European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders.

The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.

Attitudes toward pre-symptomatic screening for Alzheimer's dementia in five European countries: a comparison of family members of people with Alzheimer's dementia versus non-family members.

Introduction: Pre-symptomatic screening is getting more attention in healthcare as it detects the risk for developing neurodegenerative diseases like Alzheimer's disease (AD), which is very useful for treatment or prevention. AD screening could play an important role in individuals with at least one affected first-degree relative, but also without family history. As the demand for screening is rising worldwide, it is important to consider possible cross-cultural differences in attitudes toward pre-symptomatic screening in order to tailor healthcare services to the needs of each country. Objective: This study aims to investigate the attitudes of family members and non-family members of people with dementia toward pre-symptomatic screening and explore possible differences in attitudes across five European countries (Belgium, Germany, Greece, Spain, Turkey) using translated versions of the "Perceptions regarding pRE-symptomatic Alzheimer's Disease Screening" questionnaire (PRE-ADS). Methods: The multicultural sample (N = 650) was recruited from samples that were previously used in validation studies of the translated PRE-ADS versions. The subscale "Acceptability of Screening", consisting of five PRE-ADS items to specifically explore willingness to undergo screening, was created. Ιnternal consistency was measured, and structural validity was determined using Confirmatory Factor Analysis (CFA). Group comparisons were performed to investigate differences in attitudes toward pre-symptomatic AD screening regarding family history and country of origin using the PRE-ADS and the "Acceptability of Screening" mean scores. Results: Construct validity was acceptable for the PRE-ADS. Both the PRE-ADS (α = 0.76) and its subscale "Acceptability of Screening" (α = 0.90) had good internal consistency. Overall, 56.9% of the total sample expressed a positive intention toward pre-symptomatic AD screening. T-tests showed significantly higher mean scores of participants with an affected family member. An international comparison revealed differences in the "Acceptability of Screening" mean score across the five European countries. No cross-cultural differences were found for the PRE-ADS mean score after adjusting for confounding variables. Conclusion: The PRE-ADS and its subscale are reliable tools for assessing pre-symptomatic AD screening attitudes. Variations in the acceptability of screening seem to be linked to family history and cultural influences. Further research with larger samples is needed to explore underlying relationships.

Prevention of Alzheimer's disease: a global challenge for next generation neuroscientists.

The incidence of dementia is rapidly increasing in developed countries due to social and demographic changes. This trend is expected to worsen in the coming decades, with the number of cases possibly even tripling in the next 25 years. Therefore Alzheimer's disease (AD) prevention is becoming a global health priority. Our knowledge of the pathophysiological process leading to the development of pathological brain lesions that characterize AD has increased exponentially in recent years. However, the phenotypic expression of AD not only depends on the development of senile plaques and neurofibrillary tangles but other factors also play a role. Thus, over the last few decades, epidemiological studies have revealed several risk factors for developing AD, such as vascular or lifestyle related factors. Having the current knowledge on AD, two different strategies have been developed for the prevention of AD: one is based on primary prevention by acting on modifiable risk factors, the other is a pathophysiology-driven approach aimed to identify individuals in a preclinical stage of the disease and treating them with drugs purporting to act on molecular targets of the amyloid cascade. Several promising trials with these approaches are currently ongoing and results are expected in the next few years. The intrinsic limitations in the design of preventive trials should be overcome through a global effort involving healthy population, healthcare professionals, governments, industry, and scientific institutions. This exertion will be more than compensated if we can make AD a preventable disease.

[Human Albumin Grifols 5% in plasmapheresis: a new therapy involving beta-amyloid mobilisation in Alzheimer's disease]. / Albúmina Humana Grifols 5% en la plasmaféresis: una nueva terapia de movilización del beta-amiloide en la enfermedad de Alzheimer.

INTRODUCTION AND AIMS: Results from a pilot study and its 2-year extension (IG0502) performed on patients with mild or moderate Alzheimer's disease revealed a tendency towards clinical stabilization after a plasmapheresis program with plasma exchange with therapeutic albumin Human Albumin Grifols 5%. Plasma levels of Alphabeta(40) and Alphabeta(42) presented a saw-tooth pattern associated to plasma exchanges. These findings encouraged a new randomized, controlled, parallel, blind study (IG0602) to confirm our previous working hypotheses, i.e. that Alphabeta(40) and Alphabeta(42) concentrations in plasma were modified pre- and post plasmapheresis with Human Albumin Grifols 5% and, in the clinical area, that the cognitive capabilities of patients could be stabilized or even improved. Other aims of the study were focused on neuroimaging evaluation of structural and functional changes in the brain the by means of magnetic resonance and single-photon emission computerised tomography. RESULTS: Preliminary results from the randomized study carried out after a follow-up of one year of the first 29 patients (80% of the recruited) show a clear difference between the treated and the control groups with regard to the levels of Alphabeta(40), both in plasma and in cerebrospinal fluid, that are associated with the plasma exchanges. This pattern is not so evident for Alphabeta(42). Regarding cognitive performance, the treated group scored better than the control group after the period study, according to the evaluation performed by using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) tests. CONCLUSIONS: These preliminary results suggest that plasmapheresis with plasma exchange with Human Albumin Grifols 5% may have a promising future as a treatment of mild-moderate Alzheimer's disease.

Albúmina Humana Grifols ® 5% en la plasmaféresis: una nueva terapia de movilización del beta-amiloide en la enfermedad de Alzheimer / Human Albumin Grifols® 5% in plasmapheresis: a new therapy involving beta-amyloid mobilisation

Introducción y objetivo. El estudio piloto y su extensión a dos años (IG0502) realizados en pacientes con enfermedad de Alzheimer leve o moderada tratados mediante plasmaféresis con albúmina terapéutica Albúmina Humana Grifols® 5%, pusieron de manifiesto una tendencia a la estabilización clínica así como la presencia de un patrón en forma de dientes de sierra de los niveles plasmáticos de Ab40 y Ab42, asociados a los recambios plasmáticos. Estos resultados dieron paso a un nuevo estudio (IG0602) aleatorizado, controlado, paralelo y ciego con el doble objetivo de corroborar nuestras hipótesis de trabajo: que la plasmaféresis con Albúmina Humana Grifols® 5% era capaz de modificar la concentración de Ab40 y Ab42 en plasma pre y postratamiento, y conseguir la estabilidad o mejoría de las capacidades cognitivas en el terreno clínico. Otros objetivos del estudio se centraron en valorar los cambios estructurales y funcionales en la neuroimagen mediante estudios con resonancia magnética y tomografía computarizada por emisión de fotón único craneales. Resultados. En los resultados provisionales del estudio aleatorizado realizados al año de seguimiento en los primeros 29 pacientes (correspondiente al 80% de los reclutados) se observa una clara diferencia entre el grupo tratado y el grupo control en los niveles de Ab40, asociados con los recambios plasmáticos, tanto en plasma como en líquido cefalorraquídeo, no tan evidentes para Ab42. En este mismo periodo de estudio también se aprecian diferencias en el rendimiento cognitivo entre ambos grupos, a favor del grupo tratado comparado con el basal, según valoración efectuada mediante los tests Mini-Mental State Examination (MMSE) y Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog). Conclusión. A la vista de estos datos provisionales, se puede considerar que el recambio plasmático con Albúmina Humana Grifols® 5% puede tener un prometedor futuro como tratamiento de la enfermedad de Alzheimer en estadio levemoderado (AU)

Introduction and aims. Results from a pilot study and its 2-year extension (IG0502) performed on patients with mild or moderate Alzheimer’s disease revealed a tendency towards clinical stabilization after a plasmapheresis program with plasma exchange with therapeutic albumin Human Albumin Grifols® 5%. Plasma levels of Aß40 and Aß42 presented a saw-tooth pattern associated to plasma exchanges. These findings encouraged a new randomized, controlled, parallel, blind study (IG0602) to confirm our previous working hypotheses, i.e. that Aß40 and Aß42 concentrations in plasma were modified pre- and post plasmapheresis with Human Albumin Grifols® 5% and, in the clinical area, that the cognitive capabilities of patients could be stabilized or even improved. Other aims of the study were focused on neuroimaging evaluation of structural and functional changes in the brain the by means of magnetic resonance and single-photon emission computerised tomography. Results. Preliminary results from the randomized study carried out after a follow-up of one year of the first 29 patients (80% of the recruited) show a clear difference between the treated and the control groups with regard to the levels of Aß40, both in plasma and in cerebrospinal fluid, that are associated with the plasma exchanges. This pattern is not so evident for Aß42. Regarding cognitive performance, the treated group scored better than the control group after the period study, according to the evaluation performed by using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cog nitive (ADAS-Cog) tests. Conclusions. These preliminary results suggest that plasmapheresis with plasma exchange with Human Albumin Grifols® 5% may have a promising future as a treatment of mild-moderate Alzheimer’s disease (AU)

Creating a transatlantic research enterprise for preventing Alzheimer's disease.

In recognition of the global problem posed by Alzheimer's disease and other dementias, an international think-tank meeting was convened by Biocat, the Pasqual Maragall Foundation, and the Lou Ruvo Brain Institute in February 2009. The meeting initiated the planning of a European Union-North American collaborative research enterprise to expedite the delay and ultimate prevention of dementing disorders. The key aim is to build parallel and complementary research infrastructure that will support international standardization and inter-operability among researchers in both continents. The meeting identified major challenges, opportunities for research resources and support, integration with ongoing efforts, and identification of key domains to influence the design and administration of the enterprise.

Detection of visuoperceptual deficits in preclinical and mild Alzheimer's disease.

Exhaustive neuropsychological assessment of mild cognitive impairment (MCI) subjects frequently identifies cognitive deficits other than memory. However, visuoperception has rarely been investigated in MCI. The 15-Objects Test (15-OT), a visual discrimination task based on the Poppelreuter Test, consists of 15 overlapping objects. Poppelreuter-type tests are frequently used to detect visual agnosia. However, more complex tests, such as the 15-OT, are required to detect visuoperceptual signs in those patients who perform correctly on simple tests. The aim of the present study was to investigate visuoperceptual deficits in MCI patients and to assess the usefulness of the 15-OT to discriminate Alzheimer's disease (AD) and MCI patients from controls. The 15-OT, and a neuropsychological battery included in the diagnostic assessment, was administered to 44 healthy controls, 44 MCI patients, and 44 mild AD patients. Performance on the 15-OT was significantly different between groups. MCI scored between AD and controls. When MCI and AD patients had relatively normal performance on simple tests (Poppelreuter), increased significant abnormalities were found by a more difficult visuoperceptual test (15-OT). Regression analyses showed that the 15-OT was a significant predictor of group membership, but the Poppelreuter Test did not significantly contribute to the models. Visuoperceptual processing is impaired early in the clinical course of AD. The 15-OT allows detection of visuoperceptual deficits in the preclinical and mild AD stages, when classical tests are still unable to detect subtle deficits. So, its inclusion in neuropsychological batteries that are nowadays used in the clinical practice would allow increasing their diagnostic potential.

Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease.

Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop beta-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non-treated transgenic animals. Immunization with amyloid-beta peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis, and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid, nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of meningoencephalitis following immunization with amyloid-beta peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation with amyloid deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD4+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense (collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Abeta42 and Abeta40, in addition to severe small cerebral blood vessel disease and multiple cortical hemorrhages. Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1: SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau dependent on beta-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28a/beta inductor, and of LMP7, LMP2 and MECL1 subunits of the immunoproteasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells. Immunoproteasome subunit expression was accompanied by local presentation of MHC class I molecules. Release of antigenic peptides derived from beta-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-beta peptide immunization.

Efficacy and safety of donepezil in patients with Alzheimer's disease: results of a global, multinational, clinical experience study.

BACKGROUND: Donepezil has consistently been shown to be effective and well tolerated in the symptomatic treatment of Alzheimer's disease in placebo-controlled clinical trials. It has been shown to provide significant benefits in cognition, global function and activities of daily living in patients with mild-to-moderate Alzheimer's disease. However, in order to control for confounding factors, some clinical trials of donepezil have excluded patients with comorbid illness and concomitant medication use. OBJECTIVE: The objective of this study was to evaluate the efficacy, tolerability and safety of donepezil in a wider and more diverse sample of patients and centres than previous trials, reflecting routine clinical practice. METHODS: In this 12-week, open-label, multicentre trial, patients with probable mild-to-moderate Alzheimer's disease received donepezil 5 mg/day for 28 days, after which the dosage was increased to 10 mg/day according to the investigating clinician's judgement. Patients were enrolled at 246 study centres in 18 countries worldwide. Cognition was assessed by a trained clinician using the Mini-Mental State Examination (MMSE) at baseline, week 4 and week 12 (or last visit). Changes in patient activity and social interaction were evaluated using a caregiver diary. Each week, caregivers recorded their impression of change compared with baseline on three aspects of patient behaviour using a 5-point scale. Efficacy analyses were performed on the intent-to-treat population. Significance was determined using the paired t-test (0.05 significance level). Tolerability and safety were assessed by monitoring adverse events, physical examinations, vital signs, clinical laboratory test abnormalities and ECG findings throughout the study. RESULTS: A total of 1113 patients received donepezil (mean baseline MMSE score [+/-SD] 18.74 +/- 5.21). 989 (88.9%) patients completed the study; 59 (5%) patients discontinued because of adverse events. Most patients were taking at least one concomitant medication (n = 802; 72%) and had at least one comorbid medical condition (n = 745; 67%) on study entry. Donepezil significantly improved cognition compared with baseline at weeks 4 and 12, and at week 12 using a last observation carried forward (LOCF) analysis (all p < 0.0001). Mean change from baseline MMSE score (+/-SE) at week 12-LOCF was +1.73 +/- 0.10. Donepezil was also associated with significant improvements in patient social interaction, engagement and interest, and initiation of pleasurable activities at all weekly assessments and week 12-LOCF (all p < 0.0001). Donepezil was generally well tolerated; adverse events were consistent with the known safety profile of donepezil. CONCLUSION: Donepezil treatment resulted in statistically significant improvements in cognition and patient activity and social behaviour, and was generally well tolerated despite high levels of comorbid illness and concomitant medication use. The results of this open-label study in a large patient population are consistent with those from controlled trials and support that donepezil is effective in the treatment of mild-to-moderate Alzheimer's disease in everyday practice.

Genética y enfermedad de Alzheimer / Genetics and Alzheimer disease

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