Medial temporal lobe atrophy and white matter
hyperintensities are associated with mild cognitive deficits in
non-disabled elderly people: the LADIS study
W M van der Flier, E C W van Straaten, F Barkhof, J M Ferro, L Pantoni, A M Basile, D Inzitari,
T Erkinjuntti, L O Wahlund, E Rostrup, R Schmidt, F Fazekas, P Scheltens, on behalf of the LADIS
See end of article for
Dr Wiesje M van der Flier,
Department of Neurology
and Alzheimer Centre,
Vrije Universiteit Medical
Centre, PO Box 7057,
1007 MB Amsterdam,
Received 7 February 2005
In revised form
24 February 2005
Accepted 24 March 2005
A list of participating cen-
tres is given in the appen-
J Neurol Neurosurg Psychiatry 2005;76:1497–1500. doi: 10.1136/jnnp.2005.064998
Objective: To assess the associations of medial temporal lobe atrophy (MTA) and white matter
hyperintensities (WMH) with cognitive function in a large group of independently functioning elderly
Methods: Data were drawn from the multicentre, multinational leukoaraiosis and disability (LADIS) project
which is studying prospectively the role of WMH as an independent predictor of the transition to disability
in non-disabled elderly people. In all, 639 participants were enrolled in the LADIS study. For the present
analysis, data on 581 subjects were available. Cognitive function was assessed by the mini-mental state
examination (MMSE). Visual ratings of WMH and MTA were undertaken on magnetic resonance images
Results: The presence of either severe WMH or MTA was associated with a modest but non-significant
increase in frequency of mild cognitive deficits (severe WMH: odds ratio (OR)=1.9 (95% confidence
interval (CI), 1.0 to 3.7); MTA present: OR=1.5 (95% CI, 0.8 to 2.8)). However, subjects with the
combination of MTA and severe WMH had a more than fourfold increase in frequency of mild cognitive
deficits (OR=4.1 (95% CI, 2.3 to 7.4)). Analysis of variance with post hoc Bonferroni t tests showed that
subjects with both MTA and severe WMH performed worse on MMSE than those with either no MRI
abnormality or a single MRI abnormality (p,0.05).
Conclusions: These results provide further evidence for the combined involvement of both Alzheimer type
pathology and vascular pathology in the earliest stages of cognitive decline and suggest an additive effect
of WMH and MTA.
also plays a role in the neurodegenerative processes leading
to cognitive impairment in old age.1 2On magnetic resonance
imaging (MRI), medial temporal lobe atrophy (MTA)
presumably reflects Alzheimer type pathology, whereas white
matter hyperintensities (WMH) are probably of vascular
MTA and WMH often coexist in dementia.5 6However, the
role of the combination of these MRI abnormalities in the
early stages of cognitive decline is not known. If MTA and
WMH could be shown to influence cognitive function jointly
in non-disabled elderly people, this would provide further
evidence for the early involvement of both Alzheimer type
pathology and vascular pathology in determining cognitive
impairment. In this study, we therefore assessed the
associations of MTA and WMH with cognitive function in a
large group of independently functioning elderly people.
here is a growing body of evidence that in addition to the
classical ‘‘Alzheimer type’’ neuropathology of senile
plaques and neurofibrillary tangles, vascular pathology
Data were drawn from the multicentre and multinational
leukoaraiosis and disability (LADIS) project which is study-
ing prospectively the role of WMH as an independent
predictor of the transition to disability in non-disabled
elderly people. The design of the LADIS project has been
fully described elsewhere.7In short, 639 elderly subjects who
had no or only mild disability in their instrumental activities
of daily living (IADL) and who were stratified for WMH
severity were enrolled between 18 July 2001 and 31 January
2003. Subjects presented with complaints including mild
cognitive or motor disturbances, minor cerebral events, mood
alterations, other neurological problems, or in whom WMH
were incidentally identified on brain imaging. Subjects
participating as controls in other studies and volunteers were
also included. To be included, subjects had to meet the
N age between 65 and 84 years;
N WMH on MRI of any degree, according to the categorisa-
tion into the three severity classes of a revised version of
the Fazekas scale8;
N no or only mild disability as determined by the IADL
N presence of a regularly contactable informant;
N agreement to sign informed consent.
Exclusion criteria were: the likelihood of dropping out
because of the presence of severe illnesses (cardiac, hepatic,
or renal failure, cancer, or other relevant systemic diseases);
severe unrelated neurological diseases; leucoencephalopathy
of non-vascular origin (immunological-demyelinating, meta-
bolic, toxic, infectious, other); severe psychiatric disorders;
Abbreviations: IADL, instrumental activities of daily living; LADIS,
leukoaraiosis and disability project; MMSE, mini-mental state
examination; MTA, medial temporal lobe atrophy; WMH, white matter
inability to give informed consent; and inability or refusal to
undergo cerebral MRI. Subjects are currently followed up for
three years with repeated clinical and MRI studies. The
present paper is based on the baseline data of the LADIS
All subjects were assessed using an extensive set of clinical
and functional tests including global functioning, and
cognitive, motor, psychiatric, and quality of life measures.
For the present study, general cognitive function was
assessed by the mini-mental state examination (MMSE).10
Subjects with an MMSE score of 26 or more were considered
to have ‘‘good cognitive function,’’ whereas those with an
MMSE score below 26 were considered to have ‘‘mild
All subjects were studied by MRI following a standard
protocol, and scans were collected centrally at the Image
Analysis Centre (IAC) of the Vrije Universiteit Medical
Centre, Amsterdam. The MR protocol included T1 weighted
three dimensional MPRAGE (magnetisation prepared rapid
acquisition gradient echo), axial T2, and FLAIR (fluid
attenuated inversion recovery) sequences. Visual ratings of
WMH and MTA were carried out centrally by a single rater
(ECWvS) who was blind to clinical details. The degree of
WMH severity was rated visually on axial FLAIR images
using the Fazekas scale as grade 1 (punctate), grade 2 (early
confluent), or grade 3 (confluent).8Visual rating of MTA was
done on T1 weighted images resliced in the coronal plane
according to the 0–4 point Scheltens scale.11For 32 subjects,
no T1 weighted scan was available and in 25 subjects, the
quality of the T1 weighted scan did not allow MTA scoring.
Thus 581 subjects participated in the present study. To
determine the intrarater reliability, 18 scans were scored
twice for WMH and 15 scans for MTA (weighted Cohen’s k
for WMH=0.84 and for MTA=0.85).
For statistical analysis, both MRI measures were dichot-
omised (WMH grade 1 and 2=mild WMH, grade 3=severe
WMH; MTA score 0/1=no atrophy, MTA score 2–4=atro-
phy). Using both dichotomised MRI measures, we computed
a new four level categorical ‘‘MTA6WMH’’ variable. Crude
odds ratios (OR) were calculated by cross tabulation. In
addition, we used logistic regression analysis to correct for
age, sex, education, and the presence of lacunes or stroke.
Analysis of variance (ANOVA) with post hoc Bonferroni t
tests was used to compare differences in MMSE score
according to the presence of MTA or severe WMH or both.
There were 581 subjects (54% female). Their mean (SD) age
was 74 (5) years; their years of education, 10 (4); and their
MMSE score, 27 (2). The majority of subjects had good
cognitive function (n=486, defined as MMSE >26), but
there were 95 subjects with mild cognitive deficits (MMSE
,26). There was a predominance of women among the
subjects with an MMSE score below 26 (x2=3.8, p=0.05),
and they had received less education (t=7.1, p,0.001).
There was a significant correlation between the presence of
severe WMH and MTA (Spearman’s r=0.27, p,0.001). The
presence of either severe WMH or MTA was associated with a
modest but non-significant increase in frequency of mild
cognitive deficits (severe WMH, p=0.06; MTA present,
p=0.23, see table 1). However, subjects with the combina-
tion of MTA and severe WMH had a more than fourfold
increase inthe frequency
(p,0.001). These risk estimates did not change essentially
when age, sex, education, and the presence of stroke or
lacunes were entered as covariates. Formal testing in a
logistic regression model incorporating the interaction term
between MTA and WMH showed that there was no statistical
interaction between MTA and WMH.
In an additional analysis, we compared the MMSE score of
the four ‘‘MTA6WMH’’ groups using ANOVA. There was a
difference in MMSE score between groups (p,0.001, fig 1).
Post hoc analyses using Bonferroni t tests showed that the
group with both MTA and severe WMH performed signifi-
cantly worse than the other three groups of subjects with
either no MRI abnormality or a single abnormality (p,0.05).
The presence of either MTA but no severe WMH, or severe
WMH but no MTA was not associated with a significantly
lower MMSE score.
of mild cognitivedeficits
We showed that a combination of MTA and severe WMH was
associated with a more than fourfold increase in the
frequency of mild cognitive deficits in a large group of non-
disabled elderly people. By contrast, mild cognitive deficits
were not more frequent in the groups of patients with a
single MRI abnormality (either MTA or severe WMH). These
results suggest the combined involvement of both Alzheimer
type pathology and vascular pathology in the earliest stages
of cognitive decline.
atrophy and white matter hyperintensities
Odds ratios for mild cognitive deficits dependent on medial temporal lobe
Medial temporal lobe atrophy
White matter hyperintensities
Good cognitive function (n)
Mild cognitive deficits (n)
Crude odds ratio (95% CI)
Adjusted odds ratio (95% CI)
1.9 (1.0 to 3.7)
1.8 (0.9 to 3.9)
1.5 (0.8 to 2.8)
1.4 (0.7 to 2.8)
4.1 (2.3 to 7.4)
4.6 (2.3 to 9.0)
Data are presented as odds ratios and their 95% confidence intervals (CI). Adjusted odds ratios are corrected for
age, sex, education, and presence of stroke and/or lacunes.
MMSE, mini-mental state examination; MTA, medial temporal lobe atrophy; WMH, white matter hyperintensities.
to the presence of medial temporal lobe atrophy (MTA) and age related
white matter hyperintensities (WMH). The group with both MTA and
severe WMH had a lower MMSE score than the groups with a single MRI
abnormality or no abnormality (p,0.05).
Mean mini-mental state examination (MMSE) score according
1498 Flier, Straaten, Barkhof, et al
Former studies (both necropsy and MRI) reported that
Alzheimer type pathology and vascular pathology often
coexist in patients with dementia.1 2 5 6The present study
extends these findings, as we observed in vivo using MRI that
even in non-disabled elderly people the combination of MTA
and WMH was already associated with decreased cognitive
performance. These findings provide further evidence for the
threshold theory, which stipulates that Alzheimer type
pathology and cerebrovascular pathology summate until a
threshold is reached and clinical dementia ensues.12
In seeming contrast to earlier studies,5 13–15the presence of
MTA alone was not significantly associated with cognitive
impairment. The specific characteristics of the LADIS study
sample probably account for this finding. Subjects were
included on the basis that they had WMH on MRI in
combination with absence of disability, resulting in a study
population that is biased towards excessive vascular pathol-
ogy and relatively little Alzheimer type pathology. However,
even in this population, where cognitive impairment would
be expected to be of vascular origin, the association between
WMH and cognitive impairment could only be fully
appreciated if MTA was also taken into account.
A possible limitation of this study includes the use of
dichotomised rather than continuous measures of MTA and
WMH. In addition, we used the MMSE, which is a rather crude
measure of cognitive function. It is conceivable that the use of
continuous MRI variables and a more sensitive cognitive test
would have yielded more striking results. However, we feel that
our simple approach enhances the clinical value of our results,
as the MMSE is one of the most widely used cognitive tests. In
addition, contrasting with sophisticated, but time intensive
neuroimaging measures, simple ratings of MTA and WMH can
be used in clinical practice.
These results may have important clinical implications.
Memory clinics often evaluate patients who present with
subjective memory complaints and severe WMH on MRI, but
who have no detectable cognitive deficits. The present study
suggests that if such patients have additional MTA they may
be at increased risk of subtle cognitive impairment. Should
further studies using a longitudinal design corroborate our
finding that the combination of WMH and MTA is indeed
predictive of subsequent cognitive decline, the combination
of these simple MRI markers may be a useful tool in
identifying subjects at risk of dementia. Whether this
combination of markers predicts dementia at follow up in
the present sample will be the subject of further study.
The LADIS study is supported by the European Union within the V
European Framework Programme ‘‘Quality of life and management
of living resources’’ (1998–2002), contract No QLRT–2000-00446 as a
W M van der Flier, E C W van Straaten, P Scheltens, Department of
Neurology and Alzheimer Centre, Vrije Universiteit Medical Centre,
F Barkhof, Department of Radiology and Image Analysis Centre (IAC),
Vrije Universiteit Medical Centre
J M Ferro, Servic ¸o de Neurologia, Centro de Estudos Egas Moniz,
Hospital de Santa Maria, Lisbon, Portugal
L Pantoni, A M Basile, D Inzitari, Department of Neurological and
Psychiatric Sciences, University of Florence, Florence, Italy
T Erkinjuntti, Memory Research Unit, Department of Clinical
Neurosciences, Helsinki University, Helsinki, Finland
L O Wahlund, Neurotec department, Section of Clinical Geriatrics,
Karolinska Universitetssjukhuset, Huddinge University Hospital,
E Rostrup, Memory Disorders Research Unit, Department of Neurology,
Copenhagen University Hospital, Copenhagen, Denmark
R Schmidt, F Fazekas, Department of Neurology and MRI Institute,
Medical University, Graz, Austria
Competing interests: Philip Scheltens is an associate editor of JNNP but
had no role in reviewing or accepting this paper.
LIST OF PARTICIPATING CENTRES AND PERSONNEL
Helsinki, Finland (Memory Research Unit, Department of Clinical
Neurosciences, Helsinki University): Timo Erkinjuntti MD, PhD,
Tarja Pohjasvaara MD, PhD, Pia Pihanen MD, Raija Ylikoski
PhD, Hanna Jokinen LPsych, Meija-Marjut Somerkoski
MPsych, Riitta Ma ¨ntyla ¨ MD, PhD, Oili Salonen MD, PhD;
Graz, Austria (Department of Neurology and MRI Institute, Medical
University): Franz Fazekas MD, Reinhold Schmidt MD, Stefan
MagPsychol, Ulrike Garmehi; Lisbon, Portugal (Servic ¸o de
Neurologia, Centro de Estudos Egas Moniz, Hospital de Santa
Maria): Jose ´ M Ferro MD, PhD, Ana Verdelho MD, Sofia
Madureira PsyD; Amsterdam, Netherlands (Department of
Neurology, VU Medical Centre): Philip Scheltens MD, PhD, Ilse
van Straaten MD, Alida Gouw MD, Wiesje van der Flier PhD,
Frederik Barkhof MD, PhD; Goteborg, Sweden (Institute of
Clinical Neuroscience, Goteborg University): Anders Wallin MD,
PhD, Michael Jonsson MD, Karin Lind MD, Arto Nordlund
PsyD, Sindre Rolstad PsyD, Kerstin Gustavsson RN; Huddinge,
Sweden (Neurotec department, Section of Clinical Geriatrics,
Karolinska Universitetssjukhuset): Lars-Olof Wahlund MD,
PhD, Militta Crisby MD, PhD, Anna Pettersson, physiothera-
pist, Kaarina Amberla PsyD; Paris, France (Department of
Neurology, Hopital Lariboisiere): Hugues Chabriat MD, PhD,
Ludovic Benoit MD, Karen Hernandez, Solene Pointeau,
Annie Kurtz, Daniel Reizine MD; Mannheim, Germany
(Department of Neurology, University of Heidelberg, Klinikum
Mannheim): Michael Hennerici MD, Christian Blahak MD,
Hansjorg Baezner MD, Martin Wiarda PsyD, Susanne Seip
RN; Copenhagen, Denmark (Copenhagen University Hospital:
Memory Disorders Research Unit, Department of Neurology,
Rigshopitalet, and the Danish Magnetic Resonance Research Centre,
Hvidovre Hospital): Gunhild Waldemar MD, DMSc, Egill
Rostrup MD, MSc, Charlotte Ryberg, Tim Dyrby; Newcastle-
upon-Tyne, UK (Institute for Ageing and Health, University of
Newcastle): John O’Brien DM, Sanjeet Pakrasi MRCPsych,
Thais Minnet PhD, Michael Firbank PhD, Jenny Dean PhD,
Pascale Harrison BSc, Philip English DCR.
The Coordinating centre is in Florence, Italy (Department of
Florence): Domenico Inzitari MD (Study Coordinator);
Leonardo Pantoni MD, PhD, Anna Maria Basile MD,
Martini MD, Luciano Bartolini PhD, Emilia Salvadori PhD,
Marco Moretti MD, Mario Mascalchi MD, PhD.
The LADIS Steering Committee is formed by Domenico
Inzitari MD (study coordinator), Timo Erkinjuntti MD,
PhD, Philip Scheltens MD, PhD, Marieke Visser MD, PhD,
and Kjell Asplund MD, PhD.
Pracucci MD, Monica
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NEUROLOGICAL PICTURE .............................................................................
Hemifacial spasm, neuralgia, and syncope due to cranial nerve compression in a patient with
vertebral artery ectasia
was followed by clusters of hemifacial
spasm and paroxysms of lancinating
pain located behind the left ear and
radiating to the ipsilateral eye, the
neck, or shoulder, was admitted for re-
evaluation due to additionally mani-
fested short lasting syncope-like epi-
sodes of increasing frequency. Beneath
a mild residual facial nerve palsy no
further focal findings were documented.
Extensive cardiologic workup revealed
only a positive tilt table test, indicating
an intense vagovasal reaction.
Re-evaluation of previously performed
imaging examinations focused on an
already angiographically described tortu-
ous course of the vetrebrobasilar arteries
(panel A), which compressed the left
lateral surface of the medulla, pons, and
pontomedullar junction, as also demon-
strated on MRI (panel B). Based on the
assumed an affection of the lower cranial
nerves and additionally performed ultra
thin MRI. In this way we could impress-
ivelydemonstrate a severe compression of
the proximal stem of thecranial nerves IX
and X (panel D), and the root entry zone
of the facial nerve on the left (panel C).
Owing to the escalation of symptoms the
patient underwent microvascular decom-
pressive surgery with interposition of a
muscle graft. Two years later she remains
asymptomatic. A repeated tilt table test
was this time negative.
This is an uncommon case of neuro-
vascular compression,1characterised by
known, however previously not in this
combination, described features such as
hemifacial spasms, variant glossophar-
yngeal neuralgia, and syncope,2–5which
all ceased after surgery.
Competing interests: none declared
42 year old woman with a history
of an incompletely remitted per-
ipheral left facial nerve palsy that
K Spengos, G Tsivgoulis, G Stouraitis,
Department of Neurology, University of Athens,
Encepahlos Diagnostic Institute, Athens, Greece
Department of Cardiology, Laikon Hospital,
Correspondence to: Dr Konstantinos Spengos,
Department of Neurology, University of Athens,
Vas. Sofias 82, 11528 Athens, Greece;
1 Yu YL, Moseley IF, Pullicino P, et al. The clinical
picture of ectasia of the intracerebral arteries.
J Neurol Neurosurg Psychiatry
2 Fukuda H, Ishikawa M, Okumura R.
Demonstration of neurovascular compression
in trigeminal neuralgia and hemifacial spasm
with magnetic resonance imaging: comparison
with surgical findings in 60 consecutive cases.
Surg Neurol 2003;59:93–9.
3 Bruyn GW. Glossopharyngeal neuralgia.
4 Ozenci M, Karaoguz R, Conkbayir C, et al.
Glossopharyngeal neuralgia with cardiac
syncope treated by glossopharyngeal rhizotomy
and microvascular decompression. Europace
5 Elias J, Kuniyoshi R, Carloni WV, et al.
Glossopharyngeal neuralgia associated with
cardiac syncope. Arq Bras Cardiol
(A) Superimposed projection of the digital subtraction angiograms of both vertebral arteries
demonstrates impressively the tortuous course of the vertebrobasilar vessels. (B) Axial T1-GRE
weighted MRI sequences demonstrating the tortuous course of both vertebral arteries and their
compressing effect on the left frontolateral surface of the pontomedullar junction, the pons, and the
cerebellar peduncles. (C) Frontal T1 weighted MRI slice showing the compressing effect of both
vertebral arteries (white arrow heads) on the root entry zone of the left facial nerve. (D) Ultra thin
(0.8 mm) M3D/FSE weighted MRI slice showing the direct contact between the vertebral artery
(black arrow head) and the IX/X cranial nerve (grey arrow).
1500 Flier, Straaten, Barkhof, et al