Current Alzheimer Research
ISSN: 1567-2050
Current Alzheimer
Research
Volume 6, Number 1, February 2009
Contents
Editorial
Celebrating the Fifth Year Anniversary of Current Alzheimer
Research Pp. 1-3
Debomoy K. Lahiri
Different Cholinesterase Inhibitor Effects on CSF Cholinesterases
in Alzheimer Patients Pp. 4-14
Agneta Nordberg, Taher Darreh-Shori, Elaine
Peskind, Hilkka Soininen, Malahat Mousavi, Gina Eagle
and Roger Lane
[Abstract]
[Full
text article]
[PMID:
19199870 PubMed - indexed for MEDLINE]
Cholesterol in Alzheimer’s
Disease: Unresolved Questions Pp. 15-29
Massimo Stefani and Gianfranco
Liguri
[Abstract]
[Full
text article]
[PMID:
19199871 PubMed - indexed for MEDLINE]
Anesthesia, Calcium Homeostasis
and Alzheimer’s Disease Pp. 30-35
Huafeng Wei and Zhongcong Xie
[Abstract]
[Full
text article]
[PMID:
19199872 PubMed - indexed for MEDLINE]
DNA Damage and Repair in Alzheimer’s
Disease Pp. 36-47
Fabio Coppedè and Lucia
Migliore
[Abstract]
[Full
text article]
[PMID:
19199873 PubMed - indexed for MEDLINE]
Can a Direct IADL Measure Detect Deficits in Persons with
MCI? Pp. 48-51
Dani L. Binegar, Linda S. Hynan, Laura H.
Lacritz, Myron F. Weiner and C. Munro Cullum
[Abstract]
[Full
text article]
[PMID:
19199874 PubMed - indexed for MEDLINE]
Brain MRI, Apoliprotein E Genotype,
and Plasma Homocysteine in American Indian Alzheimer Disease
Patients and Indian Controls Pp. 52-58
Myron F. Weiner, Carlos Marquez de la Plata,
B.A. Julie Fields, Kyle B. Womack, Roger N. Rosenberg, Yun-Hua
Gong, Bao-Xi Qu, Ramon Diaz-Arrastia and Linda S.
Hynan
[Abstract]
[Full
text article]
[PMID:
19199875 PubMed - indexed for MEDLINE]
The Valsalva Maneuver and Alzheimer’s
Disease: Is there a link? Pp. 59-68
Peter Wostyn, Kurt Audenaert and
Peter Paul De Deyn
[Abstract]
[Full
text article]
[PMID:
19199876 PubMed - indexed for MEDLINE]
Planum Temporale Analysis via
a New Volumetric Method in Autoptic Brains of Demented and
Psychotic Patients Pp. 69-76
Petr Zach, Zdena Krištofiková,
Jana Mrzílková, Emerich Majer, Pavel Selinger,
Filip Španiel, Daniela Rípová and
Jana Kenney
[Abstract]
[Full
text article]
[PMID:
19199877 PubMed - indexed for MEDLINE]
The Perils of Alzheimer’s
Drug Development Pp. 77-78
Lon S. Schneider and Debomoy K.
Lahiri
[Full
text article]
[PMID:
19199878 PubMed - indexed for MEDLINE]
Resurrecting Clinical Pharmacology As
a Context for Alzheimer Disease Drug Development Pp.
79-81
Robert E. Becker, Latha K. Unni and
Nigel H. Greig
[Abstract]
[Full
text article]
[PMID:
19199879 PubMed - indexed for MEDLINE]
Is Alzheimer’s Disease a Myth?
When is Disease a Disease? Pp. 82
Rudy J. Castellani, George Perry and
Mark A. Smith
[Abstract]
[Full
text article]
Abstracts
Editorial:
Celebrating the Fifth Year Anniversary of Current Alzheimer
Research
[Back to top]
[PMID:
19199870 PubMed - indexed for MEDLINE]
Different Cholinesterase Inhibitor Effects
on CSF Cholinesterases in Alzheimer Patients
Agneta Nordberg, Taher Darreh-Shori, Elaine
Peskind, Hilkka Soininen, Malahat Mousavi, Gina Eagle
and Roger Lane
[Full
text article]
Background: The current study aimed to compare the effects
of different cholinesterase inhibitors on acetylcholinesterase
(AChE) and butyrylcholinesterase (BuChE) activities and protein
levels, in the cerebrospinal fluid (CSF) of Alzheimer disease
(AD) patients.
Methods and Findings: AD patients aged 50–85
years were randomized to open-label treatment with oral rivastigmine,
donepezil or galantamine for 13 weeks. AChE and BuChE activities
were assayed by Ellman’s colorimetric method. Protein
levels were assessed by enzyme-linked immunosorbent assay
(ELISA). Primary analyses were based on the Completer population
(randomized patients who completed Week 13 assessments). 63
patients were randomized to treatment. Rivastigmine was associated
with decreased AChE activity by 42.6% and decreased AChE protein
levels by 9.3%, and decreased BuChE activity by 45.6% and
decreased BuChE protein levels by 21.8%. Galantamine decreased
AChE activity by 2.1% and BuChE activity by 0.5%, but increased
AChE protein levels by 51.2% and BuChE protein levels by 10.5%.
Donepezil increased AChE and BuChE activities by
11.8% and 2.8%, respectively. Donepezil caused a 215.2% increase
in AChE and 0.4% increase in BuChE protein levels. Changes
in mean AChE-Readthrough/Synaptic ratios, which might reflect
underlying neurodegenerative processes, were 1.4, 0.6, and
0.4 for rivastigmine, donepezil and galantamine, respectively.
Conclusion: The findings suggest pharmacologically-induced
differences between rivastigmine, donepezil and galantamine.
Rivastigmine provides sustained inhibition of AChE and BuChE,
while donepezil and galantamine do not inhibit BuChE and are
associated with increases in CSF AChE protein levels. The
clinical implications require evaluation.
[Back to top]
[PMID:
19199871 PubMed - indexed for MEDLINE]
Cholesterol in Alzheimer’s Disease:
Unresolved Questions
Massimo Stefani and Gianfranco
Liguri
[Full
text article]
The role of cholesterol as a susceptibility
factor or a protective agent in neurodegeneration and, more
generally, in amyloid-induced cytotoxicity is still controversial.
Epidemiological studies on the hypercholesterolemia-AD risk
relation and some reports indicating a beneficial effect of
statin therapy suggest cholesterol as a susceptibility factor
in AD. The ApoE4 genotype as a prevalent genetic risk factor
for AD and the function of ApoE as main cholesterol carrier
in the brain also underlie a close cholesterol load-AD risk
relation. Finally, cell biology evidences support a critical
involvement of lipid raft cholesterol in the modulation of
β-
and γ-secretase
cleavage of APP with altered Aβ
production.
However, little exchange does exist between circulating and
brain cholesterol, the latter arising from endogenous synthesis.
In addition, increasing evidence supports the idea that amyloid
cytotoxicity in most cases is initiated by oligomer recruitment
at the cell membrane with loss of membrane integrity, Ca2+
ingress into the cell, oxidative stress and apoptosis. In
such a scenario, increased membrane cholesterol seems to be
protective by disfavouring aggregate binding to the membrane.
Recent findings also indicate that a reduction of cellular
cholesterol favours co-localization of BACE1 and APP in non-raft
membrane domains and hinders generation of plasmin, an Aβ-degrading
enzyme. Finally, recent researches on Seladin-1, involved
in cholesterol biosynthesis, show that modulation of membrane
cholesterol affects Aβ
generation and cell resistance against Aβ
oligomer toxicity. These data confirm previous findings indicating
a reduction of the cholesterol/phospholipid ratio in aged
and AD brains.
The aim of this review is to critically discuss some of the
main results reported in the recent years in this field supporting
a role of cholesterol either as a susceptibility factor or
as a protective agent in AD.
[Back to top]
[PMID:
19199872 PubMed - indexed for MEDLINE]
Anesthesia, Calcium Homeostasis and
Alzheimer’s Disease
Huafeng Wei and Zhongcong Xie
[Full
text article]
While anesthetics are indispensable
clinical tools generally safe and effective, in some situations
there is grown concern about selective neurotoxicity of these
agents; the clinical significance is unclear as of yet. The
mechanisms for inhalational anesthetics mediated cell damage
are still not clear, although a role for calcium dysregulation
has been suggested. For example, the inhaled anesthetic isoflurane
decreases endoplasmic reticulum (ER) calcium concentration
and increases that in the cytosol and mitochondria. Inhibition
of ER calcium release, via either IP3
or ryanodine receptors, significantly inhibited isoflurane
neurotoxicity. Neurons made vulnerable to calcium dysregulation
by overexpression of mutated presenilin-1 (PS1) or huntingtin
(Q-111) proteins showed enhanced apoptosis upon isoflurane
exposure. Sevoflurane and desflurane were less potent than
isoflurane in altering intracellular calcium, and produced
less apoptosis. Short exposures to inhalational anesthetics
may provide neuroprotection by preconditioning via a sublethal
stress, while prolonged exposures to inhalational anesthetics
may induce cell damage by apoptosis through direct cytotoxic
effects.
[Back to top]
[PMID:
19199873 PubMed - indexed for MEDLINE]
DNA Damage and Repair in Alzheimer’s
Disease
Fabio Coppedè and Lucia
Migliore
[Full
text article]
The vast majority of the studies
performed so far and aimed at elucidating DNA repair mechanisms
has been performed in mitotic cells, such as transformed or
cancer cell lines. Therefore, our understanding of DNA repair
mechanisms in post-mitotic cells, such as neurons, remains
one of the most exciting areas for future investigations.
Markers of DNA damage, particularly oxidative DNA damage,
have been largely found in brain regions, peripheral tissues,
and biological fluids of Alzheimer’s disease (AD) patients.
Moreover, recent studies from our and other groups in individuals
affected by Mild Cognitive Impairment provided evidence that
oxidative DNA damage is one of the earliest detectable events
within the progression from a normal brain to dementia. Almost
one decade ago a decrease in the DNA base excision repair
(BER) activity was observed in post mortem brain regions of
AD individuals, leading to the hypothesis that the brain in
AD might be subjected to the double insult of increased DNA
damage, as well as deficiencies of DNA repair pathways. Subsequent
studies have provided accumulating evidence of impaired DNA
repair in AD. Moreover, functional variants and polymorphisms
of DNA repair genes have been the focus of several cancer
association studies, but only in recent years some of them
have been investigated as possible AD risk factors. The few
studies performed so far suggest that some variants might
play a role in AD pathogenesis and deserve further investigations.
Here, we summarize the current knowledge of DNA damage and
repair in AD pathogenesis.
[Back to top]
[PMID:
19199874 PubMed - indexed for MEDLINE]
Can a Direct IADL Measure Detect Deficits in Persons with
MCI?
Dani L. Binegar, Linda S. Hynan, Laura H.
Lacritz, Myron F. Weiner and C. Munro Cullum
[Full
text article]
Objective: To determine if a direct measure of instrumental
activities of daily living (IADL) scale designed for use with
dementia patients can detect differences between persons with
mild cognitive impairment (MCI) and normal elderly control
subjects (NC).
Methods: This study used cross-sectional and longitudinal
IADL scale data from MCI and NC subjects followed at an Alzheimer’s
Disease Center.
Results: On a 52-point scale, MCI subjects (n = 30)
scored significantly lower than NC subjects (n = 30) on the
IADL scale (total score 47.17 vs. 48.77 points; t (58) = 2.34,
p = .011) and its Memory subscale (5.27 vs. 6.6 points; t
(58) = 3.29, p = .002).Examination of annualized IADL scale
change scores revealed that 50% of MCI subjects had declined
by one point, compared with 29% of NC.
Conclusion: A direct IADL measure for dementia patients
is able to detect small differences between MCI and NC and
cross-sectionally and longitudinally, but does not distinguish
between groups.
[Back to top]
[PMID:
19199875 PubMed - indexed for MEDLINE]
Brain MRI, Apoliprotein E Genotype,
and Plasma Homocysteine in American Indian Alzheimer Disease
Patients and Indian Controls
Myron F. Weiner, Carlos Marquez de la Plata,
B.A. Julie Fields, Kyle B. Womack, Roger N. Rosenberg, Yun-Hua
Gong, Bao-Xi Qu, Ramon Diaz-Arrastia and Linda S.
Hynan
[Full
text article]
We obtained brain MRIs, plasma
homocysteine levels and apolipoprotein E genotyping for 11
American Indian Alzheimer disease (AD) subjects and 10 Indian
controls. We calculated white matter hyperintensity volume
(WMHV), whole brain volume (WBV), and ratio of white matter
hyperintensity volume to whole brain volume (WMHV/WBV). There
were no significant differences between AD subjects and controls
in gender, history of hypertension, diabetes, or history of
high cholesterol, but hypertension and diabetes were more
common among AD subjects. There was no difference between
AD and control groups in age (range for all subjects was 61-89
years), % Indian heritage, waist size or body mass index.
Median Indian heritage was 50% or greater in both groups.
Range of education was 5-13 years in the AD group and 12-16
years in controls. Median plasma homocysteine concentration
was higher in AD subjects (11 μmol/L
vs. 9.8 μmol/L),
but did not achieve statistical significance. Significantly
more AD subjects had apolipoprotein Eε4
alleles than did controls (63% vs.10%). Neuroimaging findings
were not significantly different between the 2 groups, but
AD subjects had greater WMHV (median 15.64 vs. 5.52 cc) and
greater WMHV/WBV ratio (median 1.63 vs. 0.65 %) and a far
greater range of WMHV. In combined AD subjects and controls,
WBV correlated with BMI and age. WMHV and WMHV/WBV correlated
inversely with MMSE scores (p = 0.001, 0.002, respectively).
In addition, WMHV correlated positively with % Indian heritage
(p = 0.047).
[Back to top]
[PMID:
19199876 PubMed - indexed for MEDLINE]
The Valsalva Maneuver and Alzheimer’s
Disease: Is there a link?
Peter Wostyn, Kurt Audenaert and
Peter Paul De Deyn
[Full
text article]
Recent research findings provide evidence for Alzheimer’s
disease-related changes in brain diseases, such as normal
pressure hydrocephalus and traumatic brain injury, and in
glaucoma at the level of the retinal ganglion cells. This
is a group of diseases that affect central nervous system
tissue and are characterized by elevation of intracranial
or intraocular pressure and/or local shear stress and strain.
This strengthens the possibility that Alzheimer-type changes
in these diseases may result at least in part from exposure
of central nervous system tissue to elevated mechanical load.
As activities or diseases with significant Valsalva effort
can generate increased intracranial pressures, we hypothesize
that individuals who frequently perform strong Valsalva maneuvers
(e.g., long hours of repetitive heavy lifting, sequences of
blows during the playing of a wind instrument, forceful and
repetitive cough, bearing-down efforts during parturition)
may be more susceptible to developing Alzheimer’s disease.
In this paper, we discuss three hypotheses about the mechanisms
by which extensive use of the Valsalva maneuver might contribute
to the neuropathogenesis of Alzheimer’s disease: via
mechanical stress-induced events in the hippocampus and/or
via changes in the secretory process of the choroid plexus
and/or via hemodynamic changes in cerebral blood flow. If
confirmed, this hypothesis could have implications in clinical
practice.
[Back to top]
[PMID:
19199877 PubMed - indexed for MEDLINE]
Planum Temporale Analysis via
a New Volumetric Method in Autoptic Brains of Demented and
Psychotic Patients
Petr Zach, Zdena Krištofiková,
Jana Mrzílková, Emerich Majer, Pavel Selinger,
Filip Španiel, Daniela Rípová and
Jana Kenney
[Full
text article]
Investigations of alterations in
brain asymmetry often focus on the planum temporale
of patients with schizophrenia. Data also suggest changes
in laterality of demented patients associated with a more
marked impairment of the left hemisphere. Our study was performed
on autoptic brain tissue of 84 patients, out of which there
were 25 non-demented non-psychotic controls, 50 demented patients
(34 Alzheimer disease, 9 multi - infarct dementia and 7 mixed-type
dementia patients) and 9 people with schizophrenia. The plana
temporalia were evaluated via a new volumetric
method using dental resin matter. Areas, cortical thickness
and volumes of the right and left planum temporale
were evaluated without normalization to brain weight in 60
patients and with normalization in 24 people. In controls,
a mild right/left laterality of areas, cortical thickness
and volumes was found. Moreover, in control women the areas
of the left planum temporale were smaller than those observed
in control men. The shifts to left/right laterality of areas
and volumes were found in all demented groups. In the more
numerous Alzheimer group, the change in laterality of an area
was associated with a mild decrease on the right and a mild
increase on the left side. In contrast, marked but only bilateral
area shrinkage as well as reduced cortical thickness and brain
volumes were observed in schizophrenic patients.
[Back
to top]
[PMID:
19199879 PubMed - indexed for MEDLINE]
Resurrecting Clinical Pharmacology As
a Context for Alzheimer Disease Drug Development
Robert E. Becker, Latha K. Unni and
Nigel H. Greig
[Full
text article]
Commercial priorities have been
identified as negative factors in drug development. We trace
the problem to inattention to sound clinical pharmacology
practices. When properly applied, clinical pharmacology and
associated drug development sciences can, hand in hand, facilitate
success in commercial drug development.
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