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Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer
Research
Volume 6, Number 6, December 2009
Contents
Adult Neurogenesis, Neural Stem
Cells and Alzheimer’s Disease: Developments, Limitations,
Problems and Promises Pp. 461-470
Philippe Taupin
[Abstract]
[Full
text article]
[PMID:
19747153 PubMed - indexed for MEDLINE]
Is Increased Mortality
from Alzheimer’s Disease in Sweden a Reflection of Better
Diagnostics? Pp. 471-475
Örjan Hallberg
[Abstract]
[Full
text article]
[PMID:
19747157 PubMed - indexed for MEDLINE]
Agents Complexing Copper as a Therapeutic
Strategy for the Treatment of Alzheimer's Disease Pp.
476-487
Rosanna Squitti and Carlo Salustri
[Abstract]
[Full
text article]
[PMID:
19747159 PubMed - indexed for MEDLINE]
Intracranial MR Dynamics
in Clinically Diagnosed Alzheimer’s Disease: The Emerging
Concept of “Pulse Wave Encephalopathy” Pp.
488-502
Marie Cécile Henry-Feugeas
[Abstract]
[Full
text article]
[PMID:
19747161 PubMed - indexed for MEDLINE]
Prospects for Early
Detection of Alzheimer’s Disease from Serial MR Images
in Transgenic Mouse Models Pp. 503-518
M. Muskulus, A.E.H. Scheenstra, N. Braakman,
J. Dijkstra, S. Verduyn-Lunell, A. Alia, H.J.M. de Groot and
J.H.C. Reiber
[Abstract]
[Full
text article]
[PMID:
19747155 PubMed - indexed for MEDLINE]
A Possible New Diagnostic
Biomarker in Early Diagnosis of Alzheimer’s Disease
Pp. 519-524
Felix Kork, Jan Holthues, Rainer Hellweg,
Vera Jankowski, Martin Tepel, Renate Öhring, Isabella
Heuser, Jeffrey Bierbrauer, Oliver Peters, Peter Schlattmann,
Walter Zidek, and Joachim Jankowski
[Abstract]
[Full
text article]
[PMID:
19747162 PubMed - indexed for MEDLINE]
An fMRI Stroop Task
Study of Prefrontal Cortical Function in Normal Aging, Mild
Cognitive Impairment, and Alzheimer's Disease Pp.
525-530
Chuanming Li, Jian Zheng, Jian Wang, Li
Gui and Chuan Li
[Abstract]
[Full
text article]
[PMID:
19747163 PubMed - indexed for MEDLINE]
Amyloid Deposition
and Inflammation in APPswe/PS1dE9 Mouse Model of Alzheimer’s
Disease Pp. 531-540
Lingfei Ruan, Zhoujun Kang, Gang Pei and
Yingying Le
[Abstract]
[Full
text article]
[PMID:
19747158 PubMed - indexed for MEDLINE]
Impact of Alzheimer’s
Disease on the Functional Connectivity of Spontaneous Brain
Activity Pp. 541-553
Christian Sorg, Valentin Riedl, Robert Perneczky,
Alexander Kurz and Afra M. Wohlschläger
[Abstract]
[Full
text article]
[PMID:
19747154 PubMed - indexed for MEDLINE]
Microglial
Activation in Alzheimer’s Disease
Pp. 554-563
Johannes C.M. Schlachetzki, and
Michael Hüll
[Abstract]
[Full
text article]
[PMID:
19747160 PubMed - indexed for MEDLINE]
Optimized
Turmeric Extracts have Potent Anti-Amyloidogenic Effects Pp.
564-571
R. Douglas Shytle, Paula C. Bickforda,,
Kavon Rezai-zadeh, L. Houb, Jin Zeng, Jun Tan, Paul R. Sanberg,
Cyndy D. Sanberg, Bill Roschek Jr.f, Ryan C. Finkg and
Randall S. Alberte
[Abstract]
[Full
text article]
[PMID:
19715544 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[Full
text article]
[PMID:
19747153 PubMed - indexed for MEDLINE]
Adult Neurogenesis, Neural Stem Cells and Alzheimer’s
Disease: Developments, Limitations, Problems and Promises
Philippe Taupin
Alzheimer’s disease (AD) is an irreversible progressive
neurodegenerative disease, leading to severe incapacity and
death. It is the most common form of dementia among older
people. AD is characterized in the brain by amyloid plaques,
neurofibrillary tangles, neuronal degeneration, aneuploidy
and enhanced neurogenesis and by cognitive, behavioural and
physical impairments. Inherited mutations in several genes
and genetic, acquired and environmental risk factors have
been reported as causes for developing the disease, for which
there is currently no cure. Current treatments for AD involve
drugs and occupational therapy, and future developments involve
early diagnosis and stem cell therapy. In this manuscript,
we will review and discuss the recent developments, limitations,
problems and promises on AD, particularly related to aneuploidy,
adult neurogenesis, neural stem cells (NSCs) and cellular
therapy. Though adult neurogenesis may be beneficial for regeneration
of the nervous system, it may underlie the pathogenesis of
AD. Cellular therapy is a promising strategy for AD. Limitations
in protocols to establish homogeneous populations of neural
progenitor and stem cells and niches for neurogenesis need
to be resolved and unlocked, for the full potential of adult
NSCs to be realized for therapy.
[Back to top]
[Full
text article]
[PMID:
19747157 PubMed - indexed for MEDLINE]
Is Increased Mortality from
Alzheimer’s Disease in Sweden a Reflection of Better
Diagnostics?
Örjan Hallberg
Mortality data were retrieved from the Swedish death
registry for the years 1970-2006. This report presents updated
information on mortality from Alzheimer's disease (AD) through
the year 2006, as well as a statistical model of AD mortality
with predictive value. This model was developed based on a
mortality risk function acting after a specific time point,
either step-wise on the whole population or on an increasing
part of it. Data collected in recent years indicate that mortality
is increasing continuously amongst the oldest patients, while
younger age-groups show more stable mortality rates. After
fitting the statistical model to age-standardized mortality
data it also gave age-specific rates that fit well with reported
data without further adjustments in model parameters. The
data and the corresponding model for AD mortality suggest
that the ability of the body to protect itself from AD-related
neurological damage has in general became increasingly impaired
since about 1985. This impairment has mainly affected people
65 years of age and older since 1985; the model predicts that
in 2020, the age-standardized mortality in Sweden will be
13/100,000 person-years. The author concludes that the increasing
mortality is real and not only a result of increasing use
of the death classification code for AD.
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[Full
text article]
[PMID:
19747159 PubMed - indexed for MEDLINE]
Agents
Complexing Copper as a Therapeutic Strategy for the Treatment
of Alzheimer's Disease
Rosanna Squitti and Carlo Salustri
The notion that a copper dysfunction is implicated in Alzheimer’s
disease (AD) is based on a number of observations from in
vitro and clinical studies, as well as animal models.
However, there is still significant controversy over whether
it is an excess or a deficiency of copper to be involved in
the pathogenesis of AD. Numerous studies support the hypothesis
that an excess of copper contributes to AD, but experimental
evidence in transgenic mouse models seems to suggest the contrary,
and at least one clinical study shows that cognitive decline
correlates positively with low copper levels. We have recently
reported on a deregulation of the ceruloplasmin-copper relationship,
specific to AD patients, consisting of an elevation of the
copper pool not bound to ceruloplasmin, i.e. ‘free’
copper. This phenomenon could provide an explanation of the
contrasting results obtained in clinical studies. Several
clinical trials have been attempted in search of an anti-metal
effect counteracting AD progression. Some of them have delivered
encouraging results indicating that “metal protein attenuating
compounds” can indeed alter positively the progression
of the disease. This review summarizes these clinical studies
and provides an overview of those in progress and in preparation.
[Back to top]
[Full
text article]
[PMID:
19747161 PubMed - indexed for MEDLINE]
Intracranial
MR Dynamics in Clinically Diagnosed Alzheimer’s Disease:
The Emerging Concept of “Pulse Wave Encephalopathy”
Marie Cécile Henry-Feugeas
As increasingly shown in neuropathological and predementia
clinical studies, cognitive decline with altered intracranial
dynamics can fulfill current clinical criteria of dementia
of the Alzheimer’s type (DAT) and there is a marked
pathogenic complexity of this epidemic syndrome. Whereas structural
studies only suggest the unexpected frequency of cerebrovascular
changes in late life DAT, flow quantification MR sequences
now offer a great opportunity of in vivo accurate
analysis of cerebrovascular function.
Their first applications have allowed development of a modern
concept of the intracranial dynamics; a complex windkessel
system allows two processes that are crucial to insure brain
oxygenation and nutrition, a periodic systolic marked expansion
of the intracranial blood compartment within the rigid cranial
cavity on the one hand, a marked dampening of the arterial
pulse wave before it reaches capillary level on the other
hand. This modern concept has allowed better understanding
of two archetypes of windkessel failure or so-called pulse
wave encephalopathy, normal pressure hydrocephalus and subcortical
arteriosclerotic encephalopathy.
Dynamic MRI may now help to detect and classify distinct patterns
of cerebrovascular dysfunction in DAT. This dynamic approach
helps to understand the major association between aging and
DAT as well as the increasingly recognized overlap between
Alzheimer’s pathology, normal pressure hydrocephalus
and arteriosclerotic neurodegeneration. Evidence of such a
great variety of disturbances in intracranial dynamics behind
a single clinical syndrome of DAT can greatly impact the-rapeutic
research on this devastating disorder.
[Back to top]
[Full
text article]
[PMID:
19747155 PubMed - indexed for MEDLINE]
Prospects for Early Detection
of Alzheimer’s Disease from Serial MR Images in Transgenic
Mouse Models
M. Muskulus, A.E.H. Scheenstra, N. Braakman,
J. Dijkstra, S. Verduyn-Lunell, A. Alia, H.J.M. de Groot and
J.H.C. Reiber
The existing literature on the magnetic resonance imaging
of murine models of Alzheimer's disease is reviewed. Particular
attention is paid to the possibilities for the early detection
of the disease. To this effect, not only are relaxometric
and volumetric approaches discussed, but also mathematical
models for plaque distribution and aggregation. Image analysis
plays a prominent role in this line of research, as stochastic
image models and texture analysis have shown some success
in the classification of subjects affected by Alzheimer's
disease. It is concluded that relaxometric approaches seem
to be a promising candidate for the task at hand, especially
when combined with sophisticated image analysis, and when
data from more than one time-point is available. There have
been few longitudinal studies of mice models so far, so this
direction of research warrants future efforts.
[Back to top]
[Full
text article]
[PMID:
19747162 PubMed - indexed for MEDLINE]
A
Possible New Diagnostic Biomarker in Early Diagnosis of Alzheimer’s
Disease
Felix Kork, Jan Holthues, Rainer Hellweg,
Vera Jankowski, Martin Tepel, Renate Öhring, Isabella
Heuser, Jeffrey Bierbrauer, Oliver Peters, Peter Schlattmann,
Walter Zidek, and
Joachim Jankowski
Early diagnosis in patients with Alzheimer's disease
(AD) is of great importance since only a sufficient treatment
in early stages of this disease helps to keep patients in
an autonomous state for as long as possible. Until now, there
is no single diagnostic biomarker for AD derived from material
routinely obtained. In this study, proton nuclear magnetic
resonance (1H-NMR) spectra
of the cerebrospinal fluid (CSF) of AD patients were compared
with 1H-NMR spectra of the
CSF of healthy control subjects using a metabonomic approach.
The 1H-NMR spectra of CSF
of AD patients showed specific multipletts at 2.15 ppm and
2.45 ppm, which could not be detected in the majority (59.3%
and 70.4%, respectively) of healthy control subjects (positive
likelihood ratio (+LR) 2.33, 95% CI [1.46, 3.72], p<0.01;
+LR 3.22, 95% CI [1.78, 5.78], p<0.01). Moreover, CSF 1H-NMR
spectra of AD patients showed specific resonances at 7.03
ppm (+LR 3.38, 95% CI [1.60, 7.14], p<0.05), 7.19 ppm (+LR
2.89, 95% CI [1.46, 5.74], p<0.05), 7.43 ppm (+LR 3.15,
95% CI [1.47, 6.75], p<0.05), and at 7.91 ppm (+LR 3.38,
95% CI [1.60, 7.14], p<0.01).
CSF 1H-NMR spectroscopy is
obviously a capable method for detection and quantification
of substances in the CSF of AD patients even without the knowledge
of molecular structures. These substances can be used as a
biomarker in the early diagnosis of AD. We assume that this
biomarker will simplify the diagnosis of AD, especially in
early stages of the disease.
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[Full
text article]
[PMID:
19747163 PubMed - indexed for MEDLINE]
An
fMRI Stroop Task Study of Prefrontal Cortical Function in
Normal Aging, Mild Cognitive Impairment, and Alzheimer's Disease
Chuanming Li, Jian Zheng, Jian Wang, Li
Gui and
Chuan Li
Severe cortex lesions in the hippocampal, parahippocampal
and medial temporal lobe (MTL) of Alzheimer's disease subjects
have been observed by functional magnetic resonance imaging
(fMRI) during memory task performance. To date, fMRI technology
has not been used to investigate the frontal lobe function
of Alzheimer's subjects. This study determines if fMRI can
be used to assess altered prefrontal cortex activity during
Stroop task performance in subjects wih mild cognitive impairment
(MCI) and Alzheimer's disease (AD). Functional magnetic resonance
imaging (fMRI) was performed on 9 healthy elderly controls,
9 subjects with mild cognitive impairment and 10 patients
with Alzheimer's disease, to examine the prefrontal changes
in fMRI activation in relation to the Stroop color-word paradigm.
In comparison with controls, MCI subjects showed distinctly
increased cortex activity including: the dorsal anterior cingulate,
bilateral middle and inferior frontal gyri, bilateral inferior
parietal lobule, and the bilateral insular. In contrast, AD
subjects exhibited decreased fMRI responses in the regions
of the prefrontal cortex listed above. These results imply
two different neurophysiological characteristics of MCI and
AD. In MCI, a compensatory activity of the prefrontal cortex
is observed, whereas in AD a dysfunction of the prefrontal
cortex is indicated.
[Back to top]
[Full
text article]
[PMID:
19747158 PubMed - indexed for MEDLINE]
Amyloid
Deposition and Inflammation in APPswe/PS1dE9 Mouse Model of
Alzheimer’s Disease
Lingfei Ruan, Zhoujun Kang, Gang Pei and
Yingying Le
Alzheimer’s
disease (AD) is characterized by amyloid plaques and neurofibrillary
tangles associated with chronic inflammation. APPswe/PS1dE9
is an AD mouse model bearing mutant transgenes of amyloid
precursor protein and presenilin-1. Amyloid deposition is
present in this mouse model at early stage of life. However,
the progression of inflammation and its relationship with
amyloid deposition have not been characterized. Here we showed
that amyloid plaques were present at 4 months of age and increased
with age. CD11b-positive microglia clusters appeared in hippocampus
and neocortex at 4 months of age and increased with age. Clustered
glial fibrillary acidic protein (GFAP)-positive astrocytes
were observed in hippocampus and cortex after 6 months of
age and increased with age. Double staining with CD11b/GFAP
antibody and thioflavin S showed clustered microglia and astrocytes
were in close association with amyloid plaques. Expression
of TNF-α
was detected at 8 months of age, while IL-1β,
IL-6 and MCP-1 at 10 months. These cytokines increased with
age. Double immunostaining of cell specific marker and cytokine
indicated TNF-α,
IL-1β,
IL-6 and MCP-1 were expressed by activated microglia and a
small part of activated astrocytes. MCP-1 was also expressed
by neurons, which support recent finding that MCP-1 expression
was increased in neurons of AD patient. These results demonstrate
amyloid plaques and its associated inflammatory response developed
at early stage of life and progressively increased with age,
both activated glia and neurons are involved in chronic inflammation
in AD. APPswe/PS1dE9 model provides a mean for studying the
mechanisms and novel therapeutics for AD.
[Back to top]
[Full
text article]
[PMID:
19747154 PubMed - indexed for MEDLINE]
Impact
of Alzheimer’s Disease on the Functional Connectivity
of Spontaneous Brain Activity
Christian Sorg, Valentin Riedl, Robert Perneczky,
Alexander Kurz and
Afra M. Wohlschläger
Alzheimer’s disease (AD) prominently affects the
structure and function of cerebral networks. Reflecting the
complex network structure of the brain, spontaneous brain
activity is organized by synchronized activity across distinct
temporal and spatial scales. Temporal correlations of the
functional MRI (fMRI) signal during rest have been used to
characterize the impact of AD on the functional connectivity
of spontaneous brain activity. Here we review studies using
resting-state fMRI (rs-fMRI) to explore AD-induced changes
of synchronized intrinsic activity at three levels of brain
organization: the regional, inter-regional and large-scale
level. Changes in posterior areas of the default network (DN)
and the medial temporal lobes seem to be central to AD. These
areas show remarkable disturbances in neuronal communication
at all spatial levels and in very early stages of the disease.
Finally, rs-fMRI seems to have the potential to produce connectivity-related
biomarkers that distinguish AD and healthy aging.
[Back
to top]
[Full
text article]
[PMID:
19747160 PubMed - indexed for MEDLINE]
Microglial
Activation in Alzheimer’s Disease
Johannes
C.M. Schlachetzki, and
Michael Hüll
Alzheimer’s disease (AD) is a devastating
chronic neurodegenerative disease with currently no available
disease modifying treatment. In recent years, the peptide
amyloid-β
has been proposed as the major pathogenic force in the development
and progression of AD. Microglia, the resident immune and
phagocytic cells of the brain, are known to constantly scan
brain tissue and to respond to various pathological stimuli.
Thus, newly formed plaque composed of Aβ
seem to activate and recruit microglia in AD transgenic mice.
However, the role of microglia is only poorly understood in
AD. Microglia may act as a double-edged sword being either
detrimental or protective depending on the context.
In this mini-review, we discuss the importance of microglia
and its receptors in neuroinflammation and plaque clearance.
A possible disease modifying role of blood-borne monocytes,
which are close relatives of bone-marrow derived microglia,
will also be addressed.
[Back
to top]
[Full
text article]
[PMID:
19715544 PubMed - indexed for MEDLINE]
Optimized
Turmeric Extracts have Potent Anti-Amyloidogenic Effects
R.
Douglas Shytle, Paula C. Bickforda,, Kavon Rezai-zadeh, L.
Houb, Jin Zeng, Jun Tan, Paul R. Sanberg, Cyndy D. Sanberg,
Bill Roschek Jr.f, Ryan C. Finkg and
Randall S. Alberte
Inhibition of β-amyloid
(Aβ)
accumulation and Aβ
fibril (fAβ)
formation from Aβ
are attractive therapeutic targets for the treatment of Alzheimer's
disease (AD). While previous studies have shown anti-amyloidogenic
effects of curcumin in vitro and in vivo,
no studies have examined optimized turmeric extracts enriched
in curcuminoids or turmerones. Three standardized turmeric
extracts, HSS-838, HSS-848, and HSS-888, were prepared with
different chemical profiles to investigate their potential
therapeutic benefits for AD. These extracts were fingerprinted
by DART TOF-MS to reveal the significant chemical complexity.
In addition four curcuminoids (curcumin, tetrahydrocurcumin,
demethoxycurcumin and bisdemethoxycurcumin) were also examined.
We measured the effects of the extracts and curcuminoids,
on the aggregation of Aβ
by using a thioflavin T cell-free assay and the secretion
of Aβ
from human neuronal cells (SweAPP N2A cells) in vitro.
All three extracts and the curcuminoids showed dose-dependent
inhibition of fAβ
aggregation from Aβ1-42
in the cell-free assay, with IC50
values of ≤
5 μg/mL.
However, only HSS-888, curcumin and demethoxycurcumin significantly
decreased Aβ
secretion (~20%) in SweAPP N2A cells. Interaction matrices
were used to examine possible synergistic interactions between
HS-888 and the other extracts and the individual curcuminoids
on Aβ
aggregation. Only simple additive effects were observed for
the Aβ
aggregation inhibition, supporting the notion that the known
curcuminoids are not strong inhibitors of this activity. However,
HSS-888 showed strong inhibition of Aβ
aggregation and secretion, thus indicating that there are
novel bioactive molecules in this extract that might be important
leads for future AD drug discovery efforts.
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