How to Prevent and/or Revert Alzheimer's Disease Continuum During Preclinical Phases.

The development of Alzheimer's disease (AD) follows three consecutive phases: namely preclinical, prodromal or mild cognitive impairment (MCI), and dementia. In addition, the preclinical phase can be divided into subphases related to the presence of biomarkers that appear at different points before the onset of MCI. Indeed, an early risk factor could promote the appearance of additional ones through a continuum. The presence of various risk factors may trigger specific biomarkers. In this review, we comment on how modifiable risk factors for AD may be reverted, thus correlating with a possible decrease in the specific biomarkers for the disease. Finally, we discuss the development of a suitable AD prevention strategy by targeting modifiable risk factors, thereby increasing the level of "precision medicine" in healthcare systems worldwide.

Using Explainable Artificial Intelligence in the Clock Drawing Test to Reveal the Cognitive Impairment Pattern.

The prevalence of dementia is currently increasing worldwide. This syndrome produces a deterioration in cognitive function that cannot be reverted. However, an early diagnosis can be crucial for slowing its progress. The Clock Drawing Test (CDT) is a widely used paper-and-pencil test for cognitive assessment in which an individual has to manually draw a clock on a paper. There are a lot of scoring systems for this test and most of them depend on the subjective assessment of the expert. This study proposes a computer-aided diagnosis (CAD) system based on artificial intelligence (AI) methods to analyze the CDT and obtain an automatic diagnosis of cognitive impairment (CI). This system employs a preprocessing pipeline in which the clock is detected, centered and binarized to decrease the computational burden. Then, the resulting image is fed into a Convolutional Neural Network (CNN) to identify the informative patterns within the CDT drawings that are relevant for the assessment of the patient's cognitive status. Performance is evaluated in a real context where patients with CI and controls have been classified by clinical experts in a balanced sample size of [Formula: see text] drawings. The proposed method provides an accuracy of [Formula: see text] in the binary case-control classification task, with an AUC of [Formula: see text]. These results are indeed relevant considering the use of the classic version of the CDT. The large size of the sample suggests that the method proposed has a high reliability to be used in clinical contexts and demonstrates the suitability of CAD systems in the CDT assessment process. Explainable artificial intelligence (XAI) methods are applied to identify the most relevant regions during classification. Finding these patterns is extremely helpful to understand the brain damage caused by CI. A validation method using resubstitution with upper bound correction in a machine learning approach is also discussed.

Brain Structural and Functional Changes in Cognitive Impairment Due to Alzheimer's Disease.

Cognitive neuropsychology seeks a potential alignment between structural and functional brain features to explain physiological or pathological processes, such as Alzheimer's disease (AD). Several structural and functional brain changes occurring during the disease, including cognitive impairment, are found at the end of the patient's life, but we need to know more about what happens before its onset. In order to do that, we need earlier biomarkers at preclinical stages, defined by those biomarkers, to prevent the cognitive impairment. In this minireview, we have tried to describe the structural and functional changes found at different stages during AD, focusing on those features taking place before clinical diagnosis.

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.

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.

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.

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.

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.

Selecting the most important self-assessed features for predicting conversion to mild cognitive impairment with random forest and permutation-based methods.

Alzheimer's Disease is a complex, multifactorial, and comorbid condition. The asymptomatic behavior in the early stages makes the identification of the disease onset particularly challenging. Mild cognitive impairment (MCI) is an intermediary stage between the expected decline of normal aging and the pathological decline associated with dementia. The identification of risk factors for MCI is thus sorely needed. Self-reported personal information such as age, education, income level, sleep, diet, physical exercise, etc. is called to play a key role not only in the early identification of MCI but also in the design of personalized interventions and the promotion of patients empowerment. In this study, we leverage a large longitudinal study on healthy aging in Spain, to identify the most important self-reported features for future conversion to MCI. Using machine learning (random forest) and permutation-based methods we select the set of most important self-reported variables for MCI conversion which includes among others, subjective cognitive decline, educational level, working experience, social life, and diet. Subjective cognitive decline stands as the most important feature for future conversion to MCI across different feature selection techniques.

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.

The Vallecas Project: A Cohort to Identify Early Markers and Mechanisms of Alzheimer's Disease.

INTRODUCTION: Alzheimer's disease (AD) is a major threat for the well-being of an increasingly aged world population. The physiopathological mechanisms of late-onset AD are multiple, possibly heterogeneous, and not well understood. Different combinations of variables from several domains (i.e., clinical, neuropsychological, structural, and biochemical markers) may predict dementia conversion, according to distinct physiopathological pathways, in different groups of subjects. METHODS: We launched the Vallecas Project (VP), a cohort study of non-demented people aged 70-85, to characterize the social, clinical, neuropsychological, structural, and biochemical underpinnings of AD inception. Given the exploratory nature of the VP, multidimensional and machine learning techniques will be applied, in addition to the traditional multivariate statistical methods. RESULTS: A total of 1169 subjects were recruited between October 2011 and December 2013. Mean age was 74.4 years (SD 3.9), 63.5% of the subjects were women, and 17.9% of the subjects were carriers of at least one ε4 allele of the apolipoprotein E gene. Cognitive diagnoses at inclusion were as follows: normal cognition 93.0% and mild cognitive impairment (MCI) 7.0% (3.1% amnestic MCI, 0.1% non-amnestic MCI, 3.8% mixed MCI). Blood samples were obtained and stored for future determinations in 99.9% of the subjects and 3T magnetic resonance imaging study was conducted in 89.9% of the volunteers. The cohort is being followed up annually for 4 years after the baseline. CONCLUSION: We have established a valuable homogeneous single-center cohort which, by identifying groups of variables associated with high risk of MCI or dementia conversion, should help to clarify the early physiopathological mechanisms of AD and should provide avenues for prompt diagnosis and AD prevention.

Quality of life across three groups of older adults differing in cognitive status and place of residence.

BACKGROUND: Health-related quality of life (HRQOL) in older adults is determined by personal conditions, as well as by the social and physical environment. The purpose of the present study was to describe the factors related to health conditions and residential environment that influence HRQOL of older adults. METHODS: Data from 1815 cases came from three cross-sectional surveys on quality of life in older adults in Spain: non-institutionalized older adults (n = 1106), institutionalized older adults without dementia (n = 234) and institutionalized older adults with dementia (n = 475). Assessment instruments used were: Barthel Index, Short Portable Mental Status Questionnaire, Comorbidity Index, EQ-5D-3L (5 dimensions, EQ-index and EQ-VAS), and information about sociodemographic characteristics and social networks. Partial correlation and multivariate logistic regression analyses were carried out. RESULTS: In group comparisons, institutionalized older adults showed a higher percentage of problems in the EQ-5D-3L dimensions than the non-institutionalized ones. Also, older adults with dementia presented less pain/discomfort and anxiety/depression than the other groups, but showed more problems in mobility, self-care and usual activities. EQ-Index showed a high association with functional independence, perceived health status and comorbidity. According to the logistic regression models, the Barthel Index was the most common determinant for most of EQ-5D-3L dimensions in all groups. CONCLUSION: Institutionalized older adults with dementia presented lower HRQOL than the other groups. Functional independence, comorbidity and cognitive status were the main HRQOL determinants in all groups. Maintenance and improvement of the functional condition might be translated into a higher HRQOL of older adults.

Contribución de la patología vascular a la correlación clínico-patológica en una serie de casos de demencia avanzada / Vascular pathology's contribution to the clinical-pathological correlation in advanced dementia

Fundamento y objetivo: la enfermedad de Alzheimer (EA) se acompaña frecuentemente de patología vascular (PV). La utilización de un sistema de clasificación que combine ambos tipos de patología permitiría realizar un diagnóstico diferencial preciso. En el presente trabajo se aplican de manera conjunta criterios neuropatológicos de EA y PV para clasificar una cohorte de pacientes con demencia avanzada. Material y método: se analizaron los datos neuropatológicos post mórtem de 40 cerebros donados al Banco de Tejidos de la Fundación CIEN. Todos los sujetos eran mayores de 70 años (edad = 85,42 ± 7,06; 75 % mujeres) y residentes del Centro Alzheimer de la Fundación Reina Sofía. Resultados: EA y PV no mostraron ninguna relación entre sí. Las puntuaciones cognitivas correlacionaron de forma inversamente proporcional con la EA, pero no mostraron asociación con la PV. Utilizando una escala de EA y otra de PV, los casos se clasificaron en tres grupos (57,5% EA, 12,5 % demencia vascular y 30 % demencia mixta) y se estudió su rendimiento en los test cognitivos. Conclusiones: el grupo vascular evidenció un rendimiento cognitivo superior a los otros dos. Los resultados apoyan el uso combinado de escalas de EA y PV para clasificar a los pacientes con demencia avanzada (AU)

Introduction and aim: Alzheimer’s (AD) disease is often accompanied by vascular pathology (VP). The use of a classification system combining both types of pathologies would enable a precise differential diagnosis. In this paper neuropathological criteria of AD and VP are applied in order to classify a cohort of patients with advanced dementia. Material and method: Postmortem neuropathological data from 40 brains donated to the CIEN Foundation Bank Tissue were analyzed. All participants were over 70 years old (mean age = 85.42 ± 7.06; 75% women) and they were institutionalized at the Alzheimer Center Reina Sofia Foundation. Results: AD and VP did not show any relation between them. Cognitive scores correlated inversely proportional with AD, but no association with VP was found. Combination of both scales allowed a classification of cases in three groups (57.5% AD, 12.5% vascular dementia, and 30% mixed dementia). Cognitive performance of those groups was studied. Discussion: Vascular group showed a higher cognitive performance than the other two groups. These results support the combination of AD and VP scales to classify a cohort of patients with advanced dementia (AU)