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Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.

El perfil cognitivo de los pacientes con anorexia nerviosa se caracteriza por dificultades en la flexibilidad mental y en la coherencia central. El objetivo de este trabajo fue analizar si los familiares de primer grado no afectados de los pacientes presentan estas dificultades cognitivas, que podrían representar rasgos endofenotípicos de la enfermedad. Fueron estudiadas 34 mujeres: 17 familiares de primer grado (madres y hermanas) de pacientes con anorexia nerviosa y 17 controles sanos agrupados por edad y escolaridad. Se consideraron el índice de masa corporal, la ansiedad, la depresión, los síntomas obsesivo-compulsivos y los relacionados con los trastornos alimentarios. Se evaluó la coherencia central, mediante la copia de la Figura Compleja de Rey, y la flexibilidad mental, mediante el test de Stroop, el test de los trazos B y el test de fluencia fonológica. Los familiares de pacientes con anorexia nerviosa presentaron un menor rendimiento en las medidas de coherencia central (p < .05) y en fluencia fonológica (p < .05) que los controles sanos. Se observó una correlación entre el test de Stroop y los síntomas de depresión y trastornos alimentarios (p < .05). Los familiares de primer grado no afectados de pacientes con anorexia nerviosa presentaron dificultades en la coherencia central y, en menor grado, en la flexibilidad mental. Los resultados en los familiares indican que este perfil podría ser mediado genéticamente, constituyendo un rasgo característico de la anorexia nerviosa y, por ende, un posible candidato a endofenotipo neuropsicológico de esta enfermedad. Palabras clave: anorexia nerviosa, neuropsicología, coherencia central, flexibilidad mental, endofenotipo. The cognitive profile of patients with anorexia nervosa is characterized by difficulties in central coherence and mental flexibility. Central coherence is defined by the ability to integrate incoming information in its own context, and weakness in central coherence is characterized by poor overall processing and superior detail processing. Mental flexibility is defined by the ability to change the course of a thought or action according to the demands of the environment. Alterations in this cognitive domain generate rigid and inflexible behavior. An open question in the literature is whether these cognitive characteristics are a transient state derived from the disease or whether they are stable traits associated with anorexia nervosa and endophenotypical features of this disease. The concept of endophenotype refers to the internal phenotype that is not clinically appreciable but can be observed indirectly through deficits that arise in the performance of certain neuropsychological tests. In recent years the search for endophenotypes has been renewed in the field of psychiatry as they would constitute an important route for the understanding of the biological and genetic bases of mental illnesses, constituting markers that allow a diagnosis before the onset of clinical symptomatology. For a cognitive marker to be considered an endophenotype it must meet a series of characteristics such as being measurable, inherited, found in patients with and without active disease and in first-degree relatives not affected by the disease. The aim of the present study was to assess whether difficulties in central coherence and mental flexibility are shared by unaffected first-degree relatives of patients with anorexia nervosa and thus constitute an endophenotypical feature of this disease. This is a cross-sectional, descriptive-comparative study in which 34 women participated: 17 unaffected first-degree relatives of patients with anorexia nervosa (mothers and sisters) and 17 healthy controls matched by age and education. For the study of central coherence the copy of Rey’s Complex Figure was used and to assess set-shifting the Stroop test, the Trail Making Test B and the Phonological Fluency test were used. Demographic and clinical aspects such as age, educational level, body mass index, anxiety, depression, obsessive-compulsive and eating disorder related symptoms were also evaluated. First-degree relatives of patients with anorexia nervosa showed lower performance on measures of central coherence (p < .05) and phonological fluency (p < .05) than healthy controls. A correlation was observed between the Stroop test and depression and eating disorders symptoms (p < .05). The results of this study show that unaffected first-degree relatives of patients with anorexia nervosa presented alterations in central coherence and, to a lesser degree, in mental flexibility. These results, in addition to previous research in which difficulties persisted even after recovery, indicate that these alterations could be genetically mediated, constituting a characteristic trait of anorexia nervosa and therefore a possible candidate for neuropsychological endophenotype of this disease. Regarding practical implications of the study, the findings reinforce the importance of cognitive remediation treatments not only for patients with anorexia nervosa but also emphasize that they could be useful for unaffected family members. Taking into account that family intervention is a widely used tool in the psychological treatment of anorexia, improving the perception of the patient and his relatives about cognitive biases, could contribute to raising awareness of the disease, something that patients with anorexia nervosa do not usually have, and generate a positive impact on the response to treatment as a whole.

Three Words-Three Shapes (3W3S) is a bedside test that assesses verbal and non-verbal memory and has proven useful in staging memory decline in amnestic disorders and primary progressive aphasia. Given its simple structure, the 3W3S can be easily adapted to other languages maintaining the original shapes and only modifying the words. We aim to validate a Spanish version of the 3W3S test and establish whether memory loss patterns present in amnesic disorders associated with Alzheimer's etiology and PPA were correctly characterized. The translation and adaptation of the 3W3S were performed according to standardized guidelines and applied to a cohort of patients with Dementia of Alzheimer's type (DAT = 20), mild cognitive impairment (aMCI= 20), primary progressive aphasia (PPA = 20), and healthy controls (HC = 20). In verbal memory performance, PPA patients' score was lower than that of MCI and HC and similar to DAT's in the effortless encoding (p < 0.001), delayed recall (p < 0.001), and recognition (p < 0.012). For non-verbal performance, PPA patients performed better than DAT and similar to HC and MCI subjects (p < 0.001). Results show good applicability of 3W3S to determine memory function in PPA patients, independently from language ability. Visual and verbal components of memory are dissociated in PPA.

Neurodegenerative dementias have been described based on their phenotype, in relation to selective degeneration occurring in a particular neuroanatomical system. More recently however, the term proteinopathy has been introduced to describe diseases in which one or more altered proteins can be detected. Neurodegenerative diseases can be produced by more than one abnormal protein and each proteinopathy can determine different clinical phenotypes. Specific biomarkers have now been linked to certain molecular pathologies in live patients. In 2016, a new biomarker-based classification, currently only approved for research in Alzheimer’s disease, was introduced. It is based on the evaluation three biomarkers: amyloid (A) detected on amyloid-PET or amyloid- beta 42 assay in CSF; tau (T) measured in CSF as phosphorylated tau or on tau PET imaging; and neuronal injury/neurodegeneration (N), detected by total T-tau in CSF, FDG PET hypometabolism and on MRI brain scan. Results of clinical research using the ATN biomarkers at FLENI, a Neurological Institute in Buenos Aires, Argentina have, since 2011, contributed to ongoing efforts to move away from the concept of neurodegenerative dementias and more towards one of cognitive proteinopathies. Today, clinical diagnosis in dementia can only tell us “where” abnormal tissue is found but not “what” molecular mechanisms are involved. RESUMO. As demências neurodegenerativas foram descritas com base em seu fenótipo, em relação à degeneração seletiva que ocorre em um sistema neuroanatômico específico. Mais recentemente, no entanto, o termo proteinopatia foi introduzido para descrever doenças nas quais uma ou mais proteínas alteradas podem ser detectadas. As doenças neurodegenerativas podem ser produzidas por mais de uma proteína anormal e cada proteinopatia pode determinar diferentes fenótipos clínicos. Biomarcadores específicos já foram associados a certas patologias moleculares em pacientes vivos. Em 2016, uma nova classificação baseada em biomarcadores, atualmente aprovada apenas para pesquisas na doença de Alzheimer, foi introduzida. É baseado na avaliação de três biomarcadores: amiloide (A) detectado no ensaio amiloide-PET ou amiloide-beta 42 no LCR; tau (T) medida no LCR como tau fosforilada ou em imagem de tau PET; e lesão/neurodegeneração neuronal (N), detectada por T-tau total no LCR, hipometabolismo FDG PET e pela ressonância magnética. Os resultados de pesquisas clínicas usando os biomarcadores ATN no FLENI, um Instituto Neurológico de Buenos Aires, Argentina, desde 2011, contribuíram para os esforços contínuos para se afastar do conceito de demência neurodegenerativa e mover-se mais em direção às proteinopatias cognitivas. Hoje, o diagnóstico clínico da demência só pode nos dizer “onde” o tecido anormal é encontrado, mas não “quais” mecanismos moleculares estão envolvidos.

La Enfermedad de Alzheimer (EA), es pérdida paulatina de las funciones cognitivas que generan un deterioro significativo en las actividades de la vida diaria, el diagnóstico temprano determina el curso y evolución. La presente investigación pretende realizar una validación de la batería neuropsicológica Uniform Data set (UDS-3) en población colombiana con demencia tipo Alzheimer. La batería UDS, desarrollada por un grupo de NACC, está batería evalúa el cambio de las personas con deterioro cognitivo y los normales, el cual tiene como propósito detectar de manera temprano el deterioro cognitivo y unificar datos a nivel mundial, para contribuir con los datos internacionales de Alzheimer. Es un instrumento reconocido y comúnmente usado en investigaciones de biomarcadores, la versión 3 se inició a usar en el 2015, está incorpora los criterios NIA-AA para la demencia de Alzheimer, un diagnóstico de lesión cerebral vascular, así como una forma más detallada de historia familiar y una batería neuropsicológica actualizada. En este estudio con diseño instrumental participaran 384 personas, divididos en dos grupos 192 grupo control (sanos) y192 grupo de estudio (pacientes con Alzheimer, la proporción será 1:1 hombres-mujeres, con edades entre

El presente estudio tiene como objetivo evaluar el peso relativo de la educación y la complejidad laboral en la determinación del rendimiento cognitivo de sujetos con deterioro cognitivo leve (DCL). Fueron evaluados 80 sujetos con DCL, con los siguientes instrumentos: cuestionario de datos demográficos y sociales, cuestionario de agenciamiento de la actividad laboral y una batería neuropsicológica ampliada: memoria (Memoria lógica Signoret Batería, TAVEC), atención (Digit span, TMTA), lenguaje (Vocabulario WAISIII, Test de denominación de Boston, fluidez verbal), funciones ejecutivas (TMTB, analogías WAIS III, razonamiento matricial WAISIII) y construcción visual (cubos WAISIII). Los resultados muestran que la complejidad laboral tiene un peso mayor que la educación en la cognición como son el vocabulario, la flexibilidad cognitiva y las habilidades visuoconstructivas. La educación, tiene mayor peso en el razonamiento abstracto y la atención sostenida. La complejidad ocupacional y la educación desempeñan un papel diferencial e importante en el mantenimiento de las capacidades cognitivas, siendo factores amortiguadores del deterioro cognitivo en el envejecimiento. The objective of this paper is to assess the relative importance of education and occupational complexity to determine the cognitive performance on patients with mild cognitive impairment (MCI). 80 patients with MCI were assessed using the following instruments: questionnaire of sociodemogrhapical data, questionnaire on attainment of occupation, and an extended neuropsychological battery. Abilities tested were: logical memory (Signoret Memory Battery, TAVEC), attention (Digit span, TMTA), language (Vocabulary WAIS III, Boston Naming Test, Verbal Fluency), executive functions (TMTB, Analogies WAIS III, Matrix reasoning WAIS III) and visuoconstruction (Block design WAIS III). Results show that occupational complexity is more relevant than education for cognition of vocabulary, to achieve cognitive flexibility and to obtain visuoconstructive abilities. Education is more important for abstract reasoning and sustained attention. Occupational complexity and education have a unique and important role in the maintenance of cognitive abilities, working as buffers for cognitive impairment during aging. O presente estudo tem como objetivo avaliar o peso relativo da educação e da complexidade laboral na determinação do desempenho cognitivo de sujeitos com comprometimento cognitivo leve (CCL). Foram avaliados 80 sujeitos com CCL, com os seguintes instrumentos: questionário de dados demográficos e sociais, questionário de direcionamento da atividade laboral e uma bateria neuropsicológica ampliada: memória (Memória lógica Signoret Bateria, TAVEC), atenção (Digit span, TMTA), linguagem (Vocabulário WAIS III, Teste de denominação de Boston, fluência verbal), funções executivas (TMTB, analogias WAIS III, raciocínio matricial WAIS III) e construção visual (cubos WAIS III). Os resultados mostram que a complexidade laboral tem um peso maior que a educação na cognição, como no vocabulário, na flexibilidade cognitiva e nas habilidades visual-construtivas. A educação tem mais peso no raciocínio abstrato e na atenção sustentada. A complexidade ocupacional e a educação desempenham um papel diferencial e importante na manutenção das habilidades cognitivas, sendo fatores que amenizam o declínio cognitivo no envelhecimento. Fil: Feldberg, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Stefani, Dorina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina Fil: Tartaglini, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Neurociencias Buenos Aires S. A.; Argentina Fil: Hermida, Paula Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional - Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas "Prof. Dr. Alberto C. Taquini". Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional; Argentina Fil: Moya García, Lydia. Instituto de Neurociencias Buenos Aires S. A.; Argentina Fil: Somale, María Verónica. Instituto de Neurociencias Buenos Aires S. A.; Argentina Fil: Allegri, Ricardo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina