Considerations for the assessment of suicidal ideation and behavior in older adults with cognitive decline and dementia.

INTRODUCTION: Better understanding of suicide risk and its management in older adults with cognitive impairment and/or dementia remain significant unmet public health needs. Urgency to address them derives from concern that CNS treatments for dementia may impact suicide risk. Regulatory guidances requiring assessment of emergent suicidal ideation and behavior (SI/SB) at every clinical trial visit emphasize the need for understanding their prevalence. METHODS: The literature regarding SI/SB in older persons with cognitive impairment or dementia was reviewed by an Alzheimer's Association Taskforce with emphasis on epidemiology, classification, assessment, and regulatory requirements. RESULTS: Gaps in our knowledge were identified, challenges discussed and recommendations for future work provided. DISCUSSION: Currently available SI/SB data from geriatric persons with dementia do not provide adequate understanding of its epidemiology, identification, assessment, or management. The growing public health burden of this population requires greater attention from clinicians and researchers on tactics and assessment tools to meet these needs.

Suicidal ideation and behavior assessment in dementia studies: An Internet survey.

INTRODUCTION: The AARR task force on suicidal ideation and behavior (SI/SB) in dementia conducted an online survey on the extent of SI/SB in individuals diagnosed with mild cognitive impairment (MCI) or dementia who were participating in clinical trials. METHODS: Investigators with experience in conducting SI/SB assessments in clinical trial subjects with MCI or dementia were invited to complete a global 19-item online survey. RESULTS: A total of 204 evaluable responses were collected with the majority from North America and Europe (83.4%) and the remainder from Asia, Latin America, and Mideast/Africa. The mean (SD) number of subjects personally assessed by the respondents in the past year with MCI, mild-moderate dementia, or severe dementia was 12.8 (26.2), 31.2 (39.6), and 10.1 (34.7), respectively. The mean number of subjects in each diagnostic group with suicidal ideation (SI), suicidal behavior (SB), or completed suicide (CS) was on average quite low (0.3 to 1.1 for SI, 0.1 to 0.2 for SB, and 0.0 to 0.2 for CS). Confidence in subject self-reports of SI/SB over different time periods declined with increasing severity of cognitive impairment and with increasing duration of the recall time period assessed. Of respondents, 56% and 75% had low confidence in self-ratings of SI/SB from subjects with severe dementia over the past 24 hours and the past week to 1 month, respectively. Ratings of the reliability of information collected on SI/SB also decreased with increasing severity of cognitive impairment. Approximately 70% of respondents rated the reliability of the information they obtained from all sources (patient, caregiver, and others) for subjects with MCI as high, but only about half (42.0% to 55.3%) and less than a quarter (17.4% to 24.3%) rated the reliability of information obtained for subjects with mild to moderate dementia or severe dementia as high, respectively. DISCUSSION: These results support the usefulness of prospective SI/SB assessments in MCI and mild dementia, raise questions about the reliability of assessments in moderate dementia, and confirm their lack of clinical utility in severe dementia. The results highlight the need for development of validated assessment instruments adapted to the stage of cognitive decline of the patients under study and may be the most effective in the earliest stages of the disease.

Assessing cognition and function in Alzheimer's disease clinical trials: do we have the right tools?

Several lines of evidence from Alzheimer's disease (AD) research continue to support the notion that the biological changes associated with AD are occurring possibly several decades before an individual will experience the cognitive and functional changes associated with the disease. The National Institute on Aging-Alzheimer's Association revised criteria for AD provided a framework for this new thinking. As a result of this growing understanding, several research efforts have launched or will be launching large secondary prevention trials in AD. These and other efforts have clearly demonstrated a need for better measures of cognitive and functional change in people with the earliest changes associated with AD. Recent draft guidance from the US Food and Drug Administration further elevated the importance of cognitive and functional assessments in early stage clinical trials by proposing that even in the pre-symptomatic stages of the disease, approval will be contingent on demonstrating clinical meaningfulness. The Alzheimer's Association's Research Roundtable addressed these issues at its fall meeting October 28-29, 2013, in Washington, D.C. The focus of the discussion included the need for improved cognitive and functional outcome measures for clinical of participants with preclinical AD and those diagnosed with Mild Cognitive Impairment due to AD.

Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.

Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-ß burden in Alzheimer's disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent "vasogenic edema" and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2* thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research.

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics.

BACKGROUND: Growing evidence suggests that elevated cholesterol levels in mid-life are associated with increased risk of developing Alzheimer's disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitor's Effect in Alzheimer's Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily). METHODS: This is an international, multicenter, double-blind, randomized, parallel-group study with a double-blind randomized withdrawal phase of patients with mild to moderate AD (Mini-Mental State Examination [MMSE] score, 13 to 25). Inclusion criteria included age 50 to 90 years, receiving donepezil 10 mg for at least 3 months before randomization, and low-density lipoprotein cholesterol levels (LDL-C) 2.5 to 3.5 mmol/L (95 to 195 mg/dL). Co-primary end points are changes in AD Assessment Scale-cognitive subscale (ADAS-cog) and AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale scores. A confirmatory end point is rate of change in whole brain and hippocampal volumes in patients who enrolled in the magnetic resonance imaging substudy. RESULTS: Enrollment of 641 subjects is complete. The baseline mean data are age 74 +/- 8 years, 53% women, MMSE 22 +/- 3, ADAS-cog 23 +/- 10, AD Functional Assessment and Change Scale (ADFACS) 13 +/- 9, Neuropsychiatric Inventory (NPI) 10 +/- 11, and Clinical Dementia Rating-Sum of Boxes (CDR-SB) 6 +/- 3. Mean prior donepezil treatment was 409 +/- 407 days. Mean baseline lipid levels are total cholesterol 5.8 +/- 0.8 mmol/L (224 +/- 33 mg/dL), LDL-C 3.7 +/- 0.7 mmol/L (143 +/- 26 mg/dL), triglycerides 1.5 +/- 0.7 mmol/L (132 +/- 64 mg/dL), and high-density lipoprotein cholesterol 1.6 +/- 0.5 mmol/L (64 +/- 18 mg/dL). CONCLUSIONS: LEADe will report in 2008 and is expected to provide a more definitive evaluation of the potential for statins in the treatment of people with AD.

Donepezil in vascular dementia: combined analysis of two large-scale clinical trials.

BACKGROUND AND OBJECTIVE: There are currently no drugs approved to treat vascular dementia (VaD). The objective of this study was to determine if treatment with donepezil, an acetylcholinesterase inhibitor, may provide benefit for VaD patients. METHODS: Combined analysis of 2 identical randomized, double-blind, placebo-controlled, 24-week studies involving 1,219 patients enrolled at 109 investigational sites in the USA, Europe, Canada and Australia. Patients were randomized to receive donepezil 5 mg/day (n = 406) or 10 mg/day (after brief titration; n = 421) or placebo (n = 392). Patients were assessed on cognition [Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE)], global function [Clinician's Interview-Based Impression of Change plus (CIBIC-plus), Clinical Dementia Rating-Sum of the Boxes (CDR-SB)] and function [Alzheimer's Disease Functional Assessment and Change Scale (ADFACS); instrumental activities of daily living (ADFACS-IADL)]. RESULTS: Both donepezil groups showed significant improvements in cognition compared with placebo (ADAS-cog, MMSE, p < 0.01). Significant global function benefits were seen on the CIBIC-plus in the 5 mg/day group (placebo vs. 5 mg/day, p < 0.001; vs. 10 mg/day, p = 0.006) and on the CDR-SB in the 10 mg/day group (placebo vs. 5 mg/day, p = 0.09; vs. 10 mg/day, p < 0.01). Significant functional benefits were also seen (ADFACS, placebo vs. 5 mg/day, p = 0.08; vs. 10 mg/day, p = 0.02; ADFACS-IADL, p < 0.05 for both donepezil groups). Donepezil was well tolerated, with low withdrawal rates due to adverse events. CONCLUSIONS: This combined analysis of the largest trial on VaD to date showed that donepezil-treated patients had significant benefits in cognition, global function and ability to perform IADL. Based on these findings and reported tolerability, donepezil should be considered as an important therapeutic element in the overall management of patients with VaD.