June 19, 2014

Alzheimer's & Dementia: The Journal of the Alzheimer's Association March 2014

Full text articles are available to fee paying members of Alzheimer’s Australia NSW by emailing NSW.Library@alzheimers.org.au

Microvascular network alterations in the retina of patients with Alzheimer's disease
Although cerebral small-vessel disease has been implicated in the development of Alzheimer's disease (AD), the cerebral microcirculation is difficult to visualize directly in vivo. Because the retina provides a noninvasive window to assess the microcirculation, we determined whether quantitatively measured retinal microvascular parameters are associated with AD.
Patients with AD have altered microvascular network in the retina (narrower retinal venules and a sparser and more tortuous retinal vessels) compared with matched nondemented controls. These changes in retinal microvasculature may reflect similar pathophysiological processes in cerebral microvasculature in the brains of patients with AD. 

Time course of brain volume changes in the preclinical phase of Alzheimer's disease
Structural alterations of a large network characterize Alzheimer's disease (AD), but the time course of these changes remains unclear. The dynamic of these alterations was examined in the AD preclinical phase using data from the 10-year follow-up of a population-based cohort (Bordeaux-3City).Participants received neuropsychological assessments every 2 years and two identical magnetic resonance imaging (MRI) exams at baseline and 4 years later. Twenty-five incident AD cases were compared with 319 subjects who remained free of dementia. Subjects were free of dementia at baseline and at follow-up MRI. Incident AD occurred after these time points. Incident AD cases present mediotemporal lesions up to 5 years before diagnosis. This neurodegenerative process seems to progressively reach the temporoparietal cortices in the AD preclinical phase.

Simulating effects of biomarker enrichment on Alzheimer's disease prevention trials: Conceptual framework and example
We present a conceptual framework for simulations to determine the utility of biomarker enrichment to increase statistical power to detect a treatment effect in future Alzheimer's disease prevention trials. We include a limited set of simulation results to illustrate aspects of this framework.We simulated data based on the Alzheimer's Disease Anti-Inflammatory Prevention Trial, and a range of sample sizes, biomarker positive predictive values, and treatment effects. We also investigated the consequences of assuming homogeneity of parameter estimates as a function of dementia outcome.
Conclusion Biomarker enrichment can increase statistical power, but estimates of the expected increase are sensitive to a variety of assumptions outlined in the framework.

Global brain hypoperfusion and oxygenation in amnestic mild cognitive impairment
To determine if global brain hypoperfusion and oxygen hypometabolism occur in patients with amnestic mild cognitive impairment (aMCI).Conclusions
Global brain hypoperfusion, oxygen hypometabolism, and neurovascular decoupling observed in aMCI suggest that changes in cerebral hemodynamics occur early at a prodromal stage of Alzheimer's disease, which can be assessed using low-cost and bedside-available CDUS and NIRS technology. 

Accounting for functional loss in Alzheimer's disease and dementia with Lewy bodies: Beyond cognition
The relative contributions of cognitive, motor, and behavioral deficits to the impairment of physical or instrumental activities of daily living (ADLs) may differ in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).
Conclusions Cognitive, motor, and behavioral deficits contribute differently to ADL changes in DLB and AD. Thus, treatments designed to ameliorate a certain aspect of AD or DLB (e.g., cognitive dysfunction) may have a larger impact on everyday functioning in one disorder than the other. 

Personality and risk of Alzheimer's disease: New data and meta-analysis
We examine whether broad factors and specific facets of personality are associated with increased risk of incident Alzheimer's disease (AD) in a long-run longitudinal study and a meta-analysis of published studies.
ConclusionsThe current study and meta-analysis indicate that personality traits are associated with increased risk of AD, with effect sizes similar to those of well-established clinical and lifestyle risk factors. 

Infantile exposure to lead and late-age cognitive decline: Relevance to AD
Early-life lead (Pb) exposure induces overexpression of the amyloid beta precursor protein and its amyloid beta product in older rats and primates. We exposed rodents to Pb during different life span periods and examined cognitive function in old age and its impact on biomarkers associated with Alzheimer's disease (AD).
Conclusions A window of vulnerability to Pb neurotoxicity exists in the developing brain that can influence AD pathogenesis and cognitive decline in old age. 

Increased risk of dementia in people with previous exposure to general anesthesia: A nationwide population-based case–control study
Dementia, which leads to disability, is one of the important diseases occurring among older populations. However, the exact mechanism of the disease remains unknown. The potential risk factor of general anesthesia (GA) in the development of dementia is a controversial topic. Therefore, this study aimed to evaluate the association between previous exposure to different GA types and the incidence of dementia.
A history of previous exposure to surgery under GA might be associated with an increased risk of dementia, particularly in subjects who have undergone repeated exposure to GA. In addition, subjects who had received surgery under ETGA with comorbidities such as stroke, hypertension, diabetes mellitus, and atherosclerosis could have a potential relationship with dementia risk.

Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects
Genetic variants at the CLU, CR1, and PICALM loci associate with risk for late-onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects. Conclusion These results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD-protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD. 

Implications of early treatment among Medicaid patients with Alzheimer's disease
The objective of this study was to examine the effect of treatment timing on risk of institutionalization of Medicaid patients with Alzheimer's disease (AD) and to estimate the economic implications of earlier diagnosis and treatment initiation.
Conclusion Earlier treatment leads to a small delay in institutionalization among AD patients, resulting in significant costs savings to Medicaid. 

Diagnosing Alzheimer's disease: A systematic review of economic evaluations
The objective of this study is to systematically review the literature on economic evaluations of interventions for the early diagnosis of Alzheimer's disease (AD) and related disorders and to describe their general and methodological characteristics. We focused on the diagnostic aspects of the decision models to assess the applicability of existing decision models for the evaluation of the recently revised diagnostic research criteria for AD.
Conclusions Diversity among the study objective and characteristics was considerable and, despite considerable methodological quality, several flaws were indicated. Recommendations were focused on diagnostic aspects and the applicability of existing models for the evaluation of recently revised diagnostic research criteria for AD.
ADO: A disease ontology representing the domain knowledge specific to Alzheimer's disease
Biomedical ontologies offer the capability to structure and represent domain-specific knowledge semantically. Disease-specific ontologies can facilitate knowledge exchange across multiple disciplines, and ontology-driven mining approaches can generate great value for modeling disease mechanisms. However, in the case of neurodegenerative diseases such as Alzheimer's disease, there is a lack of formal representation of the relevant knowledge domain. Conclusions
Development of ADO as an open ADO is a first attempt to organize information related to Alzheimer's disease in a formalized, structured manner. We demonstrate that ADO is able to capture both established and scattered knowledge existing in scientific text.   

Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease
The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale – the Clinical Dementia Rating Scale in particular – for the primary outcome for prodromal AD clinical trials.  

Alzheimer's disease in the human eye. Clinical tests that identify ocular and visual information processing deficit as biomarkers
Alzheimer's disease (AD) is the most common form of dementia with progressive deterioration of memory and cognition. Complaints related to vision are common among AD patients. Several changes in the retina, lens, and in the vasculature have been noted in the AD eye that may be the cause of visual symptoms experienced by the AD patient. Anatomical changes have been detected within the eye before signs of cognitive impairment and memory loss are apparent. Unlike the brain, the eye is a unique organ that can be visualized noninvasively at the cellular level because of its transparent nature, which allows for inexpensive testing of biomarkers in a clinical setting. In this review, we have searched for candidate biomarkers that could enable diagnosis of AD, covering ocular neurodegeneration associated with functional tests. We explore the evidence that suggests that inexpensive, noninvasive clinical tests could be used to detect AD ocular biomarkers. 

Microdosing of scopolamine as a “cognitive stress test”: Rationale and test of a very low dose in an at-risk cohort of older adults
Abnormal β-amyloid (Aβ) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal “microdose” of scopolamine for the development of a “cognitive stress test.” Conclusions
A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (Tmax) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aβ, to identify pharmacodynamic differences between groups.

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