A Causal Analysis of the Effect of Age and Sex Differences on Brain Atrophy in the Elderly Brain.

We studied how brain volume loss in old age is affected by age, the APOE gene, sex, and the level of education completed. The quantitative characterization of brain volume loss at an old age relative to a young age requires-at least in principle-two MRI scans, one performed at a young age and one at an old age. There is, however, a way to address this problem when having only one MRI scan obtained at an old age. We computed the total brain losses of elderly subjects as a ratio between the estimated brain volume and the estimated total intracranial volume. Magnetic resonance imaging (MRI) scans of 890 healthy subjects aged 70 to 85 years were assessed. A causal analysis of factors affecting brain atrophy was performed using probabilistic Bayesian modelling and the mathematics of causal inference. We found that both age and sex were causally related to brain atrophy, with women reaching an elderly age with a 1% larger brain volume relative to their intracranial volume than men. How the brain ages and the rationale for sex differences in brain volume losses during the adult lifespan are questions that need to be addressed with causal inference and empirical data. The graphical causal modelling presented here can be instrumental in understanding a puzzling scientific area of study-the biological aging of the brain.

Prediction of Chronological Age in Healthy Elderly Subjects with Machine Learning from MRI Brain Segmentation and Cortical Parcellation.

Normal aging is associated with changes in volumetric indices of brain atrophy. A quantitative understanding of age-related brain changes can shed light on successful aging. To investigate the effect of age on global and regional brain volumes and cortical thickness, 3514 magnetic resonance imaging scans were analyzed using automated brain segmentation and parcellation methods in elderly healthy individuals (69-88 years of age). The machine learning algorithm extreme gradient boosting (XGBoost) achieved a mean absolute error of 2 years in predicting the age of new subjects. Feature importance analysis showed that the brain-to-intracranial-volume ratio is the most important feature in predicting age, followed by the hippocampi volumes. The cortical thickness in temporal and parietal lobes showed a superior predictive value than frontal and occipital lobes. Insights from this approach that integrate model prediction and interpretation may help to shorten the current explanatory gap between chronological age and biological brain age.

Loneliness as Risk Factor for Alzheimer´s disease.

There is considerable empirical evidence that unequivocally points to loneliness as a modifiable risk factor for the development of Alzheimer's disease and other related dementias. With the emergence of the COVID-19 pandemic and the resulting lockdown and social distancing, there has been a renewed interest in studying this topic. The present review examines the links between loneliness and Alzheimer's disease, with particular emphasis on the mechanisms common to both conditions.

A Comparative Analysis of MRI Automated Segmentation of Subcortical Brain Volumes in a Large Dataset of Elderly Subjects.

In this study, we perform a comparative analysis of automated image segmentation of subcortical structures in the elderly brain. Manual segmentation is very time-consuming and automated methods are gaining importance as a clinical tool for diagnosis. The two most commonly used software libraries for brain segmentation -FreeSurfer and FSL- are put to work in a large dataset of 4,028 magnetic resonance imaging (MRI) scans collected for this study. We find a lack of linear correlation between the segmentation volume estimates obtained from FreeSurfer and FSL. On the other hand, FreeSurfer volume estimates tend to be larger thanFSL estimates of the areas putamen, thalamus, amygdala, caudate, pallidum, hippocampus, and accumbens. The characterization of the performance of brain segmentation algorithms in large datasets as the one presented here is a necessary step towards partially or fully automated end-to-end neuroimaging workflow both in clinical and research settings.

Spanish Consortium for Ageing Normative Data (SCAND): Semantic Verbal Fluency Tests.

OBJECTIVE: Semantic verbal fluency constitutes a good candidate for identifying cognitive impairment. This paper offers normative data of different semantic verbal fluency tests for middle-aged and older adults natives from Spain considering sociodemographic factors, and different measures for each specific category (number of words produced, errors, and words evoked every 15 s). METHOD: Two thousand and eighty-eight cognitively unimpaired subjects aged between 50 and 89 years old, community dwelling, participated in the study. The statistical procedure includes the conversion of percentile ranges into scalar scores. Secondly, the effects of age, education and gender were verified. Linear regressions are used to calculate the scalar adjusted scores. RESULTS: Scalar scores and percentiles corresponding to all semantic verbal fluency tests across different measures are shown. Additional tables, which show the points that must be added or subtracted from direct scores, are provided for Education regarding the total number of "animals" and "clothes" evoked by participants, as well as for Age and Education in case of the total number of "clothes". Gender affects the number of "clothes" produced by participants in the first two 15-second segments. CONCLUSIONS: The current norms should provide clinically useful data for evaluating Spanish-speaking natives from Spain aged from 50 to 89 years.

Transition from mild cognitive impairment to normal cognition: Determining the predictors of reversion with multi-state Markov models.

INTRODUCTION: The theoretical framework of the Alzheimer's disease continuum considers transition between stages in a unidirectional manner. Here we examine the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) and explore a set of potential variables associated with this phenomenon. METHODS: A total of 985 Spanish community-dwelling individuals aged 70 years and over at baseline were monitored for 5 years. During this time, 173 MCI and 36 dementia cases were identified. Multi-state Markov models were performed to characterize transitions between states through the dementia continuum. RESULTS: The rate of reversion from MCI to NC was 11%. There were significant non-modifiable (age, socioeconomic status, or apolipoprotein E) and modifiable factors (cognitive training or absence of affective symptoms) associated with reversion. DISCUSSION: Overall, our results highlight that the likelihood of progression from MCI to dementia is very similar to that of reversion from MCI to NC.

Alzheimer's Disease and Empathic Abilities: The Proposed Role of the Cingulate Cortex.

In recent years there has been increasing interest in examining the role of empathic abilities in Alzheimer's disease (AD). Empathy, the ability to understand and share another person's feelings, implies the existence of emotional and cognitive processes and is a pivotal aspect for success in social interactions. In turn, self-empathy is oriented to one's thoughts and feelings. Decline of empathy and self-empathy can occur during the AD continuum and can be linked to different neuroanatomical pathways in which the cingulate cortex may play a crucial role. Here, we will summarize the involvement of empathic abilities through the AD continuum and further discuss the potential neurocognitive mechanisms that contribute to decline of empathy and self-empathy in AD.

MADRID+90 study on factors associated with longevity: Study design and preliminary data.

The progressive aging of the population represents a challenge for society. In particular, a strong increase in the number of people over 90 is expected in the next two decades. As this phenomenon will lead to an increase in illness and age-related dependency, the study of long-lived people represents an opportunity to explore which lifestyle factors are associated with healthy aging and which with the emergence of age-related diseases, especially Alzheimer's type dementia. The project "Factors associated with healthy and pathologically aging in a sample of elderly people over 90 in the city of Madrid" (MADRID+90) brings together a multidisciplinary research team in neurodegenerative diseases that includes experts in epidemiology, neurology, neuropsychology, neuroimaging and computational neuroscience. In the first phase of the project, a stratified random sampling was carried out according to the census of the city of Madrid followed by a survey conducted on 191 people aged 90 and over. This survey gathered information on demographics, clinical data, lifestyles and cognitive status. Here, the main results of that survey are showed. The second phase of the project aims to characterize individual trajectories in the course of either healthy and pathological aging, from a group of 50 subjects over 90 who will undergo a comprehensive clinical examination comprised of neurological and cognitive testing, MRI and EEG. The ultimate goal of the project is to characterize the biophysical and clinical profiles of a population that tends to receive little attention in the literature. A better understanding of the rapidly increasing group of nonagenarians will also help to design new policies that minimize the impact and future social and economic consequences of rapidly aging societies.

Spanish Consortium for Ageing Normative Data (SCAND): Screening Tests (MMSE, GDS-15 and MFE).

BACKGROUND: Detecting cognitive impairment is a priority for health systems. The aim of this study is to create normative data on screening tests (MMSE, GDS and MFE) for middle-aged and older Spanish adults, considering the effects of sociodemographic factors. METHOD: A total of 2,030 cognitively intact subjects who lived in the community, aged from 50 to 88 years old, participated voluntarily in SCAND consortium studies. The statistical procedure included the conversion of percentile ranges into scalar scores. Secondly, the effects of age, educational level and gender were verified. Linear regressions were used to calculate the scalar adjusted scores. Cut-off values for each test were also calculated. RESULTS: Scalar scores and percentiles corresponding to MMSE, GDS-15 and MFE are shown. An additional table is provided which shows the points that must be added or subtracted from MMSE score depending on the subject's educational level. CONCLUSIONS: The current norms should provide clinically useful data for evaluating Spanish people aged 50 to 88 years old and should contribute to improving the detection of initial symptoms of cognitive impairment in people living in the community, taking into account the influence of gender, age and educational level.

Residence, Clinical Features, and Genetic Risk Factors Associated with Symptoms of COVID-19 in a Cohort of Older People in Madrid.

BACKGROUND: The older population has been especially affected by the severe acute respiratory syndrome coronavirus 2 pandemic (COVID-19). OBJECTIVE: The aim of the study was to explore the incidence, severity, mortality rate, clinical features, and risk factors of symptoms of COVID-19 in home-dwelling older people, and its association with type of residence, cognitive deterioration, and neurodegenerative diseases. METHODS: Data about symptoms of COVID-19 were collected through a telephone survey in the cohort of 913 older volunteers of the Vallecas Project, aged 75-90 years, most of them (902) home-dwelling, in Madrid, Spain. The association of demographic and anthropometric measures, genetic polymorphisms, comorbidities, life habits, type of residence, and frailty surrogates were explored as potential risk factors for the incidence, severity, and mortality of COVID-19 in the older population. FINDINGS: Sixty-two cases reported symptoms compatible with COVID-19; 6 of them had died, 4 in their home and 2 in the nursing home. Moderate/severe cases were significantly older and more frequently males. The APOE ε4 allele was associated with the presence of symptoms of COVID-19. Higher systolic blood pressure, more intense smoking habit, more alcohol intake, lower consumption of coffee and tea, and cognitive impairment were associated with disease severity. CONCLUSIONS: The estimated incidence of symptomatic COVID-19 in this older cohort of Madrid was 6.8%, with an overall mortality rate of 0.7% (18.2% in those living in a nursing home) and a fatality rate of 9.9%. Our exploratory study indicates that life habits, other clinical conditions and, the ε4 variant of the APOE gene are associated with the presence and clinical severity of coronavirus infection.

Impact of individual and neighborhood dimensions of socioeconomic status on the prevalence of mild cognitive impairment over seven-year follow-up.

Objectives: There is strong evidence about the association between low socioeconomic status (SES) and higher risk of dementia. However, it has not been conveniently addressed so far the role of SES on the incidence of mild cognitive impairment (MCI). This study examines the impact of individual and neighbourhood dimensions of SES, as well as their interaction, on the risk of developing MCI in a sample of older adults.Method: Data from the Vallecas Project cohort, an ongoing community-based longitudinal study for early detection of cognitive impairment and dementia, were used to build two indices of SES namely individual and neighbourhood, as well as a global SES as a combination of both, and to investigate their effects on MCI conversion by means of a multivariate-adjusted Cox proportional hazard model.Results: A total of 1180 participants aged 70 years and older were enrolled in this study. Of these, 199 cases of MCI (16.9%) were diagnosed at any point of the follow-up. The individual and neighbourhood dimensions of SES played different roles in the dynamics of the MCI occurrence through aging. Most importantly, the risk of developing MCI was almost double for lower SES quartiles when compared to the highest one.Conclusion: The incidence of MCI in older adults was related to both individual characteristics and socioeconomic context. Public health strategies should be holistic and focus not only on promoting the classical individual preventive measures, but also on reducing social inequalities to foster healthy aging and reduce dementia burden.

Effects of commonly prescribed drugs on cognition and mild cognitive impairment in healthy elderly people.

BACKGROUND: Chronic drug intake has been associated with negative and positive cognitive effects in elderly people, although subjacent conditions may be confounding factors. AIM: To study the effects on cognitive performance of commonly prescribed medications in a cohort of cognitively normal older adults. METHODS: Medication intake was recorded during two years in 1087 individuals 70-85 years old, without neurological or psychiatric conditions. The influence of every drug, drug family and therapeutic group on six cognitive scores and on the conversion to mild cognitive impairment over two years was ascertained by cross-sectional and longitudinal analyses controlling for demographic and clinical variables. RESULTS: Small effects of several drugs on information processing were found in cross-sectional analyses but only confirmed for a positive effect of vitamin D in case-control analyses. Longitudinal analyses showed no drug effects on the cognitive slopes. Several hypotensive drugs reduced, whereas bromazepam and glucose lowering drugs increased, the conversion rate to mild cognitive impairment with very small effects (R2=0.3-1%). CONCLUSIONS: Cognitively healthy elderly individuals show minimal negative effects on information processing associated with chronic intake of some drugs probably related to the subjacent condition. Some drugs slightly affect the rate of conversion to mild cognitive impairment. Positive effects of vitamin D, chondroitin, atorvastatin and antihypertensive drugs, and negative effects of antidepressants and benzodiazepines, should be further explored in studies with longer follow-up.

Internal Consistency Over Time of Subjective Cognitive Decline: Drawing Preclinical Alzheimer's Disease Trajectories.

BACKGROUND: Early intervention to prevent, or delay, the transition from healthy cognition to cognitive impairment in older adults is an important goal. In this way, it is critical to find sensitive, reproducible, and early markers to use low cost methods for the detection of that transition. One of those early markers for symptomatic manifestation of AD is subjective cognitive decline (SCD). OBJECTIVE: To examine the internal consistency of the concept of SCD and to evaluate its clinical significance on the progression through the continuum of AD. METHODS: 1,091 cognitively healthy individuals from the Vallecas Project cohort were followed for three years. Cognitive complaints were systematically collected and analyzed along with clinical data. All participants were classified in three groups at every visit based on specific features of their complaints. RESULTS: Concordance analyses showed a good agreement in longitudinal classification of SCD. The Multi-state Markov Model highlighted a unidirectional transition from the status of no cognitive complaints to SCD. Interestingly, a more severe condition of SCD, namely SCD Plus, showed the highest risk of progression to mild cognitive impairment. CONCLUSIONS: The concept of SCD is stable over time when it is operationally defined and consistently assessed. It provides not only a fast identification of individuals at higher risk of future mild cognitive impairment, but also it allows us to track longitudinal trajectories.

Clinical Relevance of Specific Cognitive Complaints in Determining Mild Cognitive Impairment from Cognitively Normal States in a Study of Healthy Elderly Controls.

Introduction: Subjective memory complaints (SMC) in the elderly have been suggested as an early sign of dementia. This study aims at investigating whether specific cognitive complaints are more useful than others to discriminate Mild Cognitive Impairment (MCI) by examining the dimensional structure of the Everyday Memory Questionnaire (EMQ). Materials and Methods: A sample of community-dwelling elderly individuals was recruited (766 controls and 78 MCI). The EMQ was administered to measure self-perception of cognitive complaints. All participants also underwent a comprehensive clinical and neuropsychological battery. Combined exploratory factor analysis (EFA) and Item Response Theory (IRT) were performed to identify the underlying structure of the EMQ. Furthermore, logistic regression analyses were conducted to study whether single cognitive complaints were able to predict MCI. Results: A suitable five-factor solution was found. Each factor focused on a different cognitive domain. Interestingly, just three of them, namely Forgetfulness of Immediate Information (FII), Executive Functions (EF) and Prospective Memory (PM) proved to be effective in distinguishing between cognitively healthy individuals and MCI. Based on these results we propose a shortened EMQ version comprising 10 items (EMQ-10). Discussion: Not all cognitive complaints have the same clinical relevance. Only subjective complaints on specific cognitive domains are able to discriminate MCI. We encourage clinicians to use the EMQ-10 as a useful tool to quantify and monitor the progression of individuals who report cognitive complaints.

Specific Features of Subjective Cognitive Decline Predict Faster Conversion to Mild Cognitive Impairment.

BACKGROUND: Alzheimer's disease (AD) is a silent disorder that needs the earliest possible intervention in order to reduce its high economic and social impact. It has been recently suggested that subjective cognitive decline (SCD) appears at preclinical stages many years before the onset of AD. Therefore, SCD could become an ideal target for early therapeutic intervention. OBJECTIVE: The goal of this study was to evaluate the clinical significance of SCD on the conversion from a cognitively healthy stage to a mild cognitive impairment (MCI) in one-year follow-up. METHODS: A total of 608 cognitively intact individuals from the Vallecas Project's cohort, a community-based prospective study to identify early markers of AD, were enrolled in this study. Participants were classified in three groups: i) No Complaints (NCg), ii) Subjects with complaints in one or more cognitive domains (SCDg), and iii) Subjects who, besides complaints, fulfilled the features of SCD Plus proposed by the International Working Group of SCD (SCD-Pg). RESULTS: Individuals were followed up for a mean of 13.1 months (range 10.7-22.4). During this time, 41 volunteers developed MCI (6.7% of total sample). The conversion rate for SCD-Pg (18.9%) was significantly higher than SCDg (5.6%) and NCg (4.9%). CONCLUSION: Specific features associated with SCD may help to identify individuals at high risk of fast conversion to MCI. These results highlight the importance of a close follow-up of subjects with SCD-P and include them in early intervention programs because of their increased risk for the development of MCI.

Association of perceived health and depression with older adults' subjective memory complaints: contrasting a specific questionnaire with general complaints questions.

The objectives of this paper were to evaluate the association of subjective memory complaints (SMC) with perceived state of health, mood and episodic memory (associative and everyday memory). We studied these areas using two different complaint assessment methods (three general questions and a validated scale). The study included 269 older adults (aged 65-87) with age-related memory changes, but without cognitive impairment. They were evaluated with Mini-cognitive Exam, Rivermead Behavioural Memory Test (a test of everyday memory), Paired Associates Learning Test, Memory Failures of Everyday Questionnaire, three memory complaints questions, Nottingham Health Profile and Geriatric Depression Scale. The results indicated that memory for everyday performance, mood and perceived health were independent predictors of SMC, with mood and perceived health being stronger predictors than actual memory performance. Age was not associated with subjective memory and, with regard to level of education, only the illiterate level was associated with SMC. A specific questionnaire on subjective memory was found to be preferable to an aggregate of complaints questions on self-reported memory; only health profile was found to predict the outcomes on memory complaints questions. Our conclusion is that a group of underlying factors other than everyday memory were playing a role in SMC; these SMC of subjects with age-related memory changes were mainly associated with subjective evaluations of their health.

Nueva versión reducida del test de denominación de Boston para mayores de 65 años: aproximación desde la teoría de respuesta al ítem / A new shortened version of the Boston Naming Test for those aged over 65: an approach from item response theory

Introducción. Uno de los tests más utilizados para la evaluación de la afasia en la práctica clínica es el test de denominación de Boston (BNT), una prueba clásica en la que se presentan 60 láminas con dibujos en blanco y negro que valoran la capacidad de los sujetos para denominar dichos dibujos. Pese a su bondad psicométrica, resulta necesario reducir el número de ítems de la prueba con el fin de disminuir su tiempo de aplicación. Sujetos y métodos. Se reclutó una muestra de 547 sujetos mayores de 65 años a los que se les aplicó un protocolo de evaluación neuropsicológica, que incluía el BNT, para determinar sus estados cognitivos; 405 sujetos no presentaron alteraciones cognitivas relevantes, frente a 142 sujetos que fueron diagnosticados de deterioro cognitivo leve. Resultados. La reducción del número de ítems se realizó de acuerdo con los supuestos de la teoría de respuesta al ítem. Puesto que tanto la edad como el nivel educativo mostraron un efecto significativo en el rendimiento de la prueba, ambas variables fueron utilizadas para hallar los puntos de corte de la nueva versión reducida. Ésta presentó una adecuada fiabilidad (alfa = 0,765) y una elevada correlación con la prueba original (r = 0,876). Conclusiones. La nueva versión reducida consta de 15 ítems ordenados en función de su dificultad. Se trata de una tarea con un elevado poder discriminativo de utilidad en la clínica diaria para la detección de alteraciones del lenguaje en personas mayores (AU)

Introduction. One of the tests that is mostly widely used to evaluate aphasia in clinical practice is the Boston Naming Test (BNT), a classic test in which 60 black and white pictures are presented to subjects in order to evaluate their capacity to put a name to such pictures. Despite its psychometric goodness, the number of items in the test has to be reduced in order to lower the time required to apply it. Subjects and methods. Researchers recruited a sample of 547 subjects over the age of 65, who were then administered a neuropsychological evaluation protocol, including the BNT, to determine their cognitive statuses. No relevant cognitive alterations were observed in 405 subjects versus 142 who were diagnosed with mild cognitive impairment. Results. The number of items was reduced in accordance with the premises of the item response theory. Since both age and level of schooling were found to have a significant effect on performance in the test, the two variables were used to find the cut-off points of the shortened version. This new version presented an adequate degree of reliability (alpha = 0.765) and a high correlation with the original test (r = 0.876). Conclusions. The new shortened version consists of 15 items that are ordered according to the degree of difficulty. It is a task with a high level of discriminating power that is useful in day-to-day clinical practice for detecting alterations in the anguage of the elderly (AU)

[A new shortened version of the Boston Naming Test for those aged over 65: an approach from item response theory]. / Nueva versión reducida del test de denominación de Boston para mayores de 65 años: aproximación desde la teoría de respuesta al ítem.

INTRODUCTION: One of the tests that is mostly widely used to evaluate aphasia in clinical practice is the Boston Naming Test (BNT), a classic test in which 60 black and white pictures are presented to subjects in order to evaluate their capacity to put a name to such pictures. Despite its psychometric goodness, the number of items in the test has to be reduced in order to lower the time required to apply it. SUBJECTS AND METHODS: Researchers recruited a sample of 547 subjects over the age of 65, who were then administered a neuropsychological evaluation protocol, including the BNT, to determine their cognitive statuses. No relevant cognitive alterations were observed in 405 subjects versus 142 who were diagnosed with mild cognitive impairment. RESULTS: The number of items was reduced in accordance with the premises of the item response theory. Since both age and level of schooling were found to have a significant effect on performance in the test, the two variables were used to find the cut-off points of the shortened version. This new version presented an adequate degree of reliability (alpha = 0.765) and a high correlation with the original test (r = 0.876). CONCLUSIONS: The new shortened version consists of 15 items that are ordered according to the degree of difficulty. It is a task with a high level of discriminating power that is useful in day-to-day clinical practice for detecting alterations in the language of the elderly.