Initial Experiences with Amyloid-Related Imaging Abnormalities in Patients Receiving Aducanumab Following Accelerated Approval.

Aducanumab is the first FDA-approved amyloid-lowering immunotherapy for Alzheimer's disease. There is little real-world data to guide management of amyloid-related imaging abnormalities (ARIA), a potentially serious side-effect which requires surveillance with magnetic resonance imaging. We report our experiences in managing ARIA in patients receiving aducanumab at the Butler Hospital Memory and Aging Program during the year following FDA approval. We followed the Appropriate Use Recommendations for aducanumab to guide patient selection, detection, and management of ARIA (1). ARIA-E occurred in 6 out of 24 participants treated; all APOE-ε4 carriers. Treatment was discontinued in 4 cases of moderate-severe ARIA-E, temporarily held in 1 moderate case, and dosed through in 1 mild case (mean duration = 3 months, range, 1-6 months). No participants required hospitalization or high dose corticosteroids. Participants on anticoagulation were excluded and no macrohemorrhages occurred. These data support the measured approaches to treatment outlined in the Appropriate Use Recommendations.

The Effects of Subjective Cognitive Decline on APOE Genotype Disclosure in the Butler Hospital Alzheimer's Prevention Registry.

BACKGROUND: Subjective cognitive decline (SCD) and APOE genotyping are both instrumental in identifying high-risk individuals for Alzheimer's disease (AD) prevention trials. OBJECTIVE: This study examined the relationship between SCD and the impact of APOE disclosure on the psychological and behavioral health of cognitively unimpaired individuals. Design/Setting/Participant: We recruited 189 trial volunteers (mean age 66, 65% female, 96% White), from the Butler Hospital Alzheimer's Prevention Registry. Participants completed screening for cognitive impairment and a psychological readiness assessment before learning their APOE genotype, and were followed for 6 months after. RESULTS: SCD had a modest, temporary impact on mood and event-related distress following APOE disclosure, specifically on those who were ε4 carriers. The presence of SCD (SCD+) did not compound the AD genetic test-specific distress related to learning that one was an ε4 carrier. SCD also did not moderate changes in perceived AD risk, with all non-carriers showing a more rapid decrease in perceived risk over time than carriers. Counterintuitively, those without SCD (SCD-) reported taking more steps in future-directives than the SCD+ group at baseline and after disclosure, potentially suggesting that those with SCD may have subtle executive declines that limit future-oriented actions or fear-avoidance behaviors. Further, the SCD- group was more accurate in recalling their APOE status and the recall accuracy correlated with their broad knowledge about APOE as a risk gene for AD. CONCLUSION: Our findings support the safety and tolerability of APOE disclosure in research volunteers regardless of their SCD statuses, but further studies are warranted to include diverse individuals and those pursuing testing through direct-to-consumer services outside of traditional research settings.

Alzheimer's Disease Clinical Trial Research Adaptation Following COVID-19 Pandemic Onset: National Sample of Alzheimer's Clinical Trial Consortium Sites.

BACKGROUND: The COVID-19 pandemic created challenges in clinical research operations that required immediate and lasting changes. OJBECTIVES: The purpose of this study was to explore adaptations to clinical trial research due to COVID-19 and develop a theoretical framework of emergent strategies related to pandemic mitigation in a national network of Alzheimer's disease clinical trial sites. DESIGN: This qualitative study used a grounded theory approach including semi-structured interviews, constant comparative methods, and multi-level, iterative coding. PARTICIPANTS: Twenty-six member sites of the Alzheimer's Clinical Trial Consortium participated with a total of 49 participants. RESULTS: Findings demonstrate processes of adaptation following COVID-19 onset including establishing safety as priority, focus on scientific preservation, accommodations (creating policies, leadership mindset, maintaining operations, and determining research procedures), and evaluation of changes throughout the course of the pandemic. Communication and maintaining integrity were vital throughout these processes. CONCLUSION: Processes of accommodation among clinical research sites during the pandemic provide critical insights and direction for future clinical trials development and emergent methods in Alzheimer's disease and other therapeutic areas.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience.

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

The use of herbal alternative medicines in neuropsychiatry. A report of the ANPA Committee on Research.

Growing numbers of people throughout the United States (40% in 1998) are using various forms of alternative therapies. A MEDLINE literature search of journals from the past three decades and an Internet database query were performed to determine the types and frequency of alternative therapies used, with special attention given to the herbal medicines used in neuropsychiatric disorders. Clinical effects, mechanisms of action, interactions, and adverse reactions of the herbal treatments are detailed. Objective controlled trials will be needed to establish safety and efficacy of herbal supplements. Knowledge of the properties of these therapies can improve the care of neuropsychiatric patients.

Neuropsychiatric correlates and treatment of lenticulostriatal diseases: a review of the literature and overview of research opportunities in Huntington's, Wilson's, and Fahr's diseases. A report of the ANPA Committee on Research. American Neuropsychiatric Association.

This report reviews clinical neuropsychiatric findings and opportunities for research in Huntington's, Wilson's, and Fahr's diseases. Consistent, systematic methodology is lacking among neuropsychiatric studies in these lenticulostriatal diseases. Systematic cross-sectional and longitudinal assessments are needed to ascertain the prevalence of psychiatric disorders as a function of disease course. Preliminary synthesis of existing data suggests the following heuristic relationships in these diseases: depression with parkinsonian states; personality changes with caudate or putamen disease; psychosis, impulsivity, and sexual disorders with caudate disease; dementia and mania with caudate and pallidal diseases; and compulsions with pallidal disease. Correlation of neuropsychiatric findings with disease stage, clinical signs, and radiologic, metabolic, physiologic, and pathologic markers of disease will add to our understanding of these conditions.

Diagnosis and treatment of patients with "frontal lobe" syndromes.

Nine case descriptions illustrate the three major prefrontal syndromes seen in clinical practice: disorganized type, disinhibited type, and apathetic type. A mixture of symptoms from each subtype is usually seen, but dysfunction in one prefrontal system often dominates. A careful history and examination are essential for accurate diagnosis. A complete history can rarely be elicited from the patient alone. Structural brain imaging, especially MRI, and neuropsychological testing are key to the diagnostic workup. EEG, video-EEG, and functional brain imaging can be valuable in the evaluation of possible partial complex seizures of frontal lobe origin and other atypical frontal lobe disorders. Effective treatment requires educating the patient and the family about the illness and modulating environmental factors that influence the patient's behavior. Judicious use of psychoactive medication may be helpful, but adverse effects are common.

Treatment strategies for patients with dysexecutive syndromes.

Patients with prefrontal behavioral syndromes (dysexecutive, disinhibited, and apathetic) present a significant therapeutic challenge that demands the integration of psychopharmacologic, behavioral, and systemic interventions. Unfortunately, the behavioral disturbances of such patients are frequently misinterpreted and therefore inadequately treated. This article describes the various strategies that are available to the clinician in treating patients with prefrontal deficits.

Prolonged postictal encephalopathy in two patients with clozapine-induced seizures.

Two patients with prolonged postictal encephalopathy lasting 63 and 72 hours, respectively, following seizures with clozapine are reported. Clozapine alters the EEG in a majority of patients treated, with seizure frequency as high as 5-10% in doses above 600 mg/d. Prolonged postictal encephalopathy following a clozapine-induced seizure has not been previously reported but may be an important side effect of this medication. Pharmacologic and clinical issues are discussed.