Ann Marie Hake

Use of anticholinergics and the risk of cognitive impairment in an African American population

Background: Anticholinergic properties of certain medications often go unrecognized, and are frequently used by the elderly population. Few studies have yet defined the long-term impact of these medications on the incidence of cognitive impairment. Methods: We report a 6-year longitudinal, observational study, evaluating 1,652 community-dwelling African American subjects over the age of 70 years who were enrolled in the Indianapolis-Ibadan Dementia Project between 2001 and 2007 and who had normal cognitive function at baseline. The exposure group included those who reported the baseline use of possible or definite anticholinergics as determined by the Anticholinergic Cognitive Burden scale. Our main outcome measure was the incidence of cognitive impairment, defined as either dementia or cognitive impairment not dementia, or poor performance on a dementia screening instrument during the follow-up period. Results: At baseline, 53% of the population used a possible anticholinergic, and 11% used a definite anticholinergic. After adjusting for age, gender, educational level, and baseline cognitive performance, the number of definite anticholinergics was associated with an increased risk of cognitive impairment (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.07–1.99; p = 0.02), whereas the number of possible anticholinergics at baseline did not increase the risk (OR 0.96, 95% CI 0.85–1.09; p = 0.55). The risk of cognitive impairment among definite anticholinergic users was increased if they were not carriers of the APOE ε4 allele (OR 1.77, 95% CI 1.03–3.05; p = 0.04). Conclusions: Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans.

Implementing Innovative Models of Dementia Care: The Healthy Aging Brain Center

Background: Recent randomized controlled trials have demonstrated the effectiveness of the collaborative dementia care model targeting both the patients suffering from dementia and their informal caregivers. Objective: To implement a sustainable collaborative dementia care program in a public health care system in Indianapolis. Methods: We used the framework of Complex Adaptive System and the tool of the Reflective Adaptive Process to translate the results of the dementia care trial into the Healthy Aging Brain Center (HABC). Results: Within its first year of operation, the HABC delivered 528 visits to serve 208 patients and 176 informal caregivers. The mean age of HABC patients was 73.8 (standard deviation, SD 9.5), 40% were African-Americans, 42% had less than high school education, 14% had normal cognitive status, 39% received a diagnosis of mild cognitive impairment, and 46% were diagnosed with dementia. Within 12 months of the initial HABC visit, 28% of patients had at least one visit to an emergency room (ER) and 14% were hospitalized with a mean length of stay of five days. The rate of a one-week ER revisit was 14% and the 30-day rehospitalization rate was 11%. Only 5% of HABC patients received an order for neuroleptics and only 16% had simultaneous orders for both definite anticholinergic and anti-dementia drugs. Conclusion: The tools of ‘implementation science’ can be utilized to translate a health care delivery model developed in the research laboratory to a practical, operational, health care delivery program.

Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington’s disease

We compared oculomotor control among individuals in the early stages of Huntingtons disease (HD), with that of individuals who are presymptomatic HD gene carriers (PSGC) and nongene carriers (NGC). The oculomotor testing paradigm included both traditional tests and a novel experimental procedure to assess visual scanning. Traditional tests elicited saccades, pursuit and optokinetic nystagmus (OKN). HD patients demonstrated marked delay in the initiation of volitional saccades (anti-saccade and memory-guided saccades), a reduced number of correct volitional saccades, reduced velocity of saccades, and a decreased OKN gain. We also studied visual scanning while the participants completed the Digit Symbol Subscale of the Wechsler Adult Intelligence Survey-Revised (WAIS-R). The HD participants demonstrated an abnormal gaze strategy, which may be associated with attention and/or planning deficits. Differences between the PSGC and NGC groups were only observed for two measures: PSGC had a decreased number of memory-guided saccades and a subtle delay in the initiation of volitional saccades. Our results suggest that oculomotor measures are a sensitive biomarker in the early stage of HD and demonstrate that the combination of more traditional oculomotor tests with visual scanning tests is useful in the evaluation of visual performance.

Comparison of neuroimaging modalities for the prediction of conversion from mild cognitive impairment to Alzheimer's dementia.

In this study we compared Pittsburgh compound-B (PIB) positron emission tomography (PET) amyloid imaging, fluorodeoxyglucose PET for metabolism, and magnetic resonance imaging (MRI) for structure to predict conversion from amnestic mild cognitive impairment (MCI) to Alzheimers dementia using data from the Alzheimers Disease Neuroimaging Initiative cohort. Numeric neuroimaging variables generated by the Alzheimers Disease Neuroimaging Initiative-funded laboratories for each neuroimaging modality along with apolipoprotein-E genotype (n = 29) were analyzed. Performance of these biomarkers for predicting conversion from MCI to Alzheimers dementia at 2 years was evaluated in 50 late amnestic MCI subjects, 20 of whom converted. Multivariate modeling found that among individual modalities, MRI had the highest predictive accuracy (67%) which increased by 9% to 76% when combined with PIB-PET, producing the highest accuracy among any biomarker combination. Individually, PIB-PET generated the best sensitivity, and fluorodeoxyglucose PET had the lowest. Among individual brain regions, the temporal cortex was found to be most predictive for MRI and PIB-PET.

Accelerated Weight Loss and Incident Dementia in an Elderly African-American Cohort

OBJECTIVES: To examine the association between changes in body mass index (BMI), dementia, and mild cognitive impairment (MCI).

Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

BACKGROUND Alzheimers disease is characterized by amyloid‐beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double‐blind, placebo‐controlled, phase 3 trial involving patients with mild dementia due to Alzheimers disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron‐emission tomography or Aβ1‐42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14‐item cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS‐cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS‐cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between‐group difference at week 80 (difference, ‐0.80; 95% confidence interval, ‐1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was ‐3.17 in the solanezumab group and ‐3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimers disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665.)

Efficacy and safety of Galantamine in patients with Dementia with Lewy bodies: A 24-week open-label study

Background: Dementia with Lewy bodies (DLB) is a common dementia of the elderly. A significant cholinergic deficit has been demonstrated that may be responsive to treatment by cholinesterase inhibitors (ChEIs). Methods: A 24-week, open-label study was designed to assess the efficacy and safety of a ChEI, galantamine, in 50 patients with DLB. Results: This study showed beneficial effects with galantamine in 2 of the 3 primary efficacy parameters. The scores on the Neuropsychiatric Inventory (NPI-12) improved by 8.24 points from baseline (p = 0.01) especially in visual hallucinations and nighttime behaviors (p = 0.004). The scores on the Clinician’s Global Impression of Change improved by 0.5 points from baseline (p = 0.01). The third primary efficacy parameter, the Cognitive Drug Research Computerized Cognitive Assessment System, was unchanged from baseline. Adverse events were generally mild and transient. Conclusion: Galantamine appears to be an effective and safe therapy for patients with DLB.

The use of memantine in dementia with Lewy bodies

OBJECTIVE To determine the effect of memantine in the treatment of Dementia with Lewy Bodies (DLB). BACKGROUND While memantine has been used to successfully treat moderate-to-severe Alzheimers disease (AD) and some non AD dementias, no reports are available regarding the effect of the drug on DLB. METHODS We reviewed the charts of 11 subjects with DLB by McKeith Criteria that were prospectively evaluated and treated with memantine (with or without cholinesterase inhibitors (ChEIs)) for varying lengths of time. RESULTS 9 of 11 DLB subjects on memantine were also on ChEIs. Seven of eleven were stable or improved with memantine while the remaining four worsened or responded adversely when exposed to the drug. No adverse effects on motor function were observed. CONCLUSIONS Memantine can be used safely in patients with DLB, but its symptomatic effects may be variable.

A multicenter, randomized, placebo controlled, multiple-dose, safety and pharmacokinetic study of AIT-082 (Neotrofin™) in mild Alzheimer's disease patients

A phase 1, randomized, double-blind, placebo-controlled, dose escalation study of the purine derivative, AIT-082 (Neotrofin, NeoTherapeutics) was conducted in mild Alzheimers disease (AD) patients to evaluate multiple-dose safety, tolerability, and pharmacokinetics. Possible short-term effects of AIT-082 on cognition and memory were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimers disease and other neurological disorders. Pre-clinical studies indicate that AIT-082 has memory enhancing properties, stimulates neuritogenesis and the production of neurotrophic factors. Patients received an oral dose of AIT-082 or placebo daily for one week. Thirty-six AD patients were divided into three dose cohorts; each dose cohort consisted of twelve patients with 8 patients randomized to AIT-082 and 4 to placebo. The 3 doses of AIT-082 evaluated in this study were 100 mg/day, 500 mg/day, and 2,000 mg/day. There were no serious adverse events at any dose and the drug was well tolerated without significant side effects. AIT-082 was orally and rapidly absorbed, resulting in peak serum concentrations within 2 hours with an elimination half-life of approximately 20 hours. Higher doses resulted in corresponding increases in peak concentrations and areas under the curve (AUC). There was an approximate 2-fold accumulation in AIT-082 with daily dosing (as reflected by the AUC) at steady state. There were no significant differences by treatment arm on the clinical or neuropsychological evaluations. AIT-082 was rapidly absorbed by the oral route with a half-life suitable for dosing once or twice daily. No problems with tolerability or safety were found. AIT-082 appears suitable for testing in larger clinical trials for the treatment of AD and other neurologic disorders.

Mild cognitive impairment, incidence, progression, and reversion: findings from a community-based cohort of elderly African Americans.

OBJECTIVE To examine the long-term outcomes of community-based elderly African Americans by following their transitions from normal cognition to mild cognitive impairment (MCI) to dementia. METHODS Participants were from the community-based Indianapolis Dementia Project. A total of 4,104 African Americans were enrolled in 1992 or 2001 and followed until 2009 with regularly scheduled evaluation of cognitive assessment. A two-stage sampling was used at each evaluation to select individuals for extensive clinical assessment following the results of Stage 1 cognitive testing. Age- and gender-specific incidence, progression, and reversion rates for MCI were derived using the person-year method in a dynamic cohort and predicted probabilities from weighted multinomial logistic models of transitional probabilities among normal cognition, MCI, and dementia. RESULTS Annual overall incidence rate for MCI was 5.6% (95% confidence interval [CI]: 4.6%-6.6%). Annual progression rate from MCI to dementia was 5.9% (95% CI: 5.3%-6.5%), and annual reversion rate from MCI to normal was 18.6% (95% CI: 16.7%-20.4%). Both MCI incidence rates and MCI to dementia progression rates increased with age, whereas reversion rates from MCI to normal decreased with age. CONCLUSION MCI progression to dementia was much more frequent in the older age groups than in younger participants where reversion to normal cognition is more common. Future research is needed to determine factors related to the heterogeneous outcomes in MCI individuals.