Michael S. Rafii

A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease

Nerve growth factor (NGF) is an endogenous neurotrophic‐factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimers disease (AD), but safe and effective delivery has proved unsuccessful.

High-throughput, fully automated volumetry for prediction of MMSE and CDR decline in mild cognitive impairment.

Medial temporal lobe (MTL) atrophy is associated with increased risk for conversion to Alzheimer disease, but manual tracing techniques and even semiautomated techniques for volumetric assessment are not practical in the clinical setting. In addition, most studies that examined MTL atrophy in Alzheimer disease have focused only on the hippocampus. It is unknown the extent to which volumes of amygdala and temporal horn of the lateral ventricle predict subsequent clinical decline. This study examined whether measures of hippocampus, amygdala, and temporal horn volume predict clinical decline over the following 6-month period in patients with mild cognitive impairment (MCI). Fully automated volume measurements were performed in 269 MCI patients. Baseline volumes of the hippocampus, amygdala, and temporal horn were evaluated as predictors of change in Mini-mental State Examination and Clinical Dementia Rating Sum of Boxes over a 6-month interval. Fully automated measurements of baseline hippocampus and amygdala volumes correlated with baseline delayed recall scores. Patients with smaller baseline volumes of the hippocampus and amygdala or larger baseline volumes of the temporal horn had more rapid subsequent clinical decline on Mini-mental State Examination and Clinical Dementia Rating Sum of Boxes. Fully automated and rapid measurement of segmental MTL volumes may help clinicians predict clinical decline in MCI patients.

Advances in Alzheimer’s Disease Drug Development

Alzheimer’s disease (AD) is the foremost cause of dementia worldwide. Clinically, AD manifests as progressive memory impairment followed by a gradual decline in other cognitive abilities leading to complete functional dependency. Recent biomarker studies indicate that AD is characterized by a long asymptomatic phase, with the development of pathology occurring at least a decade prior to the onset of any symptoms. Current FDA-approved treatments target neurotransmitter abnormalities associated with the disease but do not affect what is believed to be the underlying etiology. In this review, we briefly discuss the most recent therapeutic strategies being employed in AD clinical trials, as well the scientific rationale with which they have been developed.

The National Task Group on Intellectual Disabilities and Dementia Practices Consensus Recommendations for the Evaluation and Management of Dementia in Adults With Intellectual Disabilities

Adults with intellectual and developmental disabilities (I/DD) are increasingly presenting to their health care professionals with concerns related to growing older. One particularly challenging clinical question is related to the evaluation of suspected cognitive decline or dementia in older adults with I/DD, a question that most physicians feel ill-prepared to answer. The National Task Group on Intellectual Disabilities and Dementia Practices was convened to help formally address this topic, which remains largely underrepresented in the medical literature. The task group, comprising specialists who work extensively with adults with I/DD, has promulgated the following Consensus Recommendations for the Evaluation and Management of Dementia in Adults With Intellectual Disabilities as a framework for the practicing physician who seeks to approach this clinical question practically, thoughtfully, and comprehensively.

The down syndrome biomarker initiative (DSBI) pilot: proof of concept for deep phenotyping of Alzheimer’s disease biomarkers in down syndrome

To gain further knowledge on the preclinical phase of Alzheimer’s disease (AD), we sought to characterize cognitive performance, neuroimaging and plasma-based AD biomarkers in a cohort of non-demented adults with down syndrome (DS). The goal of the down syndrome biomarker Initiative (DSBI) pilot is to test feasibility of this approach for future multicenter studies. We enrolled 12 non-demented participants with DS between the ages of 30–60 years old. Participants underwent extensive cognitive testing, volumetric MRI, amyloid positron emission tomography (PET; 18F-florbetapir), fluorodeoxyglucose (FDG) PET (18F-fluorodeoxyglucose) and retinal amyloid imaging. In addition, plasma beta-amyloid (Aβ) species were measured and Apolipoprotein E (ApoE) genotyping was performed. Results from our multimodal analysis suggest greater hippocampal atrophy with amyloid load. Additionally, we identified an inverse relationship between amyloid load and regional glucose metabolism. Cognitive and functional measures did not correlate with amyloid load in DS but did correlate with regional FDG PET measures. Biomarkers of AD can be readily studied in adults with DS as in other preclinical AD populations. Importantly, all subjects in this feasibility study were able to complete all test procedures. The data indicate that a large, multicenter longitudinal study is feasible to better understand the trajectories of AD biomarkers in this enriched population. This trial is registered with ClinicalTrials.gov, number NCT02141971.

A phase 3 trial of IV immunoglobulin for Alzheimer disease

Objective: We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia. Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimers Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimers Disease Cooperative Study–Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. Results: No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo. Conclusions: Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo. Clinicaltrials.gov identifier: NCT00818662. Classification of evidence: This study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.

Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer's disease.

Background: To assess the relationship between regional neocortical atrophy and psychotic symptoms in adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods: Rates of change in regional neocortical atrophy as measured by longitudinal magnetic resonance imaging scans and the occurrence of psychotic symptoms and/or the long-term use of antipsychotic medications in 389 outpatients with MCI or AD in Alzheimer’s Disease Neuroimaging Initiative. Results: Atrophy rate of 3 specific neocortical regions, lateral frontal, lateral parietal, and anterior cingulate gyrus, was significantly associated with the onset of psychosis including delusions, agitation, wandering, and hallucinations and/or the need for chronic antipsychotic medications. Atrophy rate of the lateral frontal lobe correlated most significantly with onset of psychotic symptoms or need for chronic antipsychotic medications. Conclusions: Psychosis was associated with volume loss in specific regions of the lateral frontal and parietal lobes as well as anterior cingulate gyrus.

Orolingual angioedema associated with ACE inhibitor use after rtPA treatment of acute stroke

Angioedema occurs in up to 5% of patients on angiotensin-converting enzyme inhibitor (ACEI) therapy receiving IV rtPA.1 A 58-year-old man taking the combination ACEI amlodipine/benazepril received IV rtPA for clinical left …

Outcome Measures for Clinical Trials in Down Syndrome

Increasingly individuals with intellectual and developmental disabilities, including Down syndrome, are being targeted for clinical trials. However, a challenge exists in effectively evaluating the outcomes of these new pharmacological interventions. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials with individuals with Down syndrome have been identified. To address this challenge, the National Institutes of Health (NIH) assembled leading clinicians and scientists to review existing measures and identify those that currently are appropriate for trials; those that may be appropriate after expansion of age range addition of easier items, and/or downward extension of psychometric norms; and areas where new measures need to be developed. This article focuses on measures in the areas of cognition and behavior.

An Expanded Role for Neuroimaging in the Evaluation of Memory Impairment

SUMMARY: Alzheimer disease affects millions of people worldwide. The neuropathologic process underlying this disease begins years, if not decades, before the onset of memory decline. Recent advances in neuroimaging suggest that it is now possible to detect Alzheimer-associated neuropathologic changes well before dementia onset. Here, we evaluate the role of recently developed in vivo biomarkers in the clinical evaluation of Alzheimer disease. We discuss how assessment strategies might incorporate neuroimaging markers to better inform patients, families, and clinicians when memory impairment prompts a search for diagnosis and management options.