Alzheimer's & Dementia: The Journal of the Alzheimer's Association

Research in context

Ara S. Khachaturian — 2012-05-01

The role of multidisciplinary medical journals such as Alzheimer's & Dementia is to communicate research findings to a broad audience interested in a diverse array of scientific topics. The discussion section of most scientific articles often serves an important role to present a commentary on the meaning and significance of the research. To a greater or lesser extent, most discussion sections begin with a brief summary of the main findings and often answer the question or problem stated in the introduction. Depending on the authors as well as the critiques from reviewers and editors, the papers we receive explore—with great unevenness—the limitations of the study, the relationship of the findings to other research, the implication of the research, and possible future research directions. We think this inconsistency presents an important disservice to our audience and to the scientific literature.

An investigation of PreMCI: Subtypes and longitudinal outcomes

2012-05-01

Abstract: Background/Aims: To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI).Methods: We longitudinally evaluated 269 elderly subjects who did not meet formal criteria for MCI at baseline but had: (1) a clinical history suggesting MCI without neuropsychological deficits (PreMCI-Clinical); or (2) neuropsychological deficits on one or more memory measures in conjunction with a negative clinical examination (amnestic PreMCI-NP) or were normal on both neuropsychological and clinical examination.Results: The rate of progression to MCI or dementia over an average of 2- to 3 years was 3.7% for no cognitive impairment subjects, whereas it was significantly greater for all PreMCI subtypes (22.0% for PreMCI-Clinical, 38.9% for amnestic PreMCI-NP subjects with two or more memory impairments). Among PreMCI subjects as a whole, lower baseline scores on object memory and category fluency tests were the best predictors of progression to MCI or dementia. Cardiovascular risk factors, Parkinsonian symptoms, and hippocampal atrophy were not associated with progression.Conclusion: Distinct PreMCI subtypes defined on the basis of clinical and neuropsychological evaluations were found to have distinct characteristics, but both subtypes demonstrated elevated risk for progression to MCI or dementia. Despite the lack of evidence of clinical impairment, subjects with neuropsychological deficits in two memory domains were particularly at increased risk for progression of their deficits.

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

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.

Diuretic use is associated with better learning and memory in older adults in the Ginkgo Evaluation of Memory study

2012-04-05

Abstract: Background: To investigate the association between diuretics, angiotensin-converting enzyme inhibitors (ACE-I), angiotensin II receptor blockers (AT2RB), and cognitive function.Methods: This post hoc analysis of the randomized controlled Ginkgo Evaluation of Memory Study trial focuses on 3069 nondemented community-dwelling participants aged >75 years. At baseline visit, detailed information about medication use was collected and five cognitive domains were assessed. Multivariate linear regression analyses were used to assess cross-sectional associations between medication use and cognitive function.Results: In all, 36% of participants reported history of hypertension and 53% reported antihypertensive medication use, with 17% reporting diuretic, 11% ACE-I, and 2% AT2RB use. Potassium-sparing diuretic use (N = 192) was associated with better verbal learning and memory measured by California Verbal Learning Test as compared with no antihypertensive medication users (β = 0.068, P = .01; β = 0.094, P < .001) and other antihypertensive medication users (β = 0.080, P = .03; β = 0.153, P < .001). Use of ACE-I or AT2RB was not associated with better cognitive function.Conclusion: Results warrant further investigation into possible protective effects of potassium-sparing diuretics and the role of potassium in mitigating cognitive decline.

Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease

2012-05-01

Abstract: Background: Chronic inflammation in periodontal disease has been suggested as a potential risk factor in Alzheimer’s disease (AD). The purpose of this study was to examine serum antibody levels to bacteria of periodontal disease in participants who eventually converted to AD compared with the antibody levels in control subjects.Methods: Serum samples from 158 participants in the Biologically Resilient Adults in Neurological Studies research program at the University of Kentucky were analyzed for immunoglobulin G antibody levels to seven oral bacteria associated with periodontitis, including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola, Fusobacterium nucleatum, Tannerella forsythia, and Prevotella intermedia. All 158 participants were cognitively intact at baseline venous blood draw. In all, 81 of the participants developed either mild cognitive impairment (MCI) or AD or both, and 77 controls remained cognitively intact in the years of follow-up. Antibody levels were compared between controls and subjects with AD at baseline draw and after conversion and controls and subjects with MCI at baseline draw and after conversion using the Wilcoxon rank-sum test. AD and MCI participants were not directly compared. Linear regression models were used to adjust for potential confounding.Results: Antibody levels to F nucleatum and P intermedia were significantly increased (α = 0.05) at baseline serum draw in the patients with AD compared with controls. These results remained significant when controlling for baseline age, Mini-Mental State Examination score, and apolipoprotein epsilon 4 status.Conclusions: This study provides initial data that demonstrate elevated antibodies to periodontal disease bacteria in subjects years before cognitive impairment and suggests that periodontal disease could potentially contribute to the risk of AD onset/progression. Additional cohort studies profiling oral clinical presentation with systemic response and AD and prospective studies to evaluate any cause-and-effect association are warranted.

Medical and environmental risk factors associated with frontotemporal dementia: A case-control study in a veteran population

2012-04-05

Abstract: Background: Compared with other major dementias, very little is known about the medical and environmental risk factors associated with frontotemporal dementia (FTD). In this study, we evaluated medical and environmental disorders associated with FTD in a veteran population.Methods: The medical records of 845 consecutive veterans who were evaluated for cognitive and/or behavioral complaints at a cognitive disorders clinic in an academic medical center between March 1, 2003, and June 30, 2008, were reviewed and 554 patients received a diagnosis of dementia. Medical disorders and environmental risk factors in 63 patients with behavioral variant of FTD were compared with 491 patients with non-FTD dementias.Results: The prevalence of traumatic brain injury (TBI) was significantly greater in patients with FTD versus those with non-FTD dementias (12.7% vs 3.5%; P < .05). The FTD group also had a lower prevalence of heart disease (19.0% vs 36.7%; P < .05) and cerebrovascular diseases (12.7% vs 26.1%; P < .05), although the prevalence of vascular risk factors was comparable between FTD and non-FTD dementia groups: hypertension (65.1% vs 68.2%), diabetes (31.7% vs 26.9%), hyperlipidemia (42.9% vs 48.9%), and tobacco use (7.9% vs 8.8%; P > .05 for all). In multivariate analysis, the risk for FTD was increased in patients with TBI (OR, 4.4; 95% CI, 1.6–11.8). The risk for FTD was marginally decreased in patients with heart disease (OR, 0.4; 95% CI, 0.3–0.96).Conclusions: In a clinical sample of veterans, risk of FTD was increased in patients with TBI and marginally decreased in patients with heart disease. Prospective studies are needed to confirm these associations temporally and to identify their underlying mechanisms.

Cognitive and structural magnetic resonance imaging features of Lewy body dementia and Alzheimer’s disease

2012-05-01

Abstract: Objective: To assess medial temporal atrophy (MTA) and atrophy adjacent to the third ventricle (Peri-IIIVent) on brain magnetic resonance images as biomarkers for the diagnosis of Alzheimer’s disease (AD) and Lewy body dementia (LBD), and to assess the relationship between biomarkers and clinical and functional measures.Methods: Subjects diagnosed with no cognitive impairment (n = 30), AD (n = 30), or LBD (n = 31) were evaluated with the Mini-Mental State Examination, Multiple Delayed Recall Test, Category Fluency Test, Clinical Dementia Rating Sum of Boxes score, Functional Assessment Questionnaire, and the Unified Parkinson’s Disease Rating Scale. A validated visual rating system was used to rate MTA, and volumetric studies were performed to measure total intracranial and hippocampal volumes. Additionally, linear measurements of third ventricle width, Peri-IIIVent height, and Peri-IIIVent width were performed.Results: Subjects with AD and those with LBD were equivalent with respect to age and levels of cognitive impairment. Atrophy in medial temporal and Peri-IIIVent regions was greater among both patients with AD and those with LBD compared with subjects with no cognitive impairment. The best discriminators of AD from LBD were the severity of MTA, using visual rating, and the severity of memory impairment. Only subjects with LBD showed significant correlations between Unified Parkinson’s Disease Rating Scale scores and Peri-IIIVent atrophy measures.Conclusions: Mild AD could be distinguished from mild LBD by the severity of MTA and memory impairment. The severity of parkinsonism was associated with the severity of atrophy in the third ventricular region, but was not a good discriminator between AD and LBD.

Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer’s disease

2012-05-01

Abstract: Background: Some observational studies have established an association between exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and a decreased risk of subsequently developing Alzheimer’s disease (AD). Mild cognitive impairment or cognitive impairment, not dementia (CIND) is more likely to convert to AD, and no specific preventive method is currently available. The objective of this study was to determine the association of NSAID use in 5276 cognitively normal subjects of the Canadian Study of Health and Aging, a 10-year population-based cohort study, with the incidence of CIND, AD, and all-cause dementia.Methods: Hazard ratios were calculated from Cox proportional hazards models with age as the time scale according to three study samples including 824 cases of dementia (563 cases of AD), 630 cases of dementia (435 cases of AD), and 883 cases of CIND, respectively. Adjustments were made for gender, education, lifestyle factors, comorbid diseases, and vascular risk factors.Results: Lower risks for AD and all-cause dementia were significantly associated with the use of any NSAIDs and the salicylates without barbiturates subgroup in the study sample including subjects with CIND at baseline. There was a weak association between any NSAIDs and the risk of CIND (hazard ratio, 0.87; 95% confidence interval, 0.76–1.00).Conclusion: These results suggest that there is an association between NSAID use and a lower incidence of AD and, to a lesser extent, of CIND.

Alzheimer’s disease: Pathogenesis and prevention

Heiko Braak, Kelly Del Tredici — 2012-04-05

Abstract: Tau lesions (pretangles, neuropil threads, neurofibrillary tangles) in select neuronal types are essential to the pathogenesis of Alzheimer’s disease. Pretangle formation marks the beginning of the pathological process and is of particular interest because it is temporally closer to the prevailing conditions that induce the pathological process underlying Alzheimer’s disease in contrast to late-stage disease. However, not all pretangles convert into neurofibrillary tangles. We propose that the development of tau lesions in Alzheimer’s disease is traceable to differences between early- versus late-maturing oligodendrocytes and to the exceptionally protracted myelination of late-developing portions of the human brain. Conclusions drawn from these considerations should encourage development of new preventative and disease-modifying strategies.

The draft “National Plan” to address Alzheimer's disease - National Alzheimer's Project Act (NAPA)

Zaven S. Khachaturian, Ara S. Khachaturian, William Thies — 2012-05-01

Abstract: This perspective updates the status of the “National Plan to Address Alzheimer's Disease” and the recommendations of the NAPA Advisory Council's Sub-committee on Research. Here, we identify some of the critical issues the future reiterations of the National Plan should consider during implementation phase of the plan. The Journal invites the scientific community to contribute additional ideas and suggestions towards a national research initiative.

The epidemiology of Alzheimer’s disease: Laying the foundation for drug design, conduct, and analysis of clinical trials

2012-05-01

Abstract: Epidemiological studies increasingly inform Alzheimer’s disease (AD) public health impact, prevention strategies, drug targets, therapeutic interventions, and clinical trial design. For this reason, the Alzheimer’s Association Research Roundtable convened an international group of AD experts with experience in conducting both observational and clinical trials for a meeting on October 19 and 20, 2010, in Washington, DC, to discuss the role of epidemiologic studies in AD research and therapeutic advances. Topics included wellness markers and risk factors, with a focus on special populations such as those at elevated risk, super agers, and underserved populations. Discussions also highlighted lessons learned from observational studies of aging, cardiovascular disease, and other disease areas, as well as how new technologies have enabled the gathering of data relevant to drug development and clinical trial conduct.

Alzheimer's Association Update for May 2012

2012-05-01

When the National Institute on Aging holds its Alzheimer's Disease Research Summit this month, it will be informed by a scientific agenda prepared by some of the nation's leading Alzheimer's disease (AD) researchers. In January, the Alzheimer's Association assembled the group of more than 20 researchers to develop recommendations on the scope and scale of research needed to have one or more disease-modifying drugs for AD on the market in 10 years. From those recommendations, a scientific agenda was developed not only to inform the NIA Summit, but also to be considered as a framework for implementation of the research component of the National Alzheimer's Project Act (NAPA).

2012-05-01

Editorial Board

2012-05-01

Medical and Scientific Advisory Council

2012-05-01

Subscriber information

2012-05-01

Alzheimer's & Dementia: The Journal of the Alzheimer's Association

Research in context

An investigation of PreMCI: Subtypes and longitudinal outcomes

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

Diuretic use is associated with better learning and memory in older adults in the Ginkgo Evaluation of Memory study

Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease

Medical and environmental risk factors associated with frontotemporal dementia: A case-control study in a veteran population

Cognitive and structural magnetic resonance imaging features of Lewy body dementia and Alzheimer’s disease

Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer’s disease

Alzheimer’s disease: Pathogenesis and prevention

The draft “National Plan” to address Alzheimer's disease - National Alzheimer's Project Act (NAPA)

The epidemiology of Alzheimer’s disease: Laying the foundation for drug design, conduct, and analysis of clinical trials

Alzheimer's Association Update for May 2012

Contents

Editorial Board

Medical and Scientific Advisory Council

Subscriber information