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EDITORIAL
686
Parkinson’s disease
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”Nature versus nurture” and
incompletely penetrant mutations
DK Simon, MT Lin, A Pascual-Leone
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Lessons from twin studies of Parkinson’s disease
T
he debate over the relative roles of
“nature versus nurture” remains
unresolved in many fields of study,
from childhood education to animal
behaviour or neurodegenerative disorders. Points of view frequently are polarised, either nature or nurture, rather
then exploring the ways in which both
sides play critical and complementary
roles. Proponents of “nature” argue that
human attributes are uniquely and primarily conditioned by genetics, opposing
the view of those who think that
environmental influences and experience determine individual differences.
Arguments similar to those brought to
bear regarding acquisition of skills, language, or cognitive styles also apply to
human pathology. Often, in the discussion of disease the terms used are
“genetic” versus “environmental”, but
the implication is the same as in the
“nature” versus “nurture” debate. Disorders considered to be primarily genetic
are ones in which the presence or
absence of genetic mutations is the
primary determinant of disease, independent of environmental circumstances. A disease considered to be
primarily environmental is one in which
people of virtually any genetic background can develop the disease provided
that they are exposed to the necessary
environmental factor or factors. However, for many disorders, the risk is
strongly influenced by both genetic and
environmental factors.1 2 For example, a
susceptibility gene may strongly influence the risk of developing a disease only
in response to a specific environmental
exposure. If the environmental exposure
occurs infrequently, the gene will be of
low penetrance, and it may seem that the
environmental exposure is the primary
determinant of the disease, even though
the gene is required for developing the
disease. Therefore, even when environmental agents are suspected to be a
major cause of a particular disease, this
does not exclude the possibility that
genetic factors also play a major part,
particularly genetic mutations with low
penetrance. Similarly, a critical mix of
nature and nurture is likely to determine
personal characteristics. Genetic factors
may be thought of as laying the foundation on which environmental agents
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exert their influence. If so, then although
certain environmental factors alone (regardless of genetic factors) and certain
genetic factors alone (regardless of environmental influences) may explain some
behaviours and disease states, most of
the time the interaction of both genetic
and environment factors will be required.
Deafness due to aminoglycoside toxicity is a particularly clear illustration of
this interdependence. Prolonged exposure to aminoglycosides is toxic to cochlear cells. However, a mutation at nucleotide position 1555 in the mitochondrial
12S ribosomal RNA gene is associated
with an extremely high susceptibility to
aminoglycoside induced deafness, even
at exposure levels that would not be toxic
to most people.3–5 In most cases, the
mutation does not cause deafness without aminoglycoside exposure. The “penetrance” of this mutation is therefore
dependent on the frequency with which
people are exposed to an aminoglycoside
antibiotic. If exposure to aminoglycoside
antibiotics were rare, then the mutation
would have low penetrance, and the
critical role of this mutation in determining susceptibility to non-syndromic
deafness might be difficult to recognise.
To illustrate these points further, in
this discussion, we will focus primarily
on the potential role of incompletely
penetrant mutations in late onset Parkinson’s disease (PD), although similar
arguments apply to many late onset
neurodegenerative diseases and normal
cognitive abilities.
GENETIC AND ENVIRONMENTAL
FACTORS IN PD
It is currently recognised that most late
onset neurodegenerative disorders have
both genetic and environmental influences. In the case of PD, the relative roles
of genetic and environmental factors
remain controversial. A recent epidemiological study of the Icelandic population
suggested a significant genetic component to late onset PD.6 By contrast,
another study comparing concordance
rates in monozygotic (MZ) and dizygotic
(DZ) twins failed to show evidence for a
genetic component for late onset PD.7 For
PD with onset after the age of 50, which
accounts for most cases of PD, no significant differences were found in the concordance rates between 71 MZ and 90 DZ
twin pairs in which at least one twin had
PD, though there was a non-significant
trend towards increased concordance
rates in the MZ twins. This twin study has
been interpreted by some as showing that
there is no significant genetic component
in late onset PD.8 The data from this
important study does argue against a
major role for high penetrant mutations
such as α-synuclein9 or parkin10 in sporadic late onset PD. However, other potentially major genetic contributions are not
excluded. The inability of this type of
study to address the potential role of mitochondrial genetic factors has been addressed previously.11 12 Additionally, we
show below that even large twin studies
such as this are insufficiently powered to
detect many incompletely penetrant nuclear genetic mutations, even though such
mutations could still greatly increase the
risk for PD and play a major epidemiological part. Illustrative hypothetical examples are discussed in detail below.
PREDICTIONS BASED ON A PD
SUSCEPTIBILITY GENE IN A
THEORETICAL POPULATION
Consider a theoretical population of persons over the age of 65 with a prevalence
of PD of 1%, which corresponds with
actual estimates of the prevalence of PD
in this age group.13 14 We examine three
different theoretical mutations, with
various frequencies and penetrances and
assume for each mutation that it is the
only genetic factor that influences risk of
PD. However, similar conclusions apply
to a wide range of other theoretical
incompletely penetrant mutations.
Suppose, firstly, that an autosomal
dominant mutation “z” present in 50%
of persons is associated with a 2% risk of
PD. Such a mutation would result in PD
in 2% of the 50% of those who have the
mutation, representing 1% of the total
population. That is, this mutation accounts for all cases of PD, as the
prevalence of PD in this theoretical
population is 1%. It is an absolutely necessary “permissive” mutation. The risk
of disease without the mutation is zero,
and the increase in relative risk conferred by the mutation is infinite. Such a
mutation would clearly be of enormous
epidemiological significance. However, it
is extremely unlikely that such a mutation would be detected by a study comparing MZ and DZ twin concordance
rates. The concordance rate is defined as
the number of twin pairs in which both
twins have PD (+PD,+PD) divided by
the sum of all twin pairs in which at
least one twin has PD (the number of
twin pairs that are (+PD,+PD) plus the
number that are (+PD,-PD) plus the
number that are (-PD,+PD)). With this
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EDITORIAL
687
A Mutation in 50% of population
D Power to detect mutation "z"
1
0.01
0.9
0.7
Power
Concordance rate
0.8
0.008
0.006
Mutation "z"
0.004
0.6
0.5
0.4
0.3
0.2
0.002
0.1
0
0.008
0.012
0
0.02
0.016
0
10 000
Penetrance
20 000
30 000
Number of twins
B Mutation in 5% of population
E Power to detect mutation "x"
0.15
1
0.9
0.7
0.1
Power
Concordance rate
0.8
Mutation "x"
0.05
0.6
0.5
0.4
0.3
0.2
0.1
0
0
0.05
0.1
0.15
0
0.2
0
1000
Penetrance
C Mutation in 1% of population
3000
4000
5000
F Power to detect mutation "a"
0.25
1
Mutation "a"
0.9
0.2
0.8
0.7
0.15
Power
Concordance rate
2000
Number of twins
0.1
0.6
0.5
0.4
0.3
0.05
0.2
0.1
0
0
0.1
0.2
0.3
0.4
0.5
0.6
0
0
100
Penetrance
200
300
400
Number of twins
Figure 1 (A-C) Graphs of the MZ (open symbols) and DZ (closed symbols) concordance rates as a function of the penetrance of the disease
associated allele. Graphs are shown for situations in which at least one copy of the disease associated allele is present in (A) 50%, (B) 5%, or
(C) 1% of the population. The prevalence of the disease in this hypothetical population is 1%. Note that the range of possible penetrances is
inversely proportional to the fraction of the population carrying a disease associated allele, because the product of the penetrance and the
fraction of the population carrying the allele cannot exceed the prevalence of the disease. Arrows indicate the points representing concordance
rates associated with the theoretical mutations “z” (A), ”x” (B), and ”a” (C) discussed in the text. (D-F) Graphs showing the number of affected
twin pairs in each group (MZ and DZ) required in order to have the indicated power to detect a difference in the MZ and DZ concordance
rates associated with the mutations “z”, “x”, and “a”. The sample size required to detect the difference between two proportions was
calculated using the standard formula15: N=(p1(1-p1)+p2(1-p2))*(zα+zβ)2/ (p1–p2)2 Sample sizes appropriate for a one tailed (α=0.05) z test are
shown.
definition, the concordance rates
predicted to result from mutation “z”
are 1.01% for MZ twins and 0.73% for
DZ twins (fig 1 A; details of the calculations are available on request). The
number of twins required to detect a
difference between these concordance
rates is exceedingly high. It would
require over 14 000 affected twin pairs in
each group to have 80% power to detect
a difference (fig 1 D; see figure legend
for method of calculating power15). This
is far beyond even the most exhaustive
twin study, by Tanner et al,7 in which
only 71 affected MZ twin pairs and 90
affected DZ twin pairs were identified
after reviewing a registry of nearly
20 000 twin pairs.
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EDITORIAL
688
Consider now a less prevalent but
more penetrant mutation “x”, present in
5% of the population and associated with
a 10% risk of PD. Such a mutation would
account for PD in 10% of the 5% of those
who have the mutation, or 0.5% of the
population. In this case, this would
represent half of the cases of PD.
Furthermore, the risk of PD without “x”
is 0.526%, so the increase in relative risk
conferred by the mutation is 19-fold
(10% v 0.526%). Like mutation “z”,
mutation “x” would clearly have great
epidemiological significance. However,
again, it is very unlikely that such a
mutation would be detected by a study of
MZ and DZ twin concordance rates. If
“x” were the only genetic risk for PD, the
concordance rates predicted to result
from “x” are 2.70% for MZ twins and
1.58% for DZ twins (fig 1 B). Again, the
number of twin pairs required to detect a
difference between these concordance
rates is extremely large. It would require
about 2100 affected twin pairs in each
group to have an 80% chance of detecting a difference between these concordance rates (fig 1 E).
Finally, consider a relatively highly
penetrant mutation “a”, present in 1% of
the population and associated with a
55% risk of PD. Mutation “a” would
account for 55% of cases of PD and confer a 121-fold increase in relative risk.
Therefore, like mutations “z” or “x”,
mutation “a” would be of great epidemiological significance. Furthermore,
because of its higher penetrance, the
twin concordance rates predicted from
mutation “a” are higher than those of
“z” or “x”: 17.96% for MZ twins and
8.52% for DZ twins (fig 1 C). Yet, the difference between these rates still is not
reliably detectable with the number of
twin pairs available. To achieve 80%
power to detect this difference, a study
would require about twice as many
affected twin pairs compared with the
numbers available in the study by Tanner
et al (fig 1 F).7
Thus, over a very wide range of gene
frequencies and penetrances, it is clear
that even extremely large and well
designed twin studies such as that by
Tanner et al7 are still insufficiently powered to detect incompletely penetrant
mutations. The literature contains
widely varying estimates of sibling concordance rates, depending on the methodology and populations studied. Estimates range from 2% risk of PD among
first degree siblings of patients with PD
in a community based study,16 to MZ and
DZ twin concordance rates of 16% and
11%.7 The risks of PD among siblings
associated with hypothetical mutations
“z”, “x”, and “a” span this entire range of
estimates. Even at the relatively high
concordance rates found by Tanner et al,
incompletely penetrant mutations that
may play a major part in risk of PD are
not reliably detected (fig 1 F).
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Clearly, low penetrant mutations do
not act alone. Low penetrance implies
that other factors, environmental by
hypothesis for mutations “x”, “z”, and
‘”a”, must be present for clinical expression of the mutations as PD. Thus, these
mutations cause enhanced susceptibility
to environmental agents. Already, many
genetic variants have been reported in
association with PD.17–19 Although many
of these associations have not been replicated, it is likely that susceptibility genes
play a significant part in the risk of PD
and other late onset neurodegenerative
disorders. Two well documented examples of low penetrant genetic variants
that seem to influence susceptibility to a
late onset neurodegenerative disease are
the association of the A0 tau gene allele
with progressive supranuclear palsy,20–22
and the apoE4 allele with Alzheimer’s
disease.23 Technological advances, such
as genetic microarrays, may allow rapid
screening of many polymorphisms for
associations with complex disorders,
allowing for further expansion of our
knowledge of susceptibility genes as well
as clinical application of this knowledge
for determining susceptibility to specific
disorders.
CONCLUSIONS
Studies of rare high penetrant mutations
such as the α-synuclein gene hold the
prospect of disclosing a great deal about
the pathophysiology of late onset idiopathic PD. However, α-synuclein mutations are absent in sporadic late onset
PD, and twin studies suggest that high
penetrant nuclear genetic mutations are
unlikely to play a major part. None the
less, it remains possible that susceptibility gene variations play a major part in
the pathophysiology of a large proportion of late onset cases. Genetic
mutations may induce susceptibility to
environmental toxins, and both the
presence of specific genetic mutations
and exposure to particular environmental agents may be required for the development of late onset PD. Therefore,
whereas a focus on the role of environmental factors in PD and other neurodegenerative diseases is of critical importance, this should not be done at the
expense of further genetic studies, particularly with respect to low penetrant
susceptibility genetic mutations. Studies
addressing both genetic and environmental factors, as well as their interactions, will be necessary for a complete
understanding of PD.
The example of PD serves as a pointed
illustration of the complex interactions
of nature (genetic factors) and nurture
(environmental factors) in human diseases and abilities. Studies to address the
relative contribution of each are possible,
but
complex
and
expensive.
Nevertheless, this line of inquiry addresses a fundamental organising principle of brain function that goes well
beyond the pathophysiology of diseases.
For example, exposed to certain traumatic experiences, some people develop
post-traumatic stress syndrome and can
be extremely debilitated by it for the rest
of their lives. Other people exposed to the
similar experiences seem unfazed. Some
people seem to thrive in a competitive
and result oriented environment
whereas others prosper more in a supportive, relaxed atmosphere. Are these
interindividual differences grounded on
genetic factors that condition the way
the brain is changed by certain experiences and hence develops cognitive
attributes and illnesses? Identifying
such susceptibility genes may allow us to
individualise and guide behaviour to
maximise educational goals and minimise environmentally induced diseases.
The data presented here illustrate that
one should not be dissuaded from the
potential importance of incompletely
penetrant genetic mutations to a human
disease or attribute simply due to the
lack of significantly different concordance rates detected in studies of MZ and
DZ twins.
J Neurol Neurosurg Psychiatry
2002;72:686–689
.....................
Authors’ affiliations
D K Simon, Department of Neurology, Beth
Israel Deaconess Medical Center, Boston, MA,
USA
M T Lin, Department of Neurology, Weill
Medical College of Cornell University, New
York, NY, USA
A Pascual-Leone, Department of Neurology,
Beth Israel Deaconess Medical Center, Boston,
MA, USA
DKS and MTL contributed equally to the
manuscript
Correspondence to: Dr M T Lin, Department of
Neurology and Neuroscience, Weill Medical
College of Cornell University, New York, NY
10021, USA; [email protected]
REFERENCES
1 Cooper B. Nature, nurture and mental
disorder: old concepts in the new millennium.
Br J Psychiatry 2001;178(suppl 40):S91–101.
2 Hulla JE, Miller MS, Taylor JA, et al.
Symposium overview: the role of genetic
polymorphism and repair deficiencies in
environmental disease. Toxicol Sci
1999;47:135–43.
3 Inoue K, Takai D, Soejima A, et al. Mutant
mtDNA at 1555 A to G in 12S rRNA gene
and hypersusceptibility of mitochondrial
translation to streptomycin can be
co-transferred to rho 0 HeLa cells. Biochem
Biophys Res Commun 1996;223:496–501.
4 Hutchin T, Haworth I, Higashi K, et al. A
molecular basis for human hypersensitivity to
aminoglycoside antibiotics. Nucleic Acids Res
1993;21:4174–9.
5 Prezant TR, Agapian JV, Bohlman MC, et al.
Mitochondrial ribosomal RNA mutation
associated with both antibiotic-induced and
non-syndromic deafness. Nat Genet
1993;4:289–94.
6 Sveinbjornsdottir S, Hicks AA, Jonsson T, et
al. Familial aggregation of Parkinson’s
disease in Iceland. N Engl J Med
2000;343:1765–70.
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EDITORIAL COMMENTARIES
7 Tanner CM, Ottman R, Goldman SM, et al.
Parkinson disease in twins: an etiologic study.
JAMA 1999;281:341–6.
8 Cummings JL. Understanding Parkinson
disease [editorial; comment]. JAMA
1999;281:376–8.
9 Polymeropoulos MH, Lavedan C, Leroy E, et
al. Mutation in the α-synuclein gene identified
in families with Parkinson’s disease. Science
1997;276:2045–7.
10 Kitada T, Asakawa S, Hattori N, et al.
Mutations in the parkin gene cause autosomal
recessive juvenile parkinsonism. Nature
1998;392:605–8.
11 Simon DK. Parkinson disease in twins. JAMA
1999;282:1328, 1328–9.
12 Parker WD Jr, Swerdlow RH, Parks JK, et al.
Parkinson disease in twins. JAMA
1999;282:1328.
13 Mayeux R, Marder K, Cote LJ, et al. The
frequency of idiopathic Parkinson’s disease by
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age, ethnic group, and sex in northern
Manhattan, 1988–93. Am J Epidemiol
1995;142:820–7.
de Rijk MC, Breteler MM, Graveland GA, et
al. Prevalence of Parkinson’s disease in the
elderly: the Rotterdam study. Neurology
1995;45:2143–6.
Motulsky H. Intuitive biostatistics. New York:
Oxford University Press, 1995:199.
Marder K, Tang MX, Mejia H, et al. Risk of
Parkinson’s disease among first-degree
relatives: a community-based study.
Neurology 1996;47:155–60.
Bajaj NP, Shaw C, Warner T, et al. The
genetics of Parkinson’s disease and
parkinsonian syndromes. J Neurol
1998;245:625–33.
Checkoway H, Farin FM, Costa-Mallen P, et
al. Genetic polymorphisms in Parkinson’s
disease. Neurotoxicology 1998;19:635–43.
EDITORIAL COMMENTARIES
Behavioural disorders
...................................................................................
Behavioural disorders, Parkinson’s
disease, and subthalamic stimulation
R G Brown
...................................................................................
Stimulation of the bilateral subthalamic nucleus can have
adverse consequences
T
he paper by Houeto et al1 in this issue
(pp 701–707) offers new evidence to
suggest that bilateral subthalamic
nucleus (STN) stimulation can have
adverse and potentially serious consequences for patients and their families,
despite the benefits obtained in motor
function. The study has important implications for those running surgical programmes in terms of patient selection,
preoperative counselling, and postoperative care.
The management of the motor symptoms of Parkinson’s disease has been
greatly enhanced in recent years by new
approaches to functional neurosurgery,
both stereotactic lesions to the globus
pallidus or subthalamic nucleus and
stimulation of the same structures via
chronically implanted electrodes. These
treatments can achieve remarkable clinical outcomes in some patients and
significant improvement in many, particularly in the control of levodopa
induced dyskinesia. Although research
has also investigated the impact of
surgery on cognition,2 the psychiatric
and the broader social consequences
have been largely ignored.
The paper reports data on a series of
24 patients, all of who were judged clinically to have benefited from surgery. As
in most surgical programmes, patients
with dementia or with significant psychiatric problems were excluded as part
of normal preoperative clinical screening. Social adjustment was assessed
using a standardised instrument 3–38
weeks after surgery and revealed that,
although just over a third showed evidence of good to excellent adjustment,
moderate or severe impairment was
found in the remainder affecting broad
aspects of social and interpersonal functioning. Psychiatric problems were also
common postoperatively, particularly
anxiety disorders. Five patients became
depressed after surgery and one patient
committing suicide despite having
shown dramatic improvement in motor
function.
Such results offer some important lessons. One key finding was the high level
of prior psychopathology in the sample.
Such problems were either not reported
by patients during screening (possibly
for fear that it would lead to exclusion)
or were not given sufficient priority in
the clinical decision making process. The
postoperative exacerbation of these
problems and their impact on social
adjustment suggest that great care needs
to be taken in identifying prior psychiatric disorder, and not just current problems. Although a psychiatric history
need not be a cause of exclusion, it
19 Tan EK, Khajavi M, Thornby JI, et al.
Variability and validity of polymorphism
association studies in Parkinson’s disease.
Neurology 2000;55:533–8.
20 Conrad C, Andreadis A, Trojanowski JQ, et
al. Genetic evidence for the involvement of tau
in progressive supranuclear palsy. Ann Neurol
1997;41:277–81.
21 Morris HR, Janssen JC, Bandmann O, et al.
The tau gene A0 polymorphism in progressive
supranuclear palsy and related
neurodegenerative diseases. J Neurol
Neurosurg Psychiatry 1999;66:665–7.
22 Bennett P, Bonifati V, Bonuccelli U, et al.
Direct genetic evidence for involvement of tau
in progressive supranuclear palsy. European
Study Group on Atypical Parkinsonism
Consortium. Neurology 1998;51:982–5.
23 Mayeux R, Stern Y, Ottman R, et al. The
apolipoprotein epsilon 4 allele in patients with
Alzheimer’s disease. Ann Neurol
1993;34:752–4.
should indicate the clear need for enhanced postoperative follow up and care
in at risk patients.
The paper also offers some important
anecdotal reports on the cases of social
maladjustment. The deterioration of
marital and family relations points to the
importance of psychosocial factors in the
postoperative period. For example, the
sudden breakdown in patterns of dependency and caregiving built up over
years can have a marked impact on
interpersonal relationships. Similar adverse responses, including suicide, have
been reported after other dramatically
life enhancing surgical procedures such
as sight restoration,3 and have long been
recognised in the field of organ
transplantation.4 Such responses point
to the need for careful counselling of
patients with Parkinson’s disease and
their families before surgery to help prepare them for the possible impact on
their lives, both positive and negative.
J Neurol Neurosurg Psychiatry 2002;72:689
.....................
Author’s affiliation
R G Brown, Department of Psychology, Institute
of Psychiatry, King’s College London, De
Crespigny Park, London SE5 8AF, UK;
[email protected]
REFERENCES
1 Houeto JL, Mesnage V, Mallet L et al Behavioural
disorders, Parkinson’s disease and
subthalamic stimulation. J Neurol Neurosurg
Psychiatry 2002;72:701–707.
2 Trepanier LL, Kumar R, Lozano AM, et al.
Neuropsychological outcome of GPi
pallidotomy and GPi or STN deep brain
stimulation in Parkinson’s disease. Brain Cogn
2000;42:324–47.
3 Lester D. Suicide after restoration of sight.
JAMA 1971;216:678–9.
4 Dew MA, Switzer GE, DiMartini AF, et al.
Psychosocial assessments and outcomes in
organ transplantation. ProgTransplant
2000;10:239–59.
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EDITORIAL COMMENTARIES
690
Impaired cognition
...................................................................................
Hypertension+MRI changes=impaired
cognition
S Tuhrim, S R Levine
...................................................................................
A quantifiable formula?
A
s both the average age of the population and rates of vascular dementia increase, there has been
keen interest in measuring and quantifying determinants of cognitive impairment. Koga et al (this issue pp 737–741)1
quantify brain MRI abnormalities and
relate them to loss of a normal mental
state in a single rural, independent,
elderly community. Cognitive impairment was defined as a mini mental state
examination (MMSE) score <24 with a
mean study score of 26 points.1
The work exemplifies the expanding
body of investigations utilising increasingly complex MRI techniques and data
analyses to provide insights into brain
function beyond those obtainable by
mere visual inspection of images. Emerging new structural imaging techniques
such as diffusion tensor imaging, can
provide information regarding white
matter characteristics associated with
disease states and brain response to
injury (neuroplasticity) and take us
beyond more conventional MRI images.
The work of Koga et al not only provides
confirmation of the importance of white
matter lesions and generalised atrophy
as markers of cognitive decline but also
provides a potentially useful tool for
quantifying these changes.
It is important not to lose sight, amid
this march of technical development, of
their confirmation of an important epidemiological finding: the association of
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systolic blood pressure with decreased
cognition. Although this factor did not
appear in the multivariate logistic model,
most likely because of its colinearity
with the MRI measurements of white
matter lucencies and decreased brain
volume, factors with which it is known
to be associated, its link to cognitive
decline and decreased cerebral perfusion
has long been appreciated.2 Recently,
analysis of the national Health and
Nutrition
Examination
Survey
(NHANES) in the United States indicated that 27% of the United States
population had hypertension but only
23% of these with hypertension were
taking medication that controlled their
blood pressure. Among those with untreated or uncontrolled hypertension,
isolated increased systolic blood pressure
was the most common pattern found.3
Indeed isolated mild systolic hypertension is the most prevalent form of
uncontrolled hypertension in the United
States. The work of Koga et al provides
further evidence of the importance of
addressing this silent epidemic.
We also know from the Cardiovascular
Health Study (CHS)4 that focal lesions
>3 mm on brain MRI (“silent strokes”)
were present in 28% of 3324 participants
in this study. The presence of these MRI
lesions doubled the risk of subsequent
stroke, as did increased diastolic and
systolic blood pressure, internal carotid
artery wall thickness, and the presence
of atrial fibrillation. Silent strokes as
seen on MRI were an independent
predictor of symptomatic stroke, at a rate
of 18.7/1000 person-years, over the 4
years of follow up in older people
without a clinical history of stroke.
Based on the recent results of the
PROGRESS trial,5 we should be considering more aggressive blood pressure management in patients with cerebrovascular disease, even in patients with
borderline or normal blood pressures (in
high risk patients) as data strongly suggest a causal link between blood pressure, MRI lesions, and silent and symptomatic cerebrovascular disease. We are
making progress on solving the equation
that has blood pressure, MRI changes,
and cognition as the variables.
J Neurol Neurosurg Psychiatry 2002;72:690
.....................
Authors’ affiliations
S Tuhrim, S R Levine, The Stroke Program,
Department of Neurology, The Mount Sinai
School of Medicine, New York, USA
Correspondence to: Dr S R Levine, Stroke
Program, Department of Neurology, Box 1137,
The Mount Sinai School of Medicine, One
Gustave L Levy Place, New York 10029–6574,
USA; [email protected]
REFERENCES
1 Koga H, Yuzuriha T, Yao H, et al.
Quantitative MRI findings and cognitive
impairment among community-dwelling elderly
subjects. J Neurol Neurosurg Psychiatry
2002;72:737–741.
2 Meyer JS, Rogers RL, Mortel KF. Prospective
analysis of long term control of mild
hypertension on cerebral blood flow. Stroke
1985;16:985–90.
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''Nature versus nurture'' and incompletely
penetrant mutations
DK Simon, MT Lin and A Pascual-Leone
J Neurol Neurosurg Psychiatry 2002 72: 686-689
doi: 10.1136/jnnp.72.6.686
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