APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

Virtual Reality and Serious Videogame-Based Instruments for Assessing Spatial Navigation in Alzheimer's Disease: A Systematic Review of Psychometric Properties.

Over the past decade, research using virtual reality and serious game-based instruments for assessing spatial navigation and spatial memory in at-risk and AD populations has risen. We systematically reviewed the literature since 2012 to identify and evaluate the methodological quality and risk of bias in the analyses of the psychometric properties of VRSG-based instruments. The search was conducted primarily in July-December 2022 and updated in November 2023 in eight major databases. The quality of instrument development and study design were analyzed in all studies. Measurement properties were defined and analyzed according to COSMIN guidelines. A total of 1078 unique records were screened, and following selection criteria, thirty-seven studies were analyzed. From these studies, 30 instruments were identified. Construct and criterion validity were the most reported measurement properties, while structural validity and internal consistency evidence were the least reported. Nineteen studies were deemed very good in construct validity, whereas 11 studies reporting diagnostic accuracy were deemed very good in quality. Limitations regarding theoretical framework and research design requirements were found in most of the studies. VRSG-based instruments are valuable additions to the current diagnostic toolkit for AD. Further research is required to establish the psychometric performance and clinical utility of VRSG-based instruments, particularly the instrument development, content validity, and diagnostic accuracy for preclinical AD screening scenarios. This review provides a straightforward synthesis of the state of the art of VRSG-based instruments and suggests future directions for research.

Factors influencing living space utilization among older Afro-Colombian adults.

OBJECTIVES: Investigate the factors influencing life space utilization in older Afro-descendant adults residing in Tumaco, Colombia - a marginalized region of the country. DESIGN: This cross-sectional study included 388 Afro-descendant older adults. The study assessed living space using the Life Space Assessment (LSA) scale and collected demographic data. Cognitive levels were measured with the Mini-Mental State Examination (MMSE), and depressive symptoms were assessed using the Yesavage scale. Socio-emotional indicators were determined with the Medical Outcomes Study (MOS). The research employed linear and logistic regression models for data analysis. RESULTS: On average, participants scored 27.0 on the LSA scale. A lack of perceived income resulted in a 10.44-point decrease on the LSA scale. For each unit increase in the MOS-Instrumental Dimension score, the LSA score increased by 0.52 points (95% CI 0.17-0.87). As for cognitive performance (MMSE scale), each one-point increase resulted in a 0.69 decrease in the LSA score (95% CI -1.25 to -0.12). CONCLUSION: Socioeconomic disadvantages limit living space utilization, particularly in the Afro-descendant population. Yet, social support can enhance living space use despite environmental and economic constraints.

Point of care ultrasound impact in acute heart failure hospitalization: A retrospective cohort study.

BACKGROUND: Acute decompensated heart failure (ADHF) is one of the most frequent causes of emergency department (ED) visits. Point-of-Care Ultrasound (POCUS) is a reliable, easy-to-use, and available tool for an accurate diagnosis of ADHF. We aimed to analyze the impact of introducing POCUS as an additional tool to clinical standard diagnosis in clinical times of hospitalized heart failure patients. METHODS: Retrospective cohort study comparing patients consulting to ED for heart failure acute decompensation previous to the rutinary use of POCUS versus patients who received an ultrasound-guided diagnosis at entrance. Ultrasound evaluation was additional to standard diagnosis (which included natriuretic peptides, images, etc). Cumulative incidence functions were calculated for time to treatment, time to disposition decision, and time to discharge. We used a flexible parametric model for estimate the time ratio (TR) in order to reflect the effect of POCUS. RESULTS: A total of 149 patients were included. The most frequent comorbid condition was hypertension (71.8%) followed by type 2 diabetes (36.2%). B type natriuretic peptide (BNP) was over 500 ng/ml. Most patients had Stevenson B profile (83.9%) at admission. In the cumulative incidence model (Fig. A), the TR (time ratio) for the outcome time to treatment was 1.539 (CI 95% 0.88 to 2.69). The TR for the outcome time to disposition decision was 0.665 (CI 95% 0.48 to 0.99). The TR for the outcome time to discharge (hospital length of stay) was 0.663 (CI 95% 0.49 to 0.90). CONCLUSION: In our study, the introduction of POCUS to ADHF patients decreases time to disposition decision and total length of hospital stay. Conversely, time to treatment augments. There is need for the evaluation of ultrasound as an intervention in clinical trials to confirm these findings.

Predictive Factors of Hospital-Acquired Bacterial Infections in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: We aimed to identify the predictive factors of hospital-acquired bacterial infections in patients with systemic lupus erythematosus (SLE). METHODS: This chart review study included patients with SLE who were hospitalized between 2009 and 2020 for reasons other than infection. The outcome was defined as any infection confirmed using any bacterial isolation method or diagnosed by treating physicians and required treatment with intravenous antibiotics. For statistical analysis, logistic regression analyses were performed. RESULTS: In total, 1678 patients (87.6% women) were included. The median age was 33 years (interquartile range, 24-47 years). The incidence of hospital-acquired infections was 13.9% (233 infections). Age, Systemic Lupus Erythematosus Disease Activity Index score, Systemic Lupus International Collaborating Clinics damage score, blood urea nitrogen and C-reactive protein levels, dosage of steroid in the previous month, recent use of 1 or more immunosuppressants, admission with a central venous catheter (or dialysis catheter), and use of central venous catheter or bladder catheter in the first 5 days were the predictive factors of nosocomial infections. CONCLUSION: The patients' infection risk profile should be assessed to accurately determine the risk-benefit balance of any therapeutic intervention, minimize exposure to steroids and immunosuppressants, and maintain a low threshold for the early diagnosis of infections. Further studies should assess whether the modification of some identified factors could reduce the incidence of nosocomial infections.

Subjective Cognitive Decline and its Relation to Verbal Memory and Sex in Cognitively Unimpaired Individuals from a Colombian Cohort with Autosomal-Dominant Alzheimer's Disease.

OBJECTIVE: Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance. METHODS: We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education. RESULTS: Females in both groups had greater self-reported and study partner-reported SCD than males (all p < 0.001). In female mutation carriers, greater self-reported (p = 0.02) and study partner-reported SCD (p < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported (p = 0.03), but not study partner-reported SCD (p = 0.11) was associated with worse verbal memory. CONCLUSIONS: Study partner-reported SCD may be a stronger indicator of memory decline in females versus males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.

Efficacy of high-intensity interval- or continuous aerobic-training on insulin resistance and muscle function in adults with metabolic syndrome: a clinical trial.

PURPOSE: We carried out a randomized, clinical trial in adults of both sexes with metabolic syndrome (MS) to assess the efficacy of high-intensity, low-volume interval training (HIIT) compared to moderate-intensity continuous training (MICT) on insulin resistance (IR), muscle mass, muscle activation, and serum musclin. METHODS: Fasting glycemia, insulinemia, and glycated haemoglobin were determined by conventional methods, IR by Homeostatic model assessment (HOMA), lean mass by Dual-Energy X-ray Absorptiometry, muscle activation through carnosine by Proton Magnetic Resonance Spectroscopy, and musclin by Enzyme-Linked ImmunoSorbent Assay before and after a supervised, three-times/week, 12-week treadmill programme. HIIT (n = 29) consisted of six intervals with one-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). MICT (n = 31) trained at 60% of VO2peak for 30 min. RESULTS: Patients had a mean age of 50.8 ± 6.0 years, body mass index of 30.6 ± 4.0 kg/m2, and VO2peak of 29.0 ± 6.3 mL.kg-1.min-1. Compared to MICT, HIIT was not superior at reducing Ln HOMA-IR (adjusted mean difference: 0.083 [95%CI - 0.092 to 0.257]), carnosine or musclin or at increasing thigh lean mass. HIIT increased carnosine by 0.66 mmol/kg.ww (95% CI 0.08-1.24) after intervention. Both interventions reduced IR, body fat percentage and increased total lean mass/height2 and VO2peak. Musclin showed a non-significant reduction with a small effect size after both interventions. CONCLUSION: Compared to MICT, HIIT is not superior at reducing IR, carnosine or musclin or at increasing skeletal muscle mass in adults with MS. Both training types improved IR, muscle mass and body composition. NCT03087721, March 22nd, 2017. TRIAL REGISTRATION NUMBER: NCT03087721. Registered March 22nd, 2017.

[Predictive validity of a functional classification method in older adultsValidação preditiva de método de classificação funcional em idosos]. / Validación predictiva de un método de clasificación funcional en adultos mayores.

OBJECTIVE: Evaluate the predictive validity of a functional classification (FC) method for the use of emergency services and hospitalization, mortality, and health care costs among older adults. METHODS: Retrospective cohort study that included 2 168 older adults in a chronic noncommunicable disease (CNCD) care program in Medellin, Colombia. Patients were stratified according to a FC method based on functional status, presence of risk factors, and control of comorbidity. During one year of follow-up, the predictive validity of the FC method was assessed for the studied outcomes. Discrimination and calibration were measured with the C-statistic and Hosmer-Lemeshow (HL) test, respectively. RESULTS: The average age was 74.6 ± 7.9 years; 40.8% (n = 884) were men and 7.7% (n = 168) died. The risk of death (odds ratio [OR]: 1.767; 3.411; 8.525), hospitalization (OR: 1.397; 2.172; 3.540) and high cost of health care (OR: 1.703; 2.369; 5.073) increased in proportion to a deterioration in functional classification (classes 2B, 3, and 4, respectively). The predictive model for the outcome of death showed good capacity for discrimination (C-statistic = 0.721) and calibration (HL statistic 10.200; P = 0.251). CONCLUSION: There is a dose-response relationship between deterioration in FC and a higher risk of death, hospitalization, and high cost. FC has predictive validity for the mortality rate and could be used to stratify older adults in CNCD care programs with a view to guiding interventions.

OBJETIVO: Avaliar a validade preditiva de um método de classificação funcional (CF) para a utilização de serviços de emergência e internação hospitalar, mortalidade e custos da atenção de saúde em idosos. MÉTODOS: Estudo de coorte retrospectivo com 2 168 idosos atendidos em um programa de atenção de doenças crônicas não transmissíveis (DCNT) em Medellín, Colômbia. Um método de CF foi usado para estratificar os participantes segundo o estado funcional, presença de fatores de risco e controle de comorbidades. No período de acompanhamento de um ano, a validade preditiva da CF foi avaliada para os desfechos de interesse. A capacidade discriminatória (estatística C) e a calibração (teste de Hosmer-Lemeshow [H-L]) do modelo foram avaliadas. RESULTADOS: A média de idade dos participantes do estudo foi 74,6 ± 7,9 anos, 40,8% (n = 884) eram do sexo masculino e 7,7% (n = 168) vieram a óbito. Houve aumento do risco de óbito (odds ratio [OR] 1,767; 3,411­8,525), internação hospitalar (OR 1,397; 2,172-3,540) e custo elevado da atenção de saúde (OR 1,703; 2,369­5,073) com o declínio funcional ­ classes funcionais 2B, 3 e 4, respectivamente. O modelo preditivo para o desfecho de óbito demonstrou boa capacidade discriminatória (estatística C = 0,721) e calibração (estatística H-L = 10,200; P = 0,251). CONCLUSÃO: Há uma relação de dose-resposta entre o declínio da CF e risco maior de óbito, internação hospitalar e custo elevado da atenção. A CF tem validade preditiva para a taxa de mortalidade e poderia ser utilizada na estratificação de idosos em programas de atenção de DCNT para ajudar a direcionar as medidas de intervenção.

Prevalence, Incidence, and Clinical-Epidemiological Characterization of Amyotrophic Lateral Sclerosis in Antioquia: Colombia.

INTRODUCTION: The prevalence and incidence of amyotrophic lateral sclerosis (ALS) is not fully established, and this varies depending on the studied population. OBJECTIVE: To estimate the prevalence/incidence of ALS patients in Antioquia-Colombia. METHODOLOGY: Observational/descriptive study by reviewing clinical records from 2010 to 2014. Cases with possible, probable and definite ALS were included. To estimate the prevalence/incidence, capture-recapture method was used. RESULTS: Point prevalence in December 2014 was 4.9/100,000 (95% CI 2.0-7.8), and the incidence was 1.4/100,000/year (95% CI 0.5-2.2). The median survival was 4 years. Spinal-onset was observed in 62.4% of the included patients. CONCLUSION: Prevalence, incidence and clinical presentation of ALS in Antioquia are similar to most studies reported worldwide. However, prevalence in Antioquia seems to be slightly higher than in other studies from Latin -American countries. This may derive from the inclusion criteria and case detection methodology adopted, but sociodemographic and genetic factors should be considered.

Implementation of the clinical practice guideline for individuals with amputations in Colombia: a qualitative study on perceived barriers and facilitators.

BACKGROUND: The issue of lower extremity amputation has been in the Colombian political agenda for its relationship with the armed conflict and antipersonnel mines. In 2015 the Colombian Ministry of Health published a national clinical practice guideline (CPG) for amputee patients. However, there is a need to design implementation strategies that target end-users and the context in which the CPG will be used. This study aims to identify users' perceptions about the barriers and facilitators for implementing the guideline for the care of amputee patients in a middle-income country such as Colombia. METHODS: Semi-structured interviews were conducted with 38 users, including patients, health workers, and administrative staff of institutions of the health system in Colombia. Individuals were purposively selected to ensure different perspectives, allowing a balance of individual positions. RESULTS: According to participants' perceptions, barriers to implementation are classified as individual barriers (characteristics of the amputee patient and professionals), health system barriers (resource availability, timely care, information systems, service costs, and regulatory changes), and barriers related to clinical practice guidelines (utility, methodological rigour, implementation flexibility, and characteristics of the group developing the guidelines). CONCLUSIONS: Our study advances knowledge on the perceived individual and health system barriers and facilitators for the implementation of the CPG for amputee patients in Colombia. Importantly, the governance, financial, and service delivery arrangements of the Colombian health system are determining factors in implementing CPGs. For example, the financial arrangements between the insurance companies and the health care provider institutions were identified as barriers for the implementation of recommendations related to the continuity and opportunity of care of patients with amputations. The design of implementation strategies that successfully address the individual behaviours and the contextual health systems arrangements may significantly impact the health care process for amputee patients in Colombia.

Individual, health system, and contextual barriers and facilitators for the implementation of clinical practice guidelines: a systematic metareview.

INTRODUCTION: Clinical practice guidelines (CPGs) are designed to improve the quality of care and reduce unjustified individual variation in clinical practice. Knowledge of the barriers and facilitators that influence the implementation of the CPG recommendations is the first step in creating strategies to improve health outcomes. The present systematic meta-review sought to explore the barriers and facilitators for the implementation of CPGs. METHODS: A search was conducted in the PubMed, Embase, Cochrane, Health System Evidence and International Guideline Library (G-I-N) databases. Systematic reviews of qualitative, quantitative or mixed-methods studies that identified barriers or facilitators for the implementation of CPGs were included. The selection of the title and abstract, the evaluation of the full text, extraction of the data and the quality assessment were carried out by two independent reviewers. To summarise the evidence, we grouped the barriers and facilitators according to the following contexts: political and social, health organisational system, guidelines, health professionals and patients. RESULTS: Overall, 25 systematic reviews were selected. The relevant barriers in the social-political context were the absence of a leader, difficulties with teamwork and a lack of agreement with colleagues. Relevant barriers in the health system were a lack of time, financial problems and a lack of specialised personnel. Barriers of the CPGs included a lack of clarity and a lack of credibility in the evidence. Regarding the health professional, a lack of knowledge about the CPG and confidence in oneself were relevant. Regarding patients, a negative attitude towards implementation, a lack of knowledge about the CPG and sociocultural beliefs played a role. Some of the most frequent facilitators were consistent leadership, commitment of the members of the team, administrative support of the institution, existence of multidisciplinary teams, application of technology to improve the practice and education regarding the guidelines. CONCLUSIONS: The barriers and facilitators described in this review are factors that influence the implementation of evidence in clinical practice. Knowledge of these factors should contribute to the development of a theoretical basis for the creation of CPG implementation strategies to improve professional practice and health outcomes for patients.

Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr).

INTRODUCTION: A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1. METHODS: We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing. RESULTS: Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03). DISCUSSION: Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.

Incidence of dementia in elderly Latin Americans: Results of the Maracaibo Aging Study.

INTRODUCTION: There are few longitudinal studies of dementia in developing countries. We used longitudinal data from the Maracaibo Aging Study to accurately determine the age- and sex-specific incidence of dementia in elderly Latin Americans. METHODS: The Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) was used to diagnose dementia, which was classified as Alzheimer's disease, vascular dementia, or other. Age- and sex-specific incidence was estimated as the number of new cases of dementia divided by person-years (p-y) of follow-up. RESULTS: The incidence of all dementia diagnoses was 9.10 per 1000 p-y (95% confidence interval [CI] 7.13-11.44; 8026 total p-y), 5.18 for Alzheimer's disease (95% CI 3.72-7.03; 7916 total p-y), and 3.35 for vascular dementia (95% CI 2.19-4.91; 7757 total p-y). DISCUSSION: Among Maracaibo Aging Study participants younger than 65 years, the incidence of dementia was higher than that of US Whites. Among individuals older than 65 years, the incidence was comparable to the mean of previous incidence estimates for other populations worldwide.

Diagnostic accuracy of CERAD total score in a Colombian cohort with mild cognitive impairment and Alzheimer's disease affected by E280A mutation on presenilin-1 gene.

BACKGROUND: This study aimed to determine Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Assessment Battery total score diagnostic accuracy in the diagnosis of mild cognitive impairment (MCI) and dementia in familial Alzheimer's disease (FAD) with E280A mutation on presenilin-1 gene (PSEN1). METHODS: A cross-sectional study was conducted in a cohort of PSEN1 E280A carriers and non-carriers assessed between January 1995 and February 2013. During the first neuropsychological assessment, 76 were having dementia, 46 had MCI, and 1,576 were asymptomatic. CERAD cut-off points were established for MCI and dementia using a Receiver Operating Characteristics (ROC) analysis, and were further analyzed according to education level in two groups: low education level (eight years or less), and high education level (over eight years). RESULTS: The area under curve-ROC CERAD total score for dementia was 0.994 (95% CI = 0.989-0.999), and that for MCI was 0.862 (95% CI = 0.816-0.908). The dementia diagnosis cut-off point for the low education group was 54, (98.4% sensitivity, 92.6% specificity), and that for the high education group was 67 (100% sensitivity, 94.1% specificity). The MCI diagnosis cut-off point for the low education group was 66 (91.2% sensitivity, 56.4% specificity), and that for the high education group was 72 (91.7% sensitivity, 76.3% specificity). CONCLUSIONS: The CERAD total score is a useful screening tool for dementia and MCI in a population at risk of FAD.

Neurocognitive subtypes of schizophrenia.

OBJECTIVE: To empirically identify schizophrenia neurocognitive subtypes and establish their association with clinical characteristics. METHODS: Sustained attention, executive function, facial emotion recognition, verbal learning, and working memory tests were applied to 253 subjects with schizophrenia. We identified neurocognitive subtypes by a latent class analysis of the tests results. After, we made a search for the association of these subtypes with clinic characteristics. RESULTS: We identified four neurocognitive subtypes: 1) “Global cognitive deficit”, 2) “Memory and executive function deficit”, 3) “Memory and facial emotion recognition deficit,” and 4) “Without cognitive deficit.” In comparison with the subtype “without cognitive deficit,” we found that the “memory and executive function deficit subtype” and the “global cognitive deficit subtype” had a higher frequency of male, unemployed, severe impairment, and adherence to treatment participants. However, in the “global cognitive deficit subtype” the differences were higher and there was also a lower frequency of past major depressive episodes (OR 0.39; 95%CI: 0.16 to 0.97). The “memory and facial recognition deficit subtype” had a higher probability of severe impairment (OR 5.52; 95%CI: 1.89 to 16.14) and unemployed (OR 2.43; 95%CI: 1.06 to 5.55) participants, but also a lower probability of past depressive episodes (OR 0.21; 95%CI: 0.07 to 0.66). CONCLUSION: Our results suggest the existence of four neurocognitive subtypes in schizophrenia with a spectrum of dysfunction and severity. We found higher dysfunction in those with worse cognitive dysfunction, and higher affective psychopathology and less treatment adherence in those with less cognitive dysfunction.

An 1H-MRS framework predicts the onset of Alzheimer's disease symptoms in PSEN1 mutation carriers.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (1H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD. METHODS: We studied 75 subjects from the largest multigenerational pedigree in the world (∼5000 people) that segregates a unique form of early-onset Alzheimer's disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1 p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/Cr, and Glx/Cr, respectively) with two-dimensional 1H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to 1H-MRS data while controlling for age, educational level, and sex. RESULTS: We found that (1) the combination of LPPGM Cho/Cr<0.165 and RPPGM Glx/Cr>1.54 fully excluded carriers; (2) LPPGM Cho/Cr>0.165, RPPGM Glx/Cr<1.54, and left parietal white mater NAA/Cr>1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr>1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%. CONCLUSIONS: Brain metabolites measured by 1H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by the PSEN1 p.Glu280Ala (E280 A) mutation.

Verbal working memory in individuals with schizophrenia and their first degree relatives: relationship with negative and disorganized symptoms.

OBJECTIVE: To determine whether there are differences in verbal working memory amongst subjects with schizophrenia, their first degree relatives and controls, and to evaluate the influence of symptoms on these differences, as an initial step to assess whether this cognitive function is an endophenotype. METHODS: We examined 197 cases with schizophrenia, 197 first degree relatives and 200 controls through psychiatric interviews and the Letters and Numbers Sequencing test (LNS). Performance was compared among the three groups adjusting for age, sex and education level. Adjustment for "negative symptoms" and "disorganization" was performed afterwards. RESULTS: Subjects with schizophrenia showed lower performance in the LNS than their first degree relatives and the healthy controls; the effect sizes were 0.75 and 1.18 respectively. There was a small difference between relatives and controls (effect size =0.38). These differences were significant after adjustment for negative and disorganized symptoms, but the effect sizes became smaller: 0.26 for relatives vs. subjects with schizophrenia, 0.56 for controls vs. subjects with schizophrenia and 0.33 for relatives vs. controls. Among individuals with schizophrenia, performance in the LNS was not associated with disorder duration, disease onset age, antipsychotics, history of depressive episodes or substance use disorders. CONCLUSION: Results suggest verbal working memory may be considered as an endophenotype in schizophrenia.

Comparison of the neurocognitive profile of the children of parents with bipolar disorder and controls: A transnational cross-sectional study.

INTRODUCTION: Studies that have compared the cognitive alterations of the children of parents with bipolar disorder (CPBD) versus the children of control parents (CCP), present heterogeneous results due to the studies' methodological differences, the age of the population studied, and the lack of standardisation of the measures used for the different neurocognitive domains. The objective was to compare the neurocognitive profile of CPBD versus CCP to observe if there are differences that could be proposed as possible endophenotypes of BD. RESULTS: A total of 107 individuals (51 CPBD, and 56 CCP) with ages between 6 and 16 (mean, 12.2±2.80) years of age were evaluated. Seventy-four point five percent of the CPBD group had some disorder compared to 67.9% of the CCP group. Tests such as letter-F phonemic verbal fluency, letter-S phonemic verbal fluency, overall F-A-S phonemic verbal fluency, story recall and retrieval, and Wisconsin perseverative errors showed a difference with a small effect size, but with a high degree of uncertainty. CONCLUSIONS: The CPBD did not have differences in their neurocognitive profile in comparison with CCP. Both groups have a high prevalence of psychopathology, which is a factor that could explain the lack of differences in neurocognitive performance.

Psychopathological Risk in Siblings of Subjects with Attention-Deficit/Hyperactivity Disorder: A cross-Sectional Study.

OBJECTIVE: We aim to determine the prevalence of mental disorders in siblings of children with attention deficit hyperactivity disorder (ADHD), and to determine how psychosocial adversity factors relate to this psychopathology, in a low-middle income country (Colombia). METHODS: We evaluated subjects with ADHD diagnosed according to the DSM-5 criteria, one of their parents and one of their siblings (ages 8-19). We used the ADHD rating scale and a set of instruments to assess the presence of mental disorders as well as psychosocial adversity. RESULTS: We evaluated 74 trios formed by the index case with ADHD, one sibling and one of the parents. We found that 24.3% of the participating siblings also met the criteria for ADHD and another 24.3% for other psychiatric disorders. The risk of these siblings having ADHD increased further when one of the parents reported a history of ADHD. We also found that 28.3% of the families faced high levels of psychosocial adversity as per their scores in the Rutter Adversity Index. CONCLUSIONS: Siblings of subjects with ADHD showed a significant risk for ADHD and other mental disorders. That risk increased if a parent reported a history of ADHD and also when two or more psychosocial adversity factors were present. This study supports the importance of early detection in efforts to decrease the risk for other siblings.

Subjective Cognitive and Communicative Complaints and Health-Related Quality of Life in Parkinson's Disease with and without Mild Cognitive Impairment.

INTRODUCTION: Mild Cognitive Impairment (MCI) is common in Parkinson's Disease (PD). Few studies have compared the Health-Related Quality of Life (HRQoL) in patients with and without MCI due to PD (PD-MCI), and its correlation to patients' subjective cognitive and communicative difficulties has not been explored. OBJECTIVE: We aimed to compare HRQoL in PD-MCI and PD without MCI (PD-nMCI), and explore its possible relationship to subjective cognitive and communicative complaints. METHODS: We included 29 PD-nMCI and 11 PD-MCI patients. The HRQoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39): its Cognition dimension was used as a measure of subjective cognitive complaints, its Communication dimension for subjective communicative complaints, and the summary index (PDQ-39 SI) as an indicator of HRQoL. Non-parametric partial correlations between the Cognition and Communication dimensions, and the adjusted PDQ-39 SI were conducted. RESULTS: PD-MCI patients had greater subjective cognitive and communicative complaints and worse HRQoL than PD-nMCI patients. In the PD-MCI group, both subjective cognitive and communicative complaints exhibited significant direct correlations with the adjusted HRQoL scores. CONCLUSIONS: HRQoL seems to be affected in PD-MCI, and it might be influenced by greater subjective cognitive and communicative complaints. Including patient-reported outcome measures of HRQoL, and providing cognitive and speech rehabilitation, as well as psychotherapeutic strategies to face these deficits can enhance the patient-centred approach in PD.