| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer Research
Volume 2, Number 5, December 2005
Contents
Editorial - Advances of Alzheimer’s
Disease Research: Crossroad of Basic and Translational Studies
Pp. 495
Debomoy K. Lahiri
Activity-Dependent Synapse Modulation and the
Pathogenesis of Alzheimer Disease Pp. 497-506
Phillip G. Nelson
[Abstract]
Recent Insights on the Pro-Apoptotic Phenotype
Elicited by Presenilin 2 and its Caspase and Presenilinase-Derived
Fragments Pp. 507-514
Cristine Alves da Costa
[Abstract]
Alzheimer's Disease and P300: Review and Evaluation
of Task and Modality Pp. 515-525
John Polich and Jody Corey-Bloom
[Abstract]
Cholesterol, Copper and Aβ
in Controls, MCI, AD and the AD Cholesterol-Lowering
Treatment Trial (ADCLT) Pp. 527-539
D. Larry Sparks, Suzana Petanceska, Marwan Sabbagh, Donald
Connor, Holly Soares, Charles Adler, Jean Lopez, Chuck Ziolkowski,
Jeff Lochhead and Patrick Browne
[Abstract]
A Randomized, Double-Blind, Placebo-Controlled
Trial of Two Doses of Ginkgo Biloba Extract in Dementia of
the Alzheimer's Type Pp. 541-551
Lon S. Schneider, Steven T. DeKosky, Martin R. Farlow, Pierre
N. Tariot, Robert Hoerr and Meinhard Kieser
[Abstract]
A Randomized, Double-Blind, Placebo-Controlled
Pilot Trial of Safety and Tolerability of Two Doses of Divalproex
Sodium in Outpatients with Probable Alzheimer’s Disease
Pp. 553-558
Louis A. Profenno, Laura Jakimovich, Connie J. Holt, Anton
Porsteinsson and Pierre N. Tariot
[Abstract]
Induction of RhoGAP and Pathological Changes Characteristic
of Alzheimer’s Disease by UAHFEMF Discharge in Rat Brain
Pp. 559-569
Ing-Feng Chang and Huo-Yen Hsiao
[Abstract]
Progression of Mild Cognitive Impairment to Alzheimer’s
or Vascular Dementia Versus Normative Aging among Elderly
Chinese Pp. 571-578
Juebin Huang, John Stirling Meyer, Zhenxin Zhang, Jing Wei,
Xia Hong, Jianmin Wang, Hongbo Wen, Wenjie Wu, Jixing Wu and
Munir H. Chowdhury
[Abstract]
MRI Abnormalities Associated with Mild Cognitive Impairments
of Vascular (VMCI) Versus Neurodegenerative (NMCI) Types Prodromal
for Vascular and Alzheimer’s Dementias Pp.
579-585
John Stirling Meyer, Juebin Huang and Munir Chowdhury
[Abstract]
Abstracts
[Back to top]
Editorial - Advances of Alzheimer’s Disease
Research: Crossroad of Basic and Translational Studies
Debomoy K. Lahiri
The fifth and the final issue of the second volume of Current
Alzheimer Research presents exciting and diverse research
on Alzheimer’s disease (AD) and mild cognitive impairment
(MCI), which is a possible prodromal phase of AD. The research
includes both mechanistic and translational studies. The current
issue contains nine selected articles from various aspects
of the AD field, such as neuronal cell death, cholesterol,
copper, and clinical trials for drug development, including
results from Ginkgo biloba extract (GbE). Three articles report
different randomized, placebo controlled, trial studies; two
articles discuss MCI; one article basic neurobiology related
to AD processes; and one each investigating programmed cell
death, cognitive event-related potential (ERP), and neuropathology
of AD in a unique animal model.
AD is currently one of the most prominent age-related disorders
and is associated with biochemical, genetic and environmental
causes. AD is mainly characterized by degeneration of basal
forebrain cholinergic neurons and cerebral deposition of amyloid
beta-peptide (Aβ)-laden plaques and tau proteins in the
form of neurofibrillary tangles. Inflammatory processes, oxidative
stress and synaptic loss are other neurochemical attributes
of AD. Most genetic (familial) Alzheimer’s disease is
due to mutations on the genes coding for the Aβ precursor
protein (APP) and presenilins (PS) 1 and 2. Current understanding
of the exact sequence of these events in the disease process
is slowly emerging, and so are the drug targets that can be
successfully used for AD. The main thrust of the described
nine articles is to address some of these issues from various
angles of research utilizing mechanistic, epidemiological
and translational models.
The issue begins with the theme of neuronal development. Nelson
discusses (pp 497-506) an important aspect of normal development
of the nervous system, where a major reduction occurs in the
initially excessive number of neurons and synapses. He elaborates
that this normal “pruning” process is greatly
influenced by patterns of electrical activity in the synaptic
circuits being pruned. The question is how it leads to AD.
The author describes that abnormalities in neural activity
patterns, or in the coupling between neural activity and maintenance
of neurons and synaptic circuits, may be the major determinant
in the pathogenesis of AD. The implication is that, as the
author points out from the behavioral data, an active, socially
engaged life-style is generally associated with a reduced
risk for AD.
Another important question in this field is how the early
neurobiochemical abnormality progresses to mature stage of
AD, and this leads to the issue of neuronal loss. Apoptosis
or programmed cell death (PCD) is a normal event under genetic
control. However, it is generally believed that misregulation
of apoptosis plays a pivotal role in the development of several
neurodegenerative disorders including AD. Among many proteins,
a role for presenilins has been implicated in apoptotic processes.
Herein, Alves da Costa elucidates (pp 507-514) the mechanisms
by which PS-2 affects PCD with special emphasis on the role
of the proteolytically derived PS fragments generated by presenilinase-
and caspase enzymes.In the context of neuronal development
and PCD, a holistic approach, as exemplified by neuroelectric
measures, which can provide direct imaging of central nervous
system function, assumes significance. Polich and Bloom present
(pp 515-525) results from the evaluation of early stage AD
patients with the P300 event-related brain potential. They
discuss that P300 amplitude was smaller and peak latency longer
for the AD patients compared to elderly control subjects across
tasks and modalities. They show that P300 differences between
AD patients and controls were largest for the relatively easy
tasks, with little influence of stimulus modality observed.
The authors’ results suggest that the P300 brain potential
is sensitive to AD processes during its early stages, and
that easily performed stimulus discrimination tasks are the
clinically most useful.
In addition to intrinsic apoptosis process, external factors,
such as diets and environment, play a critical part in the
disease process. For example, cholesterol has been suggested
to play an important role in promoting Aβ production
and possibly the progression of AD. In addition, a role for
copper in AD via its influence on Aβ is emerging. Sparks
and colleagues report (pp 527-539) a short clinical trial
with simvastatin and identified benefit on the MMSE, but not
the ADAS-cog in AD patients, compared to placebo. The results
from the longer AD cholesterol-lowering treatment trial (ADCLT)
with atorvastatin in a larger population showed benefit on
the ADAS-cog, and other parameters in treated patients compared
to placebo. They also assessed circulating levels of Aβ
peptides, ceruloplasmin (copper chaperone), apolipopro-tein
E and HDL-cholesterol in blood collected at each clinical
visit during the ADCLT. The authors’ result support
a role for cholesterol in AD and a possible influence of increasing
circulating copper levels.
Regarding other treatment approaches, previous studies of
GbE in patients with various forms of cognitive impairment
or dementia have shown promising results. Herein, Schneider
and colleagues present (pp 541-551) the clinical efficacy
of GbE in mild to moderate dementia of the Alzheimer type
(DAT). They report of no significant between-group differences
for the whole sample and there was little cognitive and functional
decline of the placebo-treated patients. The authors’
interpretation is that the trial did not show efficacy of
GbE, however, the lack of decline of the placebo patients
may have compromised the sensitivity of the trial to observe
any treatment effect and permit definite con-clusions with
respect to the efficacy of GbE. In another trial study, Profenno
and colleagues describe (pp 553-558) a randomized, double
blind, placebo-controlled pilot trial of safety and tolerability
of two doses of divalproex sodium in outpatients with probable
AD. The authors used these results to design a multicenter
ADCS trial and found that doses of less than 1000 mg/day of
divalproex sodium were the maximum tolerated by these outpatients
with AD. The authors rightly point out that a larger study
of divalproex sodium dose tolerability is needed to define
treatment in outpatients with AD.
Chang and Hsiao report (pp 559-569) an ‘out of the box’
approach in terms of developing a model for AD. They describe
experiments with ultrasound associated with high frequency
electromagnetic field (UAHFEMF) irradiation on animals. Interestingly,
they observed evidences of characteristic AD degenerations
including neurite plaques, neurofibrillary tangle and paired
helical filament with rats and mice irradiated up to 2454
hours. They also report an induction of a human T-cell activation
RhoGTPase-activating protein isoform in the UAHFEMF-treated
rat brain. They hypothe-size that one of the causes of AD
could be high frequency electromagnetic field discharges in
human brain. This model may be used to study the neurobiological
mechanism of AD in parallel to currently available transgenic
mouse models.
Recent studies strongly suggest that MCI represents a possible
prodromal phase of AD. Understanding of MCI is important for
clinical and research purposes and can provide an opportunity
to develop potentially useful biochemical markers and tools
of diagnosis and early intervention for AD. Huang and colleagues
(pp 571-578) report progression of MCI among elderly Chinese
to AD or vascular dementia (VaD) compared with normal aging.
In the samples tested, they noticed that annual conversion
rate calculated from MCI to all dementias was 14.1% whereas
the conversion from cognitive normals to all dementias was
1.6%. They conclude that conversion rates among MCI subjects
to dementia, and major subtypes, for elderly Chinese residents
were comparable with results reported among similar studies
world-wide. The authors suggest that risks of developing dementia,
and major subtypes, among MCI subjects in Beijing were significantly
higher than among normal subjects. In a complementary paper,
Meyer and colleagues compare (pp 579-585) their longitudinal
study and contrast MRI abnormalities among MCI subjects as
they progress to dementia of Alzheimer type versus VaD. They
report that subjects converting to DAT and VaD confirmed diagnosis
during MCI staging. In “mixed cases” the predominant
MRI pathology was judged the primary cause. The authors suggest
that identification of MCI among elderly populations raises
the possibilities for dementia diagnosis, prevention and treatment
within prodromal stages.
By reporting a broad spectrum of research from MCI to AD and
from basic to translational, I am very confident that Current
Alzheimer Research will continue to make a significant
contribution in the field of Alzheimer’s disease and
dementia. In addition to the timely print edition, the journal
is accessible online (http://www.bentham.org/car/)
which provides free access to ‘Contents’, ‘Editorial’
and ‘Abstracts’ of all papers published in the
different issues of Current Alzheimer Research. The
site is particularly helpful to all authors for electronic
submission of their papers. Current Alzheimer Research
is now abstracted in Biological Abstracts and Chemical
Abstracts. The journal is also listed in PubMed and MEDLINE
by the National Library of Medicine (NLM), USA. Finally, I
welcome your comments, advice, suggestions and manuscript
contributions to make this journal a contin-ued success.
Debomoy K. Lahiri
Editor-in-Chief
Departments of Psychiatry and of
Medical and Molecular Genetics
Institute of Psychiatric Research
Indiana University School of Medicine
Indianapolis, Indiana-46202
USA
[Back to top]
Activity-Dependent Synapse Modulation and the Pathogenesis
of Alzheimer Disease
Phillip G. Nelson
During normal development of the nervous system, a major
reduction occurs in the initially excessive number of neurons
and synapses. This “pruning” process is heavily
influenced by patterns of electrical activity in the synaptic
circuits being pruned. Many of the cell biological and molecular
mechanisms involved in this activity-dependent modification
of nervous system structure and function have been explicated,
and the area is one of intense study. Similarly, an explosive
increase has occurred in knowledge about the molecular pathogenesis
of Alzheimer disease (AD). There are significant mechanistic
commonalities between the normal neurodevelopmental process
and development of AD. We hypothesize that abnormalities in
neural activity patterns, or in the coupling between neural
activity and maintenance of neurons and synaptic circuits,
may be a key determinant in the pathogenesis of AD that is
late in onset, sporadic in nature, and in which the genes
for the presenilins and the beta amyloid precursor protein
are normal. Behavioral data suggests that an active, socially
engaged life-style may be associated with a reduced risk for
AD. If so, mechanisms linking neural activity with synaptic
circuit integrity are probably involved and provide a target
for ameliorative pharmacological intervention.
[Back to top]
Recent Insights on the Pro-Apoptotic Phenotype Elicited
by Presenilin 2 and its Caspase and Presenilinase-Derived
Fragments
Cristine Alves da Costa
Programmed cell death (PCD) also called apoptosis, is a
normal and genetically controlled event that could play, when
mis-regulated, a pivotal role in the development of several
neurodegenerative disorders such as Parkinson’s disease.
Sporadic Alzheimer’s disease is one of the most prominent
age-related syndromes whose etiology, although still unknown,
could be related to biochemical or environmental causes. A
few cases of Alzheimer’s disease are likely of genetic
origin and linked to mutations on the genes coding for the
amyloid precursor protein (βAPP) and presenilins 1 and
2. Although still discussed, the hypothesis of an implication
of apoptotic cell death in Alzheimer’s disease neuropathology
has been recently supported by a growing body of biochemical
evidences. Thus, the implication of presenilins in apoptotic
processes in vitro has been well documented but the
mechanisms underlying this function are still a matter of
intense research. The aim of this review is to focus on the
mechanisms by which presenilin 2 affects the programmed cell
death with special emphasis on the role of the proteolytically
derived presenilin fragments generated by both presenilinase-
and caspases. The distinct apoptotic phenotypes elicited by
the two parent proteins presenilins 1 and 2 and their functional
cross talk will be briefly discussed.
[Back to top]
Alzheimer's Disease and P300: Review and Evaluation
of Task and Modality
John Polich and Jody Corey-Bloom
Early stage Alzheimer disease patients and matched elderly
unaffected controls (n=16/group) were evaluated with the P300
event-related brain potential (ERP). All subjects performed
four oddball tasks that varied systematically in task difficulty
and were each presented in the auditory and visual modalities.
P300 amplitude was smaller and peak latency longer for the
Alzheimer patients compared to elderly control subjects across
tasks and modalities. P300 differences between Alzheimer patients
and controls were largest for the relatively easy tasks, with
little influence of stimulus modality observed. The results
suggest that the P300 brain potential is sensitive to Alzheimer's
disease processes during its early stages, and that easily
performed stimulus discrimination tasks are the clinically
most useful. Theoretical and practical implications are reviewed.
[Back to top]
Cholesterol, Copper and Aβ in Controls, MCI,
AD and the AD Cholesterol-Lowering Treatment Trial (ADCLT)
D. Larry Sparks, Suzana Petanceska, Marwan Sabbagh, Donald
Connor, Holly Soares, Charles Adler, Jean Lopez, Chuck Ziolkowski,
Jeff Lochhead and Patrick Browne
Cholesterol clearly plays an influential role in promoting
the production of amyloid
β (Aβ)
and possibly the progression of Alzheimer’s Disease
(AD). The AD Cholesterol-Lowering Treatment trial (ADCLT;
1 year duration) tested atorvastatin and found significant
benefit on measures of cognition and depressive symptoms in
treated patients (N=32) compared to placebo (N=31). We assessed
the circulating levels of Aβ1-40,
Aβ1-42,
ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol
in blood collected at each clinical visit during the ADCLT.
We also determined the circulating cholesterol, ceruloplasmin,
and Aβ
levels in AD and MCI (mild cognitive impairment) patients,
and controls (two groups stratified by function; high and
low) participating in our Brain Bank Program. Each Brain Bank
individual was clinically assessed for performance on the
Mini-Mental Status Exam (MMSE), Rey auditory verbal learning
test (AVLT), Clock draw, and UPSIT (smell identification test).
Among individuals of equal age and education, scores on the
MMSE were significantly reduced in AD compared to both MCI
and controls, as were scores on the UPSIT. Ability on delayed
verbal recall was significantly reduced in AD compared to
MCI, and in MCI compared to both control groups. Performance
on the Clock draw was similar for AD and MCI patients, but
was significantly reduced when comparing MCI to control. Both
cholesterol and ceruloplasmin levels were significantly increased
in low-function controls compared to the high-function control
group, but were not different from levels identified in the
MCI and AD patients. Significantly increased levels of Aβ1-40
occurred in low- compared to high-function controls, with
a further significant increase in MCI compared to low-function
controls. Circulating Aβ1-40
levels were decreased in AD compared to MCI. Levels of Aβ1-42
were not significantly different between the groups.
The slight gradual increase in circulating Aβ1-40
and Aβ1-42
levels produced by atorvastatin treatment in the ADCLT were
not significant compared placebo. There was a trend for significant
reduction in circulating ceruloplasmin levels after a year
of atorvastatin therapy compared to levels observed at screen.
The levels of HDL-cholesterol remained stable in the atorvastatin
treated AD patients for 9 months and then decreased significantly
compared to the placebo group at the 1-year time-point.
The combined data support a role for cholesterol in AD and
a possible influence of increasing circulating copper levels.
The deterioration of function in controls and transition to
MCI may be associated with concomitant incremental increases
in circulating Aβ1-40
levels. Increased cholesterol and ceruloplasmin levels may
be associated with slight deterioration in function among
controls as a precursor to impairment considered MCI. The
clinical benefit of atorvastatin therapy is clearly not associated
with decreased circulating Aβ
or increased HDL-cholesterol, but a positive influence of
reduced copper (ceruloplasmin) levels may be a consideration.
[Back to top]
A Randomized, Double-Blind, Placebo-Controlled Trial
of Two Doses of Ginkgo Biloba Extract in Dementia of the Alzheimer's
Type
Lon S. Schneider, Steven T. DeKosky, Martin R. Farlow, Pierre
N. Tariot, Robert Hoerr and Meinhard Kieser
Context: Previous studies of Ginkgo biloba
extract (GbE) in patients with various forms of cognitive
impairment or dementia have shown promising results. Objective:
To determine the clinical efficacy of GbE in mild to moderate
dementia of the Alzheimer type. Design: Randomized,
placebo-controlled, double-blind, parallel-group, multicenter
trial. Setting: Outpatient clinics of universities
and private research centers specialized in dementia. Patients:
513 outpatients with uncomplicated dementia of the Alzheimer's
type scoring 10 to 24 on the Mini-Mental State Examination
and less than 4 on the modified Hachinski Ischemic Score,
free of other serious illnesses and not requiring continuous
treatment with any psychoactive drug. Intervention:
26-week treatment with GbE at daily doses of 120 mg or 240
mg or placebo. Main Outcomes: Cognitive subscale
of the Alzheimer's Disease Assessment Scale (ADAS-cog), Alzheimer's
Disease Co-operative Study Clinical Global Impression of Change
(ADCS-CGIC). Results: There were no significant
between-group differences for the whole sample. There was
little cognitive and functional decline of the placebo-treated
patients, however. For a subgroup of patients with neuropsychiatric
symptoms there was a greater decline of placebotreated patients
and significantly better cognitive performance and global
assessment scores for the patients on GbE. Conclusion:
The trial did not show efficacy of GbE, however, the lack
of decline of the placebo patients may have compromised the
sensitivity of the trial to detect a treatment effect. Thus,
the study remains inconclusive with respect to the efficacy
of GbE.
[Back to top]
A Randomized, Double-Blind, Placebo-Controlled Pilot
Trial of Safety and Tolerability of Two Doses of Divalproex
Sodium in Outpatients with Probable Alzheimer’s Disease
Louis A. Profenno, Laura Jakimovich, Connie J. Holt, Anton
Porsteinsson and Pierre N. Tariot
OBJECTIVE: The Alzheimer's Disease Cooperative
Study (ADCS) is conducting a clinical trial to address whether
chronic valproate treatment can delay emergence of behavioral
symptoms in outpatients with AD. Since there were no data
on the safety and tolerability of divalproex sodium in outpatients
with dementia, we undertook a pilot study to inform the design
of the ADCS study. METHODS: We recruited
20 outpatients with probable AD, MMSE 10-20, without history
of agitation or psychosis. This was a 10-week randomized,
double-blind, placebo-controlled study assessing the safety
and tolerability of 1,000 mg/day and 1,500 mg/day of divalproex
sodium delayed-release for 8 weeks followed by extended-release
for 2 weeks. Other outcome measures addressed cognition, function,
global status, side effects, and laboratory data.
RESULTS: Participants assigned to active treatment
ingested approximately 30% less of their prescribed study
medication compared to those receiving placebo (p < .05
Wilcoxon Rank Sum test). The average tolerated dose for all
participants at week 8 was 810 mg/day or 11.5 mg/kg/day, similar
to the dose tolerated by nursing home patients. The most common
side effects were sleepiness and tiredness, with worse cognitive
performance in those assigned to 1500 mg/day. CONCLUSIONS:
These results were used to design the multi-center ADCS trial.
Doses of less than 1000 mg/day of divalproex sodium were the
maximum tolerated by these outpatients with AD. A larger study
of divalproex sodium dose tolerability is needed to define
treatment in outpatients with Alzheimer’s disease.
[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
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.
[Back to top]
Progression of Mild Cognitive Impairment to Alzheimer’s
or Vascular Dementia Versus Normative Aging among Elderly
Chinese
Juebin Huang, John Stirling Meyer, Zhenxin Zhang, Jing
Wei, Xia Hong, Jianmin Wang, Hongbo Wen, Wenjie Wu, Jixing
Wu and Munir H. Chowdhury
To compare differences in evolutionary progressions from
Mild Cognitive Impairment (MCI) to dementia of Alzheimer’s
type (DAT) or to vascular dementia (VaD) versus normal aging,
subjects identified as MCI or as cognitively normal (CN) during
standard cognitive evaluations among a large epidemiological
study designed to determine prevalence and incidence of dementia
and its major subtypes in Beijing, China were re-examined
after an interval of approximately 3 years, repeating the
same investigation protocol as at baseline. MCI subjects meeting
criteria for dementia and the two major subtypes, DAT and
VaD were identified at follow-up evaluation. Annual conversion
rates for combined dementias and for major subtypes of DAT
and VaD, from MCI, were compared with conversion rates among
CN subjects. Relative risks for conversion from MCI to major
subtypes of dementia were also compared with CN subjects by
Cox regression models. 175 MCI and 400 CN subjects were identified
at baseline. Among 121 MCI subjects available at follow-up,
51 were diagnosed with dementia (29 with DAT, 18 with VaD
and 4 with other dementias), compared with 14(10 DAT, 3 VaD
and 1 other type dementia) diagnosed as dementia among 281
CN subjects available at follow-up. Annual conversion rates
calculated from MCI to all dementias, compared with conversion
rates from CNs, were 14.1% versus 1.6%. Specifically for DAT,
annual conversion rates were 8.0% versus 1.1% and for VaD
were 5.0% versus 0.3%. Relative risks for developing all dementias,
DAT and VaD among MCI subjects were 9, 6 and 5 times greater
than among CN subjects. Conversion rates among MCI subjects
to dementia, and major subtypes, for elderly Chinese residents
of Beijing were comparable with results reported among similar
studies worldwide. Risks of developing dementia, and major
subtypes, among MCI subjects in Beijing were significantly
higher than among normal subjects. Identi-fication of MCI
among elderly populations provides the possibilities for dementia
prevention and treatment within prodromal stages.
[Back to top]
MRI Abnormalities Associated with Mild Cognitive Impairments
of Vascular (VMCI) Versus Neurodegenerative (NMCI) Types Prodromal
for Vascular and Alzheimer’s Dementias
John Stirling Meyer, Juebin Huang and Munir Chowdhury
Background and Objectives: Mild Cognitive
Impairments (MCIs) are identifiable clinical entities, in
neurodegenerative forms, as prodromal for Alzheimer’s
type (DAT) or in vascular forms, as prodromal for vascular
dementia (VaD). The present longitudinal study compares and
contrasts MRI abnormalities among MCI subjects as they progress
to DAT versus VaD. Subjects converting to DAT and VaD confirmed
ultimate diagnosis during MCI staging. In “mixed cases”
the predominant MRI pathology was judged the primary cause.
Subjects and Methods: Subjects (n=153) were selected
from elderly outpatient volunteers who have been enrolled
for 25 years in planned longitudinal studies of aging, stroke
and dementia. Cognitively normal (CN, n=52), MCI of neurodegen-erative
(N-MCI, n=30) and vascular (V-MCI),n=35) subtypes, plus converted
DAT (n=19) and VaD (n=17) were diag-nosed according to established
protocols. Combined Mini-Mental-Cognitive Capacity Screening
Examinations (CMC) screened, identified and confirmed MCIs
or dementias. Cerebral MRI abnormalities were analyzed utilizing
volumetric measurements and visual rating scales.
Results: Compared with persistently cognitively normal
subjects, MCI subjects and converted dementias were significantly
older without significant gender differences, but cognitively
impaired subjects were older than the CN group since age is
a risk factor for cognitive decline. Histories of hypertension,
heart disease, diabetes mellitus, TIAs and strokes were more
frequent among subjects with VMCI and VaD, confirming that
all vascular risk factors contribute to vascular cognitive
decline, but since vascular risk factors were treated, not
all progressed to VAD. Family history of neurodegenerative
disease, particularly DAT, were more prevalent among NMCI
and converted DAT subjects. VMCI showed more extensive leucoaraiosis
and lacunar infarcts than subjects with NMCI. NMCI, prodromal
for dementia of Alzheimer’s type (DAT), showed more
medial temporal lobe atrophy with enlarged temporal horns,
and fewer vascular lesions.
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