Julien Delrieu

‘Clinical trials in Alzheimer’s disease’: immunotherapy approaches

J. Neurochem. (2012) 120 (Suppl. 1), 186–193.

Managing Cognitive Dysfunction through the Continuum of Alzheimer's Disease Role of Pharmacotherapy

It has been shown that, during several years preceding the diagnosis of Alzheimer’s disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer’s disease or dementia.During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer’s disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer’s disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer’s disease.

Gantenerumab for the treatment of Alzheimer's disease

Importance of the field: Alzheimers disease is the leading cause of dementia in the elderly, and there is no disease-modifying therapy yet available. Immunotherapy directed against the β-amyloid peptide may be capable of slowing the rate of disease progression. Gantenerumab is the first fully human anti-β-amyloid monoclonal antibody. Areas covered: To review the efficacy and safety of immunotherapy drugs and in particular gantenerumab, we used the database MEDLINE. The primary literature on gantenerumab is reviewed in its entirety. We also reviewed the English-language, pre-clinical and clinical trials designed to evaluate the efficacy or/and safety of immunotherapy drugs, from 1999 through 2011. Other Alzheimers disease-passive immunotherapeutics currently in development, according to www.clinicaltrials.gov, are also discussed. Expert opinion: Gantenerumab appears capable of reducing the cerebral β-amyloid peptide burden in patients with Alzheimers disease. Its ability to slow disease progression remains uncertain because no clinical data are available at present. The next step will be to investigate whether removal of brain amyloid translates into clinical benefit for patients at doses of gantenerumab that reduce brain amyloid and are well tolerated.

Apathy as a feature of prodromal Alzheimer's disease: an FDG-PET ADNI study†

The goal of this study is to evaluate brain metabolism in mild cognitive impairment (MCI) patients with and without apathy (as determined by the Neuropsychiatric Inventory Questionnaire).

Amyloid beta peptide immunotherapy in Alzheimer disease.

Recent advances in the understanding of Alzheimers disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimers disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimers disease. Several types of amyloid β peptide immunotherapy for Alzheimers disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimers disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β 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 Alzheimers disease, highlighting the importance of diagnosing Alzheimers 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 Alzheimers disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimers disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimers disease in clinical trials, at prodromal Alzheimers disease, or at asymptomatic subjects or at risk to develop Alzheimers disease and or at asymptomatic subjects with autosomal dominant mutation.

Sensory alien hand syndrome in corticobasal degeneration: A cerebral blood flow study

The presence of alien hand syndrome (AHS) is suggestive of the diagnosis of corticobasal degeneration when it develops in a progressive way. Sensory AHS (sAHS) should be distinguished from the motor form described more commonly. The physiopathology of sAHS remains unclear. The aim of this study is to determine cerebral regions involved in sAHS. We compared perfusion single photon emission computer tomography scans of patients with sAHS (n = 3) and without (n = 4). We observed significant decrease of regional cerebral blood flow over the nondominant thalamus in sAHS+ compared to sAHS− patients. This result suggests the involvement of the nondominant thalamus in sAHS.

Iodine-123 fluoropropyl-carbomethoxy-3-β-(4-iodophenyltropane) single-photon emission computed tomography findings before and after electroconvulsive therapy in major depressive disorder with Parkinsonism.

Background To date, only a few cases of improvement of Parkinsonism in depressed patients treated with electroconvulsive therapy (ECT) have been reported. However, no functional imaging data are available to support this finding. Objective To describe the first observation of increase in dopamine transporter uptake after ECT. Methods Iodine-123 fluoropropyl-carbomethoxy-3-&bgr;-(4-iodophenyltropane) single-photon emission computed tomographic imaging was conducted in a 77-year-old depressed patient displaying symptoms of Parkinson disease (PD) before and after a series of 12 bilateral ECTs. Results The patient displayed improvement in PD symptoms and increase in dopamine transporter uptake after ECT. Conclusions Our observation suggests that the PD symptoms and decrease in striatal uptake appearing in the context of a depressive episode might warrant further attention, as they might be reversible.

Should interventions to treat or prevent Alzheimer’s disease be tested in a population or as targeted treatment of highly selected study participants?

Symptomatic treatments for Alzheimer’s disease should retain a place in the advanced stages of disease since their actions on these symptoms, even if not modifying the course of disease, are critical for improving patients’ comfort and reducing the burden felt by caregivers, especially those facing behavioral disorders. In mild or prodromal stages, the opportunity to act on specific pathophysiological targets should be considered. These targeted and tailored therapies have the greatest chance to be active in the early stages of disease, in the context of heterogeneous pathological mechanisms to be specified by reliable and accessible biomarkers. Finally, interventional approaches in large populations seem particularly appropriate for prevention strategies.

Association of cortical β-amyloid with erythrocyte membrane monounsaturated and saturated fatty acids in older adults at risk of dementia

ObjectivesWe examined the relationships between erythrocyte membrane monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) and cortical β-amyloid (Aβ) load in older adults reporting subjective memory complaints.DesignThis is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial.SettingFrench community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia.ParticipantsParticipants of this study were 61 individuals from the placebo arm of the MAPT trial with data on erythrocyte membrane fatty acid levels and cortical Aβ load.MeasurementsCortical-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 Aβ load were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 (10 comparisons) after correction for multiple testing.ResultsWe found no significant associations between fatty acids and cortical Aβ 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 Aβ (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.ConclusionFuture 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 Aβ.

NEUROPSYCHIATRIC SYMPTOMS OF MILD COGNITIVE IMPAIRMENT PREDICTING PROGRESSION TO DEMENTIA IN THE ROSAS COHORT

were more likely converted to dementia (1 year 16.7 vs 37.5 vs 69.2%; 2 year 33.3 vs 50.0%, and 76.9%) (Figure.1).The difference in conversion rates were significant at both 1 year (p<0.001) and 2 year (p1⁄40.004). The positive likelihood ratio (LR+) of mixed type MCI converting to dementia was 15.63 and 9.16 at 1 and 2 year respectively when comparing with MCI of Alzheimer’s etiology. Conclusions: The overall dementia conversion rate of MCI is high and up to 40% in 2 years. Subtype of MCI has significant impact on rates of progression to dementia.