Robert H. Brashear

Neuropsychiatric symptoms in Alzheimer’s disease

Neuropsychiatric symptoms (NPS) are core features of Alzheimers disease and related dementias. Once thought to emerge primarily in people with late‐stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia‐associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimers Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimers disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.

EVALUATION OF CEREBRAL GRAY MATTER AND PONS AS REFERENCE REGIONS FOR AMYLOID PET: RESULTS FROM A BAPINEUZUMAB SUBCUTANEOUS PHASE 2 TRIAL

ensure comparability and spatial correlations were assessed both voxelwise and using regions of interest (ROIs) from the AAL atlas. Results: Developmental effects showed reductions in GMwith advancing age that were highly correlated with both metabolism and A. All three maps (Figure, top row) showed significant spatial correlation, on a voxelwise level (GM-FDG, r 1⁄4 0.264; FDG-Ab, r1⁄4 0.546; GM-Ab, r1⁄4 0.336, all p<0.001; Figure, middle row) or with AAL ROIs (pruning-FDG, r 1⁄4 0.563; FDG-Ab, r 1⁄4 0.634; pruning-Ab, r 1⁄4 0.641, all p<0.001; Figure, bottom row). Conclusions: The regions that are prone to Ab already share common features in early life: they are very metabolically active in young adults and also show age-related gray matter reduction (“pruning”) in childhood. While these topographical correlations do not define causal relationships, they support theories that synaptic activity influences Ab deposition. In particular, these data suggest that early life pruning may result in neural systems in association cortex that are metabolically stressed and thereby susceptible to Ab deposition.

Measuring cognition and function in the preclinical stage of Alzheimer's disease

The Alzheimers Associations Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimers disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimers disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimers Prevention Initiative Autosomal Dominant Alzheimers Disease Trial, the Alzheimers Prevention Initiative Generation Study, and the Anti‐Amyloid Treatment in Asymptomatic Alzheimers to compare current approaches and tools that are being developed.

A PROSPECTIVE, SYSTEMATIC LITERATURE REVIEW AND META-ANALYSES TO EVALUATE GLOBAL AND REGIONAL BRAIN VOLUMES BY STRUCTURAL MRI AS BIOMARKERS OF ALZHEIMER'S DISEASE (AD) PROGRESSION

and MMSE was found in the occipital lobes for the combined AD+MCI+HC (Pearson 0.82, p1⁄40.0465) and AD (Pearson 0.99, p1⁄40.01) groups. Conclusions:Based on relatively small number of studies, no apparent relationship between change on brain amyloid burden and cognition in AD was found. In contrast, the negative correlation seen in MCI suggests that PiB PET changes may be a useful biomarker in earlier disease phases. The significant finding in the correlation between changes in amyloid deposition in the occipital lobe and MMSE warrants further study. Limitation included the paucity of studies having longitudinal data on both brain amyloid burden and clinical measures and heterogeneity amongst studies.

The value of subtraction MRI in detection of amyloid-related imaging abnormalities with oedema or effusion in Alzheimer’s patients: An interobserver study

AbstractBackgroundImmunotherapeutic treatments targeting amyloid-β plaques in Alzheimer’s disease (AD) are associated with the presence of amyloid-related imaging abnormalities with oedema or effusion (ARIA-E), whose detection and classification is crucial to evaluate subjects enrolled in clinical trials.PurposeTo investigate the applicability of subtraction MRI in the ARIA-E detection using an established ARIA-E-rating scale.MethodsWe included 75 AD patients receiving bapineuzumab treatment, including 29 ARIA-E cases. Five neuroradiologists rated their brain MRI-scans with and without subtraction images. The accuracy of evaluating the presence of ARIA-E, intraclass correlation coefficient (ICC) and specific agreement was calculated.ResultsSubtraction resulted in higher sensitivity (0.966) and lower specificity (0.970) than native images (0.959, 0.991, respectively). Individual rater detection was excellent. ICC scores ranged from excellent to good, except for gyral swelling (moderate). Excellent negative and good positive specific agreement among all ARIA-E imaging features was reported in both groups. Combining sulcal hyperintensity and gyral swelling significantly increased positive agreement for subtraction images.ConclusionSubtraction MRI has potential as a visual aid increasing the sensitivity of ARIA-E assessment. However, in order to improve its usefulness isotropic acquisition and enhanced training are required. The ARIA-E rating scale may benefit from combining sulcal hyperintensity and swelling.Key Points• Subtraction technique can improve detection amyloid-related imaging-abnormalities with edema/effusion in Alzheimer’s patients. • The value of ARIA-E detection, classification and monitoring using subtraction was assessed. • Validation of an established ARIA-E rating scale, recommendations for improvement are reported. • Complementary statistical methods were employed to measure accuracy, inter-rater-reliability and specific agreement.

USING SUBTRACTION MRI TO IMPROVE THE DETECTION OF AMYLOID-RELATED IMAGING ABNORMALITIES WITH EDEMA OR EFFUSION (ARIA-E) IN PATIENTS AFFECTED BY ALZHEIMER’S DISEASE RECEIVING IMMUNOTHERAPY: AN INTER-OBSERVER STUDY

Background: Amyloid-s plaques are considered the hallmark of Alzheimers disease (AD). Immunotherapeutic strategies targeting Abeta have shown promising results, although they are associated with adverse events, including amyloid-related imaging abnormalities with edema and effusion (ARIA-E). A magnetic resonance imaging (MRI) scale to improve the detection and classification of these lesions has recently been approved. The purpose of this study was to investigate the use of the subtraction technique as an adjunct to standard FLAIR to improve the detection of ARIA-E using an established rating score. Methods:We included 75 AD patients who were submitted to Bapineuzumab treatment in a phase II study, 29 of whom developed ARIA-E. Five experienced neuroradiologists rated the brain MRI scans with and without using subtraction images after image registration. The accuracy of detection, intraclass correlation coefficient (ICC) and positive and negative specific agreement were calculated. Results: The sensitivity and specificity of ARIA-E cases detection per individual rater were excellent using both native images (1.00, 0.957, respectively) and subtraction images (0.966, 0.891, respectively). Overall, the detection rate with subtraction images resulted in higher sensitivity (0.966) and lower specificity rate (0.970) compared to native images (0.959, 0.991, respectively). ICC scores in both groups ranged from good to excellent, except for gyral swelling (moderate). Excellent negative specific agreement among all ARIA-E imaging features and good positive agreement were demonstrated in both groups. Positive agreement for subtraction images increased significantly when combining sulcal hyperintensity and gyral swelling. Conclusions: The use of subtraction imaging for the evaluation of ARIA-E may improve the detection of these abnormalities and the classification of their features. Nevertheless, this method would benefit from isotropic acquisition, enhanced training, and modification of the ARIA-E rating scale to lump parenchymal and sulcal hyperintensity or swelling. (Table Presented).

Amyloid-related imaging abnormalities (ARIA) in Alzheimer’sdisease patients treated with bapineuzumab: A retrospective analysis

BACKGROUND Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimers disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. METHODS Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patients treatment, APOE ɛ4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. FINDINGS 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE ɛ4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001). INTERPRETATION ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. FUNDING Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.