Multi-modality Imaging of dementia

Robert Lavayssière (IPN Sarcelles)

Anne-Elizabeth Cabée (RMX-Paris XV, CIMH Neuilly) JFIM 2013 HK 8 november 2013

Overview Objectives

Ü  Definition/Time bomb: worldwide burden

Ü  Normal aging brain

Ü  Abnormal brain aging

Ü  Imaging of dementia Ü  Everyday practice:”basic” MRI

Ü  Other methods/advanced

Ü  Conclusion/Take Home

Dementia ? Umbrella term

Ü  Used to describe the symptoms that occur when the

brain is affected by specific diseases and conditions. Symptoms of dementia include cognitive disorders (aphasia, apraxia, agnosia) and loss of memory (AD).

Ü  Many different types, named according to the condition that has caused the dementia : Ü  Alzheimer’s disease = n°1, about 60 % of all forms Ü  Vascular disease Ü  Dementia with Lewy bodies Ü  Fronto-temporal dementia Ü  Dementia associated with other diseases (MS,

Parkinson, Steel-R…) Ü  Infectious : CJ, HIV…

Time bomb ? Worldwide burden Ü  Age related +++

Ü  2050: 2 billions > 60 yo

Ü  Worldwide: x 2 every 20 y Ü  2010: 35,6 millions Ü  2030: 65,7 millions Ü  2050: 115,4 millions Ü  = 7,7 millions new cases every

year

Ü  Cost: $ 604 billions * Ü  Global: 85 % Ü  Medical care: 15 % (* 90 % in developed countries)

Ü  France: 1 million with dementia

Source : OMS/WHO 2012

Making proper diagnosis ? Defining biomarkers

Ü  Biomarkers ? Characteristics that are objectively measured and evaluated as indicator of pathological processes

Ü  Diagnostic, Prognosis, Treatment evaluation

Ü  Existing tools: Ü  CSF : αβ1-42, Tau, P Tau

Ü  Imaging (MRI, NM): measures ?

Ü  Projects: on going…

Biomarkers changes may precede clinically detectable changes

Biomarkers assist in identifying the

underlying pathology

Is imaging recommended ?

Ü  HAS 2008: brain imaging is mandatory Ü  Other cause: Tumours, Hydrocephalus, Stroke Ü  Associations: atrophy, chronic vascular diseases

Ü  MRI first, if possible Ü  T1, T2, T2*, FLAIR, coronal views (or 3D +++) Ü  IV, if needed

Ü  CT without IV as an alternative (MRI not available, CI for MRI)

Ü  Nuclear medicine: perfusion/metabolism

Importance of clinical symptoms

MRI & Multiples tools Ü  Standard MRI 1,5 T/ 3T

Ü  3D T1 and/or STIR:

- Commissuro-mammillary plane

- Oblique coronal

« visual » quantification

Ü  FLAIR: parenchyma/WM

Ü  T2*: haemorrhage ?

Ü  Diffusion: ischemia ? Ü  Blade © or Propeller ©

Ü  Advanced MRI Ü  ASL

Ü  Volume calculation

Ü  Diffusion/Fiber Tracking

Ü  Functional MRI

Ü  Spectroscopy

Ü  (3 T vs 1,5 T)

Ü  Very high field

1,5 T 3T

Normal brain aging

Life-course approach

Unhealthy diet Diabetes Alcohol misuse

Obesity Smoking

Hypercholesterolemia

Hypertension

Physical activity

Education Mental and social activity

DEMENTIA

Brain reserve

Neuronal damage Vascular insults

APOE Other genes

0 20 60 75

Adapted rom S. Gauthier Update on AD, Montreal 11/2012

“Normal” brain aging

Ü  Macroscopic Ü  > 50 yo: weight loss = 2%/10 y

Ü  Cortex « Atrophy » frontal & temporal

Ü  Microscopic Ü  Apoptosis: frontal et temporal cortex

amygdala, locus niger Ü  Lipofuschin increase: 10 to 15 % of

cellular volume

Ü  Senile Plaques: cell debris & amyloïd substance within intercellular space

Cellular loss + senile plaques

Ü  Neurochemistry Ü  Dopaminergic System:

neurotransmitter & receptor decrease

Ü  Cholinergic System: choline-acétyl transférase decrease

Ü  Gabaergic System: glutamate decarboxylase decrease, receptors modification

Ü  Vascular: blood flow (slightly)

Ü  Performance decrease Ü  Reasoning

Ü  Acquisition (memory)/learning

Ü  Execution speed/response

Influence of sociocultural, psychoaffective and sensorial conditions

Cerebral « atrophy » Ü  « Atrophy »

Ü  Cortex: 3 cm3/y Ü  Cisternal & sulci enlargement

Ü  White matter: 3 cm3/y Ü  Vulnerable regions

Ü  Pre-frontal cortex

Ü  Anterior Cingular Gyrus

Ü  Parietal Inferior Lobule

Ü  Precuneus

Ü  Superior Temporal Gyrus

Ü  Insula

Ü  ≥ 50, frequent at 60, not constant

Ü  « Harmonious » phenomenon

Ü  Great variations

Ü  No link to function

Ü  Morphology Ü  Homogenous atrophy (W and

GM, lobes) Ü  No or little temporal atrophy

Beware !

Caution in reporting… 70

1055

84

1485

Virchow-Robin Space

Ü  Peri-vascular space dilatation Ü  Extension of sub-arachnoïd

space

Ü  Signal = CSF: hyper T2, hypo Flair

Ü  Neat borders

Ü  Clinical consequences ? Ü  Incidence increases with age

Ü  Fortuitous discovery

Ü  Associated with cognitive disorders ?

Other changes Basal ganglia

Ü  Iron load increase

Ü  > 25 yo:

Ü  Pallidum

Ü  Nucleus ruber

Ü  Locus niger

Ü  Nucleus dentata

Ü  > 65 yo: Putamen

Ü  Calcifications

Vessels Ü  Arterial wall thinning

Ü  thinning of the inner elastic layer

Ü  media fibrosis

Ü  Atherosclerosis

27 yo 56 yo Neurospin (7T)

82 yo 1,5 T

24 yo 1,5 T

77 yo 3 T

Abnormal brain aging

Ü  Dementia Ü  Global deterioration of cognitive

function, normal conscience

Ü  Progressive onset and evolution, non reversible

Ü  Pre-clinical phase, variable, unknown duration (MCI)

Ü  Alzheimer = 60 % of dementia Ü  Memory impairment +++

Ü  Evaluation methods

Ü  Simple (Folstein ou MMSE)

Ü  Specialised (Day care hosp)

Ü  Other dementia Ü  Vascular +++

Ü  Fronto-temporal dementia (Pick, < 70)

Ü  Sub-cortical and cortico-sub-cortical dementia:

Ü  Lewy’s body

Ü  Parkinson

Ü  Progressive SN palsy

Ü  Traumatic…

Clinical +++

Grid & structured report (need for)

Ü  Leukoencephalopathy (Fazekas/Walhund) ?

Ü  Fronto-temporal atrophy (Kipps) ?

Ü  Parietal atrophy (Barkhof) ?

Ü  Hippocampus atrophy (Scheltens) ?

Ü  T2*: µbleed, bleed ?

Ü  Diffusion ?

Ü  Hydrocephalus ?

White Matter lesions Age-Related White Matter Changes

Ü  “Leukoencephalopathy”…

Ü  Variable (grading Fazekas/Walhund)

Ü  Common in aging subjects:

Ü  95 % > 60

Ü  Age, Hypertension

Ü  Clinical consequences???

Associated with some risk of cognitive impairment and dementia, but limited predictive value.

Ü  REPORT: in practice

« White matter high signal lesions indicating the need for cardio-vascular risk factors exploration »

FLAIR MRI

Quantification/classification ? Fazekas

Ü  Periventricular (PVH) Ü  0: none Ü  1: horns Ü  2: halo Ü  3: irregular, extensive

Ü  Deep (DWMH) Ü  0: none Ü  1: focal Ü  2: confluence Ü  3: large confluence

Ü  Sub-cortical (SC) Ü  0: none Ü  1: patchy Ü  2: multiple Ü  3: diffuse

Walhund

Ü  White matter Ü  O: normal Ü  1: periventricular hyperintensity + small

high signal foci Ü  2: periventricular hypertensity,

extended, with confluent high signal zone

Ü  3: confluent periventricular and major sub-cortical lesions

Ü  Basal ganglia Ü  O: normal Ü  1: one lesion > 5 mm Ü  2: more than one focal lesion Ü  3: confluent lesions

HS vascular DWMH > 2 ou SC > 2 HS non vascular DWMH < 2 et SC < 2

1 = normal > 35 y 2 = normal > 70 y 3 = abnormal (any age)

White Matter Fiber loss and diffusion decrease

Ü  3 major types of sub-cortical

fibers Ü  Association (cortex to cortex)

Ü  Peri-callous (cortex to hemisphere through CC)

Ü  Projection (cortex to thalamus, midbrain & medulla)

Ü  Age : Ü  Projection fibers degradation >

global WM decrease

Ü  Diffusion modification, variable according to fibers

25 55 81

Association fibers

Pericallous fibers

Projection fibers Stadlauer Radiology 2008

Atrophy: classification ? Kipps: f-temporal atrophy

Barkhof: parietal atrophy

0 to 5 0 to 4

Neuro-degenerative Dementia

Pre frontal: Fronto-temporal lobe

Sub cortical Brainstem: Lewy’body SN progressive palsy (SRO)

Pericentral and parietal : apraxy,

dystoniq, Parkinson’s, corticobasal degenerescence

Inner/medial temporal Hippocampus Episodic Memory Alzheimer’s

Alzheimer disease (AD) Criteria

Ü  A. Multiple cognitive deficit Ü  1. Memory loss Ü  2. Cognitive malfunction:

Ü  Aphasia (language)

Ü  Apraxy (motricity)

Ü  Agnosy (identification)

Ü  Executives function (projects, organization, planification, abstraction)

Ü  B. A1 + A2: behavioural alteration (social and/or professional)

Ü  C. Progressive onset (MCI phase), continuous cognitive decline

Ü  D. Rule out Ü  Other diseases ???

Ü  Vascular

Ü  Parkinson

Ü  SDH, NPH, Tumour (Imaging methods)

Ü  General: Ü  Hypothyroidism

Ü  B12/Folates

Ü  HIV…

Ü  Toxic

Ü  E. NO consciousness disorder

Ü  F. No Psychiatric disease (schizophrenia, depression)

Misbehaviour ? Yes/No

Two sub-types : -  Onset ≤ 65 -  Onset ≥ 65

Alzheimer disease (AD) New criteria

Ü  Memory impairment/loss (not long term memory)

Ü  CRITERIA (one or more) Ü  MRI: hippocampus atrophy

Ü  PET-FDG: decreased metabolism

Ü  CSF markers

Ü  Genes

Dubois B et al. Lancet Neurol. 2007 Aug;6(8):734-46.

3T IR

7 T/NRI, Gachon, South Korea (Siemens)

Alzheimer disease (AD) « in the centre of an apparently normal cell (…) one or a more fibrillar structures

caracterized by their thickness and particular staining »

Fibrillar degeneration, within neurons: Tau protein = Tubule associated unit (gene 17p21)

Extra cellular senile plaques Amyloïd deposit: peptide αβ Accumulation

Delacourte A et al. Neurology 2000/ Niagara O JFR

1

1 1

Lesion Progression

Ü  AD lesions are similar to lesion encountered in normal aging (JJ Hauw)

Ü  Progressive increase (« hierarchical »)

Ü  Over a certain topographic and quantitative threshold, evolution toward AD.

Ü  Genetic and environment factors

Hippocampus

Ü  Complex, located on medial side of temporal circonvolution T5 bulging into temporal horn of the lateral ventricle.

Ü  Belongs to the limbic system (memory, emotion, Broca), sharing numerous connections (Papez).

Ü  Hippocampus alteration often associated with limbic and/or extra-limbic alterations

Wikipedia !

Essential role in memory formation, events memory or explicit or declarative memory, opposed to knowledge/know how, or implicit or procedural memory, depending upon other brain structures (basal ganglia).

Quantification ???

Ü  Normal temporal « Atrophy » in aging subjects Ü  Temporal « Atrophy » but

normal hippocampus Ü  Individual variations +++ Ü  Evolution ? : follow-up +++

need for reproducible MRI studies

Ü  Analysis Ü  Visual : “subjective” Ü  Quantitative :

Ü  Volumetry, Ü  Morphometry…. Anterior Body Posterior

From E. Sibileau

Choroïdal fissure width Hippocampus height Temporal horn width

Healthy

AD MCI

2 3

Corne Temporale

Hippocampe

Cortex entorhinal

Scheltens P et al. J Neurol 1999 Wahlund LO et al. JNNP 2000 Wahlund LO et al. Psych Resarch 1999

Sensitivity : 95 %

Specificity : 96 %

AD/healthy

Grade 4

1

At a glance ??? Grade 1

Grade 2

Grade 3

Hippocampus atrophy non specific

Ü  Normal: 1,5% per year

Ü  Other dementia Ü  Vascular

Ü  Parkinson, with or without dementia

Ü  Lewy’s body dementia

Ü  Atrophy rate is increased in Ü  Alzheimer disease :

Ü  Normal/MCI before conversion = 3/3.5%

Ü  AD = 3/3.5 %

Ü  Vascular dementia

Ü  Lewy’s body dementia

Ü  Follow–up +++

FT D Association

Semantic D Lewy’s body

F. Bonneville Neuro-Imagerie des démences

2009 2012

« Automatic » analysis Volumetry/Morphometry

Chupin et al, ISMRM 2009 à 7T

Segmentation Automatique Compétitive de l’Hippocampe et de l’Amygdale

Morphometric Analysis Gerardin et al. NeuroImage 2009

Cortex thickness measurement (Mc Gill, Harvard)

Results Ü AD detection: healthy vs AD

Ü Voxel based and surfacic methods: good overall performances

Ü Hippocampus analysis: lower specificity

Ü  Prodromal AD: healthy vs MCI Ü  Low sensitivity of all methods

Ü Conversion prediction: no method = hazard !

From R. Guingnet

MR in dementia, Jaap Valk, Springer ed

Enthorinal cortex atrophy (not easy to measure!)

Early stage Advanced

Normal

AD

Association

« Bleeds »

Ü  T2*

Ü  7 % > 65

Ü  Correlated with diabetes, Hypertension

Ü  Amyloïd angiopathy ???

Ü  Vascular risk marker: increased risk Ü  Spontaneous hematoma

Ü  Hematoma under anticoag. therapy (beware of Acetyl salicylic acid!)

Ü  Haemorragic transformation of stroke

Ü  REPORT, in practice: « chronic microbleeds indicating the need of blood pressure check/control »

1,5 T

3 T

Other dementia not only AD !!!

Ü  Vascular dementia: 2° cause Ü  Cardio-vascular context

Ü  CV disease Ü  Risk factors (HTA, diabetes,

smoking,…) Ü  Focal symptoms Ü  MR (CAT scan) lesions

Ü  Time course Ü  Onset 3 months > stroke Ü  Cognitive impairment step

by step or brutal, not continuous

Ü  Genes? (CADASIL) Ü  Amyloïd Angiopathy Ü  Association to AD

Ü  Other neuro-degenerative dementia… Ü  Neurological symptoms Ü  No memory loss Ü  No temporal atrophy (but…)

Ü  « Treatable » disease :

Advanced…

Other methods/advanced

Pit compound

DTI RBF Perfusion

F MRI

Healthy Alzheimer Lewy’s body

NM 123I-FP-CIT SPECT (DAT scan)

Spectroscopy

ASL

ASL

Johnson NA et al. Radiology. 2005 Mar;234(3):851-9.

Local perfusion decrease

ASL Control subjects (A, B) and AD patients (C, D) All four patients were diagnosed correctly by both readers using both modalities. Comparing -  Structural magnetic resonance imaging images (T1 and fluid-attenuated inversion recovery) -  Arterial spin labeling magnetic resonance imaging (ASL-MRI), - FDG-PET).

White arrows highlight areas of concordant hypometabolism on FDG-PET and hypoperfusion on ASL-MRI.

Erik S. Musiek & al Alzheimer’s & Dementia 24 Oct 2011

Spectroscopy

•  Valid for large groups •  Not valid for a specific individual •  Distinction AD – Healthy

NAA decrease (N-Acetyl Aspartate) Correlated with MMSE*

Lehéricy, Eur Radiol 2007

Diffusion Ü  Diminution of apparent diffusion coefficient

predominant in hippocampus, gyrus cingularis, parietal cortex.

Kejal Kantarci Radiology 2001; 219:101–107

DTI

Ü  Diminution in anisotropy fraction of association fibres (wallerian degeneration ?)

Ü  Early stage, before atrophy ?

Blue : isotropy Red : anisotropy

Normal

DTA

Naggara O. JFR 2008 MCI Alzheimer

fMRI

Ü  Functional disconnection between posterior cingular cortex and hippocampus: network default mode altered (posterior cingular cortex, prefontal cortex, lateral cortex, hippocampus).

Healthy aged patients AD

Greicius MD et al. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42.

High resolution

Neurospin

Amyloïd plaques imaging

7T Clinical Scanner Siemens 23.4 x 23.4 x 90 μm3 Tacq = 13 hours 50 min Sequence: GRE Neurospin

NM & Molecular Imaging

Perfusion SPECT

HMPAO/Neurolite

Dopamine Transporter DaT Scan

123I-FP-CIT SPECT

Metabolism FDG PET

Amyloid Plaques Florbetapir

Florbetaben Flutemetamol

2000

1990 2001-2006

2013

PET MRI

HAS 2008

Atypical dementia: Perfusion

Metabolism Lewy’s body:

DaTSCAN

Metabolism/perfusion

Ü  Atypical AD

Ü  Non AD dementia: Fronto-temporal D, Progressive Primary Aphasia, Lewy’s body dementia

Ü  At risk population screening: MCI, genetic risk (presenilin, amyloïd precursor protein, progranuline, APOEe4

Ü  Follow-up

Ü  Treatment evaluation

HAS 2008

AD Perfusion decrease: - Diffuse: posterior associative cortex (parieto-temporal+++) - Local: medial temporal area

AD

Normal

Hypoperfusion Associative post cortex

Hypoperfusion Medial Temporal lobe

Fronto-temporal dementia

99mTc-ECD

•  Decreased perfusion of fronto-temporal cortex

•  Normal posterior

cortex : Antero-posterior gradient = FTD

AD or Lewy’s body dementia ???

Perfusion decrease

-  Associative cortex (temp et occip)

-  Inner prefrontal and dorsolat D

-  Right hippocampus

Normal Dopamine uptake 123I-FP-CIT SPECT (DAT scan)

Question ??? Advanced imaging techniques in MCI & Alzheimer's disease: how much imaging is enough?

From early phase to dementia

Aisen PS, Petersen RC, Donohue MC et al. Alzheimers Dement. 2010;6:239-246

Conclusion/Take Home

General radiologist should be familiar

Ü  With normal brain aging

Ü  With abnormal brain aging

Report

Ü  Structured

Ü  Practical: strategy, recommendation

Ü  Beware of words: « atrophy », etc…

Ü  Dialogue: patient, family, other MDs

Ü  Basic imaging = MRI (HAS) Ü  Treatable disease… Ü  Diagnosis orientation Ü  Early detection Ü  Follow-up

Ü  Evolution Ü  Occurrence ?

Ü  Numerous works Ü  Quantification Ü  Advanced MRI Ü  Functional Ü  Nuclear Medicine DWI

Note of Thanks

Ü  Dr Marie-Thérèse Iba-Zizen

Ü  Dr Liliana Feldman

Ü  Dr Zoulikha Malek

Ü  Dr Emmanuel A. Cabanis

Ü  Dr Johan Le Guilloux

Ü  Dr Jean-Luc Sarrazin

Ü  Mr Julien Gervais

Siemens

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