Frdjupad demensutredning Nenad Bogdanovic nenad.bogdanovic@ki.se - - PowerPoint PPT Presentation

Fördjupad demensutredning

Nenad Bogdanovic

nenad.bogdanovic@ki.se nenad.bogdanovic@sll.se

Professor ÖL Geriatriska Kliniken Minnesmottagningen KUS Huddinge

Currently: Chair of the external safety Committee Orion Pharma co-chair of the external safety committee Kyowa-Kirin

Alzheimer’s Disease Control 102 y 76 y

ALZHEIMER

50% Vascular Dementia 10%

Levy-body Dementia Parkinson Dementia

15%

Pick’s Complex

FTLD CBD PSP

15%

• ther

10%

Prevalence of dementias < 75 years

Bogdanovic Karolinska University Hospital 2007

Prevalence of four major types of dementia > 75 y

15% 15% 5% 5%

AD VaD DLBD FLD Other

60% Pure VaD 5% Pure DLBD 3% Mixed VaD and AD 10% DLBD with AD 12%

Gearing, 1995; Kosunen, 1996, Nagy, 1998.

FLD Other 5%

AD

Tangle Only Dementia 2-5% Primary Age-Related Tauopathy (PART)

”Argyrophilic Grain Disease” Primary Age-Related Tauopathy (PART) 5-9%

5

Prevalence of dementia – a neuropathological study

Kovacs..Bogdanovic al 2008

Intraneuronal: TAU-protein Extracellular: -amyloid protein

ALZHEIMER DISEASE IS CHARACTERIZED BY PATHOLOGICAL ACCUMULATION OF TWO PROTEINS INSIDE AND OUTSIDE OF THE NEURONS: TAU AND  - AMYLOID

Bogdanovic 1998

The amyloid cascade hypothesis – 25 years later

AGING

Adapted from Armstrong RA. International Journal of Alzheimer’s Disease Volume 2011, Article ID 630865, 6 pages doi:10.4061/2011/630865 Adapted from Hardy J and Higgins GA. Science 1992;256:184, Karran 2011

1992 2017

Amyloid Ca2+ Ca2+ tau-PO4 APP 717 693

C N

Cell death Neurofibrillary tangles

AβP

Lysosomes Secretase

Lifestyle

Genetic susceptibitity

APOE4

Physiological and pathological forms of Amyloid toxic

?

Heneka 2014

CLEARANCE OF AMYLOID

Alzheimer’s disease pathologies

Bogdanovic N. 2011

? ? ? mechanism

CLINICO-PATHOLOGICAL CORRELATE

H H H Stage I +II Stage V-VI Stage III - IV Progression of the neurofibrillary changes follows the anatomical structures of the brain Braak 1992 +

Thal 2002

neocortical limbic diencephalic brainstem cerebellar

Distribution of Amyloid in AD

 amyloid

Neuropathological Changes Corresponding to Neuropsychological & Behavioural Deficits in AD Amyloid NFT N&B deficit

Episodic/recall memory, apathy, anxiety, irritability, depression Semantic memory Visuospatial functions Attention, delusions, hallucinations, aggitation, wandering, insomnia Primary memory aggressive outbursts, disinhibition

Prodromal AD / Amnestic MCI Mild/Moderate AD Moderate/Severe AD

Sources: Bogdanovic N , after Forlenz O et al, 2010; Trojanowski JQ et al, 2010; Feldman H et al, 2005

Alzheimer’s Disease Begins in the Brain Long Before Symptoms Appear and Progress

CHANGES IN THE BRAIN SYMPTOMS Mild Cognitive Impairment Due to AD

Mild Moderate Severe

Alzheimer’s Dementia ~10-20 years 8–12 years

Sources: Forlenz O et al, 2010; Trojanowski JQ et al, 2010; Feldman H et al, 2005

CHANGES IN THE BRAIN SYMPTOMS Mild Cognitive Impairment Due to AD

Mild Moderate Severe

Alzheimer’s Dementia ~10-20 years Tx 8–12 years

SCI subjective cognitive impairment

Dg Dg Dg

?

4,5 y

Making the diagnose and starting the treatment should be as early as possible SHIFT TO THE LEFT

Sources: Forlenz O et al, 2010; Trojanowski JQ et al, 2010; Feldman H et al, 2005

Making the diagnose and starting the treatment should be as early as possible SHIFT TO THE LEFT

CHANGES IN THE BRAIN SYMPTOMS Mild Cognitive Impairment Due to AD

Mild Moderate Severe

Alzheimer’s Dementia ~10-20 years

T x

8–12 years

SCI Subjective cognitive impairment

D g

Anxiety, Depression Subjective Memory Complaints, Personality changes

MEMORY / COGNITIVE IMPAIRMENT – predominantly

Bogdanovic 2010

IMAGEING IN ROUTINE PRAXIS

The common morphological and functional affected regions in AD

Medial temporal Area (MTL) Hippocampus and entorhinal area MRI Retrosplenial region, Cuneus, Precuneus PET-FDG

• Scheltens Score

Global Cortical Atrophy – GCA

• GCA scale is the mean score for cortical atrophy throughout the complete

cerebrum:

• 0: no cortical atrophy
• 1: mild atrophy: opening of sulci
• 2: moderate atrophy: volume loss of gyri
• 3: severe (end-stage) atrophy: 'knife blade' atrophy.

1 2 3

• Fazekas scale for WM lesions
• On MR, white matter hyperintensities

(WMH) and lacunes - evidence of small vessel disease.

• It is best scored on transverse

FLAIR or T2-weighted images.

• Score:
• Fazekas 0: None or a single

punctate WMH lesion

• Fazekas 1: Multiple punctate lesions
• Fazekas 2: Beginning confluency of

lesions (bridging)

• Fazekas 3: Large confluent lesions

Koedam scale grade 0-1 (Parietal cx score)

Sagittal T1-, axial FLAIR- and coronal T1-weighted images illustrating the Koedam scale of posterior atrophy.

Koedam scale grade 2-3

Sagittal T1-, axial FLAIR- and coronal T1-weighted images illustrating the Koedam scale of posterior atrophy. The yellow arrows: extreme widening of the posterior cingulate en parieto-

• ccipital sulci in a patient with grade 3 posterior atrophy.

Kipps 2007 Frontal Lobe and Basal Ganglia atrophy staging

1 2 3 4

• Use of multi-detector CT will enable coronally

reformatted images to be reconstructed perpendicular to the long axis of the temporal lobe for optimal vizualisation of the hippocampus.

Examples of the rating scores 1, 2, and 3 from CT and MRI scans.

• L. O. Wahlund et al. Stroke. 2001;32:1318-1322

Normal Aging vs. Alzheimer’s Disease Positron Emission Tomography (PET) FDG: Glucose Metabolism

Normal AD

PET FDG DAT SCAN Cingular island sign Lewy Body Dementia AD

75M LBD

Cingular island sign

In vivo Amyloid Imaging with Pittsburgh Compound B (PIB)

N S NH11CH3 HO

PET Imaging - [11C]6-OH-BTA-1 (PIB) Histology - Thioflavin T

Amyloid Plaques

N + S C H

3

C H

3

C H

3

H

3

C N

Fibrillar A

Alzheimer’s Disease Normal Aging (Amyloid Negative) Normal Aging (Amyloid Positive)

PIB Imaging in Aging

In most studies, ~30%

• f cognitively normal

people in their 70’s and above have substantial A accumulation by PET

18F-Florbetapir

AD Control

18F-Florbetaben

AD Control

18F-AZD4694

AD Control

18F-Flutemetamol

AD Control

Normal MCI AD

18F-Flutemetamol – PET

Patient from Memory Clinic / Dept of Radiology and Nuclear Medicine - Bogdanovic 2016

Core Criteria:

Cognitive complaint with

• bjectively confirmed

impairment Uncertain diagnosis (with AD as a possibility) after comprehensive evaluation by a dementia expert Knowledge of Aβ status expected to increase diagnostic certainty and alter management

Top Clinical Scenarios:

Persistent/progressive unexplained MCI “Possible” AD

Atypical or mixed course Significant co-morbidities (e.g. vascular, psychiatric, substance abuse)

Atypically early age-of-onset (<65 years)

Scans on asymptomatic people are not appropriate

-amyloid

righ t H

Cognition Tau Neurodegeneration

Novel - Tau ligand 18F-T807

43

AV-1451 - Tau images in aging

Young Adults N=5 PIB- Older Adults N=17 PIB+ Older Adults N=16 Alzheimer’s Disease N=15

Schöll, Lockhart et al, Neuron 2016

A- A+

FDG PIB AV1451 Late-onset AD 75 year old woman MMSE 17

BIOMARKERS

Biomarkers in Aging and Dementia

-amyloid

PET: PIB, Florbetapir Flute etc CSF

medial lateral

right H

Neurodegeneration

MRI: Atrophy PET: Hypometabolism

Amyloidosis A+ Neurodegeneration N+

Biomarker signature

PET Amyloid CSF Amyloid PET-FDG CSF Tau, pTau MRI H +/- Cx

Bogdanovic 2016

PET Amyloid MRI PET - FDG CSF Amyloid CSF Tau

A-/N- A+/N- + + A-/N+ + + + A+/N+ + + + + +

Presymptomatic eMCI lMCI Demencija

Time

NORMAL PATOLOGIC CSF  42 Amyloid imaging MRI Hippocampus FDG PET CSF Tau Cognitive performance Function (ADL) CSF Aβ42 Amyloid imaging FDG-PET MRI hipp CSF tau Cog Fxn Amyloid Tau Dynamic Biomarkers in the AD Pathological Cascade

Jack,2010

• Mod. Bogdanovic

Use of biomarkers at the prodromal stage of AD

Memory CSF MRI FDG-PET PET- Amyloid NINCDS-ADRDA1

not specified exclusion exclusion not specified unknown

New criteria

amnestic H type A beta T- P tau MTL atrophy P–T hypo metabolism PiB retention

Specificity for Prodromal AD

>90% Sarazin 20072 >90% Hansson 20063 >73% Colliot 20084 >80% Mosconi 20085 >95% Ng 20076

CSF: cerebrospinal fluid; MRI: magnetic resonance imaging; MTL: medial temporal lobe; NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; PET: positron emission tomography; FDG-PET:

18F-2-fluoro-deoxy-D-glucose positron emission tomography; T-P tau: threonine-proline tau

• 1. Criteria for AD dementia, June 11 2010, available at: http://www.alz.org/research/diagnostic_criteria/dementia_recommendations.pdf. Last

accessed 30 March 2011. 2. Sarazin M, et al. Neurology. 2007;69:1859-1867. 3. Hansson O, et al. Lancet Neurol. 2006;5:228-234. 4. Colliot O, et al. Radiology. 2008;248:194-201. 5. Mosconi L, et al. Neurobiol Aging. 2008;29:676-692. 6. Ng S, et al. J Nucl Med. 2007;48:547-552.

Petersen 2014

54

How do amyloid PET and CSF Aβ42 compare ?

Study design: 118 patients with cognitive complaint examined for both CSF biomarkers - as part of clinical routine – 2 years and amyloid 18F-flutemetamol PET Original cohort n= 118

Positive PET+CSF or Negative PET+CSF 92 %

Validation cohort n= 38

Positive PET+CSF or Negative PET+CSF 97 %

Cut-offs: CSF Aβ42 < 647 pg/mL

18F-flutemetamol PET > 1.42

Palmquist S, et al, JAMA Neurol 2014

50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 10 20 30 40 50 60 PET -ve PET +ve

No of cases

New cut off ? 760 -Amyloid 1-42

FTLD PDD

Depression FTLD

PTSS

PCA LBD

Current Cut-off 550 Oskar Hanson’s

Amyloidosis A+ Neurodegeneration N+

Biomarker signature

PET Amyloid CSF Amyloid PET-FDG CSF Tau, pTau MRI H +/- Cx

Bogdanovic 2016

PET Amyloid MRI PET - FDG CSF Amyloid CSF Tau

A-/N- A+/N- + + A-/N+ + + + A+/N+ + + + + +

SCI/MCI MRI NP, MRI , Lab Memory Impairment Non-Memory Impairment +

Vizamyl

AD 4A

Agnosia Apraxia Aphasia Amnesia

CSF PET – FDG

LBD

Park +

Hallucination Fluctuation

ADL - Dementia

agnosia speech behaviour executive Vizamyl

FLD, CBS, PSP MSA PDD, VD, LBD

• A+T+ A+T- A-T- A-T+

Bogdanovic 2016

MCI: NP MRIq CSF NP NP-A NP-nA MRIq MRI-H MRI-C* CSF* T+ A+ NP-A & MRI + & CSF -

PET –Flute

+

• AChE I

Follow Up, (NP, PET-FDG) Symptomatic Th NP-nA & MRI + & CSF - Frontal / Temp PET - FDG NP – nA & MRI+ & T- / A+ Pariet- / Temp

PCA,CBS,LBD

bvFLD, nfPPA, SD

NP : neuropsychology: A-amnestic , nA-nonamnestic MRIq : quantitative H-hippocampal, C-Cortical * cortical specification CSF: T tau /pTau -ve, +ve A –amylod +ve , –ve * Amyloid cut off ? Amyloid 42 positive < 550 current cut off < 760 suggested cut off ??

Bogdanovic 2016

SCI MRIq CSF MRI - CSF - MRIq+ and T- A-

PET – FDG

Follow Up RE-testing Symptomatic Th CSF + (A 550 - 760) CSF - (A > 760) T-

PET –Flute

MRIq+ and T- A+ MRIq+ and T+ A+

+

• 2-3 y

1-2 y 1 y

+

• 1 y

1 y

NP progression NP no-progression Biomarkers assessment Follow up

Bogdanovic 2016

Summary

Biomarkers for A are widely available and are sensitive and specific compared to pathological detection of neuritic plaques Models of preclinical AD include a prolonged period of asymptomatic A accumulation Amyloid biomarkers have revolutionized clinical trials Tau deposition is seen in normal aging in the medial temporal lobe Tau deposition in the neocortex is associated with cognitive decline and the presence of A

DIAGNOSTIC NOISE

Prevalence of four major types of dementia > 75 y

15% 15% 5% 5%

AD VaD DLBD FLD Other

60% Pure VaD 5% Pure DLBD 3% Mixed VaD and AD 10% DLBD with AD 12%

Gearing, 1995; Kosunen, 1996, Nagy, 1998, mod Bogdanovic 2015.

FLD Other 5%

AD

Tangle Only Dementia 2-5% Primary Age-Related Tauopathy (PART)

”Argyrophilic Grain Disease” Primary Age-Related Tauopathy (PART) 5-9%

Crary 2014

L D Neurofibrillary changes – not amyloid

control presymptomatic aMCI /PART

Hippocampus

posterior anterior

AD

ANTERIOR POSTERIOR

Encoding Retrieval

Crary 2014

Crary 2014

PART (definite) N+ A-

• rapid decline on tasks involving
• episodic memory
• semantic memory
• processing speed
• attention
• Age of death > 80
• MMSE 24 – 28
• APOE e4<e3<e2

AD PART

TAU AMYLOID TAU

MCI / DEMENTIA

THERAPY

/ PART

• Intraneuronal amyloid- accumulation is a relatively selective trait of basal forebrain

cholinergic neurons early in adult life

• Increases in the prevalence of intermediate and large oligomeric assembly states are

associated with both ageing and Alzheimer’s disease.

• Selective intraneuronal amyloid- accumulation in adult life and oligomerization

during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer’s disease.

• Abnormal degeneration in both basal forebrain and

entorhinal cortex was only observed among prodromal (mildly amnestic) individuals.

• Basal forebrain pathology precedes and predicts both

entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical

• rigin.

Age, gender genotyper APOE4+/BChEK+

Male <75y

APOE4-/BChEwt

Female >75y

APOE4+/BChEK+

Female <75y

APOE4-/BChEwt

Male <75y

Symptomatic response Yes Yes/None Slight None Respone to Specific AChEI Donepezil Beneficial Rivastigmine Detrimental Donepezil Detrimental Rivastigmine Beneficial Mixed effect from Donepezil Rivastigmine Donepezil Might ? Beneficial Rivastigmine Detrimental

APOE AND BChE GENOTYPES AND AChEI RESPONSE

Relative loss

• f

brain volume Hippocampus > Whole brain Whole brain > Hippocampus Volume loss of all brain regions A minimal loss

• f volume

Lane RM 2015

9 12 6 3 Donepezil 10 mg Rivastigmin 4,5 patch

Alzheimer’s disease pathologies

Bogdanovic N. Author‘s own slide

Symptomatic therapy Disease Modification

• Acetylcholinesterase Inhibitors
• Serotonin TH6 antagonist
• Mitochondrial enhancement
• Synapses enhancement
• Amyloid-modulating agents

ANTIBODIES

beta- , gamma- secretase inhibitors)

• Tau modulating agents
• Neuroprotective agents
• Neurorestorative agents

A concept treatment: SHIFT TO THE LEFT

Anti-amyloid antibodies – Treatment principle

Anti-Aβ Antibodies

Adapted from Neurimmune/Biogen presentation at AD/PD 2015, Nice, FR.

• 1. Adolfsson O, et al. J Neurosci 2012;32:9677-9689; 2. Doody RS, et al. NEJM;2014:370:311-321; 3. Yamada K, et al. J Neurosci 2009;29:11393-11398; 4. Kerchner

GA, Boxer AL. Expert Opin Biol Ther 2010;10:1121-1130; 5. Kaplow JM, et al. Alz Demen 2013;9:807-808; 6. Lai R, et al. Alz Demen 2014;10:689; 7. Lannfelt L, et al. Alz Res Ther 2014;6:16 8. Hang Y, et al. Neurodegener Dis 2015;15:800; 9. Sevigny J, et al. Neurodegener Dis 2015;15:311; 10. Ostrowitzki S, et al. Arch Neurol 2012;69:198-207; 11. Bohnmann B, et al. J Alz Dis 2012;28:49-69.

Crenezumab1 Solanezumab2,

3

Bapineuzumab

4

BAN24015–7 Aducanumab8,

9

Gantenerumab10,1

1

Company Roche/ Genentech Eli Lilly Pfizer/J&J Eisai/Biogen Biogen/ Neurimmune Roche/ Genentech Epitope Mid-domain Mid-domain N-Terminus N-Terminus N-Terminus N-Term & Mid Origin Humanized Humanized Humanized Humanized Human Human Isotype IgG4 IgG1 IgG1 IgG1 IgG1 IgG1 Target All forms of Aβ Soluble Aβ All forms of Aβ Aβ protofibrils Fibrillar &

• ligomeric

forms of Aβ Fibrillar &

• ligomeric

forms of Aβ MoA Microglia- mediated clearance; Sequestratio n of soluble monomeric Aβ Sequestration

• f soluble

monomeric Aβ Microglia- mediated clearance; Sequestration

• f soluble

monomeric Aβ Microglia- mediated clearance Microglia- mediated clearance Microglia- mediated clearance

One Year treatment with Aducanumab

Placebo (n=34, 34, 21) Aducanumab 1 mg/kg (n=26, 26, 21) Aducanumab 3 mg/kg (n=26, 26, 21) Aducanumab 6 mg/kg (n=23, 23, NA) Aducanumab 10 mg/kg (n=28, 27, 21) 1.50 1.40 1.30 1.20 1.10 SUVR cut-point for florbetapir = 1.13* 26 54 Analysis visit (weeks) Mean composite SUVR (±SE) Placebo (n=36, 36, 22) Aducanumab 1 mg/kg (n=28, 28, 23) Aducanumab 3 mg/kg (n=30, 30, 27) Aducanumab 6 mg/kg (n=27, 27, NA) Aducanumab 10 mg/kg (n=28, 28, 23) 2.50 2.00 1.50 1.00 26 54 0.50 0.00 Difference from Placebo at Week 54

• 0.33
• 0.71
• 1.44

*P<0.05 vs placebo * Analysis visit (weeks) Adjusted mean change in CDR-SB from baseline (±SE)

FEW CASES

Core Criteria:

Cognitive complaint with

• bjectively confirmed

impairment Uncertain diagnosis (with AD as a possibility) after comprehensive evaluation by a dementia expert Knowledge of Aβ status expected to increase diagnostic certainty and alter management

Top Clinical Scenarios:

Persistent/progressive unexplained MCI “Possible” AD

Atypical or mixed course Significant co-morbidities (e.g. vascular, psychiatric, substance abuse)

Atypically early age-of-onset (<65 years)

Scans on asymptomatic people are not appropriate P P P

Patient 1

56 y man Music teacher Problem to read musical notation MMT = 29/30 Memory Clinic - Mild Cognitive Impairment

Direct copy

Delay recall after 30 min

Aperceptual visual agnosia

PET-FDG MRI T2 Neurodegeneration N+

Atrophy of the parietal cortex Neurodegeneration N+

AD

PCA (posterior cortical atrophy)

CBS-CBD

Corticobasal SYNDROM

CSF PET - AMYLOID

Lewy Body dementia

CSF PET – 18F-Flutemetamol

PET – Amyloid (A+) PET-FDG (N+) MRI T2 (N+) Alzheimer Disease – atypical form – Posterior Cortical Atrophy

A+/N+

5/15 10/15 Galantamin 24 mg 11/14

Alzheimer Disease - atypical form Posterior Cortical Atrophy Atypically early age-of-onset (<65 years)

Patient 2

Female 1942 2009 concern for developing a dementia condition – Memory Clinic

• Mild cognitive impairment of amnestic type
• 2013. subdural hematoma
• misperception / delusion about her husband.
• Capgras syndrom

2013

2014 A A = amygdala

2015

A A

Lumbal Puncture (06/14) -Amyloid 571 ng/L (>550) Total Tau 433 ng/L (0-500) Fosfo-tau 46 ng/L (<80)

PET – AMYLOID (+) 2015

PET - FDG PET - AMYLOID Precuneus Area 2014/2015

Alzheimer Disease

• “Possible” AD
• Significant co-morbidity: psychiatric

Prospoagnosi vs.Capgras syndrome

Prosopagnosia (greek: prosopon = «face», agnosia = «not recognize») Is a specific form of agnosia characterized by inadequacy to recognize the faces. Those who suffer from prosopagnosia can see the faces, but do not remember them Capgras syndrome has a mirror image of prosopagnosia. Their ability to consciously recognize faces is intact while they have damage to the system that produces autonomous, emotional activation in response to familiar faces.

FRU = face recognition unit PIN = person identity nodes SCR = skin conductance response Fusiform g

Visual cortex

Temporal amygdala

Semantic

FRU = face recognition unit PIN = person identity nodes SCR = skin conductance response Semantic

PROSOPAGNOSI

Fusiform g

Visual cortex

Temporal amygdala

FRU = face recognition unit PIN = person identity nodes SCR = skin conductance respons Semantic

CAPGRAS SYNDROM

Fusiform g

Visual cortex

Inf Temporal amygdala

Patient 3

70 y man Clark 2009 neuroboreliosis MMT = 24/30 Memory Clinic - Mild Cognitive Impairment (amnestic type)

CSF Amyloid 1140 ( >500 ng/L) Tau 380 ( 0-500 ng/L) pTau 62 ( < 80 ng/L) PET FDG PET Vizamyl - Negative

Alzheimer Disease NO

Diff DG Hippocampal Sclerosis Tangle Only Dementia Argyrophilic Grain Dementia Progressive Age Related Tauopathy (PART) Neuroboreliosis – MCI Tauopathies, No Amyloid Persistent/progressive unexplained MCI

Lite till

Art.vertebralis

A hardly reported developmental anomaly of art Vert. and calcification

C AD

HIPPOCAMPAL BLOOD SUPPLY

ARTERIA CEREBRI POSTERIOR

Ath.

Left: infarct in the vascular territory of the Posterior Cerebral Artery (PCA), with involvement of the inferior medial temporal lobe which includes the hippocampus. This is a strategic infarction, since it is in the dominant hemisphere, it will result in cognitive dysfunction. Right: it is a transverse FLAIR image showing another infarct in the PCA-territory, with involvement of the temporo-occipital association area. This is another example of a strategic infarction that can result in cognitive dysfunction.

Capsula externa (kolinergiska bannor) och Anterior Insula (insikt)

Bilateral BG calcifications - Fahr syndrome

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencehalopathy (CADASIL)

• The FLAIR images show

classic findings in CADASIL - confluent white matter hyperintensities with lacunar infarcts and involvement of the anterior temporal lobes

CADASIL - Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy .

Miao Q et al. Stroke. 2006;37:2242-2247

Cerebral Amyloid Angiopathy