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BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.
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Enfermedad de Alzheimer/diagnóstico , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Electroencefalografía , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Punción Espinal , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND AND PURPOSE: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL). METHODS: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI -0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak. CONCLUSIONS: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.
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Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Memantina/uso terapéutico , Guías de Práctica Clínica como Asunto , HumanosRESUMEN
BACKGROUND: The Alzheimer's Disease Functional Assessment and Change Scale (ADFACS) is a functional assessment instrument widely used in clinical research. AIMS: To test the diagnostic and concurrent validity of the Spanish version of this scale and to describe the functional deficit pattern for mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. METHODS: The ADFACS, the Interview for Deterioration in Daily Living Activities in Dementia (IDDD), and the Mini Mental State Examination (MMSE) were administered to 146 control subjects (CS) and 165 patients (67 MCI and 98 AD). Nonparametric tests were used to compare the diagnostic groups. Cronbach's α and correlations with the MMSE and the IDDD were calculated. Sensitivity, specificity and predictive values were studied. RESULTS: The ADFACS had a high internal consistency (α = 0.95). Three cutoff points of 1, 4, and 17 were provided to separate CS and MCI patients, MCI and mild AD patients, and mild AD and moderate AD patients, respectively. The ADFACS strongly correlated with functional (IDDD, 0.927) and cognitive (MMSE, 0.747) measures. A similar pattern of dysfunction, but in different grades, was found for the MCI and AD groups. CONCLUSION: The ADFACS is a reliable, valid, and sensitive instrument to assess functional abilities; it is useful in dementia assessment for elderly populations.
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Actividades Cotidianas , Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND AND PURPOSE: Patients with the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) may develop atypical parkinsonian syndromes. However, there is no current biomarker to assess which patients are at high risk of developing parkinsonism. 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT)-SPECT detects striatal dopamine dysfunction in vivo. The objective of the present study was to study whether non-fluent/agrammatic patients without parkinsonism at baseline present decreased striatal 123I-FP-CIT uptake. METHODS: Visual and semi-quantitative assessments of the striatal 123I-FP-CIT uptake ratio were carried out in 15 patients with nfvPPA, eight patients with the logopenic variant of PPA (lvPPA) and 18 controls. To rule out progranulin mutations or underlying Alzheimer's disease (AD), serum progranulin levels and cerebrospinal fluid (CSF) biomarkers of AD (Aß42 , total-tau, phosphorylated-tau181 ) were determined. A second 123I-FP-CIT-SPECT analysis in the biomarker-enriched groups was also carried out. RESULTS: Patients with nfvPPA presented reduced striatal 123I-FP-CIT binding, especially in the left hemisphere (P = 0.002), compared with controls. All lvPPA patients had normal striatal 123I-FP-CIT uptake. 123I-FP-CIT striatal binding in nfvPPA patients with normal progranulin and CSF biomarker levels (nfvPPA/bio-) was also significantly reduced (P < 0.05) compared with lvPPA patients with positive AD biomarkers. Sixty-four per cent (9/14) of nfvPPA patients and 80% of nfvPPA/bio- patients (8/10) showed a diminished individual left striatal 123I-FP-CIT uptake ratio. On follow-up, seven nfvPPA/bio- patients developed parkinsonism (median 1.9 years; range 1.2-2.9), six of them with baseline reduced 123I-FP-CIT uptake. CONCLUSIONS: Reduced striatal tracer uptake in nfvPPA patients prior to clinical parkinsonism can be detected by 123I-FP-CIT-SPECT, especially in those with nfvPPA/bio-, suggesting subclinical nigrostriatal degeneration. Decreased striatal 123I-FP-CIT binding might identify PPA patients at increased risk of developing atypical parkinsonian syndromes, probably related to tau-pathology.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neostriado/metabolismo , Enfermedad de Parkinson/metabolismo , Afasia Progresiva Primaria no Fluente/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tropanos , Anciano , Biomarcadores , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neostriado/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Afasia Progresiva Primaria no Fluente/diagnóstico por imagenRESUMEN
BACKGROUND/AIM: To investigate in variants of primary progressive aphasia (PPA) the association between current clinical and neuroimaging criteria and biochemical/genetic markers at the individual level. METHODS: Thirty-two PPA patients were classified as non-ï¬uent/agrammatic (nfvPPA), semantic (svPPA), or logopenic variant (lvPPA) or as unclassifiable (uPPA). In all patients, we evaluated the neuroimaging criteria (magnetic resonance imaging and/or single photon emission computed tomography/positron emission tomography) of each variant and studied serum progranulin levels, APOE genotype and Alzheimer's disease (AD)-cerebrospinal fluid (CSF) biomarkers. Cases with a first-degree family history of early-onset dementia were genetically tested. RESULTS: Ten of 15 (66%) nfvPPA, 5/5 (100%) svPPA and 7/7 (100%) lvPPA patients showed at least one positive neuroimaging-supported diagnostic criterion. All lvPPA and 3/5 (60%) uPPA patients presented AD-CSF biomarkers, which were absent in nfvPPA and svPPA cases. Four (27%) nfvPPA patients had dementia-causing mutations: 2 carried a GRN mutation and 2 the C9ORF72 hexanucleotide expansion. CONCLUSIONS: There was an excellent association between clinical criteria and neuroimaging-supported biomarkers in svPPA and lvPPA, as well as with AD-CSF biochemical markers in the lvPPA. Neuroimaging, biochemical and genetic findings in nfvPPA were heterogeneous. Incorporating biochemical/genetic markers into the PPA clinical diagnosis would allow clinicians to improve their predictions of PPA neuropathology, especially in nfvPPA and uPPA cases.
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Afasia Progresiva Primaria/patología , Biomarcadores/sangre , Neuroimagen/métodos , Edad de Inicio , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/psicología , Afasia Progresiva Primaria/metabolismo , Afasia Progresiva Primaria/psicología , Apolipoproteínas E/sangre , Estudios de Cohortes , Expansión de las Repeticiones de ADN , Escolaridad , Femenino , Marcadores Genéticos , Variación Genética , Humanos , Procesamiento de Imagen Asistido por Computador , Péptidos y Proteínas de Señalización Intercelular/sangre , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Progranulinas , Factores Socioeconómicos , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
INTRODUCTION: There is evidence of insufficient communication abilities by medical specialists as well as of the limited retentive capacities of patients with Alzheimer disease (AD) and their caregivers. The main reasons for this include the personal limitations of the physician, as well as external, emotional and social-cultural factors associated with the patients and their caregivers. The aim of this study is to compare the clinical information on AD provided by the physicians and that perceived by caregivers and to assess factors associated with differences in perception. PATIENTS AND METHODS: We carried out an observational national multicentre study based on questionnaires assessing the information provided by the physician and that retained by the caregiver for 17 items of information. The study involved 61 researchers and included a total of 679 patients who met the selection criteria. We evaluated the factors associated with the difference in perception of the information that was transmitted. RESULTS: Participating caregivers had a mean age of 57.2 ± 14.8 years, with an average care time of 27.6 ± 28.0 months. Approximately half (50.9%) were children of the AD patient and most lived in the same household (64.9%). Caregivers assigned significantly higher ratings to information on concept of disease, aetiology, pathogenesis, dosage and treatment recommendations and adherence, while doctors assigned significantly higher ratings to information related to demystification and correcting preconceived notions, possible complications, adverse events and/or iatrogenesis, family associations, and emotional/psychological support to caregivers (P<.05). Concordance between the information provided and that received was classified between poor and weak (inter-rater agreement ≤ 0.27). The degree of disease progression using the Global Deterioration Scale (GDS) was a factor significantly associated with professional-carer information discrepancy (P=.002). CONCLUSIONS: Many areas of information showed large differences in perception between physicians and caregivers of AD patients, which highlights the need to improve the communication process in order to achieve higher quality.
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Enfermedad de Alzheimer/terapia , Cuidadores , Educación del Paciente como Asunto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Comunicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Médicos , Factores Socioeconómicos , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Many factors influence the satisfaction and quality of life of informal caregivers of non-responder patients with Alzheimer disease (AD). Among these include, the course of the disease, cognitive impairment and behavioural disturbances of the patient, the level of family support and caregiver inherent factors such as, time commitment, psychological status and awareness of the disease. The aim of this work is to determine the profile of informal caregivers of non-responder AD patients and to evaluate the different factors that affect their quality of life, burden and overall satisfaction with treatment. PATIENTS AND METHODS: We carried out a prospective and multicentre study in Spain that included a total of 249 AD patients unresponsive to anticholinesterase treatment, and their informal caregivers. We evaluated caregivers' quality of life with the SF-36 questionnaire and their associated burden with the Zarit scale, both validated for Spain. The severity and progression of the disease was quantified according to Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE). RESULTS: Caregiver burden showed a significant increase with the time elapsed since the start of the study, while treatment satisfaction increased slightly with this factor. Caregiver burden is highly correlated with CDR scale on patient symptoms, both in the initial visit (p<.0001) and final visit (p=.0001). Caregiver satisfaction with treatment was mainly affected by the degree of change in cognitive deterioration experienced by the patient between the two visits (p=.021). CONCLUSIONS: Overall satisfaction with the treatment stated by the caregiver does not correlate with compliance to treatment, but it does so with the changes in patient's cognitive impairment, a factor that also influences caregiver's burden.
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Enfermedad de Alzheimer/psicología , Enfermedad de Alzheimer/terapia , Cuidadores/psicología , Inhibidores de la Colinesterasa/uso terapéutico , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Satisfacción del Paciente , Estudios Prospectivos , Calidad de Vida , Índice de Severidad de la Enfermedad , Apoyo Social , España , Encuestas y CuestionariosRESUMEN
INTRODUCTION: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). METHODS: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. RESULTS: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the pre-symptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. CONCLUSIONS: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of pre-symptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions.
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Demencia/genética , Asesoramiento Genético , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Evaluación de Programas y Proyectos de Salud , Factores de TiempoRESUMEN
Amyloid-ß (Aß) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aß pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer's continuum is critical. Here, we compare different Aß classification approaches and we show their performance in detecting pathophysiological changes downstream Aß pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer's continuum. Participants underwent Aß PET and CSF biomarkers assessment. We classified participants as Aß -positive using five approaches: (1) CSF Aß42 < 1098 pg/ml; (2) CSF Aß42/40 < 0.071; (3) Aß PET Centiloid > 12; (4) Aß PET Centiloid > 30 or (5) Aß PET Positive visual read. We assessed the correlations between Aß biomarkers and compared the prevalence of Aß positivity. We determined which approach significantly detected associations between Aß pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher Aß-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF Aß-positive but PET Aß-negative than CSF Aß-negative but PET Aß-positive. The CSF Aß 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aß-positive group. Altogether, we highlight the need for sensitive Aß -classifications to study the preclinical Alzheimer's continuum. Approaches that define Aß positivity based on optimal discrimination of symptomatic Alzheimer's disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer.
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Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Síntomas Prodrómicos , Anciano , Biomarcadores/líquido cefalorraquídeo , Bases de Datos Factuales , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neuroimagen/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Valores de Referencia , Proteínas tau/líquido cefalorraquídeoRESUMEN
OBJECTIVE: To describe a novel mutation (K239N) in the PSEN1 associated with familial Alzheimer's disease (AD). METHODS AND RESULTS: The proband was a man who developed cognitive decline with marked behavioural abnormalities at age 57. At age 70, he was admitted into a psychiatric facility because of aggressiveness and a suicide attempt. Family history was consistent with autosomal dominant AD. One of the two other family members studied presented also with prominent behavioural symptoms at age 42 and has also been forced into a psychiatric facility because of aggressiveness at age 56. The remainder patient has presented a prototypical AD, but starting at age 71. Direct sequencing of PSEN1 in the three living affected members disclosed a heterozygous G to C transition in exon 7 of PSEN1 leading to the K239N mutation. CONCLUSION: The K239N mutation is associated with autosomal dominant AD with a wide range of age of onset and incomplete penetrance at the age of 65, prominent behavioural features and slow progression.
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Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Presenilina-1/genética , Edad de Inicio , Anciano , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/patología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Mild cognitive impairment (MCI) is considered a transitional state between normal aging and Alzheimer disease. Most MCI subjects present disturbances in multiple neuropsychological domains, including executive function. This study aimed at exploring frontal lobe cortical thinning in MCI and healthy controls, and its relationship with problem-solving abilities. Twenty-three MCI patients and 30 elderly controls underwent MRI and neuropsychological assessment. Cortical thickness was measured by means of FreeSurfer. Problem-solving was assessed by means of the Tower of London (TOL) task. MCI showed a global thinning of the cortex. With regard to specific regions of interest, a thinning in the left frontal lobe and the bilateral posterior cingulate gyri was found. Partial correlations, after controlling for age, education, Mini-Mental Status Examination, and non-frontal mean thickness revealed negative significant correlations between frontal lobe thickness and executive outcomes in the control group. This counterintuitive relationship was not observed in the MCI group, suggesting that the frontal cortical atrophy observed in MCI entails a specific pathology-related relationship with high-level executive outcomes that is qualitatively different from that observed in healthy aging.
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Envejecimiento , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/patología , Lóbulo Frontal/patología , Solución de Problemas/fisiología , Anciano , Anciano de 80 o más Años , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: The European Prevention of Alzheimer's Dementia (EPAD) Programme is a pan-European project whose objective is to deliver a platform, adaptive, Phase 2 proof of concept (PoC) trial for the secondary prevention of Alzheimer's dementia. A component of this platform is the Longitudinal Cohort Study (LCS) which acts as a readiness cohort for the PoC Trial as well as generating data for disease modelling work in the preclinical and prodromal phases of Alzheimer's dementia. OBJECTIVES: The first data wave has been collected, quality checked, released and now available for analysis to answer numerous research questions. Here we describe the results from key variables in the EPAD LCS with the objective of using these results to compliment analyses of these data in the future. DESIGN: EPAD LCS is a cohort study whose primary objective is as a readiness cohort for the EPAD PoC Trial. As such recruitment is not capped at any particular number but will continue to facilitate delivery of the EPAD PoC Trial. Research Participants are seen annually (with an additional 6 month visit in the first year). SETTING: The EPAD Trial Delivery Network comprises currently 21 centres across Europe. PARTICIPANTS: Research participants are included if they are over 50 years old and do not have a diagnosis of dementia. MEASUREMENTS: All research participants undergo multiple assessments to fully characterise the biology of Alzheimer's disease and relate this to risk factors (both fixed and modifiable) and biomarker expression of disease through brain imaging, fluid samples (CSF, blood, urine and saliva), cognitive performance, functional abilities and neuropsychiatric symptomatology. RESULTS: V500.0 represents the first 500 research participants baselined into EPAD LCS. The mean age was 66.4 (SD=6.7) and 47.8% were male. The data was split for presentation into 4 groups: [1] CDR=0 and Amyloid + (preclinical AD), [2] CDR=0 and Amyloid -, [3] CDR=0.5 and Amyloid + (prodromal AD) and [4] CDR=0.5 and Amyloid -. CONCLUSIONS: The EPAD LCS is achieving its primary objective of trial readiness and the structured approach to data release as manifest by this first data release of V500.0 will assist researchers to describe and compare their findings as well as in systematic reviews and meta-analyses. It is anticipated given current recruitment rates that V1500.0 data release will take place in Autumn 2019. V500.1 (when the 1 year follow up is completed on the V500.0 (sub)cohort will be in Autumn 2019 also.
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Enfermedad de Alzheimer/prevención & control , Anciano , Enfermedad de Alzheimer/diagnóstico , Amiloide/metabolismo , Biomarcadores/análisis , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Ensayos Clínicos Fase II como Asunto , Europa (Continente) , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neuroimagen , Síntomas Prodrómicos , Proyectos de InvestigaciónAsunto(s)
Afasia Progresiva Primaria no Fluente/diagnóstico , Tauopatías/diagnóstico , Atrofia/metabolismo , Atrofia/patología , Ganglios Basales/metabolismo , Ganglios Basales/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Afasia Progresiva Primaria no Fluente/etiología , Tauopatías/complicacionesRESUMEN
Efforts to develop effective disease-modifying treatments for Alzheimer's disease (AD) have mostly targeted the amyloid ß (Aß) protein; however, there has recently been increased interest in other targets including phosphorylated tau and other forms of tau. Aggregated tau appears to spread in a characteristic pattern throughout the brain and is thought to drive neurodegeneration. Both neuropathological and imaging studies indicate that tau first appears in the entorhinal cortex and then spreads to the neocortex. Anti-tau therapies currently in Phase 1 or 2 trials include passive and active immunotherapies designed to prevent aggregation, seeding, and spreading, as well as small molecules that modulate tau metabolism and function. EU/US/CTAD Task Force members support advancing the development of anti-tau therapies, which will require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and Aß protein, and development of multiple targets and candidate agents addressing the tauopathy of AD. Incorporating tau biomarkers in AD clinical trials will provide additional knowledge about the potential to treat AD by targeting tau.
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Enfermedad de Alzheimer/tratamiento farmacológico , Proteínas tau/antagonistas & inhibidores , Comités Consultivos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Ensayos Clínicos como Asunto , Desarrollo de Medicamentos , Humanos , Proteínas tau/metabolismoRESUMEN
AIM: To investigate the relationship between performance in language tests and levels of brain metabolites in two selected left temporal lobe regions. METHODS: Ninety-five subjects were included: 26 controls, 30 amnestic mild cognitive impairment subjects, 27 Alzheimer's disease and 12 frontotemporal lobar degeneration (FTLD) patients. Language was assessed by a naming test: Boston Naming Test (BNT) and by a semantic verbal fluency test. Other cognitive functions: verbal and visual memory, visual perception, attention and executive function, and praxis were also assessed. Single voxel magnetic resonance spectroscopy was obtained in the left temporal pole (L-TPOLE), and in the left posterior temporoparietal region (L-TPAR). RESULTS: BNT scores were significantly associated with N-acetylaspartate/creatine ratios (r = 0.45; p < 0.001) and choline/creatine ratios (r = 0.33; p < 0.005) in the L-TPOLE. No significant associations were found between BNT and metabolite levels in the L-TPAR. No significant associations were found between the semantic verbal fluency test and other cognitive tests and metabolite levels either in the L-TPOLE or in the L-TPAR. CONCLUSION: Naming performance is related to metabolite levels in the anterior L-TPOLE.
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Anomia/etiología , Demencia , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patología , Anciano , Amnesia/diagnóstico , Amnesia/etiología , Amnesia/fisiopatología , Anomia/diagnóstico , Anomia/epidemiología , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Colina/metabolismo , Trastornos del Conocimiento/diagnóstico , Creatina/metabolismo , Demencia/complicaciones , Demencia/metabolismo , Demencia/patología , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Prevalencia , Índice de Severidad de la EnfermedadRESUMEN
Recurrent deletions of the 17q21.31 region encompassing the microtubule-associated protein tau (MAPT) gene have recently been described in patients with mental retardation. This region is flanked by segmental duplications that make it prone to inversions, deletions and duplications. Since gain-of-function mutations of the MAPT gene cause frontotemporal lobar degeneration (FTLD) characterized by deposition of tau protein, we hypothesize that MAPT duplication affecting gene dosage could also lead to disease. Gene dosage alterations have already been found to be involved in the etiology of neurodegenerative disorders caused by protein or peptide accumulation, such as Alzheimer's and Parkinson's diseases. To determine whether MAPT gene copy number variation is involved in FTLD, 70 patients with clinical diagnosis of FTLD and no MAPT mutation (including 12 patients with pathologically proven tau-positive FTLD) were screened by using multiplex ligation probe amplification (MLPA) with specific oligonucleotide probes. No copy number variation in the MAPT gene was observed in cases. Although our study was limited by the relatively small number of patients, it does not support the theory that chromosomal rearrangements in this region are a cause of FTLD.
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Demencia/genética , Duplicación de Gen , Genes Duplicados/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Proteínas tau/genética , Adulto , Anciano , Química Encefálica/genética , Cromosomas Humanos Par 17/genética , Análisis Mutacional de ADN , Demencia/metabolismo , Demencia/fisiopatología , Femenino , Dosificación de Gen/genética , Marcadores Genéticos/genética , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The aim of this study was to describe a novel mutation in exon 8 of the presenilin gene (L286P) associated with early-onset autosomal dominant Alzheimer's disease (AD) and lobar haematomas. The proband was a woman who developed cognitive decline with predominant memory loss at the age of 35 years. The patient died at the age of 54 years and the neuropathological examination confirmed the diagnosis of AD. Three of her four siblings, one parent and one sibling of her parent had suffered from cognitive decline at ages between 35 and 42 years. Three of them also presented lobar haematomas. The neuropathological examination, available in one of them, disclosed the presence of severe amyloid angiopathy as the cause of the haematoma. The study of PSEN1 gene with single strand conformation polymorphism technique failed to show abnormalities suggestive of mutations. Direct sequencing disclosed the presence of a missense mutation in codon 286 (L286P) in the proband and her already affected descendent, which was absent in the healthy sibling. L286P is a novel mutation in PSEN1 that causes familial early-onset AD and brain haematomas related to amyloid angiopathy.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Encéfalo/metabolismo , Hemorragia Cerebral/genética , Predisposición Genética a la Enfermedad/genética , Presenilina-1/genética , Edad de Inicio , Enfermedad de Alzheimer/fisiopatología , Encéfalo/patología , Encéfalo/fisiopatología , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/fisiopatología , Arterias Cerebrales/metabolismo , Arterias Cerebrales/patología , Arterias Cerebrales/fisiopatología , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/fisiopatología , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Polimorfismo Genético/genéticaRESUMEN
INTRODUCTION: There are some neuropsychological test with a good sensibility for cognitive disorders affecting frontal lobe damage. AIM. To provide normative data for test that assess frontal cognitive function in population over 60 years old. SUBJECTS AND METHODS: 110 neurologically healthy volunteers over 60 years old, recruited from different primary care centers from Barcelona, participated in the study and were assessed by the Trail Making Test-A (TTA), the verbal fluency test FAS and the similarities test. RESULTS: The mean age of the sample was 71.5 years-old (DE: 6.7). The mean years of education was 8.6 (DE: 4.4). 60% of the subjects were women. The mean score obtained in TTA was 64.2 (DE: 26.0), 24.5 (DE: 11.8) in FAS and 12.5 (DE: 5.2) in similarities test. Years of education result a high significant factor for predicting the performance in all the frontal test. Gender only influenced the performance in TTA. Age did not influence the performance in any of these test. CONCLUSIONS: These findings support the idea that years of education is the most influencing factor in the performance in frontal cognitive test in normal aged population.
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Cognición/fisiología , Pruebas Neuropsicológicas/normas , Factores de Edad , Anciano , Anciano de 80 o más Años , Escolaridad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estándares de Referencia , Valores de Referencia , Factores SexualesRESUMEN
Misfolding and aggregation of amyloid ß (Aß) are key features of Alzheimer's disease (AD) pathogenesis, but the molecular events controlling this process are not known in detail. In vivo, Aß aggregation and plaque formation occur in the interstitial fluid of the brain extracellular matrix. This fluid communicates freely with cerebrospinal fluid (CSF). Here, we examined the effect of human CSF on Aß aggregation kinetics in relation to AD diagnosis and carrier status of the apolipoprotein E (APOE) ε4 allele, the main genetic risk factor for sporadic AD. The aggregation of Aß was inhibited in the presence of CSF and, surprisingly, the effect was more pronounced in APOE ε4 carriers. However, by fractionation of CSF using size exclusion chromatography, it became evident that it was not the ApoE protein itself that conveyed the inhibition, since the retarding species eluted at lower volume, corresponding to a much higher molecular weight, than ApoE monomers. Cholesterol quantification and immunoblotting identified high-density lipoprotein particles in the retarding fractions, indicating that such particles may be responsible for the inhibition. These results add information to the yet unresolved puzzle on how the risk factor of APOE ε4 functions in AD pathogenesis.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/química , Apolipoproteína E4/genética , Líquido Cefalorraquídeo/química , Fragmentos de Péptidos/química , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E4/metabolismo , Benzotiazoles , Estudios de Casos y Controles , HDL-Colesterol/líquido cefalorraquídeo , HDL-Colesterol/metabolismo , Cromatografía en Gel , Femenino , Heterocigoto , Humanos , Immunoblotting , Cinética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Multimerización de Proteína , TiazolesRESUMEN
The EU/US/CTAD Task Force, an international collaboration of AD investigators from industry and academia, met in Barcelona, Spain, on November 4th, 2015, to explore existing and planned patient registries and other clinical trial infrastructure meant to expedite recruitment of large numbers of participants into clinical trials and improve their productivity. The Task Force identified a number of approaches currently being tested around the world, including the use of predictive algorithms to identify individuals likely to have prodromal or preclinical AD, the establishment of clinical trial networks to streamline trials, and reforming the informed consent process to make it less burdensome to both investigators and trial participants. Multi-national systems such as the European Prevention of Alzheimer's Dementia (EPAD) and the Global Alzheimer's Platform (GAP) offer value for sponsors, trial sites, and patients by optimizing efforts to find effective disease-modifying and symptomatic treatments.