified as responders and 86 as non-responders. We found statistical differences (p=0.02) between the mean SUV max and TRG with greater SUV values for G5 compared to the other TRG. Good responders showed greater mean SUV max ± SD compared to partial responders and non-responders (10.51 ± 6.64 for good responders, 6.94 ± 5.81 for partial responders, and 5.23 ± 2.76 for non-responders; p=0.001). Baseline tumor metabolism assessing by FDG PET/CT was associated with the final histopathologic status after neoadjuvant chemotherapy, with greater SUV max values for good responders compared to the less responder cancers.

Early and delayed prediction of axillary lymph node neoadjuvant response by (18)F-FDG PET/CT in patients with locally advanced breast cancer.

PURPOSE: To determine the utility of (18)F-FDG (FDG) PET/CT performed in an early and delayed phase during neoadjuvant chemotherapy in the prediction of lymph node histopathological response in patients with locally advanced breast cancer. METHODS: FDG PET/CT studies performed in 76 patients (mean age 53 years) at baseline (PET-1), after the second course of chemotherapy (PET-2) and after the last course of chemotherapy (PET-3) were prospectively analysed. Inclusion criteria were lymph node involvement detected by PET/CT and non-sentinel node biopsy before or after the baseline PET/CT scan. Following the recommendations of the 12th International Breast Conference (St. Gallen), the patients were divided into five subgroups in relation to biological prognostic factors by immunohistochemistry. For diagnosis visual and semiquantitative analyses was performed. Absence of detectable lymph node uptake on the PET-2 or PET-3 scan with respect to the PET-1 scan was considered metabolic complete response (mCR). Lymph nodes were histopathologically classified according the lymph node regression grade and in response groups as pathological complete response (pCR) or not pCR (type A/D or B/C of the Smith grading system, respectively). ROC analysis was performed to determine a cut-off value of Δ% SUV1-2 and SUV1-3 for prediction of nodal status after chemotherapy. An association between mCR and pCR was found (Cohen's kappa analysis), and associations between phenotypes and metabolic behaviour and the final histopathological status were also found. RESULTS: Lymph node pCR was seen in 34 patients. The sensitivity, specificity, and positive and negative predictive values of PET-2 and PET-3 in establishing the final status of the axilla after chemotherapy were 52 %, 45 %, 50 % and 47 %, and 33 %, 84 %, 67 % and 56 %, respectively. No significant relationship was observed between mCR on PET-2 and PET-3 and pCR (p = 0.31 and 0.99, respectively). Lymph node metabolism on PET-1 was not able to predict the final histopathological status, whereas basal carcinomas showed a higher rate of pCR (70.6 %) than the other groups (p = 0.03). CONCLUSION: FDG PET/CT seems to have limitations in both the early and delayed evaluation of lymph node status after chemotherapy, with reduced predictive values.

Semi-quantitative lymph node assessment of (18)F-FDG PET/CT in locally advanced breast cancer: correlation with biological prognostic factors.

PURPOSE: The aim of this study was to analyse the correlation between dual-time-point (18)F-2-deoxy-2-fluoro-D-glucose (FDG) uptakes in lymph nodes assessed by positron emission tomography (PET)/CT and histopathological and immunohistochemical prognostic factors. METHODS: Seventy-five women with locally advanced breast cancer were prospectively evaluated. PET/CT was requested in the initial staging previous to adjuvant chemotherapy (multicentre study). All of the patients underwent (18)F-FDG PET/CT with a dual-time-point acquisition. Both examinations were evaluated qualitatively and semi-quantitatively with calculation of maximum standardized uptake values (SUV(max)) in PET-1 (SUV-1) and in PET-2 (SUV-2) and the percentage variation of the SUV or retention index (RI) between PET-1 and PET-2 in lymph nodes with the greater (18)F-FDG uptake. The biological prognostic parameters such as the steroid receptor status, p53 and HER2 expression, proliferation rate (Ki-67) and grading were determined from tissue of the primary tumour. Metabolic and biological parameters were correlated using Spearman's rank-order correlation coefficient and Mann-Whitney U and Kruskal-Wallis tests. RESULTS: Negative receptor status was correlated with higher SUV-1, SUV-2 and RI in lymph nodes. The results were significant for progesterone receptor status. p53 over-expression and triple-negative status were associated with greater semi-quantitative parameters in lymph nodes. Higher tumoural grades were related with greater semi-quantitative parameters (p > 0.05). CONCLUSION: Biological factors of bad prognosis were correlated with higher semi-quantitative metabolic values in lymph nodes. Therefore these results appear to reveal biological significance of lymph node (18)F-FDG accumulation.

18F-FDG retention index and biologic prognostic parameters in breast cancer.

AIM: To analyze the correlation between [(18)F]-fluoro-2-deoxy-D-glucose (F-FDG) uptake assessed by positron emission tomography/computed tomography (PET/CT) in breast tumors and histopathologic and immunohistochemical prognostic factors. MATERIAL AND METHODS: Sixty-eight women with breast cancer were prospectively evaluated. PET/CT was requested in the initial staging previous to neoadjuvant chemotherapy (multicentric study).All the patients underwent a standard (18)F-FDG PET/CT followed by a delayed acquisition, 1 hour (PET-1) and 3 hours (PET-2) after FDG administration. Both examinations were evaluated qualitatively and semiquantitatively (SUV(max) values) in PET-1 (SUV-1) and in PET-2 (SUV-2). The percentage variation of the standard uptake values (retention index) between PET-1 and PET-2 was calculated.Clinical and metabolic stages were assessed according to TNM classification. All biologic prognostic parameters, such as the receptor status, p53 and c-erbB-2 expression, proliferation rate (Ki-67), and grading were determined from tissue of the primary tumor. Metabolic, clinical, and biologic parameters were correlated. RESULTS: A positive relationship was found between the SUV(max), tumor size, clinical, and metabolic stages. SUV-1 and SUV-2 values showed significant statistical correlation (P < 0.05) with PET stage and tumor size assessed by PET. On the contrary, the retention index showed relation with clinical stage (P < 0.05).When related to the biologic parameters, retention index showed the best results, with positive and significant relation (P < 0.05), with histologic grade, and Ki-67 and c-erbB-2 expression. Isolated SUV values only showed significant relation to Ki-67 expression. CONCLUSION: The retention index showed the best relation with biologic and clinical parameters compared with isolated SUVmax values for what could be a predictive marker of tumor biologic behavior.