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

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Presentation on theme: "CADASIL Mary Quiceno, M.D. Clinical Assistant Professor Department of Neurology UT Southwestern Medical Center."— Presentation transcript:

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 1977: family w/hereditary, multi-infarct dementia syndrome Presents in mid-20s to age 45 Presents in mid-20s to age 45 Stroke, dementia, migraine with aura, mood disorders Stroke, dementia, migraine with aura, mood disorders Shortened life span Shortened life span Most die by age 65 Most die by age 65 Unknown prevalence Unknown prevalence 400 families world-wide 400 families world-wide 2/100,000 2/100,000 Largely undiagnosed Largely undiagnosed

5 Case Studies Most reported cases from Europe Most reported cases from Europe 105 people from 33 affected families 105 people from 33 affected families Vascular risk factors are uncommon Vascular risk factors are uncommon Mean age of initial symptom onset years Mean age of initial symptom onset years Migraine in 40% ( yrs) Migraine in 40% ( yrs) Stroke/ TIA 43% ( yrs) Stroke/ TIA 43% ( yrs) Depression 8% Depression 8% Cognitive decline 6% Cognitive decline 6% Seizure 3% Seizure 3%

6 overall, 67% had a TIA or stroke overall, 67% had a TIA or stroke overall, 42% had dementia overall, 42% had dementia >30% with migraine w/aura and 15% w/mood d/o >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 years overall, age of death, in the 20% of the cohort that was deceased, was 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. 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 Often initial feature 1/3 of families 1/3 of families Occurs earlier as compared to stroke Occurs earlier as compared to stroke Consider CADASIL in migraineur with diffuse white matter lesions on MRI 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 Not small, scattered hyperintensities, which can be seen in migraineurs (16%) who don’t have CADASIL

8 STROKE TIAs and subcortical ischemic strokes TIAs and subcortical ischemic strokes Accumulating sensory, motor, and cognitive deficits Accumulating sensory, motor, and cognitive deficits Most common feature Most common feature Typical stroke risk factors NOT present Typical stroke risk factors NOT present Cerebral non-atherosclerotic, nonamyloid angiopathy Cerebral non-atherosclerotic, nonamyloid angiopathy Primarily affecting small vessels that penetrate white matter and basal ganglia Primarily affecting small vessels that penetrate white matter and basal ganglia

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

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

11 COGNITIVE DEFICITS Slowly progressive in addition to stepwise deterioration Slowly progressive in addition to stepwise deterioration Typically appears after stroke symptoms appear Typically appears after stroke symptoms appear Can be presenting feature Can be presenting feature Frontal lobe dysfunction Frontal lobe dysfunction Memory impairment Memory impairment Pseudobulbar palsy, gait disturbances, pyramidal signs, sphincter incontinence Pseudobulbar palsy, gait disturbances, pyramidal signs, sphincter incontinence Subcortical dementia Vascular dementia

12 Cognitive profile CADASIL compared to normals CADASIL compared to normals Impaired on executive function and speed measures Impaired on executive function and speed measures Delis-Kaplan Executive Function System (D-KEFS) Delis-Kaplan Executive Function System (D-KEFS) Trails motor speed subtest from the D-KEFS Trails motor speed subtest from the D-KEFS CADASIL w/stroke and cerebral small vessel disease (SVD) CADASIL w/stroke and cerebral small vessel disease (SVD) SVD typically older SVD typically older Both impaired similarly on executive fx and speed Both impaired similarly on executive fx and speed CADASIL worse on verbal fluency (letter) 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 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 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 organizes, activates, focuses, integrates, and directs Executive functions require several higher-level cognitive abilities for successful performance. Executive functions require several higher-level cognitive abilities for successful performance. These can be assessed with tasks that require: These can be assessed with tasks that require: – initiation of effortful and novel thinking – initiation of effortful and novel thinking – isolation of a common feature or attribute from among the array of target stimuli – 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 – 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 – 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 In some patients w/CADASIL silent retinal microvascular circulatory changes silent retinal microvascular circulatory changes 18 pts: No visual symptoms. VA was normal in all. Ophthalmologic abnormalities were found in 8 patients. 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%. 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. may be considered as peripheral markers of this genetic disease. high frequency of myocardial infarction in a single series of Dutch patients 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. 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 Diffuse white matter hyperintensities on T2 and FLAIR weighted images Subcortical white matter Subcortical white matter Basal ganglia Basal ganglia Changes on MRI may be evident in persons who are in their 20s Changes on MRI may be evident in persons who are in their 20s Penetrance complete by age 35 and all will have MRI findings 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 The syndrome may not be suspected until affected individuals are in their 50s or older Lesion volume is inversely correlated with cognitive function 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 Ischemic small-vessel disease Usually occurs after fifth decade Usually occurs after fifth decade Vascular risk factors present Vascular risk factors present Multiple Sclerosis Multiple Sclerosis More likely to see spinal cord and corpus callosum lesions More likely to see spinal cord and corpus callosum lesions Periventricular lesions are ovoid and/or oriented perpendicular to lateral ventricles 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 Recurrent subcortical ischemic strokes Esp. <60 yrs old Esp. <60 yrs old Esp. in absence of vascular risk factors Esp. in absence of vascular risk factors Early cognitive decline Early cognitive decline Migraine with aura Migraine with aura Comorbid psychiatric symptoms Comorbid psychiatric symptoms Depression Depression Bipolar Bipolar

22 When to Suspect CADASIL Abnormal MRI Abnormal MRI Significant white matter lesions before age 35 Significant white matter lesions before age 35 Multiple T2 hyperintensities w/o vascular risk factors Multiple T2 hyperintensities w/o vascular risk factors Bilateral T2 hyperintensities in white matter, esp. w/lesions in ant. Temporal poles Bilateral T2 hyperintensities in white matter, esp. w/lesions in ant. Temporal poles Family history Family history Stroke, dementia, depression, migraine w/aura, other white matter diseases (which may be misdiagnosed) Stroke, dementia, depression, migraine w/aura, other white matter diseases (which may be misdiagnosed) Premature CAD Premature CAD

23 Diagnostic Approach History History MRI with involvement of anterior temporal poles OR external capsule *** MRI with involvement of anterior temporal poles OR external capsule *** & Positive gene testing *** Positive gene testing *** Sensitivity of 100% with Hx, MRI, & gene test in one study from England 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 positive in approximately half of the 18 patients tested Skin biopsy was negative in all of the gene negative patients Skin biopsy was negative in all of the gene negative patients Sensitivity of 100% Sensitivity of 100% Granular osmiophilic material seen on EM Granular osmiophilic material seen on EM Sensitivity 50%, specificity 100% Sensitivity 50%, specificity 100% Tissue samples stained with monoclonal Ab top Notch3 protein Tissue samples stained with monoclonal Ab top Notch3 protein Sensitivity 96%, specificity 100% 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. 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. This is pathognomic for CADASIL. The deposition of GOM in skin arterioles may vary depending on the exact mutation involved. 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. 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) w/ basophilic granular material (below) EM (to right) EM (to right)

27 Blood vessels in CADASIL 2 types of changes in arteries, veins in body 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 Notch3 immunoreactivity in vascular smooth muscle cells Normal controls on left (a, c, e) Normal controls on left (a, c, e) CADASIL patients on right (b, d, f) CADASIL patients on right (b, d, f)

29 What leads to CADASIL? Mutations in notch3 gene Mutations in notch3 gene Odd number of cysteine residues in Notch3 receptor extracellular domain Odd number of cysteine residues in Notch3 receptor extracellular domain Impaired clearance of cleavage product Impaired clearance of cleavage product Alterations of vascular smooth muscle Alterations of vascular smooth muscle Presence of granular osmiophilic deposits Presence of granular osmiophilic deposits

30 Notch3 gene mutation Usually missense mutation Usually missense mutation More than 50 have been found More than 50 have been found Spontaneous mutations have been described Spontaneous mutations have been described The protein folds incorrectly The protein folds incorrectly Leads to accumulation of protein in membranes of smooth muscles and, ultimately, fibrosis and luminal narrowing of them 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 Mutation in Notch3 gene on chromosome 19 Just downstream from a mutation found in familial hemiplegic migraine Just downstream from a mutation found in familial hemiplegic migraine Notch 3 gene encodes a transmembrane receptor Notch 3 gene encodes a transmembrane receptor Functions in signaling pathways essential for maturation of blood vessels 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 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. 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 Notch 3 expression is limited to vascular smooth muscle cells Mature vascular smooth muscle cells require continued function of the Notch 3 pathway Mature vascular smooth muscle cells require continued function of the Notch 3 pathway Continued survival Continued survival Blood vessels are narrowed and weak and do not react to fluctuations of CO 2 and BP Blood vessels are narrowed and weak and do not react to fluctuations of CO 2 and BP Capillaries, veins are involved Capillaries, veins are involved Generalized vasculopathy Generalized vasculopathy

34 Brain Predilection Cerebral vessels have fewer smooth muscle cells than vessels of other organs Cerebral vessels have fewer smooth muscle cells than vessels of other organs Increased susceptibility Increased susceptibility Limited ability for regeneration of CNS tissue Limited ability for regeneration of CNS tissue White matter predilection White matter predilection Insufficient collateral circulation Insufficient collateral circulation Density less than in grey matter Density less than in grey matter

35 What can be done for these patients? Treatment Treatment Control vascular disease risk factors Control vascular disease risk factors BP BP Increased SBP independent risk factor for progression of CADASIL Increased SBP independent risk factor for progression of CADASIL Cholesterol Cholesterol DM DM Smoking Smoking Obesity Obesity Avoid OCP, HRT Avoid OCP, HRT

36 Treatment Antiplatelet therapy Antiplatelet therapy Investigate for other causes of stroke (cardiac, afib, hypercoag state, etc.) Investigate for other causes of stroke (cardiac, afib, hypercoag state, etc.) Cholinesterase inhibitors Cholinesterase inhibitors Work in vascular dementia Work in vascular dementia Screen for mood disorders, cognitive decline, seizure Screen for mood disorders, cognitive decline, seizure Life expectancy may be shortened by 6 years Life expectancy may be shortened by 6 years

37 NP36015 The key finding 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 Abundant basophilic (blue on H&E), PAS positive, osmiophilic (black on EM) granular material seen in the markedly thickened blood vessel walls Differential diagnosis Differential diagnosis Atheroscerotic disease Atheroscerotic disease Blood vessel walls are also thickened Blood vessel walls are also thickened Granular material is not usually present (if present, it differs from that seen in CADASIL) Granular material is not usually present (if present, it differs from that seen in CADASIL)

38 No treatment No treatment Screening not indicated, unless family member is affected Screening not indicated, unless family member is affected Family may wish to seek genetic counseling Family may wish to seek genetic counseling Control vascular risk factors Control vascular risk factors Do not smoke Do not smoke Screen for mood disorders, cognitive decline, focal neurologic signs, seizure Screen for mood disorders, cognitive decline, focal neurologic signs, seizure

39 Questions?


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