Description and Durability of the Various Indirect Restoration Techniques in Molar-Incisor Hypomineralisation: A Systematic Review.

Molar-incisor hypomineralisation (MIH) is a qualitative defect of the enamel structure. Indirect restorations may represent the most suitable therapeutic solutions for patients presenting MIH with tooth restorative procedures. This systematic review aims to determine the feasibility of indirect restorations. MATERIALS AND METHODS: A systematic review has been performed and is reported following the PRISMA guidelines. It was performed on three databases (PubMed, Science Direct, and Google Scholar). Ten articles were included. RESULTS: Only two articles reported the use of CAD/CAM technologies, whereas the other eight preferred conventional registration and handmade stratification for ceramics. All indirect bonded restorations made of composite resins or ceramics had significant success rates. A temporary material was placed in most of the articles. There was no clear consensus for tissue conditioning before bonding. Depending on the authors and the articles, the follow-up period extended from 2 months to 6 years. CONCLUSIONS: The survival rate and the non-invasive procedures of indirect restorations are two main arguments that can help dental practitioners in daily practice. Development of CAD/ CAM technologies adds new perspectives in the registration, the design and production. However, more clinical trials are needed to confirm the conclusions.

Reliability of Self-Screening for Intrinsic Capacity Impairments Using the ICOPE Monitor App.

AIM: To verify the inter-rater agreement of the Integrated Care for Older People (ICOPE) STEP 1 screening tool using the ICOPE Monitor app, comparing self-assessment to a screening performed by a health professional. METHODS: We compared the results of the ICOPE Step 1 obtained by self-screening with those obtained by a professional screening using Gwet's agreement coefficient in two studies. Study 1 tested inter-rater reliability in participants to the INSPIRE-T cohort who agreed to undergo the self-and the professional screening on the same day. Study 2 used data from the INSPIRE-ICOPE care cohort. We included real-life users of the French health system whose first ICOPE Step 1 was a self-assessment followed by a professional Step 1within 130 days (mean=76 days, SD=60). RESULTS: Study 1 included 79 participants (45 aged less than 60, 34 aged 60 and over, 60% female, mean (SD) age of 54.5 (18.5) years). Of the 207 participants in Study 2, 49 were less than 60, and 158 were 60 and over (54% female, mean (SD) age 67 (16.1) years). Agreement coefficients in Study 1 ranged from 0.49 (CI95% 0.24; 0.66) in the cognition domain - moderate agreement) to 0.99 (CI95% 0.96;1.00) in the nutrition domain - very good agreement); and in Study 2 from 0.36 (CI95% 0.23;0.49) in the cognition domain to 0.97 (95% 0.95;1.00) in the nutrition domain. The agreement coefficients for the cognition and hearing domains were higher for the participants aged <60 than those aged 60 and over. The time orientation items (cognition) showed high reliability. CONCLUSION: Our study supports using ICOPE Step 1 as a self-assessment screening tool. High reliability was found for intrinsic capacity's nutrition, psychological, and locomotion domains, regardless of age. We discuss aspects of the self-assessment of cognition, vision, and hearing domains when using the ICOPE monitor app in older adults.

Impact of Finishing and Polishing Procedures on CAD/CAM In Vitro Milled Ceramics Surfaces: A Systematic Review.

INTRODUCTION AND OBJECTIVES: CAD/CAM prostheses may be produced in prosthetic laboratories or directly by practitioners. Quality of ceramic polishing procedures is a controversial topic and it would be interesting for practitioners working with CAD/CAM devices to determine which method is the most efficient regarding finishing and polishing. This systematic review aims to evaluate the impact of different finishing and polishing procedures on the surface of milled ceramics. MATERIALS AND METHODS: A precise request was launched on the PubMed database. Studies included if they met the criteria of a specifically prepared PICO search. A first selection was performed by analysing titles and abstracts: the articles presenting a study conducted on non-CAD/CAM milled ceramics and research not containing comparisons of finishing procedures were not included. Roughness was evaluated in 15 articles. Nine papers recommended mechanical polishing over glazing regardless of the type of ceramic used. However, no significant differences were detected between the surface roughness of glazed and polished ceramics in nine other publications. CONCLUSIONS: there is no scientific evidence demonstrating the superiority of hand polishing over glazing on CAD/CAM-milled ceramics.

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

The Future of AD Clinical Trials with the Advent of Anti-Amyloid Therapies: An CTAD Task Force Report.

BACKGROUND: Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.

Longitudinal Course of Agitation and Aggression in Patients with Alzheimer's Disease in a Cohort Study: Methods, Baseline and Longitudinal Results of the A3C Study.

BACKGROUND: To present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer's Disease Cohort (A3C) study. OBJECTIVES: The central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings. DESIGN: A3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities. SETTING: Clinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design. PARTICIPANTS: Alzheimer's Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities. MEASUREMENTS: Clinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association "Provisional Diagnostic Criteria for Agitation", socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed. RESULTS: A3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively -11.36 (Standard Error (SE)=1.32; p<0.001) and -6.72 (SE=0.77; p<0.001). CONCLUSION: Little is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer's Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer's Disease.

Framework Implementation of the INSPIRE ICOPE-CARE Program in Collaboration with the World Health Organization (WHO) in the Occitania Region.

INTRODUCTION: Limiting the number of dependent older people in coming years will be a major economic and human challenge. In response, the World Health Organization (WHO) has developed the «Integrated Care for Older People (ICOPE)¼ approach. The aim of the ICOPE program is to enable as many people as possible to age in good health. To reach this objective, the WHO proposes to follow the trajectory of an individual's intrinsic capacity, which is the composite of all their physical and mental capacities and comprised of multiple domains including mobility, cognition, vitality / nutrition, psychological state, vision, hearing. OBJECTIVE: The main objective of the INSPIRE ICOPE-CARE program is to implement, in clinical practice at a large scale, the WHO ICOPE program in the Occitania region, in France, to promote healthy aging and maintain the autonomy of seniors using digital medicine. METHOD: The target population is independent seniors aged 60 years and over. To follow this population, the 6 domains of intrinsic capacity are systematically monitored with pre-established tools proposed by WHO especially STEP 1 which has been adapted in digital form to make remote and large-scale monitoring possible. Two tools were developed: the ICOPE MONITOR, an application, and the BOTFRAIL, a conversational robot. Both are connected to the Gerontopole frailty database. STEP 1 is performed every 4-6 months by professionals or seniors themselves. If a deterioration in one or more domains of intrinsic capacity is identified, an alert is generated by an algorithm which allows health professionals to quickly intervene. The operational implementation of the INSPIRE ICOPE-CARE program in Occitania is done by the network of Territorial Teams of Aging and Prevention of Dependency (ETVPD) which have more than 2,200 members composed of professionals in the medical, medico-social and social sectors. Targeted actions have started to deploy the use of STEP 1 by healthcare professionals (physicians, nurses, pharmacists,…) or different institutions like French National old age insurance fund (CNAV), complementary pension funds (CEDIP), Departmental Council of Haute Garonne, etc. Perspective: The INSPIRE ICOPE-CARE program draws significantly on numeric tools, e-health and digital medicine to facilitate communication and coordination between professionals and seniors. It seeks to screen and monitor 200,000 older people in Occitania region within 3 to 5 years and promote preventive actions. The French Presidential Plan Grand Age aims to largely implement the WHO ICOPE program in France following the experience of the INSPIRE ICOPE-CARE program in Occitania.

Cognitive Function and Amyloid Marker in Frail Older Adults: The COGFRAIL Cohort Study.

BACKGROUND: Frailty and cognitive impairment are common manifestations of the ageing process and are closely related. But the mechanisms linking aging, physical frailty, and cognitive disorders, are complex and remain unclear. OBJECTIVES: We aim to explore the role of cerebral amyloid pathology, but also a range of nutritional, physical, biological or brain-aging marker in the development of cognitive frailty. METHOD: COGFRAIL study is a monocentric prospective study of frail older patients with an objective cognitive impairment (Clinical Dementia Rating Scale global score at 0.5 or 1). Three-hundred-and-twenty-one patients are followed up every 6 months, for 2 years. Clinical assessment at baseline and during follow-up included frailty, physical, mood, sensory, nutritional, and cognitive assessment (with a set of neuropsychological tests). Cerebral amyloid pathology is measured by amyloid Positron Emission Tomography (PET) or amyloid-ß-1-42 level in cerebrospinal fluid. Brain magnetic resonance imaging, measurement of body composition using Dual X Ray Absorptiometry and blood sampling are performed. The main outcome of the study is to assess the prevalence of positive cerebral amyloid status according to amyloid PET or amyloid-ß-1-42 level CSF. Secondary outcomes included biological, nutritional, MRI imaging, cognitive, clinical, physical and body composition markers to better understand the mechanisms of cognitive frailty. PERSPECTIVE: COGFRAIL study will give the opportunity to better understand the link between Gerosciences, frailty, cognitive impairment, and Alzheimer's disease, and to better characterize the physical and cognitive trajectories of frail older adults according to their amyloid status. Understanding the relationship between physical frailty and cognitive impairment is a prerequisite for the development of new interventions that could prevent and treat both conditions.

Amiodarone-induced Ataxia: A Case Report of Severe Cerebellar Dysfunction and Review of Literature.

Amiodarone therapy is widely prescribed in patients with atrial fibrillation. The higher prevalence of this arrhythmic heart disease, and the specific age-related issues of homeostasis in the elderly population, makes this group particularly exposed to its adverse effects. Among the many described side-effects, neurological impairments are the less documented and studied. Because amiodarone can be responsible for severe complications, as described in the case below, a close monitoring is necessary throughout its prescription. Awareness should be brought on the amiodarone-induced neurological side-effects as they could be overlooked.

Can We Distinguish Age-Related Frailty from Frailty Related to Diseases ? Data from the MAPT Study.

BACKGROUND: No study has tried to distinguish subjects that become frail due to diseases (frailty related to diseases) or in the absence of specific medical events; in this latter case, it is possible that aging process would act as the main frailty driver (age-related frailty). OBJECTIVES: To classify subjects according to the origin of physical frailty: age-related frailty, frailty related to diseases, frailty of uncertain origin, and to compare their clinical characteristics. MATERIALS AND METHODS: We performed a secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT), including 195 subjects ≥70 years non-frail at baseline who became frail during a 5-year follow-up (mean age 77.8 years ± 4.7; 70% female). Physical frailty was defined as presenting ≥3 of the 5 Fried criteria: weight loss, exhaustion, weakness, slowness, low physical activity. Clinical files were independently reviewed by two different clinicians using a standardized assessment method in order to classify subjects as: "age-related frailty", "frailty related to diseases" or "frailty of uncertain origin". Inconsistencies among the two raters and cases of uncertain frailty were further assessed by two other experienced clinicians. RESULTS: From the 195 included subjects, 82 (42%) were classified as age-related frailty, 53 (27%) as frailty related to diseases, and 60 (31%) as frailty of uncertain origin. Patients who became frail due to diseases did not differ from the others groups in terms of functional, cognitive, psychological status and age at baseline, however they presented a higher burden of comorbidity as measured by the Cumulative Illness Rating Scale (CIRS) (8.20 ± 2.69; vs 6.22 ± 2.02 frailty of uncertain origin; vs. 3.25 ± 1.65 age-related frailty). Time to incident frailty (23.4 months ± 12.1 vs. 39.2 ± 19.3 months) and time spent in a pre-frailty condition (17.1 ± 11.4 vs 26.6 ± 16.6 months) were shorter in the group of frailty related to diseases compared to age-related frailty. Orthopedic diseases (n=14, 26%) were the most common pathologies leading to frailty related to diseases, followed by cardiovascular diseases (n=9, 17%) and neurological diseases (n = 8, 15%). CONCLUSION: People classified as age-related frailty and frailty related to diseases presented different frailty-associated indicators. Future research should target the underlying biological cascades leading to these two frailty classifications, since they could ask for distinct strategies of prevention and management.

Association of Cortical ß-Amyloid with Erythrocyte Membrane Monounsaturated and Saturated Fatty Acids in Older Adults at Risk of Dementia.

OBJECTIVES: We examined the relationships between erythrocyte membrane monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) and cortical ß-amyloid (Aß) load in older adults reporting subjective memory complaints. DESIGN: This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial. SETTING: French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia. PARTICIPANTS: Participants of this study were 61 individuals from the placebo arm of the MAPT trial with data on erythrocyte membrane fatty acid levels and cortical Aß load. MEASUREMENTS: Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Fatty acids were measured in erythrocyte cell membranes using gas chromatography. Associations between erythrocyte membrane MUFAs and SFAs and cortical Aß load were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 (10 comparisons) after correction for multiple testing. RESULTS: We found no significant associations between fatty acids and cortical Aß load using multiple linear regression adjusted for age, sex, education, cognition, PET-scan to clinical assessment interval, PET-scan to blood collection interval and apolipoprotein E (ApoE) status. The association closest to significance was that between erythrocyte membrane stearic acid and Aß (B-coefficient 0.03, 95 % CI: 0.00,0.05, p = 0.05). This association, although statistically non-significant, appeared to be stronger amongst ApoE ε4 carriers (B-coefficient 0.04, 95 % CI: -0.01,0.09, p = 0.08) compared to ApoE ε4 non-carriers (B-coefficient 0.02, 95 % CI: -0.01,0.05, p = 0.18) in age and sex stratified analysis. CONCLUSION: Future research in the form of large longitudinal observational study is needed to validate our findings, particularly regarding the potential association of stearic acid with cortical Aß.

The ROSAS Cohort: A Prospective, Longitudinal Study of Biomarkers for Alzheimer's Disease. Strategy, Methods and Initial Results.

OBJECTIVE: The aims of the Research Of biomarkers in Alzheimer's diseaSe (ROSAS) study were to determine the biofluid and imaging biomarkers permitting an early diagnosis of Alzheimer's disease and better characterisation of cognitive and behavioural course of the pathology. This paper outlines the overall strategy, methodology of the study, baseline characteristics of the population and first longitudinal results from the ROSAS cohort. METHODS: Longitudinal prospective monocentric observational study performed at the Alzheimer's disease Research centre in Toulouse. A total of 387 patients were studied and analyzed in 3 groups: 184 patients with dementia of Alzheimer's type, 96 patients with memory disorders without dementia (Mild Cognitive Impairment) and 107 patients without abnormal memory tests (control group), and were followed up during 4 years. Patient's sociodemographic characteristics, risk factors, medical conditions, previous and current medications, neuropsychological assessment and overall cognitive status were recorded. Blood and urine samples were collected at every year, Magnetic Resonance Imaging were performed at inclusion, after one year of follow-up and at the end of the study. RESULTS: At baseline, three different groups of the cohort differed interestingly in age, level of education, and in percentage of ApoEε4 carriers whereas the history of cardiovascular and endocrine pathologies were similar among the groups. During the follow-up period (3-4 years) 42 mild cognitive impairment patients (43.8%) progressed to dementia, 7 controls progressed into mild cognitive impairment and 1 patient in the control group converted from mild cognitive impairment group to dementia of Alzheimer's type group. During the first year of follow up, the incidence of progression from mild cognitive impairment to dementia of Alzheimer's type was 12.7 per 100, during the second year 33.9 per 100 and 46.7 per 100 for the third year. CONCLUSION: This paper presents the baseline characteristics of the unique French prospective monocenter study in which the natural course of dementia of Alzheimer's type was evaluated. Future analysis of blood and urine samples collection from the ROSAS study will permit to identify possible biofluid biomarkers predicting the early stages of the dementia of Alzheimer's type and risk of progression from Mild Cognitive Impairment to Alzheimer's disease.

Neuropsychological Profile of "Cognitive Frailty" Subjects in MAPT Study.

OBJECTIVES: An international group proposed the existence of "cognitive frailty", a condition defined by simultaneous presence of physical frailty and cognitive impairment in the absence of dementia. The objective was to compare the neuropsychological profiles in subgroups of elders differentiated across their physical frailty (Fried phenotype) and cognitive status (Clinical Dementia Rating score) to characterize the "cognitive frailty" entity. METHOD: We studied baseline characteristics of 1,617 subjects enrolled in Multidomain Alzheimer Disease Preventive Trial (MAPT). Included subjects were aged 70 years or older and presented at least 1 of the 3 following clinical criteria: (1) Memory complaint spontaneously reported to a general practitioner, (2) limitation in one instrumental activity of daily living, (3) slow gait speed. Subjects with dementia were not included in the trial. RESULTS: "Cognitive frailty individuals" significantly differed from "individuals with cognitive impairment and without physical frailty", scoring worse at executive, and attention tests. They presented subcortico-frontal cognitive pattern different of Alzheimer Disease. Cognitive performance of subjects with 3 criteria or more of the frailty phenotype are cognitively more impaired than subjects with only one. DISCUSION: The characterization of "cognitive frailty" must be done in frail subjects to set up specific preventive clinical trials for this population.

Cognitive and functional patterns of nondemented subjects with equivocal visual amyloid PET findings.

PURPOSE: Despite good to excellent inter-reader agreement in the evaluation of amyloid load on PET scans in subjects with Alzheimer's disease, some equivocal findings have been reported in the literature. We aimed to describe the clinical characteristics of subjects with equivocal PET images. METHODS: Nondemented subjects aged 70 years or more were enrolled from the MAPT trial. Cognitive and functional assessments were conducted at baseline, at 6 months, and annually for 3 years. During the follow-up period, 271 subjects had (18)F-AV45 PET scans. Images were visually assessed by three observers and classified as positive, negative or equivocal (if one observer disagreed). After debate, equivocal images were reclassified as positive (EP+) or negative (EP-). Scans were also classified by semiautomated quantitative analysis using mean amyloid uptake of cortical regions. We evaluated agreement among the observers, and between visual and quantitative assessments using kappa coefficients, and compared the clinical characteristics of the subjects according to their PET results. RESULTS: In 158 subjects (58.30 %) the PET scan was negative for amyloid, in 77 (28.41 %) the scan was positive and in 36 (13.28 %) the scan was equivocal. Agreement among the three observers was excellent (kappa 0.80). Subjects with equivocal images were more frequently men (58 % vs. 37 %) and exhibited intermediate scores on cognitive and functional scales between those of subjects with positive and negative scans. Amyloid load differed between the EP- and negative groups and between the EP+ and positive groups after reclassification. CONCLUSION: Equivocal amyloid PET images could represent a neuroimaging entity with intermediate amyloid load but without a specific neuropsychological pattern. Clinical follow-up to assess cognitive evolution in subjects with equivocal scans is needed.

The Road Ahead To Cure And Prevent Alzheimer's Disease: Implementing Prevention into Primary Care.

Most old adults receive their health care from their primary care practitioner; as a consequence, as the population ages, the manifestations and complications of cognitive impairment and dementia impose a growing burden on providers of primary care. Current guidelines do not recommend routine cognitive screening for older persons by primary care physicians, although the vast majority recommend a cognitive status assessment and neurological examination for subjects with a cognitive complaint. Also, no clinical practice guidelines recommend interventions in older adults with cognitive impairment in primary care settings. However, primary care physicians need to conduct a review of risks and protective factors associated with cognitive decline and organize interventions to improve or maintain cognitive function. Recent epidemiological studies have indicated numerous associations between lifestyle-related risk factors and incidental cognitive impairment. The development of biomarkers could also help in diagnosis, prognosis, selection for clinical trials, and objective assessment of therapeutic responses. Interventions aimed at cognitive impairment prevention should be pragmatic and easy to implement on a large scale in different health care systems, without generating high additional costs or burden on participants, medical and social care teams.

Amyloid beta peptide immunotherapy in Alzheimer disease.

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid ß peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid ß peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid ß peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid ß peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation.

Amyloid imaging in Alzheimer's disease: a literature review.

Therapies targeting amyloid-ß peptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aß immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloid-ß peptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation.

MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER'S DISEASE: DESIGN AND BASELINE DATA.

OBJECTIVE: The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans). DESIGN PATIENTS: 1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study). INTERVENTIONS: 1/Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6-8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24. BASELINE POPULATION: For cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit. DISCUSSION: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.

Is Alzheimer's Disease Drug Development Broken? What Must Be Improved.

During the decade from 2002 to 2012, 99.6% of the 244 agents tested for efficacy in slowing the progression of Alzheimer's' disease (AD) failed to achieve their primary endpoints. At a CTAD symposium on November 14, 2013, in San Diego, USA, an international group of AD researchers met to discuss the evolution of trials over the past 10 years and proposed a number of changes intended to streamline and enhance the efficiency of clinical trials. Approximately 1,031 AD trials were conducted between 2000 and 2012. The number of patients per trial site tended to decrease over time necessitating a larger number of sites. The use of biomarkers for enrichment purposes, or as measures of target engagement or surrogate outcomes, results in higher screen failure and drop-out rates, adding to trial duration and/or costs. Present disease modifying AD trials ask for increasing logistical and technical requirements, necessitating the creation of highly specialized trial facilities and limiting the participation of smaller sites. Due to heavy administrative and regulatory task, only about 13% of the team's time is used for the essential recruitment. Proposals and perspectives: Strategies suggested to improve the efficiency of recruitment include establishing "ready to go cohorts" in advance of trials using biomarkers and clinical measures. Simplification and harmonization of administrative procedures, including harmonization of certification procedures, are urgently needed. Alternative approaches, such as using the Internet to screen volunteers for possible inclusion needs to be evaluated. The AD drug development enterprise from discovery through clinical trials requires re-examination and re-organization if new drugs are to be delivered to patients in a timely way.

[Dementia: Where are the Lewy bodies?]. / Démences : où sont les corps de Lewy ?

Dementia with Lewy bodies (DLB) is the second cause of degenerative dementia in autopsy studies. In clinical pratice however, the prevalence of DLB is much lower with important intercenter variations. Among the reasons for this low sensitivity of DLB diagnosis are (1) the imprecision and subjectivity of the diagnostic criteria; (2) the underestimation of non-motor symptoms (REM-sleep behavior disorder, dysautonomia, anosmia); mostly (3) the nearly constant association of Lewy bodies with Alzheimer's disease pathology, which dominates the clinical phenotype. With the avenue of targeted therapies against the protein agregates, new clinical scales able to apprehend the coexistence of Lewy pathology in Alzheimer's disease are expected.