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Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer
Research
Volume 7, Number 6, September 2010
Contents
Alzheimer’s Disease: SPECT and PET Tracers for Beta-Amyloid
Imaging Pp.
477-486
V. Valotassiou, S. Archimandritis, N. Sifakis, J. Papatriantafyllou
and P. Georgoulias
[Abstract] [Purchase
Article]
Diagnosis of Alzheimer’s Disease from EEG
Signals: Where Are We Standing? Pp.
487-505
J. Dauwels, F. Vialatte and A. Cichocki
[Abstract] [Purchase
Article]
Is Elevated Norepinephrine an Etiological Factor in
Some Cases of Alzheimer’s Disease? Pp.
506-516
P.J. Fitzgerald
[Abstract] [Purchase
Article]
Prevalence of Neuropsychiatric Symptoms
in Mild Cognitive Impairment and Alzheimer’s Disease,
and its Relationship with Cognitive Impairment
Pp. 517-526
M. Fernández-Martínez, A. Molano, J. Castro
and J.J. Zarranz
[Abstract] [Purchase
Article]
Impacts of Hyper-Homocysteinemia and White Matter
Hyper-Intensity in Alzheimer’s Disease Patients with
Normal Creatinine: An MRI-Based Study with Longitudinal Follow-up
Pp. 527-533
C.W. Huanga, W.N. Changa, C.C. Luib, C.F. Chenb, C.H. Lua,
Y.L. Wangc, C. Chenc, Y.Y. Juanga, Y.T. Lina, M.C. Tua and
C.C. Chang
[Abstract] [Purchase
Article]
Low Levels of High Density Lipoprotein Increase the Severity
of Cerebral White Matter Changes:Implications for Prevention
and Treatment of Ce-rebrovascular Diseases Pp.
534-539
M. Crisby, L. Bronge and L.-O. Wahlund
[Abstract] [Purchase
Article]
Bone Marrow-Derived Mesenchymal Stem Cells Attenuate Amyloid
β-Induced
Memory Impairment and Apoptosis by Inhibiting Neuronal Cell
Death Pp.
540-548
J.K. Lee, H.K. Jin and J.-S. Bae
[Abstract] [Purchase
Article]
[Supplementary
Material]
Ubiquitin Enzymes, Ubiquitin and Proteasome
Activity in Blood Mononuclear Cells of MCI, Alzheimer and
Parkinson Patients Pp.
549-555
C. Ullrich, R. Mlekusch, A. Kuschnig,
J. Marksteiner and C. Humpel
[Abstract] [Purchase
Article]
Atheromatosis Extent in Coronary Artery Disease
is not Correlated with Apolipoprotein-E Polymorphism and its
Plasma Levels, but Associated with Cognitive Decline
Pp. 556-563
L.M. Lima, M.d.G. Carvalho, C.N. Ferreira, A.P. Fernandes,
C.P.d.F. Neto, J.C.F. Garcia, H.J. Reis, Z. Janka, A. Palotás
and M.d.O. Sousa
[Abstract] [Purchase
Article]
Abstracts
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Alzheimer’s Disease: SPECT and PET Tracers for
Beta-Amyloid Imaging
V. Valotassiou, S. Archimandritis, N. Sifakis, J. Papatriantafyllou
and P. Georgoulias
The definite diagnosis of Alzheimer’s disease (AD) is
based on the detection of beta amyloid (Aβ)
plaques and neurofibrillary tangles (NFTs) - which are the
pathological hallmarks of the disease- in the postmortem brains.
Although regional Cerebral Blood Flow (rCBF) and Cerebral
Glucose Metabolism (CGM) abnormalities have already been studied
in AD patients with Single Photon Emission Computed Tomography
(SPECT) and Positron Emission Tomography (PET), the development
of specific imaging agents for direct mapping of Aβ
plaques in the living brain, is a great challenge. Aβ
probes could significantly contribute to the early diagnosis
of AD, the elucidation of the underlying neuropathological
processes and the evaluation of anti-amyloid therapies which
are currently under investigation. The development of SPECT
and PET tracers for Aβ
imaging represents an active area in radiopharmaceutical design.
A substantial number of potential Aβ
imaging radioligands have been designed and used in-vitro.
They are either monoclonal antibodies to Aβ
and radiolabeled Aβ
peptides, or derivatives of histopathological stains such
as Congo red (CR), chrysamine-G (CG) and Thioflavin T (TT).
Though, only few of them, that display high binding affinity
to Aβ
as well as sufficient brain penetration, have been used primarily
in in-vivo studies and to a smaller degree on human
subjects. Since Aβ
plaques are not homogenous and contain multiple binding sites
that can accommodate structurally diverse compounds, they
offer flexibility in designing various different probes, as
potential amyloid imaging agents.
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Diagnosis of Alzheimer’s Disease from EEG
Signals: Where Are We Standing?
J. Dauwels, F. Vialatte and A. Cichocki
This paper reviews recent progress in the diagnosis of Alzheimer’s
disease (AD) from electroencephalograms (EEG). Three major
effects of AD on EEG have been observed: slowing of the EEG,
reduced complexity of the EEG signals, and perturbations in
EEG synchrony. In recent years, a variety of sophisticated
computational approaches has been proposed to detect those
subtle perturbations in the EEG of AD patients. The paper
first describes methods that try to detect slowing of the
EEG. Next the paper deals with several measures for EEG complexity,
and explains how those measures have been used to study fluctuations
in EEG complexity in AD patients. Then various measures of
EEG synchrony are considered in the context of AD diagnosis.
Also the issue of EEG preprocessing is briefy addressed. Before
one can analyze EEG, it is necessary to remove artifacts due
to for example head and eye movement or interference from
electronic equipment. Pre-processing of EEG has in recent
years received much attention. In this paper, several state-of-the-art
pre-processing techniques are outlined, for example, based
on blind source separation and other non-linear filtering
paradigms.
In addition, the paper outlines opportunities and limitations
of computational approaches for diagnosing AD based on EEG.
At last, future challenges and open problems are discussed.
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Is Elevated Norepinephrine an Etiological Factor in Some Cases
of Alzheimer’s Disease?
P.J. Fitzgerald
Loss of norepinephrine (NE) releasing neurons, in the locus
coeruleus of the brainstem, is well documented to occur in
Alzheimer’s disease (AD). However, this process does
not necessarily result in decreased release of NE, since compensatory
mechanisms may produce increased release of this neurotransmitter.
Independent of potential loss of locus coeruleus cells, brain
NE levels may be elevated in some persons with AD, both before
and during disease progression. Here I examine evidence that
elevated, endogenous brain NE is an etiological factor in
some cases of AD, and not merely an epiphenomenon of the disease.
To explore this etiological hypothesis in AD, I examine the
following eight lines of evidence: 1) direct evidence of elevated
NE or its metabolites in AD; 2) studies of tricyclic antidepressants,
which may principally boost NE; 3) studies of clonidine and
other alpha2 adrenergic agonist drugs, which may principally
lower the concentration of NE; 4) studies of beta adrenoceptor
blocking drugs, including propranolol; 5) comorbidity of AD
and bipolar disorder, where both disorders may involve elevated
NE; 6) comorbidity of AD and hypertension; 7) comorbidity
of AD and obesity; and 8) potential interaction between AD
and psychological stress, where stressors are known to release
NE. These lines of evidence tend to support the elevated NE
etiological hypothesis.
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Prevalence of Neuropsychiatric Symptoms in Mild Cognitive
Impairment and Alzheimer’s Disease, and its Relationship
with Cognitive Impairment
M. Fernández-Martínez, A. Molano, J. Castro
and J.J. Zarranz
Objective The study aimed
to describe the prevalence of Neuropsychiatric symptoms (NPS)
in Alzheimer’s disease (AD), amnestic mild cognitive
impairment (MCI) and controls using the 12-item Neuropsychiatric
Inventory (NPI) and to analyze the relationships between neuropsychiatric
symptoms with specific neuropsychological tests.Patients
and methods; We prospectively studied 485 patients from
the Memory Unit in Cruces Hospital (Spain), 344 met the criteria
of NINCDS-ADRDA for probable AD (99 were classified as mild
and 245 as moderate-severe), 91 for MCI and 50 were controls.
Mini-mental State Examination (MMSE) and CDR (Clinical Dementia
Rating) were used to evaluate global cognitive function and
to classify the severity of cognitive impairment. The neuropsychological
test battery included memory test, verbal fluency, visuoespatial
skills and daily living scales. The 12-items Neuropsychiatric
Inventory (NPI) version was used to assess neuropsychiatric
symptoms. All patients underwent a neuroimaging study (CT
scan and/or MRI). Patients were not treated with antidementia
or psychotropic drugs. Results;Apathy and depression
were more prevalent NPS in moderate-severe AD (78.4% and 44.1%,
respectively), mild AD (64.6% and 41.4%, respectively) and
MCI (50.5% and 33%, respectively) patients than in controls
(6% and 8%, respectively). The prevalence and the mean scores
of all symptoms increased along the severity of the disease,
except for sleep and appetite disorders. In patients with
mild AD a relationship was found between the presence of NPS
and RDRS-2 scale (p = 0.003); and between NPS and RDRS-2 (p
= 0.029) and SS-IQCODE scales (p = 0.039) in moderate-severe
patients.Conclusions; NPS were more prevalent in
AD and MCI patients than in controls. In AD and MCI patients
apathy and depression were the most prevalent NPS. The prevalence
and the mean scores of all symptoms gradually increased along
the severity of the disease, except for sleep and appetite
disorders. We have no found a relationship between neuropsycological
test and the presence of NPS, but in patients with mild and
moderate-severe AD there is a relationship with daily living
scales.
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Impacts of Hyper-Homocysteinemia and
White Matter Hyper-Intensity in Alzheimer’s Disease
Patients with Normal Creatinine: An MRI-Based Study with Longitudinal
Follow-up
C.W. Huang, W.N. Chang, C.C. Lui, C.F. Chen, C.H. Lu, Y.L.
Wangc, C. Chen, Y.Y. Juang, Y.T. Lin, M.C. Tu and
C.C. Chang
Background: White matter hyper-intensities
(WMHs) on magnetic resonance imaging (MRI) are commonly found
in Alzheimer’s disease (AD). Cerebro-vascular risk factors
including plasma total homocysteine (tHcy) may result in WMHs.
This study examined the association between tHcy and WMHs,
and their effects on cognitive functions in AD patients over
a two-year follow-up period.
Methods: One hundred and fifty-seven AD patients
with a clinical dementia rating of 1 or 2 were enrolled and
follow-up for two years. tHcy, biochemistry tests, and mini-mental
state examination (MMSE) scores were collected. WMHs were
visually rated on brain MRI and classified as deep white matter
hyper-intensities (DWMHs) or peri-ventricular white matter
hyper-intensities (PWMHs). MMSEs were performed every six
months to survey cognitive decline.
Results: In the cross sectional study, tHcy
was significantly associated with total WMHs especially in
DWMHs even after adjusting for age and other cerebrovascular
risk factors. Initial MMSE was inversely correlated with WMH
severity but not with tHcy level. In the longitudinal analysis,
no differences were found either in tHcy or WMHs score in
the two AD groups defined by the cognitive decline rate.
Conclusions: tHcy is an independent risk factor
for developing moderate to severe DWMHs in AD but shows non-significant
effect on cognitive performance. The close association between
high WMH score and poor initial MMSE suggests an additive
impact in AD. The long-term effect of elevated tHcy on cognitive
decline was not conclusive in the two-year follow-up period.
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Low Levels of High Density Lipoprotein Increase the Severity
of Cerebral White Matter Changes:Implications for Prevention
and Treatment of Ce-rebrovascular Diseases
M. Crisby, L. Bronge and L.-O. Wahlund
Background and Purpuse: Cerebral White matter
changes (WMC) are a frequent finding on CT and MRI scans of
elderly individuals, particularly in those with vascular risk
factors, cerberovascular disease, and cognitive impairment.
Methods: 56 subjects were included in the
study after the review of reports of more than 200 consecutive
brain Computerized Tomography (CT) and magnetic resonance
imaging (MRI) examinations from the out-patient and in-patient
units of the Department of Geriatric Medicine at Karolinska
University Hospital, Huddinge during 2001-2002. MRI was performed
using a 1.5 T system and WMC lesions were graded 1-3 using
a visual scale. Total-cholesterol (TC), high density lipoprotein
(HDL), low density lipoprotein (LDL) and triglyceride (TG)
levels were determined using enzymatic techniques after 12
hours overnight fasting. Apo E genotyping was performed as
described. Results: Low HDL levels were associated
with higher severity of WMC on MRI (p=0.002). Subjects with
the Apo E4 allele had higher LDL (p=0.002) and apoB levels
(p=0.005). The presence of the Apo E4 allele was higher in
the group of subjects with severe WMC (grade 3). However,
there was no statistically significant group difference in
severity of WMC lesions between carriers and non-carriers
of Apo E4 allele. Conclusions: Low HDL is
strongly associated with adverse coronary and cerebrovascular
outcomes. Our results indicate that low HDL levels are also
associated with more severe WMC lesions on MRI. Dietary or
medical adjustment of HDL levels could have important implications
for treatment and prevention of cerebral WMC, cerebrovascular
and neurodegenerative diseases such as stroke and dementia.
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Bone Marrow-Derived Mesenchymal Stem Cells Attenuate Amyloid
β-Induced
Memory Impairment and Apoptosis by Inhibiting Neuronal Cell
Death
J.K. Lee, H.K. Jin and J.-S. Bae
Amyloid β
(Aβ)
peptide plays a central role in neuronal apoptosis, promoting
oxidative stress, lipid peroxidation, caspase pathway activation
and neuronal loss. Our previous study has shown that bone
marrow-derived mesenchymal stem cells (BM-MSCs) reduce Aβ
deposition when transplanted into acutely-induced Alzheimer’s
disease (AD) mice brain. However, the impact of reduced Aβ
deposition on memory impairment and apoptosis by BM-MSCs has
not yet been investigated. Therefore, the aim of the present
study was to investigate the neuroprotective mechanism of
BM-MSCs in vitro and in vivo. We found that
BM-MSCs attenuated Aβ-induced
apoptotic cell death in primary cultured hippocampal neurons
by activation of the cell survival signaling pathway. These
anti-apoptotic effects of BM-MSCs were also observed in an
acutely-induced AD mice model produced by injecting Aβintrahippocampally.
In addition, BM-MSCs diminished Aβ-induced
oxidative stress and spatial memory impairment in the in
vivo model. These findings lead us to hypothesize that
BM-MSCs ameliorate Aβ-induced
neurotoxicity and cognitive decline by inhibiting apoptotic
cell death and oxidative stress in the hippocampus. These
findings provide support for a potentially beneficial role
for BM-MSCs in the treatment of AD.
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Ubiquitin Enzymes, Ubiquitin and Proteasome Activity
in Blood Mononuclear Cells of MCI, Alzheimer and Parkinson
Patients
C. Ullrich, R. Mlekusch, A. Kuschnig,
J. Marksteiner and C. Humpel
Alzheimer´s disease (AD) is a
severe chronic neurodegenerative disease. During aging and
neurodegeneration, misfolded proteins accumulate and activate
the ubiquitin-proteasome system. The aim of the present study
is to explore whether ubiquitin-activating enzyme E1, ubiquitin-conjugating
enzyme E2, ubiquitin or proteasome activity are affected in
peripheral blood mononuclear cells (PBMC) of AD, mild cognitive
impairment (MCI) and Parkinson´s disease (PD) patients
compared to healthy subjects. PBMCs were isolated from EDTA
blood samples and extracts were analyzed by Western Blot.
Proteasome activity was measured with fluorogenic substrates.
When compared to healthy subjects, the concentration of enzyme
E1 was increased in PBMCs of AD patients, whereas the concentration
of the enzyme E2 was decreased in the same patients. Ubiquitin
levels and proteasome activity were unchanged in AD patients.
No changes in enzyme expression or proteasome activity was
observed in MCI patients compared to healthy and AD subjects.
In PD patients E2 levels and proteasomal activity were significantly
reduced, while ubiquitin and E1 levels were unchanged. The
present investigation demonstrates the differences in enzyme
and proteasome activity patterns of AD and PD patients. These
results suggest that different mechanisms are involved in
regulating the ubiquitin-proteasomal system in different neurodegenerative
diseases.
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Atheromatosis Extent in Coronary Artery Disease
is not Correlated with Apolipoprotein-E Polymorphism and its
Plasma Levels, but Associated with Cognitive Decline
L.M. Lima, M.d.G. Carvalho, C.N. Ferreira, A.P. Fernandes,
C.P.d.F. Neto, J.C.F. Garcia, H.J. Reis, Z. Janka, A. Palotás
and M.d.O. Sousa
Background: Apolipoprotein-E
(apoE) e4 allele is a known risk factor for Alzheimer’s
disease (AD). Polymorphism of apoE is also one of the most
important genetic markers for coronary artery disease (CAD).
The allelic variation in the apoE gene has a significant effect
on inter-individual variation of lipids and lipoprotein plasma
levels as well. This study investigated whether apoE polymorphism
affects the plasma levels of apoE and the possible association
to CAD extent and cognitive functions. Methods:
Plasma apoE levels and apoE genotypes were evaluated of subjects
with normal coronary arteries, and individuals with angiographycally
confirmed mild/moderate or severe atheromatosis. The cognitive
performance of the volunteers was also measured by mini-mental
state examination (MMSE). Results: Out of
the 6 expected genotypes, only 5 were detected in participants:
E3/3 (56.0%), E3/4 (23.6%), E4/4 (8.2%), E2/4 (3.3%), E2/3
(8.9%). The e3 allele (72%) was the most frequent, followed
by e4 (22%) and e2 (6%). No difference was found in plasma
levels of either apoE or in apoE genotype frequencies among
the groups, however MMSE scores of CAD patients irrespective
of their atheromatosis extent were significantly lower than
that seen in the normal population. Conclusions:
Although neither apoE plasma levels, nor apoE polymorphism
in patients presenting with mild/moderate or severe atheromatosis
showed to be associated with CAD severity, the presence of
atheromatosis in the heart vessels positively correlated with
cognitive dysfunction.
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