Ribosomal s6 kinase 2 is a growth factor activated serine/threonine kinase and member of the ERK signaling pathway. Mutations in the Rsk2 gene cause Coffin-Lowry syndrome, a rare syndromic form of intellectual disability. The Rsk2 KO mouse model was shown to have learning and memory defects. We focused on the investigation of the emotional behavioral phenotype of Rsk2 KO mice mainly in the IntelliCage. They exhibited an anti-depressive, sucrose reward seeking phenotype and showed reduced anxiety. Spontaneous activity was increased in some conventional tests. However, KO mice did not show defects in place learning, working memory and motor impulsivity. In addition, we found changes of the monoaminergic system in HPLC and qRT-PCR experiments. Taken together, RSK2 not only plays a role in cognitive processes but also in emotional and reward-related behaviors.

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Frontotemporal dementia (FTD) includes a group of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders, affecting the fronto-insular-temporal regions of the brain. Clinically, FTD is characterized by progressive deficits in behavior, executive function, and language and its diagnosis relies mainly on the clinical expertise of the physician/consensus group and the use of neuropsychological tests and/or structural/functional neuroimaging, depending on local availability. The modest correlation between clinical findings and FTD neuropathology makes the diagnosis difficult using clinical criteria and often leads to underdiagnosis or misdiagnosis, primarily due to lack of recognition or awareness of FTD as a disease and symptom overlap with psychiatric disorders. Despite advances in understanding the underlying neuropathology of FTD, accurate and sensitive diagnosis for this disease is still lacking. One of the major challenges is to improve diagnosis in FTD patients as early as possible. In this context, biomarkers have emerged as useful methods to provide and/or complement clinical diagnosis for this complex syndrome, although more evidence is needed to incorporate most of them into clinical practice. However, most biomarker studies have been performed using North American or European populations, with little representation of the Latin American and the Caribbean (LAC) region. In the LAC region, there are additional challenges, particularly the lack of awareness and knowledge about FTD, even in specialists. Also, LAC genetic heritage and cultures are complex, and both likely influence clinical presentations and may modify baseline biomarker levels. Even more, due to diagnostic delay, the clinical presentation might be further complicated by both neurological and psychiatric comorbidity, such as vascular brain damage, substance abuse, mood disorders, among others. This systematic review provides a brief update and an overview of the current knowledge on genetic, neuroimaging, and fluid biomarkers for FTD in LAC countries. Our review highlights the need for extensive research on biomarkers in FTD in LAC to contribute to a more comprehensive understanding of the disease and its associated biomarkers. Dementia research is certainly reduced in the LAC region, highlighting an urgent need for harmonized, innovative, and cross-regional studies with a global perspective across multiple areas of dementia knowledge.

Frontotemporal dementia (FTD) is the third most common form of dementia across all age groups and is a leading cause of early-onset dementia. The Frontotemporal dementia (FTD) includes a spectrum of diseases that are classified according to their clinical presentation and patterns of neurodegeneration. There are two main types of FTD: behavioral FTD variant (bvFTD), characterized by a deterioration in social function, behavior, and personality; and primary progressive aphasias (PPA), characterized by a deficit in language skills. There are other types of FTD-related disorders that present motor impairment and/or parkinsonism, including FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The FTD and its associated disorders present great clinical heterogeneity. The diagnosis of FTD is based on the identification through clinical assessments of a specific clinical phenotype of impairments in different domains, complemented by an evaluation through instruments, i.e., tests and questionnaires, validated for the population under study, thus, achieving timely detection and treatment. While the prevalence of dementia in Latin America and the Caribbean (LAC) is increasing rapidly, there is still a lack of standardized instruments and consensus for FTD diagnosis. In this context, it is important to review the published tests and questionnaires adapted and/or validated in LAC for the assessment of cognition, behavior, functionality, and gait in FTD and its spectrum. Therefore, our paper has three main goals. First, to present a narrative review of the main tests and questionnaires published in LAC for the assessment of FTD and its spectrum in six dimensions: (i) Cognitive screening; (ii) Neuropsychological assessment divided by cognitive domain; (iii) Gait assessment; (iv) Behavioral and neuropsychiatric symptoms; (v) Functional assessment; and (vi) Global Rating Scale. Second, to propose a multidimensional clinical assessment of FTD in LAC identifying the main gaps. Lastly, it is proposed to create a LAC consortium that will discuss strategies to address the current challenges in the field.

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Background Dementia is one of the mean causes of disability in elderly. Peripheral inflammatory biomarkers and ApoE‐ε4 allele have been described as important biological risk factors of dementia in Caucasian population. Currently, there is scarce information about the specific age‐related and predisposition factors to develop dementia in Latino populations. The aim of this study is to investigate these biological risks factors in Chilean elderly with healthy and pathological brain ageing. Method We evaluated and quantified plasma samples obtained from the GERO cohort (114 elderly subjects, >70 years, classified in 51 subjects with subjective cognitive complaint (SCC) and 63 with mild cognitive impairment (MCI)), in addition to 36 healthy brain controls (HBC) and 31 subjects with Alzheimer’s disease dementia (ADD). Genotyping of ApoE gene was analyzed by qPCR. We analyzed inflammatory biomarkers using Luminex technique including IL‐2, IL‐6, IL‐10, TNF‐α, CRP and SAP proteins. All subjects receive a clinical and neuropsychological assessment. Result CRP protein was found significant decrease expression in SCC and ADD groups compared to MCI and HBC (p=0.048). In SAP protein was found a significant decrease in expression in the SSC (p=0.04) and MCI (p=0.0178) groups compared to HBC. It was observed a positive correlation in the SCC, MCI and ADD groups with the IL‐6 and TNFα, and, SAP and CRP. A negative correlation between IL‐2, IL‐6 and IL‐10 cytokines was found with Direct Span Digit test, which assess attentional capacity. Also was identified a negative correlation between SAP protein and the Free and Cued Selective Reminding Test (FCSRT), which assess verbal episodic memory, and IL‐10 cytokine and Montreal Cognitive Assessment (MoCA), which assess global cognition. Finally, a positive correlation was found in CRP protein with Pfeffer Functional Activity Questionnaire. Frequency of the ApoE‐ε4 allele, was significantly higher in ADD (52%) and SCC (27%) patients than controls and MCI (p=1x10‐4). Conclusion The results shown correlations between the different inflammatory proteins and performance in neuropsychological test suggesting that inflammatory biomarkers are associated with pathological brain ageing. The correlations in SCC and MCI are not being reported previously. Additionally, the frequency of ApoE‐ε4 allele in ADD group is higher than worldwide populations.

Background: Access to medical care vary across the world and is related to different health systems with an impact in recurrence.Objective: To evaluate disparities in breast cancer(BC) diagnosis and treatment between public and private services in southwest Brazil and at two public safety net hospitals in Houston, Texas.Methods: Women diagnosed with BC stages I-III between 2009 to 2011, and treated at the four hospitals in Brazil and two health centers in US were included. All statistical analyses were performed in R studio software, and p<0.05 was considered significant.Results: 1245 women were included: 967 from public health system (PHS) (20.3% from Houston, Texas) and 274 from private system(PS). Recurrence rate was higher in PHS (14.6% vs. 2.6%, p<0.001) Table 1. Clinical and demographic characteristics of the patientsCharacteristicsPublic (%), n=967Private (%), n=274pDiscovery of BC   By patient530 (54.8)92 (33.5) Routine exam87 (9)109 (39.8) Screening mammography270 (27.9)23 (8.4) Other80 (8.3)50 (18.3)<0.001Initial treatment   Surgery687 (71)241 (88) Neo-adjuvant chemotherapy224 (23.2)27 (9.8) Neo-adjuvant hormone therapy23 (2.3)27 (9.8) Not available33 (3.4)3 (1.1)<0.001Clinical Stage   I293 (30.3)113 (41.2) II342 (35.4)52 (19) III271 (28)15 (5.5) Unknown61 (6.3)94 (34.3)<0.001Subtype   HR+/HER2 -561 (58)192 (70.1) HR-/HER2+108 (11.1)29 (10.6) HR-/HER2+76 (7.9)14 (5.1) Triple negative149 (15.4)28 (10.2) Unknown73 (7.6)11 (4)0.012Symptomatic at Diagnosis   Yes591 (61.1)100 (36.5) No306 (31.6)97 (35.4) Unknown70 (7.2)77 (28.1)<0.001Recurencen=772n=146 No719 (74.4)193 (70.4) Yes142 (14.6)7 (2.6) Unknown106 (11)74 (27)<0.001 . Considering the interval in weeks: symptoms to diagnosis, diagnosis to first treatment (either surgery or neoadjuvant chemotherapy), diagnosis to first systemic treatment, diagnosis to surgical treatment and diagnosis to radiotherapy were longer in public patients (24.1 vs. 8.7; 11.1 vs. 3.5; 18.6 vs. 9.8; 16.9 vs. 5.6; 51.4 vs. 26.1; p<0.001). Table 2. Delay disparities between public and private health system PublicPrivatepSymptoms to diagnosis   Number of patients575146 Time (weeks)24.1 (0.4-104.9)8.7 (0.0-43.7)<0.001Diagnosis to first treatment   Number of patients663180 Time (weeks)11.1 (2.0-31.5)3.5 (0.0-11.0)<0.001Diagnosis to first systemic treatment   Number of patients526106 Time (weeks)18.6 (2.6-44.7)9.8 (1.9-29.3)<0.001Diagnosis to surgical treatment   Number of patients657178 Time (weeks)16.9 (3.4-45.6)5.6 (0.0-32.9)<0.001Diagnosis to radiotherapy   Number of patients465127 Time (weeks)51.4 (18.7-88.4)26.1 (5.6-66.4)<0.001 In multivariate analysis, PHS (HR 1.72; 95% CI 1.34-1.88; p adj=0.003), presence of symptoms (HR 2.29; 95% CI 1.39-3.78; p adj=0.001), clinical stage III (HR 1.62; 95% CI 1.35-1.93; p adj<0.001), and triple negativity and HER2neu positivity (1.18; 95% CI 1.03-1.35; p adj=0.021) were all associated with a higher recurrence rate.Conclusions: There were significant disparities between PHS and PS. Women in the PHS presented higher rates of recurrence, advanced clinical stages at diagnosis, symptoms and more aggressive subtypes by IHC. additionally, the interval between symptoms to diagnosis and diagnosis to treatments was longer in PHS. Citation Format: NematiShafaee M, Natal RA, Ramalho S, Dória MT, Conz L, Cabello V, Pavanello M, Mano MS, Linck RDM, Batista LS, Pedro EP, Bines J, de Paula BH, Zucca-Matthes G, Bondy ML, Ellis MJ, Podany E, Debord L, Makawita S, Stewart K, Cabello C. Impact of delay in breast cancer diagnosis and treatment according to health insurance status in southwest Brazil and Houston, Texas [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-15.

Objective: To assess the association of MRI BPE and pathological response in women diagnosed with stage II/III breast cancer submitted to NAC. Methods: This observational and cross-sectional retrospective study was performed in consecutive women who underwent NAC and had MRI exams before and after chemotherapy. The MRI was done before and after 2 weeks of completing NAC. BPE was classified according to ACR-BIRADS 5th edition. The type of BPE before NAC, its changes and the relationship to total pathologic complete response (TpCR) were evaluated. Data were paired with patient age, size on MRI before and after NAC, features of clinical response according to the RECIST criteria, tumor grade and immunohistochemical (IHC) subtypes. MRI assessment included amount of fibroglandular tissue, symmetry of BPE and measurement of tumor at the longest diameter. All images were blinded reviewed by a radiologist. We used for the changes of the BPE the Bowker symmetry test or the McNemar test and to analyze the factors related to the clinical and pathologic responses, logistic regression analysis. The level of significance adopted was 5% (p<0.05). Results: We studied 71 women between 2009 and 2016. The medium age was 37 years old. BPE was symmetrical in 68 women (95.8%). Moderate and marked BPE was present in 28 (39.4%) of the affected breasts and in 25 (34.2%) of the contralateral breasts. After NAC all BPE were symmetrical and just 3% of them were moderate or marked. Regarding the IHC subtype, 40 women (56.3%) were triple negative or HER2 positive, and these women had a higher frequency of TpCR (55% for each, compared to 12.9% in patients with luminal subtypes). We found to be independently associated with pCR: the reduction of BPE (in the affected or contralateral breast) and the molecular subtypes triple negative and HER2 positive Table 1. Multivariate Analysis related to TpCR (n=71).VariableCategoryP-ValueO.R.*CI 95% O.R.*Tumor Size on MR pre-MAC (cm) 0.1710,8590.691-1.068Luminal subtypeLuminal B (ref.)---1.00--- Luminal A0.3120.450.10-2.11 HER2pos/ Luminal B HER20.0055.781.71-19.58 Triple negative0.0493.271.01-10.64Age (years) 0.3870.9820.942-1.023Nottingham grade1 (ref.)---1.00--- 20.0817.830.78-79.16 30.0967.100.71-71.31BPE pre-NAC (S or A)Asymmetric (ref.)---1.00--- Symmetric0.3273.030.33-27.76BPE pre-NAC affected breastMinimal (ref.)---1.00--- Mild0.8120.860.24-3.09 Moderate0.3711.890.47-7.64 Marked0.5911.570.30-8.17BPE pre-NAC contralateral breastMinimal (ref.)---1.00--- Mild0.7130.790.22-2.81 Moderate0.2502.330.55-9.77 Marked0.4701.880.34-10.43BPE ChangeSame/increased (ref.)---1.00--- Reduction0.0263.011.14-7.96* OR (Odds Ratio) = Risk ratio to pCR; (n=26 pCR, n=7 DpCR, n=31 PR e n=7 ED, where Total pCR is pathological complete response (without invasive and DCIS in the breast and axilla) DpCR is pathological response with just DCIS, PR is partial response and ED is stable disease – we haven't progression disease). CI 95% OR = Confidence interval of 95% to risk ratio. Ref.: reference level. Proportional risk models. Conclusion: BPE reduction was significantly associated with TpCR. Nevertheless, patterns of BPE pre-NAC have no association with pathological response. Citation Format: Teixeira SRC, Camargo HSAd, Ramalho S, Natal R, Machado HdC, Camargo MMAd, Azevedo J, Arruda MdS, Negrão EMS, Almeida NR, Teixeira AL, Cabello V, Cabello C. Breast cancer and magnetic resonance imaging (MRI): Background parenchymal enhancement (BPE) predicting response to neoadjuvant chemotherapy (NAC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-02-09.