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Atherosclerosis and dementia Leading by association.

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EDITORIALS
Atherosclerosis and
Dementia: Leading by
Association
In this issue of Annals, Van Oijen and colleagues1
present results from the Rotterdam study that demonstrate longitudinal associations between several surrogate measures of atherosclerosis and incident dementia.
The results provide important confirmatory evidence
for a large opus of observational epidemiology that has,
on the whole, repeatedly linked both risk factors for
atherosclerosis and markers of atherosclerotic burden
with various indicators of cognitive function and impairment.2–7 Given the overwhelming societal costs of
dementia, there is excitement about the major hypothesis generated by this work, namely, that treating atherosclerosis and its risk factors will prevent dementia.8
In such situations, there is often an obvious need to
move beyond observational data and validate the findings in randomized trials. There are a number of established reasons, however, for doctors to intervene
when a patient is at risk for, or shows early manifestations of, atherosclerosis. Therefore, it is worth considering how the typical progression from association
studies to randomized trials will impact the existing biological and clinical implications of the atherosclerosis–
dementia relationship.
Many find it quite plausible that processes that collectively fall under the rubric of “atherosclerosis” may
injure the brain and at times cause or, at least contribute to, the clinical expression of dementia. As early as
the 16th century, physicians made the conceptual connection between the brain injury caused by stroke and
the clinical syndrome of impairment now recognized as
dementia.9 More recently, investigators from large
population-based studies such as the Rotterdam study
and the Cardiovascular Health Study have provided
seminal empiric evidence that the incidence of brain
infarction, as defined by cranial MRI, dwarfs the incidence of clinically recognized stroke, and that these infarctions are strongly associated with longitudinal cognitive decline and dementia.10 –12 Furthermore, large
autopsy studies have demonstrated that most cases with
dementia have a combination of vascular and neurodegenerative pathologies, and that each predict the extent
of cognitive impairment, regardless of clinical history.13–15 Such findings have led to a fundamental rethinking of clinical diagnoses such as “vascular dementia,” as well as to a major expansion of the dementia
risk potentially attributable to vascular injury in the
brain.16 From these observations, it is easy to make a
simple syllogistic leap of faith: Because we know that
atherosclerosis, or at least the processes integrated
within that term, causes injury in the brain and because that injury is a widely accepted substrate of dementia, therefore, of course, atherosclerosis causes dementia.
Many others will be quick to point out that observational epidemiology can easily lead us astray. Perhaps
the repeated association of atherosclerosis and its risk
factors with cognitive impairment will prove as misleading about causality as early studies of hormone replacement therapy. Unquestionably, vascular risk factors and atherosclerosis are strongly associated with
major but poorly quantifiable socioeconomic factors
that could account for observed dementia associations.
This problem of confounding appears to be a bigger
concern for interpretation than the minor heterogeneities in risk observed in Van Oijen and colleagues’1
study. For example, although the authors found no significant association between carotid intima media
thickness (IMT) and the vascular subtype of dementia,
their best estimate of vascular dementia risk associated
with carotid IMT was well within the confidence interval estimated for the main association with all dementia. Similarly, although there were differences in
dementia risk based on the dichotomization of the
follow-up period into “short” and “long” terms, such
heterogeneity may have been due to chance or, as favored by the authors, the competing hazard of mortality. Allowing for the expected effects of sampling errors, Van Oijen and colleagues’1 study appears entirely
consistent with, if not strongly confirmatory of, past
observations that vascular risk factors and markers of
systemic atherosclerosis predict cognitive decline. By
confirming the association between atherosclerosis and
dementia, Van Oijen and colleagues’1 study provides
critical testimony to the magnitude and clinical significance of the cognitive decline associated with these
processes. Nevertheless, with respect to causality, the
crucial validation that is provided by randomized intervention trials remains lacking, or when available, has
produced inconsistent conclusions.17,18
The value of association studies is not always to
serve as a pretext for performing randomized trials.
The current body of evidence linking atherosclerosis to
undesirable changes in cognition is sufficiently compelling to provide an additional incentive for patients to
adhere to existing antiatherogenic therapies. When the
goal is simply to identify a population at high risk for
a given outcome, the issue of confounding is less important; for example, current findings indicate that individuals with atherosclerosis, at least as assessed by carotid IMT, are at increased risk for dementia and may
therefore constitute a useful population in which to
test a novel dementia prevention therapy. Finally, this
and similar studies have raised the compelling question
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
377
of whether vascular injury in the brain simply adds to
the cognitive burden of coexisting Alzheimer’s pathology or, rather, causes this pathology through a direct or
synergistic pathway.19,20 It is unlikely that randomized
trials will resolve this question as the ability to make
biological inferences from statistical interactions remains rudimentary.21 The association studies alone,
however, have provided sufficient cause to move from
the bedside back to the bench.
In coming years, a wealth of data about the
atherosclerosis-dementia pathway will come from randomized trials of vascular therapies that have modified
their outcomes to include cognitive measures alongside
the more traditional composite of cardiovascular
events.22 This practice makes sense as the inclusion of
cognitive outcomes has the potential to increase the
power of a study to detect a treatment effect, as well as
to improve the cost utility of adopting the intervention. For many of these trials, however, the cognitive
results will play second fiddle to the cardiovascular
data, as the study power, cognitive testing protocols,
and subject selection criteria remain oriented toward
identifying vascular as opposed to cognitive events.
When randomized trials test the effects of atherosclerosis treatments on cognitive outcomes, it will be essential to consider whether the impact of treatment is
affected by the extent of other pathologies related to
dementia. For example, although lowering blood pressure could help to preserve cognition by preventing
atherosclerotic brain injury in most patients, it could
worsen cognitive impairment through hypoperfusion in
those patients with advanced leukoaraiosis.23 Although
high doses of atorvastatin were recently shown to prevent recurrent stroke, treatment also appeared to cause
a greater incidence of hemorrhagic stroke.24 In a population where amyloid deposition in cerebral blood vessels is more common, it is possible that such adverse
effects could overwhelm the cardiovascular benefits
seen in the general stroke population. Therefore, when
the question changes from whether to treat atherosclerosis to how to treat atherosclerosis, the atherosclerosis–
dementia relation takes on new importance for clinical
decision making. Although association studies have so
far led the way for suggesting a causal relation between
atherosclerosis and dementia, proving that causality
will be most important when the complex, nonatherosclerotic pathophysiology of dementia informs the interpretation and implementation of the results.
Jacob S. Elkins, MD, MAS
Department of Neurology
University of California, San Francisco
San Francisco, CA
378
Annals of Neurology
Vol 61
No 5
May 2007
References
1. van Oijen M, de Jong FJ, Witteman JCM, et al. Atherosclerosis
and risk for dementia. Ann Neurol 2007;61:403– 410.
2. Elias MF, Wolf PA, D’Agostino RB, et al. Untreated blood
pressure level is inversely related to cognitive functioning: the
Framingham Study. Am J Epidemiol 1993;138:353–364.
3. Launer LJ, Masaki K, Petrovitch H, et al. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA 1995;274:
1846 –1851.
4. Haan MN, Shemanski L, Jagust WJ, et al. The role of APOE
epsilon4 in modulating effects of other risk factors for cognitive
decline in elderly persons. JAMA 1999;282:40 – 46.
5. Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E
epsilon4 allele, elevated midlife total cholesterol level, and high
midlife systolic blood pressure are independent risk factors for
late-life Alzheimer disease. Ann Intern Med 2002;137:
149 –155.
6. Johnston SC, O’Meara ES, Manolio TA, et al. Cognitive impairment and decline are associated with carotid artery disease
in patients without clinically evident cerebrovascular disease.
Ann Intern Med 2004;140:237–247.
7. Price JF, McDowell S, Whiteman MC, et al. Ankle brachial
index as a predictor of cognitive impairment in the general
population: ten-year follow-up of the Edinburgh Artery Study.
J Am Geriatr Soc 2006;54:763–769.
8. Kuller LH, Lopez OL, Jagust WJ, et al. Determinants of vascular dementia in the Cardiovascular Health Cognition Study.
Neurology 2005;64:1548 –1552.
9. Roman G. The early history of vascular dementia. In: Erkinjuntti T, Gauthier S, eds. Vascular cognitive impairment.
London: Martin Dunitz, 2002.
10. Longstreth WT Jr, Dulberg C, Manolio TA, et al. Incidence,
manifestations, and predictors of brain infarcts defined by serial
cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2002;33:2376 –2382.
11. Vermeer SE, Koudstaal PJ, Oudkerk M, et al. Prevalence and
risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 2002;33:21–25.
12. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts
and the risk of dementia and cognitive decline. N Engl J Med
2003;348:1215–1222.
13. Lim A, Tsuang D, Kukull W, et al. Clinico-neuropathological
correlation of Alzheimer’s disease in a community-based case
series. J Am Geriatr Soc 1999;47:564 –569.
14. Pathological correlates of late-onset dementia in a multicentre,
community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive
Function and Ageing Study (MRC CFAS). Lancet 2001;357:
169 –175.
15. Vinters HV, Ellis WG, Zarow C, et al. Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 2000;59:931–945.
16. Hachinski V. Vascular dementia: a radical redefinition. Dementia 1994;5:130 –132.
17. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia
in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998;352:
1347–1351.
18. Prince MJ, Bird AS, Blizard RA, Mann AH. Is the cognitive
function of older patients affected by antihypertensive treatment? Results from 54 months of the Medical Research Council’s trial of hypertension in older adults. BMJ 1996;312:
801– 805.
19. Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction
and the clinical expression of Alzheimer disease. The Nun
Study. JAMA 1997;277:813– 817.
20. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 2004;363:1139 –1146.
21. Thompson WD. Effect modification and the limits of biological inference from epidemiologic data. J Clin Epidemiol 1991;
44:221–232.
22. Peters R, Beckett N, Nunes M, et al. A substudy protocol of
the hypertension in the Very Elderly Trial assessing cognitive
decline and dementia incidence (HYVET-COG): an ongoing
randomised, double-blind, placebo-controlled trial. Drugs Aging 2006;23:83–92.
23. Birns J, Markus H, Kalra L. Blood pressure reduction for vascular risk: is there a price to be paid? Stroke 2005;36:
1308 –1313.
24. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose
atorvastatin after stroke or transient ischemic attack. N Engl
J Med 2006;355:549 –559.
DOI: 10.1002/ana.21101
A Single Episode of
Neonatal Seizures
Permanently Alters
Glutamatergic Synapses
Neonatal seizures are often associated with long-term
neurological consequences including postneonatal epilepsy, behavioral problems, and mental retardation.1–3 Although it is widely recognized that the
cause of the seizures is the primary determinant of
outcome, controversy remains regarding whether the
occurrence of seizures themselves in the neonate contributes to the poor outcome.4 The notion that neonatal seizures do not result in adverse long-term consequence received some support from animal studies
showing that young animals are far less vulnerable to
cell loss in the hippocampus after a prolonged seizure
than the mature animal.5,6 In addition, reactive plasticity of mossy fibers, a signature of adult temporal
lobe epilepsy, is also less prominent in young animals
subjected to prolonged seizures.7,8
However, increasing experimental animal data
strongly suggest that frequent or prolonged seizures in
the developing brain produce sequelae by intervening
with developmental programs leading to inadequate
construction or function of cortical networks rather
than inducing neuronal cell loss (reviewed in Ben-Ari
and Holmes9). Cornejo and colleagues’10 important
study, which appears in this issue of Annals, adds further support to the concept that neonatal seizures
have long-standing adverse behavioral and physiological consequences. The authors initiated seizures by
administering kainate, an excitotoxin, to 1-week-old
rats. The seizures were brief, lasting less than 10 minutes, and intermittent. These seizures mimicked the
clinical situation well because neonates typically do
not have status epilepticus, but rather frequent recurrent seizures.11,12
The investigators studied the effect of these early-life
seizures on memory using tests of visuospatial memory.
In the radial arm water maze, the rat is placed in a
tank of water and learns which of the eight arms contains the escape platform. The test is similar to the
widely used “dry” radial arm maze where rats learn
which arm of a maze contains a food award. Whereas
rats with neonatal seizures and control rats learned to
find the escape platform equally well, rats with a history of neonatal seizures entered more incorrect arms
than did the control rats during the first trial, suggesting that neonatal seizures lead to a subtle defect in
working memory. The investigators then used the twotrial water radial arm maze, a test of episodic or event
memory, a form of memory for something that may
happen only once, rather than repeatedly. Rats with
neonatal seizures entered more incorrect arms and took
longer to find the escape platform than did the control
rats. The rats with neonatal seizures also demonstrated
impaired long-term potentiation (LTP) and enhanced
long-term depression (LTD), two electrophysiological
measures of synaptic plasticity that closely parallel
memory.13
The behavioral and electrophysiological clues directed the investigators to study glutamate receptors
(GluRs), which are critical in learning and memory
and induction of LTP and LTD.13 Rats with neonatal
seizures had a selective decrease in the membrane
pool of the GluR1 subunits, a decrease in the total
amount of the NR2A subunit of the ␣-amino-3hydroxy-5 methylisoxazole-4-proprionic acid (AMPA)
receptor, and an increase in the primary subsynaptic
scaffold, PSD-95 (Figs. 1, 2).
What does this mean? AMPA receptors are the
principal transducers of excitatory neurotransmission
in the mammalian brain. The AMPA receptor consists of tetramers composed of four glutamate subunits, GluR1-GluR4. In the hippocampus, most
AMPA receptors are heteromers composed of GluR2
plus GluR1 or GluR3 subunits.14 Although the subunits are highly homologous, both their functional
properties and trafficking are determined by their
subunits.15 The carboxyl (C) terminus contains regulating domains that are affected by multiple signal
transduction pathways. In addition, the C terminus
interacts with scaffold proteins that bind signaling
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
379
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