Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (ß = 12.85; P < 0.001) that was independent of amyloid deposits (ß = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (ß = 3.64; P = 0.03) and argyrophilic grain disease (ß = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.

Plasma Phosphorylated Tau 231 Increases at One-Year Intervals in Cognitively Unimpaired Subjects.

Background: Plasma biomarkers of Alzheimer's disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid.

[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.

Validation of Picture Free and Cued Selective Reminding Test for Illiteracy in Lima, Peru.

Dementia in Latin America is a crucial public health problem. Identifying brief cognitive screening (BCS) tools for the primary care setting is crucial, particularly for illiterate individuals. We evaluated tool performance characteristics and validated the free and total recall sections of the Free and Cued Selective Reminding Test-Picture version (FCSRT-Picture) to discriminate between 63 patients with early Alzheimer's disease dementia (ADD), 60 amnestic mild cognitive impairment (aMCI) and 64 cognitively healthy Peruvian individuals with illiteracy from an urban area. Clinical, functional, and cognitive assessments were performed. FCSRT-Picture performance was assessed using receiver operating characteristic curve analyses. The mean ± standard deviation scores were 7.7 ± 1.0 in ADD, 11.8 ± 1.6 in aMCI, and 29.5 ± 1.8 in controls. The FCSRT-Picture had better performance characteristics for distinguishing controls from aMCI compared with several other BCS tools, but similar characteristics between controls and early ADD. The FCSRT-Picture is a reliable BCS tool for illiteracy in Peru.

Behavioral Lifestyles and Survival: A Meta-Analysis.

The aim of the study is to determine the association between Behavioral Lifestyles (regular physical activity, healthy diet, sleeping, and weight control) and longevity in the elderly. A search strategy was conducted in the PsycInfo, Medline, PubMed, Web of Science (WoS), and Scopus databases. The primary outcome was mortality/survival. Four variables (mean of participant's age at the baseline of the study, follow-up years of the study, gender, and year of publication) were analyzed to evaluate the role of potential moderators. Ninety-three articles, totaling more than 2,800,000 people, were included in the meta-analysis. We found that the lifestyles analyzed predict greater survival. Specifically, doing regular physical activity, engaging in leisure activities, sleeping 7-8 h a day, and staying outside the BMI ranges considered as underweight or obesity are habits that each separately has a greater probability associated with survival after a period of several years.

Validación y precisión de la escala de deterioro global (GDS) para establecer severidad de demencia en una población de Lima / Validation and diagnostic accuracy of the global deterioration scale (GDS) to establish severity of dementia in a population of Lima

Resumen Objetivo : validar y evaluar el rendimiento de la Global Deteriorarion Scale (GDS) en una población que acude a una unidad especializada de Lima. Pacientes y métodos: investigación de tipo transversal con un diseño descriptivo comparativo. El estudio incluyó 215 individuos seleccionados de forma abierta, que acudieron a la unidad de diagnóstico de deterioro cognitivo y prevención de demencia. Se estudiaron tres grupos: 60 controles, 40 con diagnóstico de deterioro cognitivo leve y 115 con demencia. Los individuos fueron sometidos a evaluaciones sucesivas: cribado, diagnóstico y estadiaje de demencia y tipo de demencia. La validez y fiabilidad de la clasificación de severidad fue demostrada mediante la concordancia entre la medición del Global Deteriorarion Scale con el Clinical Dementia Rating (CDR). El rendimiento de Global Deteriorarion Scale se valoró mediante la obtención de los valores de sensibilidad y especificidad. Resultados : los promedios de edad fueron de 69, 70, y 74 años para los controles, los pacientes con deterioro cognitivo leve y los pacientes con demencia, respectivamente. La Global Deteriorarion Scale tuvo una buena correlación con Clinical Dementia Rating (r de Spearman =0,97; P=0,0001). La sensibilidad de la escala para establecer estadio de demencia fue de 79 %, con especificidad del 100 % para cualquier categoría de demencia según los criterios diagnósticos estándares y según Clinical Dementia Rating. Conclusiones : se encontró una correlación casi perfecta entre Global Deteriorarion Scale y Clinical Dementia Rating; sin embargo, la Global Deteriorarion Scale presenta una sensibilidad moderada para establecer el estadio de demencia con respecto a Clinical Dementia Rating, mostrando además ser utilidad en el diagnóstico de deterioro cognitivo leve.

Abstract Objective: To validate and evaluate diagnostic accuracy of the Global Deteriorarion Scale (GDS) in a population of a specialized unit of Lima. Patients and Methods: This research is a comparative cross-sectional descriptive design. The study included 215 individuals selected openly, who attending in the diagnostic unit of cognitive impairment and dementia prevention. Three groups were studied: 60 controls, 40 individuals diagnosed with mild cognitive impairment (MCI) and 115 with dementia diagnosis. They were assessments in three phases: screening, diagnosis and staging of dementia, and type of dementia. The validity and reliability of the classification of severity was demonstrated by measuring the correlation between the GDS with the CDR (Clinical Dementia Rating). The diagnostic accuracy of GDS was evaluated by obtaining the values of sensitivity and specificity. Results: The average age was 69, 70, and 74 years for controls, patients with MCI and patients with dementia respectively. GDS had a good correlation with CDR (Spearman r = 0.97, P = 0.0001). The sensitivity of the GDS to set stage of dementia for any category of dementia was 79 % and specificity of 100 % according to standard diagnostic criteria and according to CDR. Conclusions: We demonstrated an almost perfect correlation between GDS and CDR, however GDS has a moderate sensitivity to set the stage dementia regarding CDR also proving to be useful in the diagnosis of MCI.

Terapia musical en el manejo de síntomas cognitivos, psicológicos y conductuales de demencia: Una revisión narrativa / Music therapy in the management of cognitive, psychological and behavioral symptoms of dementia: A narrative review

El tratamiento integral de un paciente con demencia incluye el manejo de síntomas cognitivos, psicológicos y conductuales y la preservación de un nivel adecuado de funcionalidad. Las estrategias farmacológicas han demostrado un beneficio marginal con eventos adversos que limitan las dosis óptimas y disminuyen la adherencia a los tratamientos. La terapia musical es una estrategia no farmacológica que podría mejorar levemente algunos aspectos cognitivos como la memoria autobiográfica; la evidencia existente indica que este enfoque podría generar también un modesto efecto de disminución de ansiedad, agitación y depresión concomitantes. Se requieren, sin embargo, estudios adicionales con muestras mayores de pacientes y mejoría de sus diseños metodológicos.

The comprehensive treatment of a patient with dementia includes management of cognitive, psychological and behavioral symptoms, and the preservation of adequate levels of functionality. Pharmacological strategies have demonstrated a marginal benefit with adverse events that limit optimal doses, and decrease treatment adherence. Music therapy is a non-pharmacological strategy that could slightly improve some cognitive aspects such as autobiographical memory; further evidence indicates that it could also generate a modest decrement of concomitant anxiety, agitation and depression Additional studies are required, however, with larger patient samples and better methodological designs.

Rendimiento en pruebas cognitivas breves, de adultos mayores con demencia en estadios avanzados, residentes de una comunidad urbana de Lima, Perú / Performance of cognitive brief test in elderly patients with dementia in advanced stage living in an urban community of Lima, Peru

RESUMEN Objetivos. Evaluar el rendimiento de la prueba de dibujo de reloj en versión de Manos (PDR-M) y Mini Mental State Examination (MMSE) en su versión peruana, para detectar demencia de cualquier tipo en adultos mayores residentes de una comunidad urbana de Lima, Perú. Materiales y métodos. Análisis secundario de base de datos, de tipo observacional, analítico y transversal; con diseño de prueba diagnóstica, teniendo como prueba estándar a las evaluaciones clínica y neuropsicológica en conjunto. Se evaluó el rendimiento de las pruebas individualmente, así como de forma combinada. Resultados. El rendimiento de MMSE para la evaluación de pacientes con demencia de cualquier tipo presentó sensibilidad de 64,1%, especificidad de 84,1%, VPP de 24,4%, VPN de 96,7%, LR (+) de 4,03 y LR (-) de 0,43. La PDR-M presentó sensibilidad de 89,3%, especificidad de 98,1%, VPP de 79,3%, VPN de 99,1%, LR (+) de 47,79 y LR (-) de 0,11. Cuando se aplicaron ambas pruebas, y al menos una de ellas fue positiva, presentaron sensibilidad de 98,1%, especificidad de 84,1%, VPP de 33,1%, VPN de 99,8%, LR (+) de 6,17 y LR (-) de 0,02. Al realizar el análisis, por separado, de demencia tipo alzhéimer y no alzhéimer, los valores de los parámetros no se diferencian sustancialmente de los obtenidos para demencias de cualquier tipo. Conclusiones. La combinación de MMSE y PDR-M demuestran un buen rendimiento para detectar demencia en estadios moderado y severo en población residente de una comunidad urbana de Lima.

ABSTRACT Objectives. Evaluate the performance of clock drawing test- Manos versión (PDR-M) and Mini Mental State Examination -Peruvian version (MMSE) to detect dementia in a sample based on urban community of Lima, Peru. Materials and methods. This study is a secondary analysis database, observational, analytical and cross-sectional, the gold standard was the clinical and the neuropsychological evaluations together. Performance testing individually and in combination were evaluated.. Data were obtained from prevalence study conducted in 2008 in Cercado de Lima. Results. MMSE performance for evaluation of patients with dementia of any kind showed sensitivity of 64,1%, specificity of 84,1%, PPV of 24.4%, NPV of 96.7%, PLR of 4,03 and NLR of 0,43. PDR-M showed sensitivity of 89,3%, specificity of 98,1%, PPV of 79.3%, NPV of 99.1%, PLR of 47,79 and NLR of 0,11. When both tests were applied, and at least one of them was positive, they showed sensitivity 98.1%, specificity 84.1%, PPV of 33.1%, NPV of 99.8%, PLR of 6,17 and NLR of 0,02. When performing separate analysis of Alzheimer-type dementia and non- Alzheimer dementia, the values of the parameters do not differ substantially from those obtained for dementia of any kind. Conclussions. The combination of MMSE and PDR-M show good discriminative ability to detect moderate and severe dementia in population living in urban community in Lima.

Pronóstico en cirugía de epilepsia: ¿puede influir la reserva cognitiva? / Prognosis in EpilepsyÆs surgery: Can Cognitive Reserve influence it?

Hasta un tercio de individuos diagnosticados de epilepsia continúan teniendo crisis a pesar del tratamiento antiepiléptico apropiado. Estos pacientes pueden ser referidos para evaluación pre-quirúrgica y la cirugía es considerada un tratamiento efectivo para epilepsia relacionada a localización refractaria. Los factores que predicen un mejor resultado de la cirugía son contradictorios, y las recomendaciones incluyen evaluación detallada del rendimiento cognitivo antes y después de la cirugía; sin embargo no se considera la evaluación de la reserva cognitiva (RC). La incorporación de un instrumento que valore la RC de los pacientes permitiría incrementar la fuerza predictiva de la evaluación neuropsicológica respecto al pronóstico post-quirúrgico y aportaría a la investigación de los factores neuroprotectores en aquellos pacientes con un perfil de rendimiento cognitivo post-quirúrgico superior a la etapa pre-quirúrgica, y además permitiría conocer cómo la actividad educacional, ocupacional, y de tiempo libre de los pacientes se ven afectadas por la epilepsia y su variación después de la cirugía.

Up to one-third of individuals diagnosed as having epilepsy continue to have seizures despite appropriate antiepileptic drug treatment. Patients with refractory localization-related epilepsy can be referred for presurgical evaluation, and resective surgery is considered an effective treatment for such cases. Predictive factors of a better outcome for epilepsyÆs surgery are contradictory, and recomendations include a detailed assessment of cognitive performance before and after surgery; this process, however does not consider the evaluation of Cognitive Reserve (CR). The use of an instrument that assesses the CR of patient-candidates would increase the predictive power of neuropsychological assessment regarding post-surgical prognosis and outcome; in turn, it could contribute to research of neuroprotective factors in patients with a superior pre- and post-surgical profile of cognitive performance, and also allow knowing how the patientÆs educational and occupational activity, and use of leisure time are affected by epilepsy and its post-surgical variations.

[Performance of cognitive brief test in elderly patients with dementia in advanced stage living in an urban community of Lima, Peru]. / Rendimiento en pruebas cognitivas breves, de adultos mayores con demencia en estadios avanzados, residentes de una comunidad urbana de Lima, Perú.

OBJECTIVES.: Evaluate the performance of clock drawing test- Manos versión (PDR-M) and Mini Mental State Examination -Peruvian version (MMSE) to detect dementia in a sample based on urban community of Lima, Peru. MATERIALS AND METHODS.: This study is a secondary analysis database, observational, analytical and cross-sectional, the gold standard was the clinical and the neuropsychological evaluations together. Performance testing individually and in combination were evaluated.. Data were obtained from prevalence study conducted in 2008 in Cercado de Lima. RESULTS.: MMSE performance for evaluation of patients with dementia of any kind showed sensitivity of 64,1%, specificity of 84,1%, PPV of 24.4%, NPV of 96.7%, PLR of 4,03 and NLR of 0,43. PDR-M showed sensitivity of 89,3%, specificity of 98,1%, PPV of 79.3%, NPV of 99.1%, PLR of 47,79 and NLR of 0,11. When both tests were applied, and at least one of them was positive, they showed sensitivity 98.1%, specificity 84.1%, PPV of 33.1%, NPV of 99.8%, PLR of 6,17 and NLR of 0,02. When performing separate analysis of Alzheimer-type dementia and non- Alzheimer dementia, the values of the parameters do not differ substantially from those obtained for dementia of any kind. CONCLUSSIONS.: The combination of MMSE and PDR-M show good discriminative ability to detect moderate and severe dementia in population living in urban community in Lima.

Utilidad de la batería ejecutiva y cognición social de INECO en la evaluación de funciones ejecutivas de una serie de pacientes peruanos con demencia fronto-temporal, variante conductual / Utility of the INECO's executive and social cognition battery in the evaluation of executive functions in Peruvians patients with behavioral variant fronto-temporal dementia

Los síntomas característicos de la demencia fronto-temporal, variante conductual reflejan disfunción del cortex prefrontal ventromedial, y no existe consenso respecto a las pruebas neuropsicológicas más sensibles y específicos para evaluarlos. Objetivos: El objetivo de este estudio fue detectar alteraciones específicas de funciones ejecutivas y de cognición social en pacientes con demencia fronto-temporal variante conductual. Material y Métodos: Evaluamos la batería ejecutiva y cognición social del Instituto de Neurología Cognitiva (INECO), la cual incluye pruebas de teoría de la mente (test de la mirada y test de metida de pata), tareas del hotel, tests de diligencias multiples-versión del hospital y el Iowa Gambling Test para toma de decisiones. Los pacientes fueron divididos en dos grupos según su desempeño en el Addenbrooke´s Cognitive Examination. Resultados: Pacientes del grupo de Addenbrooke´s Cognitive Examination Bajo mostró resultados significativamente menores, respecto a los controles en muchas de las tareas de la batería ejecutiva estándar y en la batería ejecutiva y cognición social de INECO. Pero, el grupo de Addenbrooke´s Cognitive Examination Alto no difirió de los controles en muchas de las tareas de la batería ejecutiva estándar, mientras que encontramos diferencias significativas en los pacientes con demencia fronto-temporal con Addenbrooke´s Cognitive Examination Alto y los controles en la mayoría de las tareas de la batería ejecutiva y cognición social. Conclusiones: La batería ejecutiva y cognición social de INECO es más sensible para detectar alteraciones ejecutivas y de cognición social en estadios precoces de demencia fronto-temporal, variante conductual que las tareas empleadas en la batería ejecutiva estándar...

Behavioral variant frontotemporal dementia (bvFTD) is characterized by early and substantial ventromedial prefrontal cortex (VMPFC) dysfunction and there is no consensus regarding which tests are most sensitive and specific to assess it. Objectives: To detect specific executive and social cognitive deficits in patients with early behavioural variant frontotemporal dementia. Material and Methods: In this study we assessed with theINECO´s Executive and Social Cognition Battery, which included Theory of Mind tests (Mind in the Eyes, Faux Pas), the Hotel Task, Multiple Errands Task-hospital version and the Iowa Gambling Task for complex decision-making. Patients were divided into two groups according to their AddenbrookeÆs Cognitive Examination scores. Results: We found that low AddenbrookeÆs Cognitive Examination patients differed from controls onmost tasks of the standard battery and the Executive and Social Cognition Battery. But high AddenbrookeÆs Cognitive Examination patients did not differ from controls on most traditional neuropsychological tests, while significant differences were found between this high-functioning behavioural variant of frontotemporal dementia group and controls on most measures of Executive and Social Cognition Battery. Conclusions: The INECO´s Executive and Social Cognition Battery used are more sensitive in detecting executive and social cognitive impairment deficits in early behavioural variant of frontotemporal dementia than the classical cognitive measures...