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Current
Alzheimer Research
ISSN: 1567-2050
OPEN ACCESS PLUS
Contents
Long-Term Response to Galantamine in Relation to Short-Term
Efficacy Data: Pooled Analysis in Patients with Mild to Moderate
Alzheimer’s Disease, 2011, 8, 175-186
S. Kavanagh, I. Howe, H.R. Brashear, D. Wang, B. Van Baelen,
M. Todd and S. Schwalen
[Abstract] [Full
Text Article]
High PIB Retention in Alzheimer’s Disease is an Early
Event with Complex Relationship with CSF Biomarkers and Functional
Parameters, 2010, 7, 56-66
A. Forsberg, O. Almkvist, H. Engler, A. Wall,
B. Långström and A. Nordberg
[Abstract]
[Full
Text Article]
Baseline MRI Predictors of Conversion from MCI to Probable
AD in the ADNI Cohort, 2009, 6, 347-361
S.L. Risacher, A.J. Saykin, J.D. West, L.
Shen, H.A. Firpi, B.C. McDonald and the
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
[Abstract]
[Full
Text Article]
Towards Retinoid Therapy for Alzheimer’s Disease,
2009, 6, 302-311
K. Shudo, H. Fukasawa, M. Nakagomi and
N. Yamagata
[Abstract]
[Full
Text Article]
Natural Non-Trasgenic Animal Models for Research
in Alzheimer’s Disease, 2009, 6, 171-178
Manuel Sarasa and Pedro Pesini
[Abstract]
[Full
Text Article]
Long-Term Follow-Up of Patients Immunized with AN1792: Reduced
Functional Decline in Antibody Responders, 2009,
6, 144-151
Bruno Vellas, R. Black, Leon J. Thal, Nick
C. Fox, M. Daniels, G. McLennan, C. Tompkins, C. Leibman,
M. Pomfret, Michael Grundman; for the AN1792 (QS-21)-251 Study
Team
[Abstract]
[Full
Text Article]
Assembly of the Asparagine- and Glutamine-Rich
Yeast Prions into Protein Fibrils, 2008, 5, 251-259
Luc Bousset, Jimmy Savistchenko and Ronald Melki
[Abstract]
[Full
Text Article]
A New Glucocorticoid Hypothesis of Brain Aging: Implications
for Alzheimer’s Disease, 2007, 4, 205-212
Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen and
Nada M. Porter
[Abstract]
[Full
Text Article]
De Novo and Molecular Target-Independent
Discovery of Orally Bioavailable Lead Compounds for Neurological
Disorders, 2006, 3, 205-214
Laura K. Wing, Heather A. Behanna, Linda J. Van Eldik,
D. Martin Watterson and Hantamalala Ralay Ranaivo
[Abstract]
[Full
Text Article]
Induction of RhoGAP and Pathological Changes Characteristic
of Alzheimer’s Disease by UAHFEMF Discharge in Rat Brain,
2005, 2, 559-569
Ing-Feng Chang and Huo-Yen Hsiao
[Abstract]
[Full
Text Article]
Abstracts
[Back to top]
Long-Term Response to Galantamine in Relation to Short-Term
Efficacy Data: Pooled Analysis in Patients with Mild to Moderate
Alzheimer’s Disease
S. Kavanagh, I. Howe, H.R. Brashear, D. Wang, B. Van Baelen,
M. Todd and S. Schwalen
[Full
Text Article]
Background: This analysis aimed to identify
an operational, clinically relevant definition of response
achieved in short-term clinical trials to support the identification
of patients with Alzheimer’s disease (AD) who would
benefit most from long-term galantamine therapy.
Methods: Data were analyzed from 6 randomized placebo-controlled
trials of up to 6 months’ duration, which included patients
with mild to moderate AD receiving maintenance doses of galantamine
16-24 mg/day, and from 12 open-label extensions (galantamine
24 mg/day maintenance therapy). Assessments included changes
from baseline in the 11-item AD Assessment Scale-Cognitive
subscale (ADAS-Cog 11).
Results: Pooled analysis of the 5- 6 month trial
data showed that at the trial endpoint (2-5 months after reaching
maintenance doses), the proportions of galantamine- (n=1,173)
versus placebo-treated patients (n=801) with probable AD categorized
according to “improved”, “stable”
or “non-rapid decline” criteria, were 45.8% versus
27.2%, 59.5% versus 37.1%, and 87.6% versus 69.7%, respectively
(observed cases analysis), whilst changes in ADAS-Cog 11 scores
versus baseline were -4.9, -4.7 and -2.9 points, respectively,
for “improved”, “stable” and “non-rapid
decline” galantamine-treated patients (-1.5 points for
galantamine recipients overall). “Improved” or
“stable” galantamine-treated patients displayed
mean improvement in ADAS-Cog 11 scores over baseline until
18 months after starting treatment, and attenuated deterioration
thereafter; for galantaminetreated patients exhibiting “non-rapid
decline”, mean ADAS-Cog 11 score returned to baseline
after approximately 12 months.
Conclusions: Patients who demonstrate improvement,
stability, or limited cognitive decline 2-5 months after reaching
maintenance doses of galantamine are more likely to experience
continued benefit from long-term galantamine therapy.
[Back to top]
High PIB Retention in Alzheimer’s Disease is an Early
Event with Complex Relationship with CSF Biomarkers and Functional
Parameters, 2010, 7, 56-66
A. Forsberg, O. Almkvist, H. Engler, A. Wall,
B. Långström and A. Nordberg
[Full
Text Article]
Background: New in vivo amyloid PET
imaging tracers, such as 11C-PIB,
provide possibilities to deeper understand the underlying
pathological processes in Alzheimer’s disease (AD).
In this study we investigated how 11C-PIB
retention is related to cerebral glucose metabolism, episodic
memory and CSF biomarkers.
Method: Thirty-seven patients with mild AD
and 21 patients with mild cognitive impairment (MCI) underwent
PET examinations with the amyloid tracer 11C-PIB,
18F-FDG for measurement of
regional cerebral metabolic rate of glucose (rCMRglc), assessment
of episodic memory and assay of cerebral spinal fluid (CSF)
levels of amyloid-β
(Aβ1-42),
total tau and phosphorylated tau respectively. Analyses were
performed using Statistical Parametric Mapping (SPM) and regions
of interest (ROIs).
Results: Pooled data from AD and MCI patients
showed strong correlations between 11C-PIB
retention, levels of CSF biomarkers (especially Aβ1-42),
rCMRglc and episodic memory. Analysis of the MCI group alone
revealed significant correlations between 11C-PIB
retention and CSF biomarkers and between CSF biomarkers and
episodic memory respectively. A strong correlation was observed
in the AD group between rCMRglc and episodic memory as well
as a significant correlation between 11C-PIB
retention and rCMRglc in some cortical regions. Regional differences
were observed as sign for changes in temporal patterns across
brain regions.
Conclusions: A complex pattern was observed
between pathological and functional markers with respect to
disease stage (MCI versus AD) and brain regions. Regional
differences over time were evident during disease progression.
11C-PIB PET and CSF Aβ42
allowed detection of prodromal stages of AD. Amyloid imaging
is useful for early diagnosis and evaluation of new therapeutic
interventions in AD.
[Back to top]
Baseline MRI Predictors of Conversion from MCI to
Probable AD in the ADNI Cohort
S.L. Risacher, A.J. Saykin, J.D. West, L.
Shen, H.A. Firpi, B.C. McDonald and the
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
[Full
Text Article]
The Alzheimer’s Disease Neuroimaging Initiative (ADNI)
is a multi-center study assessing neuroimaging in diagnosis
and longitudinal monitoring. Amnestic Mild Cognitive Impairment
(MCI) often represents a prodromal form of dementia, conferring
a 10-15% annual risk of converting to probable AD. We analyzed
baseline 1.5T MRI scans in 693 participants from the ADNI
cohort divided into four groups by baseline diagnosis and
one year MCI to probable AD conversion status to identify
neuroimaging phenotypes associated with MCI and AD and potential
predictive markers of imminent conversion. MP-RAGE scans were
analyzed using publicly available voxel-based morphometry
(VBM) and automated parcellation methods. Measures included
global and hippocampal grey matter (GM) density, hippocampal
and amygdalar volumes, and cortical thickness values from
entorhinal cortex and other temporal and parietal lobe regions.
The overall pattern of structural MRI changes in MCI (n=339)
and AD (n=148) compared to healthy controls (HC, n=206) was
similar to prior findings in smaller samples. MCI-Converters
(n=62) demonstrated a very similar pattern of atrophic changes
to the AD group up to a year before meeting clinical criteria
for AD. Finally, a comparison of effect sizes for contrasts
between the MCI-Converters and MCI-Stable (n=277) groups on
MRI metrics indicated that degree of neurodegeneration of
medial temporal structures was the best antecedent MRI marker
of imminent conversion, with decreased hippocampal volume
(left >
right) being the most robust. Validation of imaging biomarkers
is important as they can help enrich clinical trials of disease
modifying agents by identifying individuals at highest risk
for progression to AD.
[Back to top]
Towards Retinoid Therapy for Alzheimer’s Disease
K. Shudo, H. Fukasawa, M. Nakagomi and
N. Yamagata
[Full
Text Article]
Alzheimer’s disease(AD) is associated with a variety
of pathophysiological features, including amyloid plaques,
inflammation, immunological changes, cell death and regeneration
processes, altered neurotransmission, and age-related changes.
Retinoic acid receptors (RARs) and retinoids are relevant
to all of these. Here we review the pathology, pharmacology,
and biochemistry of AD in relation to RARs and retinoids,
and we suggest that retinoids are candidate drugs for treatment
of AD.
[Back to top]
Natural Non-Trasgenic Animal Models
for Research in Alzheimer’s Disease
Manuel Sarasa and Pedro Pesini
[Full
Text Article]
The most common animal models currently used for Alzheimer
disease (AD) research are transgenic mice that express a mutant
form of human Aβ
precursor protein (APP) and/or some of the enzymes implicated
in their metabolic processing. However, these transgenic mice
carry their own APP and APP-processing enzymes, which may
interfere in the production of different amyloid-beta (Aβ)
peptides encoded by the human transgenes. Additionally, the
genetic backgrounds of the different transgenic mice are a
possible confounding factor with regard to crucial aspects
of AD that they may (or may not) reproduce. Thus, although
the usefulness of transgenic mice is undisputed, we hypothesized
that additional relevant information on the physiopathology
of AD could be obtained from other natural non-transgenic
models. We have analyzed the chick embryo and the dog, which
may be better experimental models because their enzymatic
machinery for processing APP is almost identical to that of
humans. The chick embryo is extremely easy to access and manipulate.
It could be an advantageous natural model in which to study
the cell biology and developmental function of APP and a potential
assay system for drugs that regulate APP processing. The dog
suffers from an age-related syndrome of cognitive dysfunction
that naturally reproduces key aspects of AD including Aβ
cortical pathology, neuronal degeneration and learning and
memory disabilities. However, dense core neuritic plaques
and neurofibrillary tangles have not been consistently demonstrated
in the dog. Thus, these species may be natural models with
which to study the biology of AD, and could also serve as
assay systems for Aβ
-targeted drugs or new therapeutic strategies against this
devastating disease.
[Back to top]
Long-Term Follow-Up of Patients Immunized with AN1792:
Reduced Functional Decline in Antibody Responders
Bruno Vellas, R. Black, Leon J. Thal, Nick
C. Fox, M. Daniels, G. McLennan, C. Tompkins, C. Leibman,
M. Pomfret, Michael Grundman; for the AN1792 (QS-21)-251 Study
Team
[Full
Text Article]
Background: Immunization
of patients with Alzheimer’s disease (AD) with synthetic
amyloid-β
peptide (Aβ42)
(AN1792) was previously studied in a randomized, double-blind,
placebo-controlled phase 2a clinical trial, Study AN1792(QS-21)-201.
Treatment was discontinued following reports of encephalitis.
One year follow-up revealed that AN1792 antibody responders
showed improvements in cognitive measures as assessed by the
neuropsychological test battery (NTB) and a decrease in brain
volume compared with placebo.
Methods: A follow-up study, Study AN1792(QS-21)-251,
was conducted to assess the long-term functional, psychometric,
neuroimaging, and safety outcomes of patients from the phase
2a study 4.6 years after immunization with AN1792. The results
were analyzed by comparing patients originally identified
as antibody responders in the AN1792 phase 2a study with placebo-treated
patients. Results: One hundred and
fifty-nine patients/caregivers (30 placebo; 129 AN1792) participated
in this follow-up study. Of the 129 AN1792-treated patients,
25 were classified in the phase 2a study as antibody responders
(anti-AN1792 titers ≥1:2,200 at any time after the first
injection). Low but detectable, sustained anti-AN1792 titers
were found in 17 of 19 samples obtained from patients classified
as antibody responders in the phase 2a study. No detectable
anti-AN1792 antibodies were found in patients not classified
as antibody responders in the phase 2a study. Significantly
less decline was observed on the Disability Assessment for
Dementia scale among antibody responders than placebo-treated
patients (p=0.015) after 4.6 years. Significant differences
in favor of responders were also observed on the Dependence
Scale (p=0.033). Of the small number of patients
who underwent a follow-up MRI, antibody responders showed
similar brain volume loss during the follow-up period subsequent
to the AN1792 phase 2a study compared with placebo-treated
patients.
Conclusions: Approximately 4.6 years after immunization
with AN1792, patients defined as responders in the phase 2a
study maintained low but detectable, sustained anti-AN1792
antibody titers and demonstrated significantly reduced functional
decline compared with placebo-treated patients. Brain volume
loss in antibody responders was not significantly different
from placebo-treated patients approximately 3.6 years from
the end of the original study. No further cases of encephalitis
were noted. These data support the hypothesis that Aβ
immunotherapy may have long-term functional benefits.
[Back to top]
Assembly of the Asparagine- and Glutamine-Rich
Yeast Prions into Protein Fibrils
Luc Bousset, Jimmy Savistchenko and Ronald Melki
[Full
Text Article]
The proteins Ure2, Sup35 and Rnq1 from the baker’s yeast
have infectious properties, termed prions, at the origin of
heritable and transmissible phenotypic changes. It is widely
believed that prion properties arise from the assembly of
Ure2p, Sup35p and Rnq1p into insoluble fibrils.
Yeast prions possess regions crucial for their propagation
that can be either N- or C-terminal. These regions have unusual
amino acid composition. They are very rich in glutamine and
asparagine residues and resemble in that to huntingtin, a
protein involved in the neurodegenerative Huntington’s
disease.
Yeast prions assembly process has been hypothesized to be
the consequence of the properties of glutamines and asparagines
to engage in polar protein-protein interactions, termed polar-zippers.
While this can certainly occur under certain conditions, glutamine
and asparagine residues can establish other kinds of interactions
with a variety of amino acid residues thus mediating protein-protein
interactions involved in the assembly of polypeptide chains
into high molecular weight oligomers.
This review details the interactions that can be established
by glutamine and asparagine residues that may allow a better
understanding of their role in mediating protein-protein interactions
and prion propagation.
[Back to top]
A New Glucocorticoid Hypothesis of Brain Aging: Implications
for Alzheimer’s Disease
Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen and
Nada M. Porter
[Full
Text Article]
The original glucocorticoid (GC) hypothesis of brain
aging and Alzheimer’s disease proposed that chronic
exposure to GCs promotes hippocampal aging and AD. This proposition
arose from a study correlating increasing plasma corticosterone
with hippocampal astrocyte reactivity in aging rats. Numerous
subsequent studies have found evidence consistent with this
hypothesis, in animal models and in humans. However, several
results emerged that were inconsistent with the hypothesis,
highlighting the need for a more definitive test with a broader
panel of biomarkers. We used microarray analyses to identify
a panel of hippocampal gene expression changes that were aging-dependent,
and also corticoster-one-dependent. These data enabled us
to test a key prediction of the GC hypothesis, namely, that
the expression of most target biomarkers of brain aging should
be regulated in the same direction (increased or decreased)
by both GCs and aging. This prediction was decisively contradicted,
as a majority of biomarker genes were regulated in opposite
directions by aging and GCs, particularly inflammatory and
astrocyte-specific genes. Thus, the initial hypothesis of
simple positive co-operativity between GCs and aging must
be rejected. Instead, our microarray data suggest that in
the brain GCs and aging interact in more complex ways that
depend on the cell type. Therefore, we propose a new version
of the GC-brain aging hypothesis; its main premise is that
aging selectively increases GC efficacy in some cell types
(e.g., neurons), enhancing catabolic processes, whereas aging
selectively decreases GC efficacy in other cell types (e.g.,
astrocytes), weakening GC anti-inflammatory activity. We also
propose that changes in GC efficacy might be mediated in part
by cell type specific shifts in the antagonistic balance between
GC and insulin actions, which may be of relevance for Alzheimer’s
disease pathogenesis.
[Back to top]
De Novo and Molecular Target-Independent Discovery
of Orally Bioavailable Lead Compounds for Neurological Disorders
Laura K. Wing, Heather A. Behanna, Linda J. Van Eldik,
D. Martin Watterson and Hantamalala Ralay Ranaivo
[Full
Text Article]
There is immediate potential to enhance success and innovation
in drug development by pairing newly emerging approaches in
medicinal chemistry and computational biology with knowledge
gained from the recent era of high throughput screens and
the early years of modern drug discovery when in vivo
efficacy was an early “Go/No Go” project management
decision. Focused, in-parallel synthetic chemistry platforms,
combined with computational analyses serving as decision aids
in planning, minimize the total number of compounds synthesized
while maximizing the probability of creating bioavailable
compounds that sample diverse chemical space. Incorporating
a hierarchal strategy that emphasizes early selection of synthesized
compounds based on biological or biophysical endpoints presents
fewer and more relevant compounds for secondary evaluation
of in vivo efficacy using animal screens with disease
relevant or clinically translatable endpoints. We summarize
here an interdisciplinary approach at the chemistry-biology
interface that is used for the rapid discovery of novel lead
compounds for neurodegenerative disorders, such as Alzheimer’s
disease (AD). The chemistry platform uses established chemistries
amenable to in-parallel strategies to create synthetic diversifications
of the privileged pyridazine chemotype that sample a restricted
chemical space. The hierarchal biology platform uses primary
screens for in vitro activity and selectivity with
the target cell type, and rapid secondary screens for in
vivo efficacy and toxicity in animal models with good
phenotypic penetrance for disease relevant pathophysiological
endpoints or clinically translatable surrogate endpoints.
For the AD case study, novel lead compounds were developed
in less than two years by a small academic group, and corporate
sponsored clinical trials are planned.
[Back to top]
Induction of RhoGAP and Pathological
Changes Characteristic of Alzheimer’s Disease by UAHFEMF
Discharge in Rat Brain
Ing-Feng Chang and Huo-Yen Hsiao
[Full
Text Article]
Novel experiments with Ultrasound Associated with High
Frequency Electromagnetic Field (UAHFEMF) irradiation on rats
and mice found evidences of characteristic Alzheimer’s
disease (AD) degenerations including neurite plaques, beta-amyloid,
TAU plaque and deposition in cells, Neuro-Fibrillary Tangle
and Paired Helical Filament (PHF) with rats and mice irradiated
up to 2454 hours. Concomitant passive avoidance test was performed
on six mice, and all showed signs of visual and auditory agnosia
and lost cognition of threatening condition. The post section
Thioflavin-S fluorescent microscopy found dilated ventricles
and dense amyloid-deposition in Ca3 and dentate gyrus. In
addition, PHF was identified in the 2454 hours-irradiated
rat brain by electron microscope. A human T-cell activation
RhoGTPase-activating protein (TAGAP) isoform b homolog (GenBank
accession # P84107) induced in the UAHFEMF-treated rat brain
was identified using electron spray ionization (ESI) liquid
chromatography tandem mass spectrometry (LC/MS/MS). We hypothesized
that one of the causes of AD can be the UAHFEMF discharges
in human brain.
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