Alzheimer's & Dementia: The Journal of the Alzheimer's Association - Articles in Press

Citalopram for agitation in Alzheimer’s disease: Design and methods - Corrected Proof

2012-02-03

Abstract: Background: Agitation is one of the most common neuropsychiatric symptoms of Alzheimer’s disease (AD), and is associated with serious adverse consequences for patients and caregivers. Evidence-supported treatment options for agitation are limited. The citalopram for agitation in Alzheimer’s disease (CitAD) study was designed to evaluate the potential of citalopram to ameliorate these symptoms.Methods: CitAD is a randomized, double-masked, placebo-controlled multicenter clinical trial, with two parallel treatment groups assigned in a 1:1 ratio and randomization stratified by clinical center. The study included eight recruiting clinical centers, a chair’s office, and a coordinating center located in university settings in the United States and Canada. A total of 200 individuals having probable AD with clinically significant agitation and without major depression were recruited for this study. Patients were randomized to receive citalopram (target dose of 30 mg/d) or matching placebo. Caregivers of patients in both treatment groups received a structured psychosocial therapy. Agitation was compared between treatment groups using the NeuroBehavioral Rating Scale and the AD Cooperative Study- Clinical Global Impression of Change, which are the primary outcomes. Functional performance, cognition, caregiver distress, and rates of adverse and serious adverse events were also measured.Conclusion: The authors believe the design elements in CitAD are important features to be included in trials assessing the safety and efficacy of psychotropic medications for clinically significant agitation in AD.

Effects of Food and Drug Administration-approved medications for Alzheimer’s disease on clinical progression - Corrected Proof

2012-02-03

Abstract: Background: Observational studies suggest that cholinesterase inhibitors and/or memantine may delay clinical progression of Alzheimer’s disease (AD) in 40% of individuals taking the medications. Given this response and existence of side effects, we sought to quantify medication use and benefits in a population-based study of incident AD cases.Methods: The Cache County Dementia Progression Study enrolled and followed a cohort of 327 incident AD cases for a maximum of 9 years. Drug exposure was expressed using a persistency index (PI), calculated as total years of drug use divided by total years of observation. Linear mixed-effects models examined PI, and interactions with sex and apolipoprotein E (APOE) as predictors of clinical progression on the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes.Results: A total of 69 participants (21.1%) reported having ever used cholinesterase inhibitors or memantine. There was a strong three-way interaction between PI, sex, and time. Among women, a higher PI (i.e., greater duration of use) of cholinesterase inhibitors was associated with slower progression on the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes, particularly among those with an APOE ɛ4 allele. In contrast, higher PI was associated with faster progression in males.Conclusion: A low percentage of individuals with AD in the community are taking cholinesterase inhibitors or memantine. This study suggests that women, particularly those with an APOE ɛ4 allele, may benefit the most from these medications. With the newly approved increased dose of donepezil, it will be imperative to determine whether a higher dose is needed in men or whether other factors warrant consideration.

Analysis of case management programs for patients with dementia: A systematic review - Corrected Proof

2012-01-30

Abstract: Background: People suffering from dementia are particularly vulnerable to the gaps between the health and social service systems. Case management is a professional field that seeks to fill in these gaps and remedy this fragmentation.Methods: We report the results of a systematic literature review of the impact of case management programs on clinical outcomes and the utilization of resources by persons with dementia. We focused on randomized controlled trials (RCTs) and attempted to identify the factors that might contribute to greater program efficacy. Because the evaluation methods in these studies varied, we used the effect size method to estimate the magnitude of the statistically significant effects reported.Results: Our search strategy identified 17 references relating to six RCTs. Four of these six RCTs reported moderately statistically significant effects (effect size, 0.2–0.8) on their primary end point: the clinical outcome in three and resource utilization in one. Two of the RCTs reported weak or no effects (effect size, <0.2) on their primary end point. Because of the wide variety of the end points used, an overall effect size could not be calculated. Parameters that appear to be related to greater case management efficacy are the integration level between the health and social service organizations and the intensity of the case management.Conclusions: Integration and case management intensity seem to determine the magnitude of the clinical effects in this new professional field. Further studies are needed to clarify the economic impact.

Amyloid imaging in dementias with atypical presentation - Corrected Proof

2012-01-30

Abstract: Background: With the potential emergence of disease specific therapies, an accurate biomarker of Alzheimer’s Disease pathology is needed in cases in which the underlying etiology is uncertain. We explored the potential value of amyloid imaging in patients with atypical presentations of dementia.Methods: Twenty-eight patients with atypical dementia underwent positron emission tomography imaging with the amyloid imaging tracer Pittsburgh compound B (PiB). Twenty-six had [18F]fluoro-2-deoxy-D-glucose positron emission tomography scans. After extensive clinical evaluation, this group of patients generated considerable diagnostic uncertainty and received working diagnoses that included possible Alzheimer’s disease (AD), focal dementias (e.g., posterior cortical atrophy [PCA]), or cases in which no clear diagnostic category could be determined (dementia of uncertain etiology). Patients were classified as PiB-positive, PiB-negative, or PiB-intermediate, based on objective criteria. Anterior–posterior and left–right indices of PiB and [18F]fluoro-2-deoxy-D-glucose uptake were calculated to examine differences in distribution of amyloid pathology and metabolic changes associated with clinical phenotype.Results: Eleven patients (39%) were PiB positive, 16 were PiB negative (57%), and one (4%) was PiB intermediate. By diagnostic category, three of 10 patients (30%) with dementia of uncertain etiology, one of five (20%) with primary progressive aphasia, three of five (60%) with PCA, and four of seven (57%) with possible AD were PiB positive. Brain metabolism of both PiB-positive and PiB-negative patients was generally similar by phenotype, but appeared to differ from typical AD. PCA patients also appeared to differ in their relative distribution of PiB compared with typical AD, consistent with their atypical phenotype.Conclusions: AD pathology is frequently present in atypical presentations of dementia and can be identified by amyloid imaging. Clinical phenotype is more related to the pattern of cerebral hypometabolism than the presence/absence of amyloid pathology. These findings have diagnostic, prognostic, and therapeutic implications.

Impact of the Food and Drug Administration’s antipsychotic black box warning on psychotropic drug prescribing in elderly patients with dementia in outpatient and office-based settings - Corrected Proof

Vibha C.A. Desai, Pamela C. Heaton, Christina M.L. Kelton — 2012-01-30

Abstract: Background: Most patients with dementia also suffer from behavioral and psychological symptoms of dementia, for which there is no Food and Drug Administration-approved treatment.Objectives: To determine whether the Food and Drug Administration’s black box warning in April 2005 has led to a decline in prescriptions of atypical antipsychotics for behavioral and psychological symptoms of dementia, as well as whether prescriptions for other psychotropic drugs, including antidepressants, anxiolytics, and antiepileptics, as substitutes, have increased.Methods: Data on outpatient visits by elderly dementia patients were obtained from two large national surveys from 2003 to 2008. Any psychotropic drug mentions were identified. Percentage utilization statistics were calculated.Results: The percentage of visits mentioning an atypical antipsychotic decreased from 12.5% prewarning to 11.5% postwarning. Postwarning, 34.4% of patients were taking none of the study medications, as opposed to 26.1% prewarning.Conclusion: After the warning, there was a small decline in the use of atypical antipsychotics and no evidence of substitution of other psychotropic medications.

Vascular risk factors, apolipoprotein E, and hippocampal decline on magnetic resonance imaging over a 10-year follow-up - Corrected Proof

2012-01-16

Abstract: Background: Decline of hippocampal volume on magnetic resonance imaging (MRI) may be considered as a surrogate biomarker of accumulating Alzheimer disease (AD) pathology. Previously, we showed in the prospective population-based Rotterdam Scan Study that a higher rate of decline of hippocampal volume on MRI precedes clinical AD or memory decline. We studied potential risk factors for decline of hippocampal volume.Methods: At baseline (1995–1996), 518 nondemented elderly subjects were included, and the cohort was re-examined in 1999 and in 2006. At each examination, hippocampal volume was determined using an automated segmentation procedure. In all, 301 persons had at least two three-dimensional MRI scans to assess decline in hippocampal volume.Results: Persons carrying the apolipoprotein E (APOE) ɛ4 allele had lower hippocampal volumes than persons with the ɛ3/ɛ3 genotype, but the rate of decline was not influenced by APOE genotype. In persons who did not use antihypertensive treatment, both a high (>90 mm Hg) and a low (<70 mm Hg) diastolic blood pressure were associated with a faster decline in hippocampal volume. Also, white matter lesions on baseline MRI were associated with a higher rate of decline in hippocampal volume.Conclusions: In a nondemented elderly population, persons with the APOE ɛ4 allele have a smaller hippocampal volume but not a higher rate of decline. Rate of decline of hippocampal volume was influenced by white matter lesions and diastolic blood pressure, supporting their hypothesized role in the pathogenesis of AD.

Cardiovascular fitness is associated with altered cortical glucose metabolism during working memory in ɛ4 carriers - Corrected Proof

2012-01-09

Abstract: Background: The possibility that ɛ4 may modulate the effects of fitness in the brain remains controversial. The present exploratory FDG-PET study aimed to better understand the relationship among ɛ4, fitness, and cerebral metabolism in 18 healthy aged women (nine carriers, nine noncarriers) during working memory.Methods: Participants were evaluated using maximal level of oxygen consumption, California Verbal Learning Test, and FDG-PET, which were collected at rest and during completion of the Sternberg working memory task.Results: Resting FDG-PET did not differ between carriers and noncarriers. Significant effects of fitness on FDG-PET during working memory were noted in the ɛ4 carriers only. High fit ɛ4 carriers had greater glucose uptake in the temporal lobe than the low fit ɛ4 carriers, but low fit ɛ4 carriers had greater glucose uptake in the frontal and parietal lobes.Conclusions: We demonstrate that fitness differentially affects cerebral metabolism in ɛ4 carriers only, consistent with previous findings that the effects of fitness may be more pronounced in populations genetically at risk for cognitive decline.

Are dental X-rays causing Alzheimer’s? Ten reasons to take a closer look - Corrected Proof

Caroline Rodgers — 2012-01-09

The speed with which Alzheimer’s disease has become a killer worldwide argues against a complex etiology because the more factors required for an outcome, the more difficult it is to meet all of the conditions necessary to cause it. In the United States, Alzheimer’s is the sixth leading cause of death for people of any age, with fatalities increasing 66% over the same period of time that deaths due to other leading causes, such as stroke, heart disease and diabetes, decreased. While important genetic causes and associations to Alzheimer’s have been made, the fact that these genetic factors do not always cause Alzheimer’s and do not explain the majority of cases suggest that something else is directly responsible for Alzheimer’s. Likewise, significant discoveries regarding Abeta plaques have indicated that plaques removal is not the key to slowing or stopping Alzheimer’s.

Association of environmental tobacco smoke with dementia and Alzheimer’s disease among never smokers - Corrected Proof

Ruoling Chen — 2011-12-26

Abstract: Background: Environmental tobacco smoke (ETS) is known to be harmful; however, its association with dementia remains controversial and with Alzheimer’s disease (AD) is unknown.Methods: Using a standard interview method, the author carried out a multicenter cross-sectional study of dementia in China by examining 2692 never-smoking people aged ≥60 years. Relative risks (RRs) of AD and all dementia, as diagnosed by psychiatrists, in relation to ETS were calculated in a multivariate regression model.Results: The adjusted RR for all dementia was 1.78 (95% confidence interval [CI]: 1.18–2.68). The increased risk was mainly from exposure to ETS at home (1.87, 95% CI: 1.19–2.93), and it was associated with exposure duration. The adjusted RR for AD was 2.28 (95% CI: 1.82–2.84); the matched figure for ETS exposure at home, at work, and at other places was 2.15 (95% CI: 1.69–2.74), 2.04 (95% CI: 1.72–2.42), and 1.80 (95% CI: 0.96–3.38), respectively. The association of the increased risk with a total cumulative exposure dose was at borderline significance.Conclusions: The risk of dementia and AD increased with ETS exposure. Banning smoking in public areas may help reduce a dementia epidemic worldwide.

Some evolutionary perspectives on Alzheimer’s disease pathogenesis and pathology - Corrected Proof

Daniel J. Glass, Steven E. Arnold — 2011-12-05

Abstract: There is increasing urgency to develop effective prevention and treatment for Alzheimer’s disease (AD) as the aging population swells. Yet, our understanding remains limited for the elemental pathophysiological mechanisms of AD dementia that may be causal, compensatory, or epiphenomenal. To this end, we consider AD and why it exists from the perspectives of natural selection, adaptation, genetic drift, and other evolutionary forces. We discuss the connection between the apolipoprotein E (APOE) allele and AD, with special consideration to APOE ɛ4 as the ancestral allele. The phylogeny of AD-like changes across species is also examined, and pathology and treatment implications of AD are discussed from the perspective of evolutionary medicine. In particular, amyloid-β (Aβ) neuritic plaques and paired helical filament tau (PHFtau) neurofibrillary tangles have been traditionally viewed as injurious pathologies to be targeted, but may be preservative or restorative processes that mitigate harmful neurodegenerative processes or may be epiphenoma of the essential processes that cause neurodegeneration. Thus, we raise fundamental questions about current strategies for AD prevention and therapeutics.

Safety profile of Alzheimer’s disease populations in Alzheimer’s Disease Neuroimaging Initiative and other 18-month studies - Corrected Proof

2011-12-05

Abstract: Background: Demonstration of a disease-modifying effect of a therapeutic agent on Alzheimer’s disease (AD) requires a trial lasting for at least 18 months. An understanding of expected rates of adverse events (AEs), overall discontinuations, and discontinuations due to AEs, serious AEs, and deaths would be useful in planning such trials.Methods: We examined safety information for patients taking placebo from five published 18-month AD trials and for patients from the Alzheimer’s Disease Neuroimaging Initiative study.Results: AEs reported consistently across multiple studies were dyspnea (occurring in 5.3%–5.8% of patients), headache (4.0%–5.5%), constipation (4.3%–4.7%), nausea (2.0%–5.8%), joint swelling (3.6%–3.7%), vomiting (3.6%–3.7%), and anxiety (3.2%–3.6%). Larger multinational studies, as compared with smaller studies with fewer sites and geographies, demonstrated greater overall discontinuations (24.6%–33.0% vs 8.2%–21.0%) and greater discontinuations due to AEs (9.5%–11.6% vs 2.7%–3.2%). Rates of death (1.8%–2.4%) and SAEs (19.9%–21.2%) were consistent across 18 month published studies and in ADNI; fall was the most common SAE (2.6%–4.0%) where SAEs were reported.Conclusions: In general, comparable types of AEs, frequency of deaths, and serious AEs were seen for patients taking placebo in five randomized, controlled 18-month AD trials and in Alzheimer’s Disease Neuroimaging Initiative, whereas rates of discontinuations were more variable. Evaluation across studies was complicated by inconsistent methods of reporting safety information. Evaluation of large databases of placebo patients from therapeutic AD trials is needed to further enhance the understanding of expected safety outcomes in clinical trials of AD patients.

Cognitive impairment in nondemented oldest-old: Prevalence and relationship to cardiovascular risk factors - Corrected Proof

Carrie B. Peltz, María M. Corrada, Daniel J. Berlau, Claudia H. Kawas — 2011-11-07

Abstract: Objective: To determine the prevalence and types of cognitive impairment in a sample of nondemented participants aged ≥90 (the oldest-old) and to examine the relationships between cognitive impairment and cardiovascular risk factors.Participants: The participants were 420 nondemented individuals from The 90+ Study, a study of aging and dementia in the oldest-old. These participants were categorized into four nonoverlapping groups: normal cognition, amnestic mild cognitive impairment (aMCI), nonamnestic MCI (naMCI), and other cognitive impairment (OCI). History of cardiovascular risk factors was assessed through self-report.Results: The overall prevalence of cognitive impairment in nondemented participants was 34.0% (95% CI: 29.5–38.5). The prevalence of OCI was highest (17.4%; 95% CI: 13.9–21.4), followed by aMCI (8.3%; 95% CI: 5.9–11.4) and naMCI (8.3%; 95% CI: 5.9–11.4). Normal cognition was present in 66.0% (95% CI: 61.2–70.5) of participants. History of hypertension and stroke were the only risk factors that varied between the groups, occurring more frequently in participants with naMCI (χ2 = 3.82; P < .05) and OCI (χ2 = 5.51; P < .05).Conclusions: This study found a high prevalence of cognitive impairment in a sample of nondemented oldest-old. We did not find a strong relationship between cardiovascular risk factors and the cognitive impairment groups, other than between hypertension and naMCI and stroke and OCI. Future studies comparing the incidence of dementia in these groups will ultimately determine their predictive utility in the oldest-old.

Clinical and neurobiological correlates of soluble amyloid precursor proteins in the cerebrospinal fluid - Corrected Proof

2011-11-07

Abstract: Background: According to a widely accepted hypothesis, the amyloid precursor protein (APP) is processed by two competing pathways: the amyloidogenic β-secretase–mediated pathway or the nonamyloidogenic α-secretase–mediated pathway. APP is cleaved preferentially through the nonamyloidogenic pathway in normal brain, whereas the balance shifts to the amyloidogenic pathway in Alzheimer’s disease (AD). The levels of the α-secretase–cleaved soluble APP (sAPPα) and β-secretase–cleaved soluble APP (sAPPβ) in cerebrospinal fluid (CSF) are likely to reflect these competing mechanisms.Methods: We investigated the levels and the relationship between sAPPα and sAPPβ in the CSF of 64 patients with mild AD, 76 patients with mild cognitive impairment, and 12 cognitively healthy control subjects, as well as the effect of apolipoprotein E genotype and sex on soluble APP levels.Results: There was a significant positive correlation between sAPPα and sAPPβ levels in all three groups. sAPPα and sAPPβ concentrations were higher in patients with mild cognitive impairment compared with patients with AD. In the AD group, females exhibited higher sAPPα and sAPPβ levels than males. No influence of the apolipoprotein E genotype on soluble APP concentrations was detected.Discussion: The positive correlation between sAPPα and sAPPβ challenges the hypothesis that AD is caused by an imbalance of the α- and β-secretase APP proteolysis through competing mechanisms. Moreover, the differences in CSF levels of sAPPα and sAPPβ between male and female patients with AD may reflect a “sexual dimorphism” in the activity of the two APP processing pathways in AD.

Effect of human cerebrospinal fluid sampling frequency on amyloid-β levels - Corrected Proof

2011-11-03

Abstract: Background: β-amyloid peptide (Aβ) is associated with neurodegeneration in Alzheimer’s disease. Emerging evidence indicates that Aβ levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aβ production or Aβ clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aβ are consistent between sampling intervals to determine whether Aβ can be used as a pharmacodynamic biomarker for drug candidates. Previous studies have produced seemingly conflicting observations for the intrasubject stability of CSF Aβ levels; we attempt to reconcile these conflicting observations.Methods: The current study examined the Aβ levels in CSF collected with various sampling frequencies from three clinical studies conducted in healthy young or elderly subjects at the same investigative site for the purpose of designing future studies.Results: The results suggest that CSF sampling frequency and/or sampling volume contributes to intrasubject variability in CSF Aβ levels, and that lowering the CSF sampling frequency may help minimize this effect.Conclusion: These results will help guide clinical trial design for Alzheimer’s disease therapy.

Is Alzheimer’s disease amyloidosis the result of a repair mechanism gone astray? - Corrected Proof

Tyler A. Kokjohn, Chera L. Maarouf, Alex E. Roher — 2011-11-03

Abstract: Here, we synthesize several lines of evidence supporting the hypothesis that at least one function of amyloid-β is to serve as a part of the acute response to brain hemodynamic disturbances intended to seal vascular leakage. Given the resilient and adhesive physicochemical properties of amyloid, an abluminal hemostatic repair system might be highly advantageous, if deployed on a limited and short-term basis, in young individuals. However, in the aged, inevitable cardiovascular dysfunction combined with brain microvascular lesions may yield global chronic hypoperfusion that may lead to continuous amyloid deposition and consequential negative effects on neuronal viability. A large body of experimental evidence supports the hypothesis of an amyloid-β rescue function gone astray. Preventing or inducing the removal of amyloid in Alzheimer’s disease (AD) has been simultaneously successful and disappointing. Amyloid deposits clearly play major roles in AD, but they may not represent the preeminent factor in dementia pathogenesis. Successful application of AD preventative approaches may hinge on an accurate and comprehensive view of comorbidities, including cardiovascular disease, diabetes, and head trauma.

Effects of n-3 fatty acids on cognitive decline: A randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients - Corrected Proof

Johanna M. Geleijnse, Erik J. Giltay, Daan Kromhout — 2011-10-04

Abstract: Background: Epidemiological studies suggest a protective effect of n-3 fatty acids derived from fish (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) against cognitive decline. For α-linolenic acid (ALA) obtained from vegetable sources, the effect on cognitive decline is unknown. We examined the effect of n-3 fatty acid supplementation on cognitive decline in coronary heart disease patients.Methods: The analysis included 2911 coronary patients (78% men) aged 60 to 80 years who participated in a double-blind placebo-controlled trial of n-3 fatty acids and cardiovascular diseases (Alpha Omega Trial). By using a 2 × 2 factorial design, patients were randomly assigned to margarines that provided 400 mg/d of EPA–DHA, 2 g/d of ALA, both EPA–DHA and ALA, or placebo for 40 months. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at baseline and after 40 months. The effect of n-3 fatty acids on change in MMSE score was assessed using analysis of variance. Logistic regression analysis was used to examine the effects on risk of cognitive decline, defined as a decrease of 3 or more points in MMSE score or incidence of dementia.Results: Patients in the active treatment groups had an additional intake of 384 mg of EPA–DHA, 1.9 g of ALA, or both. The overall MMSE score in this cohort was 28.3 ± 1.6 points, which decreased by 0.67 ± 2.25 points during follow-up. Changes in MMSE score during intervention did not differ significantly between EPA–DHA and placebo (−0.65 vs −0.69 points, P = .44) or between ALA and placebo (−0.60 vs −0.74 points, P = .12). The risk of cognitive decline was 1.03 (95% confidence interval: 0.84–1.26, P = .80) for EPA–DHA (vs placebo) and 0.90 (0.74–1.10, P = .31) for ALA (vs placebo).Conclusion: This large intervention study showed no effect of dietary doses of n-3 fatty acids on global cognitive decline in coronary heart disease patients.