Effect of Transcranial Pulse Stimulation for the Treatment of Alzheimer´s Disease and its Related Symptoms.

Alzheimer's disease (AD) is the most common cause of neurodegenerative cognitive impairment. Brain stimulation techniques based on the delivery of transcranial shockwaves are currently being studied for their increasing popularity as an approach to modulate the human brain in a focal and targeted manner making this therapy a promising line of action against AD. In the present manuscript, we review for further understanding whether transcranial pulse stimulation (TPS) is a beneficial treatment for AD patients. PubMed, Google Scholar, and Cochrane databases were accessed with the search criteria set from year 2001 to 2022 and the following keywords were used: "transcranial pulse stimulation", "focused ultrasound", "noninvasive treatment and Alzheimer" and "TPS". The search was focused on papers that provide evidence on the biological bases of the method, as well as its safety and tolerability. Even though more studies are needed with greater scientific rigor, such as a doubleblind and randomized study versus a placebo, TPS is an excellent and safe therapeutic option for AD. This novel approach accompanies currently available treatments and complements them, helping to maintain greater stability of the disease and slowing its progression. The biological effects and potential mechanisms of action of TPS for the improvement of cognitive function are further discussed.

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.

Dimensions of cognitive reserve and their predictive power of cognitive performance and decline in the elderly.

Background: The relative importance of different components of cognitive reserve (CR), as well as their differences by gender, are poorly established. Objective: To explore several dimensions of CR, their differences by gender, and their effects on cognitive performance and trajectory in a cohort of older people without relevant psychiatric, neurologic, or systemic conditions. Methods: Twenty-one variables related to the education, occupation, social activities, and life habits of 1,093 home-dwelling and cognitively healthy individuals, between 68 and 86 years old, were explored using factorial analyses to delineate several dimensions of CR. These dimensions were contrasted with baseline cognitive performance, follow-up over 5 years of participants' cognitive trajectory, conversion to mild cognitive impairment (MCI), and brain volumes using regression and growth curve models, controlling for gender, age, marital status, number of medications, trait anxiety, depression, and ApoE genotype. Results: Five highly intercorrelated dimensions of CR were identified, with some differences in their structure and effects based on gender. Three of them, education/occupation, midlife cognitive activities, and leisure activities, were significantly associated with late-life cognitive performance, accounting for more than 20% of its variance. The education/occupation had positive effect on the rate of cognitive decline during the 5-year follow up in individuals with final diagnosis of MCI but showed a reduced risk for MCI in men. None of these dimensions showed significant relationships with gray or white matter volumes. Conclusion: Proxy markers of CR can be represented by five interrelated dimensions. Education/occupation, midlife cognitive activities, and leisure activities are associated with better cognitive performance in old age and provide a buffer against cognitive impairment. Education/occupation may delay the clinical onset of MCI and is also associated with the rate of change in cognitive performance.

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.

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.

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.

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.

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.

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) / Consorcio Español para la Obtención de Datos Normativos del Envejecimiento: Pruebas de Cribado (MMSE, GDS-15 y 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

ANTECEDENTES: detectar el deterioro cognitivo es una prioridad del sistema sanitario. El objetivo de este estudio es la presentación de datos normativos de pruebas de cribado (MMSE, GDS y MFE) para adultos españoles de mediana edad y adultos mayores, considerando los efectos de factores sociodemográficos. MÉTODO: en los estudios realizados por el consorcio SCAND participaron voluntariamente 2.030 personas cognitivamente sanas, de 50 a 88 años, residentes en su comunidad. El procedimiento estadístico supuso la conversión de rangos percentiles en puntuaciones escalares. Posteriormente, se comprobaron los efectos de la edad, el nivel educativo y el género. Se utilizaron regresiones lineales para calcular las puntuaciones escalares ajustadas. También se calcularon los puntos de corte para cada prueba. RESULTADOS: se muestran las puntuaciones escalares y los percentiles correspondientes a MMSE, GDS-15 y MFE. Además, se presenta una tabla que muestra los puntos que deben sumarse o restarse a la puntuación del MMSE dependiendo del nivel educativo del individuo. CONCLUSIONES: los datos normativos presentados tienen una utilidad clínica para evaluar a población española de 50 a 88 años, y contribuyen a mejorar la detección de los síntomas iniciales del deterioro cognitivo teniendo en cuenta la influencia del género, la edad y el nivel educativo

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.

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.