CADASIL is a rare inherited small vessel disease caused by mutations in the Notch3 gene. It results in stroke and subcortical vascular dementia starting in early adulthood. Characteristic features include migraine with aura, mood disorders, and diffuse white matter lesions on MRI, particularly involving the anterior temporal poles and external capsule. Over time, patients experience stepwise cognitive and physical decline due to recurrent strokes. There is currently no cure or treatment to slow progression, so management focuses on controlling vascular risk factors and screening for complications.

1. CADASIL
Mary Quiceno, M.D.
Clinical Assistant Professor
Department of Neurology
UT Southwestern Medical Center

2. Neuropathology report on NP36015
What is CADASIL?

3. CADASIL
 Cerebral
 Autosomal
Dominant
 Arteriopathy with
 Subcortical
Infarcts &
 Leuko-
encephalopathy
 Inherited small vessel disease
causing stroke and
subcortical vascular dementia
that starts in early adulthood
and progresses over time.
 This is a nonatherosclerotic,
nonamyloid angiopathy
involving small arteries and
capillaries of the brain and
other organs.
 Caused by missense
mutations in the Notch3
gene on chromosome 19p13.

4. 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

5. 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%

6.  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.

7. 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

8. 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

9. MOOD DISORDERS
 Depression
 Bipolar disorder
 Like migraine, CADASIL should only be
considered when MRI changes are present
 Tend to predate cognitive decline

10. Mood Disorders in an affected family
 29 yr old son
 4th psychiatric hosp. admission
 Depression and psychosis
 52 yr old father
 Migraines, stroke
 Antisocial and withdrawn
 72 yr old paternal
grandmother
 Depression at age 50
 Dementia at age 61
 Frontal lobe dysfunction
 Retrieval deficits

11. 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

12. 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)

13. 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

14. 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.

15. 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

16. MRI Changes
 Axial FLAIR images
 59 yr old woman
 Multiple confluent
hyperintensities in deep
and periventricular white
matter

17. MRI
 Most specific finding to
differentiate CADASIL
from ischemic
leukoaraiosis
 T2 hyperintenisties in
anterior temporal pole

18. MRI in CADASIL w/characteristic MRI findings of involvement of the
external capsule and anterior temporal lobes.

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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%

25.  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.

26. Blood vessels in CADASIL
 w/ basophilic granular
material (below)
 EM (to right)

27. 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)

28. 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)

29. 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

30. 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

31. 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.

32. 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

33. 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 CO2 and BP
 Capillaries, veins are involved
 Generalized vasculopathy

34. 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

35. 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

36. 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

37. 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)

38.  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

39. Questions?