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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
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
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
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
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