CADASILCADASIL

Mary Quiceno, M.D.Mary Quiceno, M.D.Clinical Assistant Professor Clinical Assistant Professor

Department of NeurologyDepartment of NeurologyUT Southwestern Medical UT Southwestern Medical

CenterCenter

Neuropathology report on Neuropathology report on NP36015NP36015

What is CADASIL?What is CADASIL?

CADASILCADASIL

Cerebral Autosomal Dominant Arteriopathy

with Subcortical Infarcts & Leuko-

encephalopathy

Inherited small vessel Inherited small vessel disease causing stroke and disease causing stroke and subcortical vascular subcortical vascular dementia that starts in dementia that starts in early adulthood and early adulthood and progresses over time. progresses over time.

This is a This is a nonatherosclerotic, nonatherosclerotic, nonamyloid angiopathy nonamyloid angiopathy involving small arteries involving small arteries and capillaries of the brain and capillaries of the brain and other organs.and other organs.

Caused by missense Caused by missense mutations in the Notch3 mutations in the Notch3 gene on chromosome gene on chromosome 19p13.19p13.

CADASILCADASIL 1977: family w/hereditary, multi-infarct 1977: family w/hereditary, multi-infarct

dementia syndromedementia syndrome Presents in mid-20s to age 45Presents in mid-20s to age 45 Stroke, dementia, migraine with aura, Stroke, dementia, migraine with aura,

mood disordersmood disorders Shortened life spanShortened life span

Most die by age 65Most die by age 65 Unknown prevalenceUnknown prevalence

400 families world-wide400 families world-wide 2/100,0002/100,000 Largely undiagnosedLargely undiagnosed

Case StudiesCase Studies

Most reported cases from EuropeMost reported cases from Europe 105 people from 33 affected families105 people from 33 affected families

Vascular risk factors are uncommonVascular risk factors are uncommon Mean age of initial symptom onset 36 Mean age of initial symptom onset 36

++ 12 years 12 years Migraine in 40% (28 Migraine in 40% (28 ++ 11 yrs) 11 yrs) Stroke/ TIA 43% (41 Stroke/ TIA 43% (41 ++ 9 yrs) 9 yrs) Depression 8%Depression 8% Cognitive decline 6%Cognitive decline 6% Seizure 3%Seizure 3%

overall, 67% had a TIA or strokeoverall, 67% had a TIA or stroke overall, 42% had dementiaoverall, 42% had dementia >30% with migraine w/aura and 15% w/mood >30% with migraine w/aura and 15% w/mood

d/od/o overall, age of death, in the 20% of the cohort overall, age of death, in the 20% of the cohort

that was deceased, was 54.8 that was deceased, was 54.8 ++ 10 years 10 years

Course is heterogeneous even in the same Course is heterogeneous even in the same family: some remain asymptomatic until their family: some remain asymptomatic until their 70s whereas others are severely affected by the 70s whereas others are severely affected by the age of 50.age of 50.

MIGRAINE with auraMIGRAINE with aura

Often initial featureOften initial feature 1/3 of families1/3 of families Occurs earlier as compared to stroke Occurs earlier as compared to stroke Consider CADASIL in migraineur Consider CADASIL in migraineur

with diffuse white matter lesions on with diffuse white matter lesions on MRIMRI Not small, scattered hyperintensities, Not small, scattered hyperintensities,

which can be seen in migraineurs (16%) which can be seen in migraineurs (16%) who don’t have CADASILwho don’t have CADASIL

STROKESTROKE TIAs and subcortical ischemic strokesTIAs and subcortical ischemic strokes Accumulating sensory, motor, and Accumulating sensory, motor, and

cognitive deficitscognitive deficits Most common featureMost common feature

Typical stroke risk factors NOT presentTypical stroke risk factors NOT present Cerebral non-atherosclerotic, Cerebral non-atherosclerotic,

nonamyloid angiopathynonamyloid angiopathy Primarily affecting small vessels that Primarily affecting small vessels that

penetrate white matter and basal penetrate white matter and basal gangliaganglia

MOOD DISORDERSMOOD DISORDERS

DepressionDepression Bipolar disorderBipolar disorder Like migraine, CADASIL should only Like migraine, CADASIL should only

be considered when MRI changes be considered when MRI changes are presentare present

Tend to predate cognitive declineTend to predate cognitive decline

Mood Disorders in an Mood Disorders in an affected familyaffected family

29 yr old son29 yr old son 44thth psychiatric hosp. psychiatric hosp.

admissionadmission Depression and Depression and

psychosispsychosis 52 yr old father52 yr old father

Migraines, strokeMigraines, stroke Antisocial and Antisocial and

withdrawnwithdrawn 72 yr old paternal 72 yr old paternal

grandmothergrandmother Depression at age 50Depression at age 50 Dementia at age 61Dementia at age 61

Frontal lobe Frontal lobe dysfunctiondysfunction

Retrieval deficitsRetrieval deficits

COGNITIVE DEFICITSCOGNITIVE DEFICITS

Slowly progressive in addition to stepwise Slowly progressive in addition to stepwise deteriorationdeterioration Typically appears after stroke symptoms appearTypically appears after stroke symptoms appear Can be presenting featureCan be presenting feature

Frontal lobe dysfunctionFrontal lobe dysfunction Memory impairmentMemory impairment Pseudobulbar palsy, gait disturbances, Pseudobulbar palsy, gait disturbances,

pyramidal signs, sphincter incontinencepyramidal signs, sphincter incontinence Subcortical dementia Vascular dementia

Cognitive profileCognitive profile

CADASIL compared to normalsCADASIL compared to normals Impaired on executive function and speed Impaired on executive function and speed

measuresmeasures Delis-Kaplan Executive Function System (D-KEFS)Delis-Kaplan Executive Function System (D-KEFS) Trails motor speed subtest from the D-KEFSTrails motor speed subtest from the D-KEFS

CADASIL w/stroke and cerebral small vessel CADASIL w/stroke and cerebral small vessel disease (SVD)disease (SVD)

SVD typically olderSVD typically older Both impaired similarly on executive fx and speedBoth impaired similarly on executive fx and speed CADASIL worse on verbal fluency (letter)CADASIL worse on verbal fluency (letter)

Executive FunctionExecutive Function refers to a wide range of central control processes in the brain that refers to a wide range of central control processes in the brain that

connect, prioritize, and integrate operation of subordinate brain connect, prioritize, and integrate operation of subordinate brain functionsfunctions

this central management system, often attributed to operations in the this central management system, often attributed to operations in the prefrontal cortex, is crucial to organizing and integrating cognitive prefrontal cortex, is crucial to organizing and integrating cognitive processes over time and plays an increasingly important role as we processes over time and plays an increasingly important role as we mature mature

organizes, activates, focuses, integrates, and directsorganizes, activates, focuses, integrates, and directs

Executive functions require several higher-level cognitive abilities for Executive functions require several higher-level cognitive abilities for successful performance.successful performance.

These can be assessed with tasks that require:These can be assessed with tasks that require: – – initiation of effortful and novel thinkinginitiation of effortful and novel thinking – – isolation of a common feature or attribute from among the array of target isolation of a common feature or attribute from among the array of target

stimulistimuli – – formation of a higher-level concept that captures the defining properties formation of a higher-level concept that captures the defining properties

of those common featuresof those common features – – flexibility of thinking in order to abandon one conceptual relationship in flexibility of thinking in order to abandon one conceptual relationship in

order to apprehend new onesorder to apprehend new ones

Other organ diseaseOther organ disease In some patients w/CADASILIn some patients w/CADASIL

silent retinal microvascular circulatory changes silent retinal microvascular circulatory changes 18 pts: No visual symptoms. VA was normal in all. 18 pts: No visual symptoms. VA was normal in all.

Ophthalmologic abnormalities were found in 8 patients. Ophthalmologic abnormalities were found in 8 patients. FE and FA revealed silent retinal abnormalities in CADASIL FE and FA revealed silent retinal abnormalities in CADASIL

patients with nerve fiber loss in 22% and cotton wool spots in patients with nerve fiber loss in 22% and cotton wool spots in 17%. 17%.

may be considered as peripheral markers of this genetic may be considered as peripheral markers of this genetic disease. disease.

high frequency of myocardial infarction in a single high frequency of myocardial infarction in a single series of Dutch patientsseries of Dutch patients

Distinct from CADASIL, hereditary Distinct from CADASIL, hereditary endotheliopathy with retinopathy, nephropathy, endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is an autosomal dominant and stroke (HERNS) is an autosomal dominant multi-infarct syndrome with systemic involvement. multi-infarct syndrome with systemic involvement.

Brain Imaging in Brain Imaging in CADASILCADASIL

Diffuse white matter hyperintensities on T2 Diffuse white matter hyperintensities on T2 and FLAIR weighted imagesand FLAIR weighted images Subcortical white matterSubcortical white matter Basal gangliaBasal ganglia

Changes on MRI may be evident in persons Changes on MRI may be evident in persons who are in their 20swho are in their 20s Penetrance complete by age 35 and all will have Penetrance complete by age 35 and all will have

MRI findingsMRI findings The syndrome may not be suspected until The syndrome may not be suspected until

affected individuals are in their 50s or olderaffected individuals are in their 50s or older Lesion volume is inversely correlated with Lesion volume is inversely correlated with

cognitive functioncognitive function

MRI ChangesMRI Changes

Axial FLAIR Axial FLAIR imagesimages

59 yr old woman59 yr old woman Multiple confluent Multiple confluent

hyperintensities in hyperintensities in deep and deep and periventricular periventricular white matterwhite matter

MRIMRI

Most specific finding Most specific finding to differentiate to differentiate CADASIL from CADASIL from ischemic ischemic leukoaraiosisleukoaraiosis

T2 hyperintenisties T2 hyperintenisties in anterior temporal in anterior temporal polepole

MRI in CADASIL w/characteristic MRI findings of involvement of the external capsule and anterior

temporal lobes.

Differentiating CADASIL Differentiating CADASIL from other diseases from other diseases

affecting the white matteraffecting the white matter Ischemic small-vessel disease Ischemic small-vessel disease

Usually occurs after fifth decadeUsually occurs after fifth decade Vascular risk factors presentVascular risk factors present

Multiple SclerosisMultiple Sclerosis More likely to see spinal cord and More likely to see spinal cord and

corpus callosum lesionscorpus callosum lesions Periventricular lesions are ovoid and/or Periventricular lesions are ovoid and/or

oriented perpendicular to lateral oriented perpendicular to lateral ventriclesventricles

When to consider MRI in When to consider MRI in migraineurmigraineur

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 When to Suspect CADASILCADASIL

Recurrent subcortical ischemic strokesRecurrent subcortical ischemic strokes Esp. <60 yrs oldEsp. <60 yrs old Esp. in absence of vascular risk factorsEsp. in absence of vascular risk factors

Early cognitive declineEarly cognitive decline Migraine with auraMigraine with aura Comorbid psychiatric symptomsComorbid psychiatric symptoms

DepressionDepression BipolarBipolar

When to Suspect When to Suspect CADASILCADASIL

Abnormal MRIAbnormal MRI Significant white matter lesions before age Significant white matter lesions before age

3535 Multiple T2 hyperintensities w/o vascular Multiple T2 hyperintensities w/o vascular

risk factorsrisk factors Bilateral T2 hyperintensities in white matter, Bilateral T2 hyperintensities in white matter,

esp. w/lesions in ant. Temporal polesesp. w/lesions in ant. Temporal poles Family historyFamily history

Stroke, dementia, depression, migraine w/aura, Stroke, dementia, depression, migraine w/aura, other white matter diseases (which may be other white matter diseases (which may be misdiagnosed)misdiagnosed)

Premature CADPremature CAD

Diagnostic ApproachDiagnostic Approach HistoryHistory MRI with involvement of anterior temporal poles MRI with involvement of anterior temporal poles OROR external capsule *** external capsule ***

&& Positive gene testing ***Positive gene testing ***

Sensitivity of 100% with Hx, MRI, & gene test in one Sensitivity of 100% with Hx, MRI, & gene test in one study from Englandstudy from England

BiopsyBiopsy

Skin biopsy was positive in approximately Skin biopsy was positive in approximately half of the 18 patients testedhalf of the 18 patients tested Skin biopsy was negative in all of the gene Skin biopsy was negative in all of the gene

negative patientsnegative patients Sensitivity of 100%Sensitivity of 100% Granular osmiophilic material seen on EMGranular osmiophilic material seen on EM

Sensitivity 50%, specificity 100%Sensitivity 50%, specificity 100% Tissue samples stained with monoclonal Ab top Tissue samples stained with monoclonal Ab top

Notch3 proteinNotch3 protein Sensitivity 96%, specificity 100%Sensitivity 96%, specificity 100%

The hallmark of the disease is the presence of The hallmark of the disease is the presence of granular osmiophilic material which is seen granular osmiophilic material which is seen adjacent to the basement membrane of the adjacent to the basement membrane of the smooth muscle cells of arterioles on electron smooth muscle cells of arterioles on electron microscopy. microscopy.

This is pathognomic for CADASIL. This is pathognomic for CADASIL. The deposition of GOM in skin arterioles may The deposition of GOM in skin arterioles may

vary depending on the exact mutation involved.vary depending on the exact mutation involved. The vascular defects are present in every tissue The vascular defects are present in every tissue

and may be detected histologically by examining and may be detected histologically by examining arterioles in skin biopsy, where accumulation of arterioles in skin biopsy, where accumulation of granular and osmiophilic material within the granular and osmiophilic material within the smooth muscle cell basement membrane and smooth muscle cell basement membrane and the surrounding extracellular matrix.the surrounding extracellular matrix.

Blood vessels in Blood vessels in CADASILCADASIL

w/ basophilic w/ basophilic granular material granular material (below)(below)

EM (to right)EM (to right)

Blood vessels in Blood vessels in CADASILCADASIL

2 types of changes in 2 types of changes in arteries, veins in bodyarteries, veins in body

1.1. Basophilic degeneration Basophilic degeneration and thickening of the and thickening of the media (top picture)media (top picture)

2.2. Fibrinoid necrosis of Fibrinoid necrosis of the media sometimes the media sometimes associated with delicate associated with delicate perivascular perivascular inflammatory infiltrates inflammatory infiltrates (bottom picture)(bottom picture)

Notch3 ab in brain blood Notch3 ab in brain blood vesselsvessels

Notch3 Notch3 immunoreactivity immunoreactivity in vascular smooth in vascular smooth muscle cells muscle cells

Normal controls on Normal controls on left (a, c, e)left (a, c, e)

CADASIL patients CADASIL patients on right (b, d, f)on right (b, d, f)

What leads to CADASIL?What leads to CADASIL? Mutations in Mutations in notch3notch3

genegene Odd number of Odd number of

cysteine residues in cysteine residues in Notch3 receptor Notch3 receptor extracellular domainextracellular domain

Impaired clearance of Impaired clearance of cleavage productcleavage product

Alterations of Alterations of vascular smooth vascular smooth musclemuscle

Presence of granular Presence of granular osmiophilic depositsosmiophilic deposits

Notch3 gene mutationNotch3 gene mutation

Usually missense mutationUsually missense mutation More than 50 have been foundMore than 50 have been found Spontaneous mutations have been Spontaneous mutations have been

describeddescribed The protein folds incorrectlyThe protein folds incorrectly Leads to accumulation of protein in Leads to accumulation of protein in

membranes of smooth muscles and, membranes of smooth muscles and, ultimately, fibrosis and luminal ultimately, fibrosis and luminal narrowing of themnarrowing of them

Notch3 geneNotch3 gene Mutation in Notch3 gene on Mutation in Notch3 gene on

chromosome 19chromosome 19 Just downstream from a Just downstream from a

mutation found in familial mutation found in familial hemiplegic migrainehemiplegic migraine

Notch 3 gene encodes a Notch 3 gene encodes a transmembrane receptortransmembrane receptor Functions in signaling Functions in signaling

pathways essential for pathways essential for maturation of blood vesselsmaturation of blood vessels

In adults, it is maximally In adults, it is maximally expressed in vascular smooth expressed in vascular smooth muscle in small to medium muscle in small to medium arteries arteries

Interaction of notch receptor Interaction of notch receptor with its ligand leads to cleavage with its ligand leads to cleavage of the transmembrane receptor of the transmembrane receptor which migrates into the nucleus which migrates into the nucleus and, associated with a and, associated with a transcription factor, activates transcription factor, activates transcription of primary target transcription of primary target genes. genes.

The notch in the The notch in the DrosophilaDrosophila wing wing

In fruit fly In fruit fly heterozygotes for heterozygotes for Notch3 gene have a Notch3 gene have a “notch” in their wing“notch” in their wing The mutation is lethal in The mutation is lethal in

homozygoteshomozygotes Notch proteinsNotch proteins

Encode transmembrane Encode transmembrane receptors involved in receptors involved in determination of cell determination of cell fate during developmentfate during development

Proliferation, Proliferation, differentiation, apoptosisdifferentiation, apoptosis

Pathogenic HypothesisPathogenic Hypothesis Notch 3 expression is limited to vascular Notch 3 expression is limited to vascular

smooth muscle cellssmooth muscle cells Mature vascular smooth muscle cells Mature vascular smooth muscle cells

require continued function of the Notch 3 require continued function of the Notch 3 pathwaypathway Continued survivalContinued survival

Blood vessels are narrowed and weak and Blood vessels are narrowed and weak and do not react to fluctuations of COdo not react to fluctuations of CO22 and BP and BP

Capillaries, veins are involvedCapillaries, veins are involved Generalized vasculopathyGeneralized vasculopathy

Brain PredilectionBrain Predilection

Cerebral vessels have fewer smooth Cerebral vessels have fewer smooth muscle cells than vessels of other muscle cells than vessels of other organsorgans Increased susceptibilityIncreased susceptibility

Limited ability for regeneration of Limited ability for regeneration of CNS tissueCNS tissue

White matter predilectionWhite matter predilection Insufficient collateral circulationInsufficient collateral circulation Density less than in grey matterDensity less than in grey matter

What can be done for these What can be done for these patients?patients?

TreatmentTreatment Control vascular disease risk factorsControl vascular disease risk factors

BPBP Increased SBP independent risk factor for Increased SBP independent risk factor for

progression of CADASILprogression of CADASIL CholesterolCholesterol DMDM SmokingSmoking ObesityObesity Avoid OCP, HRTAvoid OCP, HRT

TreatmentTreatment

Antiplatelet therapyAntiplatelet therapy Investigate for other causes of stroke Investigate for other causes of stroke

(cardiac, afib, hypercoag state, etc.)(cardiac, afib, hypercoag state, etc.) Cholinesterase inhibitorsCholinesterase inhibitors

Work in vascular dementiaWork in vascular dementia Screen for mood disorders, cognitive Screen for mood disorders, cognitive

decline, seizuredecline, seizure Life expectancy may be shortened by Life expectancy may be shortened by

6 years6 years

NP36015NP36015

The key findingThe key finding Abundant basophilic (blue on H&E), PAS Abundant basophilic (blue on H&E), PAS

positive, osmiophilic (black on EM) positive, osmiophilic (black on EM) granular material seen in the markedly granular material seen in the markedly thickened blood vessel wallsthickened blood vessel walls

Differential diagnosisDifferential diagnosis Atheroscerotic diseaseAtheroscerotic disease

Blood vessel walls are also thickenedBlood vessel walls are also thickened Granular material is not usually present (if Granular material is not usually present (if

present, it differs from that seen in CADASIL)present, it differs from that seen in CADASIL)

No treatmentNo treatment Screening not indicated, unless family Screening not indicated, unless family

member is affectedmember is affected Family may wish to seek genetic Family may wish to seek genetic

counselingcounseling Control vascular risk factorsControl vascular risk factors Do not smokeDo not smoke Screen for mood disorders, cognitive Screen for mood disorders, cognitive

decline, focal neurologic signs, seizuredecline, focal neurologic signs, seizure

Questions?Questions?