CADASIL

Mary Quiceno, M.D.

Clinical Assistant Professor
Department of Neurology
UT Southwestern Medical
Center
Neuropathology report on
NP36015

What is CADASIL?
 CADASIL
Inherited small vessel
 Cerebral 
disease causing stroke and
 Autosomal subcortical vascular
dementia that starts in
Dominant early adulthood and
progresses over time.
 Arteriopathy with  This is a nonatherosclerotic,
nonamyloid angiopathy
 Subcortical involving small arteries and
capillaries of the brain and
Infarcts & other organs.
 Caused by missense
 Leuko- mutations in the Notch3
encephalopathy gene on chromosome
19p13.
 CADASIL
 1977: family w/hereditary, multi-infarct
dementia syndrome
 Presents in mid-20s to age 45
 Stroke, dementia, migraine with aura, mood
disorders
 Shortened life span
 Most die by age 65
 Unknown prevalence
 400 families world-wide
 2/100,000
 Largely undiagnosed
 Case Studies
 Most reported cases from Europe
 105 people from 33 affected families
 Vascular risk factors are uncommon
 Mean age of initial symptom onset 36 +
12 years
 Migraine in 40% (28 + 11 yrs)
 Stroke/ TIA 43% (41 + 9 yrs)
 Depression 8%
 Cognitive decline 6%
 Seizure 3%
 overall, 67% had a TIA or stroke
 overall, 42% had dementia
 >30% with migraine w/aura and 15% w/mood d/o
 overall, age of death, in the 20% of the cohort
that was deceased, was 54.8 + 10 years

 Course is heterogeneous even in the same family:

some remain asymptomatic until their 70s
whereas others are severely affected by the age
of 50.
 MIGRAINE with aura
 Often initial feature
 1/3 of families
 Occurs earlier as compared to stroke
 Consider CADASIL in migraineur with
diffuse white matter lesions on MRI
 Not small, scattered hyperintensities,
which can be seen in migraineurs (16%)
who don’t have CADASIL
 STROKE
 TIAs and subcortical ischemic strokes
 Accumulating sensory, motor, and
cognitive deficits
 Most common feature
 Typical stroke risk factors NOT present
 Cerebral non-atherosclerotic,
nonamyloid angiopathy
 Primarily affecting small vessels that
penetrate white matter and basal
ganglia
 MOOD DISORDERS
 Depression
 Bipolar disorder
 Like migraine, CADASIL should only
be considered when MRI changes
are present
 Tend to predate cognitive decline
 Mood Disorders in an
affected family
 29 yr old son  Frontal lobe
 4th psychiatric hosp. dysfunction
admission
 Depression and psychosis
 52 yr old father
 Retrieval deficits
 Migraines, stroke
 Antisocial and withdrawn
 72 yr old paternal
grandmother
 Depression at age 50
 Dementia at age 61
 COGNITIVE DEFICITS
 Slowly progressive in addition to stepwise
deterioration
 Typically appears after stroke symptoms appear
 Can be presenting feature
 Frontal lobe dysfunction
 Memory impairment
 Pseudobulbar palsy, gait disturbances,
pyramidal signs, sphincter incontinence
 Subcortical dementia
 Vascular dementia
 Cognitive profile
 CADASIL compared to normals
 Impaired on executive function and speed
measures
 Delis-Kaplan Executive Function System (D-KEFS)
 Trails motor speed subtest from the D-KEFS

 CADASIL w/stroke and cerebral small vessel

disease (SVD)
 SVD typically older
 Both impaired similarly on executive fx and speed

 CADASIL worse on verbal fluency (letter)

 Executive Function
 refers to a wide range of central control processes in the brain that
connect, prioritize, and integrate operation of subordinate brain
functions

 this central management system, often attributed to operations in the

prefrontal cortex, is crucial to organizing and integrating cognitive
processes over time and plays an increasingly important role as we
mature

 organizes, activates, focuses, integrates, and directs

 Executive functions require several higher-level cognitive abilities for

successful performance.

 These can be assessed with tasks that require:

 – initiation of effortful and novel thinking
 – isolation of a common feature or attribute from among the array of target
stimuli
 – formation of a higher-level concept that captures the defining properties of
those common features
 – flexibility of thinking in order to abandon one conceptual relationship in
order to apprehend new ones
 Other organ disease
 In some patients w/CADASIL
 silent retinal microvascular circulatory changes
 18 pts: No visual symptoms. VA was normal in all.
Ophthalmologic abnormalities were found in 8 patients.
 FE and FA revealed silent retinal abnormalities in CADASIL
patients with nerve fiber loss in 22% and cotton wool spots in
17%.
 may be considered as peripheral markers of this genetic disease.
 high frequency of myocardial infarction in a single series
of Dutch patients
 Distinct from CADASIL, hereditary
endotheliopathy with retinopathy, nephropathy,
and stroke (HERNS) is an autosomal dominant
multi-infarct syndrome with systemic involvement.
 Brain Imaging in
CADASIL
 Diffuse white matter hyperintensities on T2
and FLAIR weighted images
 Subcortical white matter
 Basal ganglia
 Changes on MRI may be evident in persons
who are in their 20s
 Penetrance complete by age 35 and all will have
MRI findings
 The syndrome may not be suspected until affected
individuals are in their 50s or older
 Lesion volume is inversely correlated with
cognitive function
MRI Changes
 Axial FLAIR
images
 59 yr old woman
 Multiple confluent
hyperintensities in
deep and
periventricular
white matter
MRI

 Most specific finding

to differentiate
CADASIL from
ischemic
leukoaraiosis

 T2 hyperintenisties
in anterior temporal
pole
MRI in CADASIL w/characteristic MRI findings of
involvement of the external capsule and anterior
temporal lobes.
 Differentiating CADASIL
from other diseases
affecting the white matter
 Ischemic small-vessel disease
 Usually occurs after fifth decade
 Vascular risk factors present

 Multiple Sclerosis
 More likely to see spinal cord and
corpus callosum lesions
 Periventricular lesions are ovoid and/or
oriented perpendicular to lateral
ventricles
 When to consider MRI in
migraineur
 Consider MRI if
 Migraine attacks with aura begin in
mid-adulthood
 Atypical aura
 Hemiplegic, basilar, prolonged
 Family history of stroke, dementia,
depression
 Focal neurological signs
 When to Suspect
CADASIL
 Recurrent subcortical ischemic strokes
 Esp. <60 yrs old
 Esp. in absence of vascular risk factors
 Early cognitive decline
 Migraine with aura
 Comorbid psychiatric symptoms
 Depression
 Bipolar
 When to Suspect
CADASIL
 Abnormal MRI
 Significant white matter lesions before age 35
 Multiple T2 hyperintensities w/o vascular risk
factors
 Bilateral T2 hyperintensities in white matter,
esp. w/lesions in ant. Temporal poles
 Family history
 Stroke, dementia, depression, migraine w/aura, other
white matter diseases (which may be misdiagnosed)
 Premature CAD
 Diagnostic Approach
 History
 MRI with involvement of anterior temporal poles
OR external capsule ***
&
 Positive gene testing ***
 Sensitivity of 100% with Hx, MRI, & gene test in one
study from England
 Biopsy
 Skin biopsy was positive in approximately
half of the 18 patients tested
 Skin biopsy was negative in all of the gene
negative patients
 Sensitivity of 100%
 Granular osmiophilic material seen on EM
 Sensitivity 50%, specificity 100%
 Tissue samples stained with monoclonal Ab top
Notch3 protein
 Sensitivity 96%, specificity 100%
 The hallmark of the disease is the presence of
granular osmiophilic material which is seen
adjacent to the basement membrane of the
smooth muscle cells of arterioles on electron
microscopy.
 This is pathognomic for CADASIL.
 The deposition of GOM in skin arterioles may
vary depending on the exact mutation involved.
 The vascular defects are present in every tissue
and may be detected histologically by examining
arterioles in skin biopsy, where accumulation of
granular and osmiophilic material within the
smooth muscle cell basement membrane and the
surrounding extracellular matrix.
 Blood vessels in
CADASIL
 w/ basophilic
granular material
(below)
 EM (to right)
 Blood vessels in
CADASIL
 2 types of changes in
arteries, veins in body
1. Basophilic degeneration
and thickening of the
media (top picture)
2. Fibrinoid necrosis of
the media sometimes
associated with delicate
perivascular
inflammatory infiltrates
(bottom picture)
Notch3 ab in brain blood
vessels
 Notch3
immunoreactivity
in vascular smooth
muscle cells
 Normal controls on
left (a, c, e)
 CADASIL patients
on right (b, d, f)
 What leads to CADASIL?
 Mutations in notch3
gene
 Odd number of
cysteine residues in
Notch3 receptor
extracellular domain
 Impaired clearance of
cleavage product
 Alterations of
vascular smooth
muscle
 Presence of granular
osmiophilic deposits
 Notch3 gene mutation
 Usually missense mutation
 More than 50 have been found
 Spontaneous mutations have been
described
 The protein folds incorrectly
 Leads to accumulation of protein in
membranes of smooth muscles and,
ultimately, fibrosis and luminal
narrowing of them
 Notch3 gene
 Mutation in Notch3 gene on
chromosome 19
 Just downstream from a
mutation found in familial
hemiplegic migraine
 Notch 3 gene encodes a
transmembrane receptor
 Functions in signaling
pathways essential for
maturation of blood vessels
 In adults, it is maximally
expressed in vascular smooth
muscle in small to medium
arteries
 Interaction of notch receptor with
its ligand leads to cleavage of the
transmembrane receptor which
migrates into the nucleus and,
associated with a transcription
factor, activates transcription of
primary target genes.
The notch in the
Drosophila wing
 In fruit fly
heterozygotes for
Notch3 gene have a
“notch” in their wing
 The mutation is lethal
in homozygotes
 Notch proteins
 Encode transmembrane
receptors involved in
determination of cell
fate during
development
 Proliferation,
differentiation, apoptosis
 Pathogenic Hypothesis
 Notch 3 expression is limited to vascular
smooth muscle cells
 Mature vascular smooth muscle cells
require continued function of the Notch 3
pathway
 Continued survival
 Blood vessels are narrowed and weak and
do not react to fluctuations of CO 2 and BP
 Capillaries, veins are involved
 Generalized vasculopathy
 Brain Predilection
 Cerebral vessels have fewer smooth
muscle cells than vessels of other
organs
 Increased susceptibility
 Limited ability for regeneration of CNS
tissue
 White matter predilection
 Insufficient collateral circulation
 Density less than in grey matter
What can be done for these
patients?
 Treatment
 Control vascular disease risk factors
 BP
 Increased SBP independent risk factor for
progression of CADASIL
 Cholesterol
 DM

 Smoking

 Obesity

 Avoid OCP, HRT

 Treatment
 Antiplatelet therapy
 Investigate for other causes of stroke
(cardiac, afib, hypercoag state, etc.)
 Cholinesterase inhibitors
 Work in vascular dementia
 Screen for mood disorders, cognitive
decline, seizure
 Life expectancy may be shortened by 6
years
 NP36015
 The key finding
 Abundant basophilic (blue on H&E), PAS
positive, osmiophilic (black on EM)
granular material seen in the markedly
thickened blood vessel walls
 Differential diagnosis
 Atheroscerotic disease
 Blood vessel walls are also thickened
 Granular material is not usually present (if
present, it differs from that seen in CADASIL)
 No treatment
 Screening not indicated, unless family
member is affected
 Family may wish to seek genetic
counseling
 Control vascular risk factors
 Do not smoke
 Screen for mood disorders, cognitive
decline, focal neurologic signs, seizure
Questions?