Superagers resist typical age-related white matter structural changes.

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age 81.9; 59% women) and 55 typical older adults (mean age 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibres and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional ageing pattern is in line with the last-in-first-out hypothesis.Significance Statement Episodic memory is one of the cognitive abilities most vulnerable to ageing. Although memory normally declines with age, some older people may have memory performance similar to that of people 30 years younger, and this phenomenon is often conceptualised as superageing. Understanding the superager phenotype can provide insights into mechanisms of protection against age-related memory loss and dementia. We studied the white matter structure of a large sample of 64 superagers over the age of 80 and 55 age-matched typical older adults during 5 years with yearly follow-ups showing evidence of slower age-related changes in the brains of superagers especially in protracted maturation tracts, indicating resistance to age-related changes and a regional ageing pattern in line with the last-in-first-out hypothesis.

Validez discriminante y concordancia interobservador de 2 métodos de puntuación del test del reloj / Discriminant validity and inter-rater concordance of two scoring systems for the clock test

Objetivos Comparar la validez discriminante y la fiabilidad interobservador de los 2 métodos de corrección del test del reloj más usados en España. Metodología Se han evaluado 2 colecciones de dibujos del reloj obtenidos en un contexto clínico (116 casos; 56,8% mujeres, edad media 73,1±7,7 años) y en una cohorte de voluntarios (2.039 dibujos de 579 sujetos; 59,5% mujeres, edad media 78,3±3,8 años). Todos los sujetos fueron clasificados como sin deterioro cognitivo (DC−) o con deterioro cognitivo (DC+) tras una extensa evaluación clínica y neuropsicológica. Evaluadores expertos han valorado estos dibujos de forma independiente y sin conocimiento del diagnóstico con los métodos de Sunderland y Solomon estandarizados en español por Cacho (rango: 0 a 10) y del Ser (rango: 0 a 7), respectivamente. Se ha calculado la validez discriminante de cada método mediante el área bajo la curva ROC (aROC) en las 2 muestras, y la fiabilidad interobservador mediante el coeficiente de correlación intraclase (CCI) y el coeficiente kappa en la muestra clínica que fue valorada por los 2 evaluadores. Resultados No hay diferencias significativas en la validez discriminante de los métodos de Sunderland y Solomon en ninguna de las muestras (clínica: aROC: 0,73 [IC 95%: 0,64-0,81] y 0,77 [IC 95%: 0,69-0,85], respectivamente, p=0,19; voluntarios: aROC: 0,69 [IC 95%: 0,67-0,71] y 0,72 [IC 95%: 0,69-0,73], respectivamente, p=0,08). Los puntos de corte ≤8 y ≤5 clasifican correctamente al 71 y 73% de la muestra clínica y al 82 y 84% de la muestra de voluntarios, respectivamente. Los 2 métodos tienen una buena concordancia en la muestra clínica (AU)

Objective To compare the discriminant validity and inter-rater reliability of the two scoring systems for the Clock test that are most used in Spain. Methodology Two collections of clock drawings obtained in a clinical context (116 cases; 56.8% women, mean age 73.1±7.7 years) and in a cohort of volunteers (2039 drawings of 579 subjects; 59.5% women, mean age 78.3±3.8 years) have been assessed. All subjects were classified as cognitively normal (CN) or cognitively impaired (CI) after extensive clinical and neuropsychological evaluation. Expert raters have evaluated these drawings independently and without knowledge of the diagnosis using the Sunderland and Solomon systems standardized in Spanish by Cacho (range 0 to 10) and del Ser (range 0 to 7) respectively. The discriminant validity of each method was calculated in the two samples using the area under the ROC curve (aROC), and the inter-rater reliability was calculated in the clinical sample, that was assessed by the two evaluators, using the intraclass correlation coefficient (ICC) and the kappa coefficient. Results There are no significant differences in the discriminant validity of the Sunderland and Solomon systems in any of the samples (clinical: aROC 0.73 [CI95%: 0.64-0.81] and 0.77 [CI95%: 0.69-0.85] respectively, P=.19; volunteers: aROC 0.69 [CI95%: 0.67-0.71] and 0.72 [CI95%: 0.69-0.73] respectively, P=.08). The cut-off points ≤8 and ≤5 correctly classify 71% and 73% of the clinical sample and 82% and 84% of the volunteer sample, respectively. Both systems have good agreement in the clinical sample (Sunderland: ICC 0.90 [CI95%: 0.81-0.93], kappa 0.76 [CI95%: 0.70-0.83]; Solomon: 0.92 [CI95%: 0.88-0.95] and 0.77 [CI95%: 0.71-0.83] respectively), somewhat higher in the second, although the differences are not significant (AU)

[Discriminant validity and inter-rater concordance of two scoring systems for the clock test]. / Validez discriminante y concordancia interobservador de 2 métodos de puntuación del test del reloj.

OBJECTIVE: To compare the discriminant validity and inter-rater reliability of the two scoring systems for the Clock test that are most used in Spain. METHODOLOGY: Two collections of clock drawings obtained in a clinical context (116 cases; 56.8% women, mean age 73.1±7.7 years) and in a cohort of volunteers (2039 drawings of 579 subjects; 59.5% women, mean age 78.3±3.8 years) have been assessed. All subjects were classified as cognitively normal (CN) or cognitively impaired (CI) after extensive clinical and neuropsychological evaluation. Expert raters have evaluated these drawings independently and without knowledge of the diagnosis using the Sunderland and Solomon systems standardized in Spanish by Cacho (range 0 to 10) and del Ser (range 0 to 7) respectively. The discriminant validity of each method was calculated in the two samples using the area under the ROC curve (aROC), and the inter-rater reliability was calculated in the clinical sample, that was assessed by the two evaluators, using the intraclass correlation coefficient (ICC) and the kappa coefficient. RESULTS: There are no significant differences in the discriminant validity of the Sunderland and Solomon systems in any of the samples (clinical: aROC 0.73 [CI95%: 0.64-0.81] and 0.77 [CI95%: 0.69-0.85] respectively, P=.19; volunteers: aROC 0.69 [CI95%: 0.67-0.71] and 0.72 [CI95%: 0.69-0.73] respectively, P=.08). The cut-off points ≤8 and ≤5 correctly classify 71% and 73% of the clinical sample and 82% and 84% of the volunteer sample, respectively. Both systems have good agreement in the clinical sample (Sunderland: ICC 0.90 [CI95%: 0.81-0.93], kappa 0.76 [CI95%: 0.70-0.83]; Solomon: 0.92 [CI95%: 0.88-0.95] and 0.77 [CI95%: 0.71-0.83] respectively), somewhat higher in the second, although the differences are not significant. CONCLUSIONS: The discriminant validity and inter-observer reliability of these two Clock Test correction systems are similar. Solomon's method, shorter and simpler, may be more advisable in pragmatic terms.

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.

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.

Social robots in advanced dementia.

AIMS: Pilot studies applying a humanoid robot (NAO), a pet robot (PARO) and a real animal (DOG) in therapy sessions of patients with dementia in a nursing home and a day care center. METHODS: In the nursing home, patients were assigned by living units, based on dementia severity, to one of the three parallel therapeutic arms to compare: CONTROL, PARO and NAO (Phase 1) and CONTROL, PARO, and DOG (Phase 2). In the day care center, all patients received therapy with NAO (Phase 1) and PARO (Phase 2). Therapy sessions were held 2 days per week during 3 months. Evaluation, at baseline and follow-up, was carried out by blind raters using: the Global Deterioration Scale (GDS), the Severe Mini Mental State Examination (sMMSE), the Mini Mental State Examination (MMSE), the Neuropsychiatric Inventory (NPI), the Apathy Scale for Institutionalized Patients with Dementia Nursing Home version (APADEM-NH), the Apathy Inventory (AI) and the Quality of Life Scale (QUALID). Statistical analysis included descriptive statistics and non-parametric tests performed by a blinded investigator. RESULTS: In the nursing home, 101 patients (Phase 1) and 110 patients (Phase 2) were included. There were no significant differences at baseline. The relevant changes at follow-up were: (Phase 1) patients in the robot groups showed an improvement in apathy; patients in NAO group showed a decline in cognition as measured by the MMSE scores, but not the sMMSE; the robot groups showed no significant changes between them; (Phase 2) QUALID scores increased in the PARO group. In the day care center, 20 patients (Phase 1) and 17 patients (Phase 2) were included. The main findings were: (Phase 1) improvement in the NPI irritability and the NPI total score; (Phase 2) no differences were observed at follow-up.

Efecto de los fármacos anticolinérgicos en el rendimiento cognitivo de las personas mayores / Effect of anticholinergic drugs on cognitive impairment in the elderly

El empleo de fármacos anticolinérgicos es frecuente en personas mayores, incluso con deterioro cognitivo. Se ha realizado una revisión bibliográfica en PubMed (anticholinergic effects y anticholinergic and dementia) acerca de los efectos de los fármacos anticolinérgicos en población anciana. Se ha enfatizado en determinar patrones de consumo, uso combinado con fármacos inhibidores de la acetilcolinesterasa (IACE), medida de la carga anticolinérgica y efectos cognitivos a corto y a largo plazo. Las conclusiones son que estos fármacos se emplean de forma habitual en población anciana, incluso tras la prescripción de IACE en la enfermedad de Alzheimer. Su empleo puede producir alteraciones cognitivas. Si el consumo es prolongado puede provocar un empeoramiento de la cognición a largo plazo originando falsos diagnósticos de deterioro, o incluso precipitando cuadros de demencia. Los efectos cognitivos son mayores ante un déficit preexistente, pero desaparecen en la demencia avanzada. La presencia de ApoE ¿4 marca una vulnerabilidad a la afectación cognitiva por estos fármacos (AU)

The use of anticholinergic drugs is common in the elderly, even in people with cognitive impairment. A systematic search was conducted in PubMed (anticholinergic effects, anticholinergic and dementia) to define the effects of anticholinergic drugs in the elderly. We emphasized the search in patterns of use, the combined use with AChEIs, the measurement of the Serum Anticholinergic Activity, and the short-term and long-term cognitive effects. The conclusions are that the use of anticholinergic drugs is common in the elderly, even more so than the medical prescription of AChEIs in Alzheimer‘s disease. The use of anticholinergic drugs may result in cognitive impairment. In long-term use it may generate a worsening of cognitive functions. It can lead to a wrong diagnosis of mild cognitive impairment or dementia, and they can also initiate signs of dementia. Greater cognitive effects appear when there is a previous deficit, but cognitive effects from anticholinergic drugs disappear in severe dementia. The presence of ApoE ¿4 increases the vulnerability for cognitive impairment when these drugs are employed (AU)

A blood-based, 7-metabolite signature for the early diagnosis of Alzheimer's disease.

Accurate blood-based biomarkers of Alzheimer's disease (AD) could constitute simple, inexpensive, and non-invasive tools for the early diagnosis and treatment of this devastating neurodegenerative disease. We sought to develop a robust AD biomarker panel by identifying alterations in plasma metabolites that persist throughout the continuum of AD pathophysiology. Using a multicenter, cross-sectional study design, we based our analysis on metabolites whose levels were altered both in AD patients and in patients with amnestic mild cognitive impairment (aMCI), the earliest identifiable stage of AD. UPLC coupled to mass spectrometry was used to independently compare the levels of 495 plasma metabolites in aMCI (n = 58) and AD (n = 100) patients with those of normal cognition controls (NC, n = 93). Metabolite alterations common to both aMCI and AD patients were used to generate a logistic regression model that accurately distinguished AD from NC patients. The final panel consisted of seven metabolites: three amino acids (glutamic acid, alanine, and aspartic acid), one non-esterified fatty acid (22:6n-3, DHA), one bile acid (deoxycholic acid), one phosphatidylethanolamine [PE(36:4)], and one sphingomyelin [SM(39:1)]. Detailed analysis ruled out the influence of potential confounding variables, including comorbidities and treatments, on each of the seven biomarkers. The final model accurately distinguished AD from NC patients (AUC, 0.918). Importantly, the model also distinguished aMCI from NC patients (AUC, 0.826), indicating its potential diagnostic utility in early disease stages. These findings describe a sensitive biomarker panel that may facilitate the specific detection of early-stage AD through the analysis of plasma samples.

[Effect of anticholinergic drugs on cognitive impairment in the elderly]. / Efecto de los fármacos anticolinérgicos en el rendimiento cognitivo de las personas mayores.

The use of anticholinergic drugs is common in the elderly, even in people with cognitive impairment. A systematic search was conducted in PubMed (anticholinergic effects, anticholinergic and dementia) to define the effects of anticholinergic drugs in the elderly. We emphasized the search in patterns of use, the combined use with AChEIs, the measurement of the Serum Anticholinergic Activity, and the short-term and long-term cognitive effects. The conclusions are that the use of anticholinergic drugs is common in the elderly, even more so than the medical prescription of AChEIs in Alzheimer's disease. The use of anticholinergic drugs may result in cognitive impairment. In long-term use it may generate a worsening of cognitive functions. It can lead to a wrong diagnosis of mild cognitive impairment or dementia, and they can also initiate signs of dementia. Greater cognitive effects appear when there is a previous deficit, but cognitive effects from anticholinergic drugs disappear in severe dementia. The presence of ApoEɛ4 increases the vulnerability for cognitive impairment when these drugs are employed.

A novel rating scale for the measurement of apathy in institutionalized persons with dementia: the APADEM-NH.

OBJECTIVE: Apathy is one of the most frequent symptoms of dementia, still needing better measurement methods. The objective of this study was to validate a new scale for apathy in institutionalized persons with dementia (APADEM-NH). METHODS: The scale includes 26 items distributed in three dimensions: Deficit of Thinking and Self-Generated behaviors (DT): 13 items, Emotional Blunting (EB): 7 items, and Cognitive Inertia (CI): 6 items. The sample included 100 institutionalized patients (90% female) with probable Alzheimer disease (AD) (57%), possible AD (13%), AD + cerebral vascular disease (17%), Lewy body dementia (11%), and Parkinson associated to dementia (2%), covering all stages of dementia severity according to the Global Deterioration Scale and Clinical Dementia Rating. Additional assessments were the Apathy Inventory, Neuropsychiatric Inventory, Cornell Scale for Depression, and the tested scale. Re-test and inter-rater reliability were carried out in 50 patients. RESULTS: All subscales lacked relevant floor and ceiling effects (<15%). Internal consistency for each dimension was (Cronbach's α): DT = 0.88, EB = 0.83, CI = 0.88; item-total correlations were >0.40; and item homogeneity 0.36-0.51. Test-retest reliability for the items was kW = 0.48-0.92; for the subscales, intraclass correlation coefficient (ICC) = 0.80-0.88; and for the total score, ICC = 0.90. Inter-rater reliability reached kW values of 0.84-1.00; subscales ICC, 0.97-0.99, and total score ICC, 0.99. Standard error of measurement for total score was 6.41 and internal validity ranged from rS = 0.69-0.80. CONCLUSIONS: APADEM-NH proved to be feasible, reliable, and valid for apathy assessment in institutionalized patients suffering mild to severe dementia, discerning well between apathy and depression.

Quality of life (QoL) in community-dwelling and institutionalized Alzheimer's disease (AD) patients.

The purpose of this study was to describe and compare QoL and its determinants in two groups of patients with AD that differed in place of residence: community or nursing home. This study covered 200 patients with AD (mean age 79.3 ± 8.2 years, 74% female). Fifty-four per cent of the subjects were living in a nursing home and 46% lived at home. QoL was measured using the Alzheimer's Disease Related Quality of Life Scale (ADRQL). The ADRQL was answered by the family caregiver (community group) or the professional caregiver (nursing home group). Descriptive statistics, Chi-square test, Mann-Whitney test and multiple regression analysis were used to compare sociodemographic and clinical variables between the two study groups. The institutionalized patients were predominantly women (87.0% vs. 58.7%, p<0.001), were older (84 years vs. 74 years, p<0.001), and had more advanced dementia (Global Deterioration Scale (GDS)>5 79.6% vs. 19.6%, p<0.001). ADRQL total score was higher (i.e., better QoL) for patients living at home than for institutionalized patients (72.6 ± 19.9 vs. 64.8 ± 18.2, p<0.01). Neuropsychiatric symptoms, severity of dementia, depression and functional dependence were significant predictors of worst QoL. Once those variables were controlled a marginal effect of setting on QoL was found, which favored the nursing home (ß=0.20, p<0.05).