Comparative Analysis of Different Definitions of Amyloid-ß Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer.

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.

The European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study: Baseline Data Release V500.0.

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.

Anti-Tau Trials for Alzheimer's Disease: A Report from the EU/US/CTAD Task Force.

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.

Cerebrospinal fluid-induced retardation of amyloid ß aggregation correlates with Alzheimer's disease and the APOE ε4 allele.

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.

Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

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.

Registries and Cohorts to Accelerate Early Phase Alzheimer's Trials. A Report from the E.U./U.S. Clinical Trials in Alzheimer's Disease Task Force.

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.

Nonlinear cerebral atrophy patterns across the Alzheimer's disease continuum: impact of APOE4 genotype.

The progression of Alzheimer's disease (AD) is characterized by complex trajectories of cerebral atrophy that are affected by interactions with age and apolipoprotein E allele ε4 (APOE4) status. In this article, we report the nonlinear volumetric changes in gray matter across the full biological spectrum of the disease, represented by the AD-cerebrospinal fluid (CSF) index. This index reflects the subject's level of pathology and position along the AD continuum. We also evaluated the associated impact of the APOE4 genotype. The atrophy pattern associated with the AD-CSF index was highly symmetrical and corresponded with the typical AD signature. Medial temporal structures showed different atrophy dynamics along the progression of the disease. The bilateral parahippocampal cortices and a parietotemporal region extending from the middle temporal to the supramarginal gyrus presented an initial increase in volume which later reverted. Similarly, a portion of the precuneus presented a rather linear inverse association with the AD-CSF index whereas some other clusters did not show significant atrophy until index values corresponded to positive CSF tau values. APOE4 carriers showed steeper hippocampal volume reductions with AD progression. Overall, the reported atrophy patterns are in close agreement with those mentioned in previous findings. However, the detected nonlinearities suggest that there may be different pathological processes taking place at specific moments during AD progression and reveal the impact of the APOE4 allele.

EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease.

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.

Diagnostic validity of the Alzheimer's disease functional assessment and change scale in mild cognitive impairment and mild to moderate Alzheimer's disease.

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.

Decreased striatal dopamine transporter uptake in the non-fluent/agrammatic variant of primary progressive aphasia.

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.

Neuroimaging and biochemical markers in the three variants of primary progressive aphasia.

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-fluent/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.

Evaluación de la información suministrada por el médico especialista sobre la enfermedad de Alzheimer y de la retención lograda por los cuidadores del enfermo / Assessment of the information provided by the medical specialist on Alzheimer's disease and that retained by the patient caregivers

Existen evidencias de la insuficiente capacidad informativa por parte de los especialistas médicos, así como de las dificultades retentivas de los pacientes con enfermedad de Alzheimer (EA) y de sus cuidadores. Entre las diversas causas figuran tanto las limitaciones personales del profesional como los determinantes externos, emocionales y socioculturales del paciente y de su cuidador. Contrastar la información clínica proporcionada por los médicos sobre la EA y la percibida por los cuidadores y evaluar los factores asociados a las diferencias de percepción. Pacientes y métodosSe llevó a cabo un estudio observacional, multicéntrico y nacional mediante cuestionarios que evalúan la información suministrada por el médico y la retenida por el paciente en 17 aspectos informativos. Participaron 61 investigadores que incluyeron a un total de 679 pacientes que cumplían los criterios de selección. Se evaluaron los factores asociados a la diferencia de percepción sobre la información transmitida.Resultados: Los cuidadores participantes tenían una media de 57,2±14,8 años, habiendo dedicado un tiempo medio como cuidadores de 27,6±28,0 meses, y siendo el 50,9% hijos del paciente que mayoritariamente vivían en el mismo domicilio (64,9%). Los cuidadores valoraron significativamente mejor la información recibida sobre: concepto de la enfermedad, aspectos etiopatogénicos, posología y recomendaciones sobre el tratamiento y adherencia terapéutica, mientras que los médicos consideraron significativamente mejor la información referente a desmitificación y corrección de concepciones previas, posibles complicaciones, riesgos, efectos adversos y/o yatrogenia, asociaciones de familiares, y ayuda emocional/psicológica a cuidadores (p<0,05). La concordancia en la información suministrada y la recibida fue entre pobre y débil (Kappa ≤ 0,27). El grado de evolución de la enfermedad (escala GDS) fue un factor significativamente asociado con la discordancia profesional-cuidador (p=0,002) (AU)

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) (AU)

Assessment of the information provided by the medical specialist on Alzheimer's disease and that retained by the patient caregivers.

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.

Perfil del cuidador informal asociado al manejo clínico del paciente con enfermedad de Alzheimer no respondedor al tratamiento sintomático de la enfermedad / Profile of the informal carer associated with the clinical management of the Alzheimer's disease patient refractory to symptomatic treatment of the disease

Introducción: Numerosos factores influyen en la satisfacción y la calidad de vida del cuidador informal del paciente con enfermedad de Alzheimer (EA) no respondedor. Entre ellos, destacan el curso de la enfermedad, el deterioro cognitivo y los trastornos conductuales de los pacientes, el grado de apoyo familiar y los factores inherentes al cuidador (tiempo de dedicación, estado psicológico y conocimiento de la enfermedad). El objetivo del trabajo fue determinar el perfil del cuidador informal del paciente con EA no respondedor, así como evaluar los diferentes factores que intervienen en su calidad de vida, carga soportada y satisfacción global con el tratamiento.Pacientes y métodos: Se llevó a cabo un estudio epidemiológico, prospectivo, multicéntrico y nacional que incluyó a 249 pacientes con EA no respondedores al tratamiento anticolinesterásico y a sus cuidadores. Se evaluó la calidad de vida del cuidador según el cuestionario de salud Short Form-36 (SF-36) y la carga asociada según escala de sobrecarga del cuidador Zarit, ambas validadas para España. La gravedad y la evolución de la patología se cuantificaron según el Clinical Dementia Rating (CDR) y el estado cognitivo mediante el Mini-Mental State Examination (MMSE). Resultados: La sobrecarga del cuidador mostró un incremento significativo en función del tiempo transcurrido desde el inicio del estudio, mientras que la satisfacción con el tratamiento aumentaba ligeramente con este mismo factor. La sobrecarga del cuidador resulta altamente correlacionada con el inventario CDR sobre sintomatología del paciente, tanto en visita inicial (p<0,0001) como final (p=0,0001). La satisfacción del cuidador con el tratamiento se vio afectada por el grado de cambio en el deterioro cognitivo padecido por el paciente entre las dos visitas (p=0,021)

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

[Profile of the informal carer associated with the clinical management of the Alzheimer's disease patient refractory to symptomatic treatment of the disease]. / Perfil del cuidador informal asociado al manejo clínico del paciente con enfermedad de Alzheimer no respondedor al tratamiento sintomático de la enfermedad.

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.

Clinical features and APOE genotype of pathologically proven early-onset Alzheimer disease.

OBJECTIVES: Early-onset Alzheimer disease (EOAD) diagnosis often represents a challenge because of the high frequency of atypical presentations. Our aim was to describe the clinical features, APOE genotype, and its pathologic correlations of neuropathologic confirmed EOAD. METHODS: Retrospective review of clinical data (age at onset, family history, clinical presentation, diagnostic delay, diagnosis) and APOE genotype of patients with neuropathologically confirmed EOAD (<60 years). RESULTS: Forty cases were selected. Mean age at onset was 54.5 years (range 46-60). The mean disease duration was 11 years with a mean diagnostic delay of 3.1 years. A total of 37.5% had a nonmemory presentation. Behavioral/executive dysfunction was the most prevalent atypical presentation. Incorrect initial clinical diagnoses were common (53%) in patients with atypical presentations, but rare when anterograde amnesia was the presenting symptom (4%). The incorrect initial clinical diagnoses were 2 behavioral variant frontotemporal lobar degeneration, 2 normal pressure hydrocephalus, 1 semantic dementia, 1 primary progressive aphasia, 1 corticobasal degeneration, 1 pseudodementia with depression, and 1 unclassifiable dementia. APOE genotype was ε3/ε3 in 59%, with no significant differences between typical and atypical presentations. APOE ε4 was 3.3 times more frequent in subjects with family history of AD. A total of 97.5% of the cases presented advanced neurofibrillary pathology. A total of 45% of the patients had concomitant Lewy body pathology although localized in most cases and without a significant clinical correlate. CONCLUSION: One third of patients with pathologic confirmed EOAD presented with atypical symptoms. Patients with EOAD with nonamnestic presentations often receive incorrect clinical diagnoses.

PICOGEN: experiencia de 5 años de un programa de asesoramiento genético en demencia / PICOGEN: Five years experience with a genetic counselling program for dementia

Introducción: Describimos la experiencia del Programa de Información y Consejo Genético para demencias familiares (PICOGEN) en sus 5 a˜nos de funcionamiento. Métodos: Todos los sujetos fueron asesorados por un neurólogo que seleccionó los candidatos a estudio genético según la historia familiar y el diagnóstico (enfermedad de Alzheimer [EA], degeneración lobular frontotemporal [DLFT] o enfermedad priónica). Los sujetos asintomáticos que decidieron conocer su estatus genético siguieron un protocolo estructurado de evaluación antes y después de la realización del test genético. Resultados: Ochenta y siete pacientes de 72 familias fueron candidatos a estudio genético, 20 de 72 familias presentaban historia familiar autosómica dominante de inicio precoz (HADp). En 22 se detectó una mutación patogénica (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 no descritas previamente. Todos los casos con mutación, excepto uno PSEN1 (12,5%) y 4 PRNP (50%) presentaban HADp. En 3 casos con HADp (15%) no se encontró ninguna mutación. 24 de 54 sujetos asintomáticos de familias con mutación conocida decidieron realizarse el estudio presintomático, 10 resultaron portadores. En el seguimiento de los sujetos que realizaron el estudio predictivo no se observó ninguna complicación psiquiátrica mayor. Conclusiones: En nuestra serie la HADp resultó un criterio sensible para la detección de mutaciones patogénicas en EA y DLFT, pero no en enfermedades priónicas. Un 15% de los casos HADp no presentaron alteraciones genéticas causales en estudios diagnósticos convencionales. El 43% de los sujetos en riesgo que recibieron asesoramiento genético individual realizaron el estudio presintomático. El estudio presintomático resultó seguro en este contexto (AU)

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 presymptomatic 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 presymptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions (AU)

[Memantine: the value of combined therapy]. / Memantina: el valor de la terapia combinada.

The symptomatic treatment of Alzheimer's disease is currently carried out using a twofold therapeutic approach involving acetylcholinesterase inhibitors, whose mechanism of action is based on the selective inhibition of this enzyme, and memantine, which acts by blocking the pathological tonic activation of NMDA receptors. Both drugs have been approved for the treatment of Alzheimer's disease and present a therapeutic indication spectrum that is shared in the moderate phase (MMSE: 10-20). Since both therapeutic approaches offer the same complementary mechanisms of action and share the same therapeutic indication over a wide symptomatic disease spectrum, the aim of this article is to review the existing evidence on the effectiveness of combined therapy so as to be able to discern its usefulness from the moment treatment begins.

Donepezil provides greater benefits in mild compared to moderate Alzheimer's disease: implications for early diagnosis and treatment.

We assessed the cognitive and functional outcomes of donepezil treatment in mild versus moderate Alzheimer's disease (AD) patients. We performed a 6-month prospective, observational, multicenter study of the progression of cognitive and functionality abilities in a large sample patients with AD who initiated treatment with donepezil in monotherapy. According to baseline mini mental state examination (MMSE), patients were divided in two groups: mild AD (MMSE ≥ 21) and moderate AD (MMSE <21). Patients were evaluated with the memory alteration test (M@T) and the Alzheimer's disease functional assessment and change scale (ADFACS) at baseline and at 6 months. A total of 403 patients finished the study (mild AD=152; moderate AD=251). The MMSE total score and M@T score remained stable at 6 months in the whole sample, with MMSE memory domain and M@T free and cued recall domains improving significantly from baseline. Total ADFACS, instrumental (IADL) and basic activities of daily living (BADL) got significantly worse, with the worsening being significantly greater in the moderate AD group. Significant differences between the groups favoring mild AD were observed for MMSE memory, orientation and language domains, M@T temporal orientation and semantic memory domains, and for IADL. We concluded that in AD patients on donepezil, cognition remains stable at 6 months. The beneficial effect of donepezil treatment, in terms of cognition and functionality, is greater for mild than for moderate AD.