Current Topics in Care

Detection of Early Cognitive Impairment
Using AD8 in a Young Patient With Stroke
With Cerebral Autosomal Dominant
Arteriopathy With Subcortical Infarcts
and Leukoencephalopathy Syndrome:
A Case Report

American Journal of Alzheimer’s
Disease & Other Dementias®
2014, Vol. 29(2) 133-137
ª The Author(s) 2013
Reprints and permission:
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DOI: 10.1177/1533317513511289
aja.sagepub.com

I-Chieh Hsieh, MD1, Ta-Shen Kuan, MD, MSc1,2,
Pei-Chun Hsieh, MD1, Shu-Min Chen, MD1, Wei-Jang Yen, MD1,
Wen-Chen Chang, MD1, I-Ling Lin, BSc, MSc4,
and Yu-Ching Lin, MD, MSc1,2,3

Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome is a
hereditary disease resulting from NOTCH3 gene mutation. The clinical presentations include migraine, recurrent stroke, and
cognitive impairment. The severity of cognitive impairment varies in different stages, and early recognition poses a challenge. A
47-year-old lady presented with chronic migraine and sudden onset of hemiparesis. Magnetic resonance imaging revealed compatible findings of CADASIL, which was confirmed by mutation analysis of NOTCH3 gene. Early cognitive impairment was detected
by her score of 3 in Ascertain Dementia 8 (AD8) questionnaire and confirmed by detailed neuropsychological assessments. After
21 months of follow-up, deterioration in her cognition and ability to perform instrumental activities of daily living were significant
with a follow-up AD8 score of 7. Ascertain Dementia 8 questionnaire is an easy and valid screening tool for early cognitive impairment in patients with CADASIL syndrome.
Keywords
young stroke, cognitive impairment, CADASIL syndrome, AD8

Introduction
Cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) syndrome is an
inherited small vessel disease that is caused by mutation of
NOTCH3 gene.1,2 In CADASIL, the arterioles penetrating to the
cortex have vessel wall thickening and lumen stenosis which
compromise circulation of cortex. As a result, the individual who
carried mutated NOTCH3 gene would easily have cerebral
infarcts with periventricular white matter change that mimics
hypertensive encephalopathy.3 The clinical manifestations of
patients with CADASIL syndrome are characterized by
migraine with or without aura, recurrent ischemic stroke, cognitive impairment, and even dementia.1,2 Cognitive impairment is
the second most common manifestation in CADASIL syndrome.1 Early and recurrent stroke with cognitive impairment
in CADASIL may lead to dementia eventually,4 and about
60% of the patients with CADASIL with stroke become demented after 60 years.2 Even in the patients with CADASIL who had

not experienced stroke, there was evidence of deficits in shortterm memory and working memory.5 The spectrum of cognitive
impairment in CADASIL has been documented, including
pronounced impairment in processing speed and error

1
Department of Physical Medicine and Rehabilitation, National Cheng Kung
University Hospital, College of Medicine, National Cheng Kung University,
Tainan, Taiwan
2
Department of Physical Medicine and Rehabilitation, College of Medicine,
National Cheng Kung University, Tainan, Taiwan
3
Medical Device Innovation Center, National Cheng Kung University, Tainan,
Taiwan
4
Department of Medical Laboratory Sciences and Biotechnology, Kaohsiung
Medical University, Kaohsiung, Taiwan

Corresponding Author:
Yu-Ching Lin, MD, MSc, Department of Physical Medicine and Rehabilitation,
National Cheng Kung University Hospital, College of Medicine, National Cheng
Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan.
Email: richelin@mail.ncku.edu.tw

134
monitoring4 as well as alterations in visuospatial abilities, memory, attention, and executive function.6 In the patients older than
60 years of age, cognitive impairment will be more profound in
all domains, while cognitive impairment in younger patients,
especially those less than 50 years old, might begin with abnormal executive functions, including alterations in attention and
memory, difficulties in organizing daily activities and thoughts,
prioritizing tasks, and decision making.6 Some patients also had
mood problems, that is, depression or apathy.1,2 Because cognitive impairment is usually insidious as compared to more localized symptoms associated with ischemic stroke, it poses a
special challenge to detect the occurrence of neuropsychological
decline of the patients.
For patients with Alzheimer’s disease, the Ascertain Dementia 8 (AD8) questionnaire7 has been used to detect very mild
dementia in the Western and Asian populations.7-11 It queries
memory, orientation, judgment, and function with 8 questions,
and both informant-rated AD8 (iAD8) and participant-rated
AD8 (pAD8) could be used easily in the primary care setting.12
When using cutoff score of 2 in iAD8 and 1 in pAD8, both iAD8
and pAD8 reliably differentiate nondemented individuals from
individuals with dementia at the very mild stage,7-11 and iAD8
seems a relatively good discriminative tool in differentiating
between mild Alzheimer’s disease and moderate-to-severe
Alzheimer’s disease.11 There were no published data using
AD8 in patients with CADASIL syndrome in the literature.
Here, we reported a case of CADASIL syndrome with early
cognitive impairment detected by AD8 questionnaire but not
by conventional Mini-Mental State Examination (MMSE).

Case Report
A 47-year-old female, a senior high school graduate and a vendor selling betel nuts for living, presented with migraine for
8 years with visual aura. She was admitted due to sudden onset
of left hemiparesis along with numbness over left face, trunk,
and limbs in March 2011. She had body mass index of 19.2 and
had no previous history of hypertension or diabetes mellitus.
Positive family history of stroke (maternal grandfather and
grandmother) as well as family history of young stroke at
age of 40s (mother, maternal uncle, and aunt) was present. The
brain magnetic resonance imaging (MRI) of T2-weighted
and axial fluid-attenuated inversion recovery images revealed
diffuse hyperintensity of white matter at periventricular
and subcortical areas, in particular at both temporal lobes and
frontoparietal regions (Figure 1A). The characteristic clinical
and neuroimaging findings suggest the diagnosis of CADASIL.
Mutation analysis of the NOTCH3 gene revealing a missense
mutation of 406C>T (R110C) in exon 3 confirmed the diagnosis. Of note, she was the first diagnosed case in her family.
She was transferred to rehabilitation ward for further
training due to first-ever ischemic stroke. During admission,
we paid special attention to her symptoms of memory loss and
cognitive impairment, since insidious decline in cognition usually happens to patients with CADASIL. Before the ischemic
event, she still could work without problems in cash deal with

American Journal of Alzheimer’s Disease & Other Dementias® 29(2)
customers. In recent months, even the patient herself did not
have any subjective cognitive complaint; some odd behavior
and poor memory had been noticed by her husband. She sometimes gave irrelevant answers to questions, and she lost interest
in her previous hobby including dancing gradually. Initial
screening with MMSE13 (score of 28) failed to show the evidence of dementia. The iAD8 questionnaire7 was then used for
screening. The score of 3, slightly above the cutoff value of 2,
indicates that she had prodromal stage of dementia as well as
mild cognitive impairment. The endorsement of each question
was as follows: question 2: reduced interest in hobbies/activities, question 7: trouble remembering appointments, and
question 8: consistent problems with thinking and/or memory.
Several detailed neuropsychological assessments were further exercised. She had poor short-term memory with Digit
Span Test,14 which included backward test (her score of 5 of
14) and forward test (her score of 13 of 16). Impairment in
visual conceptual and visuomotor tracking was also demonstrated by Trail Making Test,15 particularly with excessive time
consumed in timed tasks (type A/type B, processing time: 220s/
348s, errors: 0/1). Moreover, the Knox’s Cube Imitation Test16
revealed forward score of 9 and backward score of 3, showing
that her ability to accomplish the number sequences equaled to
the performance of a 7-year-old children. In Wisconsin Card
Sorting Test,17 we observed that no specific matching rule is
followed when she matched response cards to key cards. When
performing card sorting with a total of 128 cards, the number of
psychometric scores obtained was as follows: total errors of 65
cards, perservation response 56 times, perservation errors 49
times, and nonperservation errors 16 times. The percentile
norms in both perservation response and perservation errors
were below first percentile. All of the above-mentioned tests
confirmed cognitive impairment of the present case.
During 21 months of follow-up, additional symptoms of
emotional problems, childish personality change, and poor
social skills gradually appeared. She could not perform daily
household activities as she did before. She closed the stall due
to frequent faults in cash deal. The follow-up MMSE score of
25 and informant AD8 score of 7 suggested decline in her
cognitive function. This time only the question 5: ‘‘Forgets
correct month or year’’ in the informant AD8 questionnaire was
adequately answered. The brain MRI also revealed deterioration of white matter lesions compared with 1 of the 21 months
before, especially at periventricular area and frontoparietal
lobes (Figure 1B).

Discussion
The characteristics of CADASIL syndrome include a history of
migraine headaches, midadult onset of cerebrovascular disease
progressing to dementia, and diffuse white matter lesions and
subcortical infarcts on neuroimaging.1,2 The histopathological
feature of CADASIL is the presence of electron-dense granules
in the media of arterioles that can be identified by electron
microscopy of the skin biopsies. More than 90% of patients
have mutations in NOTCH3, the only gene known to be

Hsieh et al

135

Figure 1. MRI FLAIR imaging demonstrates (A) white matter hyperintensity involving bilateral temporal lobes, frontoparietal lobes, and
periventricular areas, and (B) deterioration of white matter hyperintensity after 21 months of follow-up, especially at both periventricular areas
and frontoparietal lobe. FLAIR indicates fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

associated with CADASIL.1,2 Differential diagnosis for
CADASIL is wide and includes sporadic small vessel disease
such as Binswanger’s disease, hereditary small vessel diseases,
multiple sclerosis, mitochondrial encephalopathy, and familial
hemiplegic migraine. Our patient is normotensive, and the
results of her neurological image study and mutation analysis
could help reach the diagnosis.
The AD8 questionnaire is developed as a quick screening tool
for early diagnosis of dementia in the primary care setting.7 The
AD8 scores correlated well with the MMSE and Clinical
Dementia Rating18 to assess cognitive functions in dementia.7-11
In Asian population, the use of AD8 questionnaire shows
minimal limitation due to ethnicity.9-11 In a Taiwanese study,
informant-rated AD8 questionnaire yield a sensitivity of 97.6%
and a specificity of 78.1% with a cutoff value of 2.10 In the
present case, although MMSE score of 28 indicates no cognitive
deficits, her iAD8 score of 3 reveals early impairment of cognition. In the first AD8 scores of our patient, the endorsement of
the questions was question 7: trouble remembering appointments
and question 8: consistent problems with thinking and/or
memory. These 2 questions were mainly related to decline in
short-term memory. The other one was question 2: reduced interest in hobbies/activities, which would remind us that she might
have apathy, mood disturbance, or depression, which is also a
characteristic manifestation in patients with CADASIL.1 Once
there is no accompanying informant, AD8 questionnaire could
also be participant rated. However, the utility of pAD8 may be
greater in patients with very mild cognitive impairment, since

patients with more severe dementia may be unaware of their
symptoms.8,11 Our case report is the first one to use AD8
questionnaire for detecting mild cognitive impairment in
patients with CADASIL and in facilitating standardized neuropsychological evaluation and thus early intervention.
Several cognitive screening measures are currently in use,
some of those are performance based, like MMSE and
Montreal Cognitive Assessment (MoCA),19 and others are informant based, including Functional Activity Questionnaire
(FAQ)20 and the AD8 questionnaire.12 The widely used MMSE
is a useful global assessment of cognition in mild-to-moderate
dementia but it may be culturally insensitive and may fail to
identify very mild dementia in high-functioning individuals.21,22
Montreal Cognitive Assessment, which addresses decline in
frontal and executive function, is a 10-minute screening tool for
early-stage cognitive impairment and is sensitive in detecting
mild dementia in patients with normal scores of MMSE.23 On
the other hand, FAQ, an informant-based functional assessment
with only 10 questions, is developed from the instrumental activity of daily living (IADL) scale.12 As a standardized assessment
of IADL, FAQ also help distinguish mild cognitive impairment
from mild Alzheimer’s disease.24 Although it works well in
different ethnicity,25,26 the application of this questionnaire on
Asian population is still lacking. Also, the cultural factors that
may influence scores are not studied intensively yet.26
These cognitive deficits in CADASIL can be detected by
some standardized neuropsychological assessments such as
Trail Making Test, Digital Span Test, Knox’s Cube Imitation

136
Test, and Wisconsin Card Sorting Test.4,6 Trail Making Test
type A and Digit Span Forwards Test can reflect attention span
and temporary memory storage abilities.27 Trail Making Test
type B and Digit Span Backwards Test are more related to
higher executive functions.27 The performance of Trail Making
Test and Digit Span Test is thought to be sensitive to brain
damage.27 The Knox’s Cube Imitation Test is a nonverbal test
of intelligence, with satisfactory reliability in attention, concentration, and executive efficiency.28 The Wisconsin Card
Sorting Test is another test particularly sensitive to changes
in executive performances, especially frontal lobe damages.29-31 The Digit Span Test, Trail Making Test, and Knox’s
Cube Imitation Test revealed her cognitive impairment in
processing speed, attention, memory, visuospatial abilities, and
executive functions, while the Wisconsin Card Sorting Test
indicated that she had disturbed strategy and deficits in her
executive functions, abstract thinking, and planning skill as she
completed the tasks. These findings are consistent with
previous reports of CADASIL.4,6 However, these standardized
neuropsychological assessments are time consuming and are
not routinely used by physicians in daily practice.
Mild cognitive deficits may have vital influences on activities
of daily livings and social life. Intervention for early cognitive
impairment may help intrinsic neuroplasticity and improve outcome.32 Patients with CADASIL may not be aware of their
cognitive deficits until the symptoms become obvious. We suggest routine screening for the mild cognitive impairment with the
AD8 questionnaire in patients with suspected CADASIL
syndrome.

Conclusions
Our case shows that cognitive impairment may appear very
early without cognitive complaints in patient with CADASIL.
We suggest that in young patients with migraine and recurrent
ischemic strokes, the possibility of CADASIL syndrome
should be considered, and an easy and valid screening test such
as the AD8 questionnaire may be exercised promptly before
standardized neuropsychological assessments.
Author’s Note
I-Ling Lin and Yu-Ching Lin contributed equally to this work. No
previous presentation of this manuscript or abstract is given in any
form. All authors have read the final manuscript draft and approved
it for submission.

Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.

Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.

American Journal of Alzheimer’s Disease & Other Dementias® 29(2)
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