3. 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 :
Alzheimer’s disease = n°1, about 60 % of all forms
Vascular disease
Dementia with Lewy bodies
Fronto-temporal dementia
Dementia associated with other diseases (MS,
Parkinson, Steel-R…)
Ü Infectious : CJ, HIV…
Ü
Ü
Ü
Ü
Ü
4. 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
5. Making proper diagnosis ?
Defining biomarkers
Ü Biomarkers ? Characteristics
that are objectively measured
and evaluated as indicator of
pathological processes
Ü Diagnostic, Prognosis, Treatment
evaluation
Biomarkers changes may precede
clinically detectable changes
Biomarkers assist in identifying the
underlying pathology
Ü Existing tools:
Ü CSF : αβ1-42, Tau, P Tau
Ü Imaging (MRI, NM): measures ?
Ü Projects: on going…
6. 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
9. Life-course approach
Hypercholesterolemia
Alcohol misuse
Unhealthy diet
Diabetes
Hypertension
Smoking
APOE
Other
genes
Vascular insults
Neuronal damage
Obesity
DEMENTIA
0
20
Education
60
Physical
activity
75 Brain reserve
Mental and social
activity
Adapted rom S. Gauthier
Update on AD, Montreal 11/2012
10. “Normal” brain aging
Ü Macroscopic
Ü Neurochemistry
Ü > 50 yo: weight loss = 2%/10 y
Ü Cortex « Atrophy »
frontal &
temporal
neurotransmitter & receptor decrease
Ü Cholinergic System:
choline-acétyl
transférase decrease
Ü Gabaergic System:
Ü Microscopic
glutamate
decarboxylase decrease, receptors modification
Ü Apoptosis:
frontal et temporal cortex
amygdala, locus niger
Ü Lipofuschin increase:
Ü Dopaminergic System:
Ü Vascular:
blood flow (slightly)
10 to 15 % of
cellular volume
Ü Senile Plaques:
cell debris & amyloïd
substance within intercellular space
Ü Performance decrease
Ü Reasoning
Ü Acquisition (memory)/learning
Cellular loss + senile plaques
Ü Execution speed/response
Influence of sociocultural, psychoaffective and sensorial conditions
11. 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 Great variations
Ü No link to function
Ü Morphology
Ü Homogenous atrophy (W and
GM, lobes)
Ü No or little temporal atrophy
1485
Ü ≥ 50, frequent at 60, not
constant
Ü « Harmonious » phenomenon
Beware !
Caution in reporting…
70
84
1055
12. 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 ?
13. Other changes
Basal ganglia
Ü
Iron load increase
Ü
Ü
> 25 yo:
Nucleus ruber
Ü
Locus niger
Ü
thinning of the inner elastic layer
Ü
Pallidum
Ü
Ü
Arterial wall thinning
Ü
Ü
Ü
Vessels
media fibrosis
Nucleus dentata
Ü
Atherosclerosis
77 yo 3 T
> 65 yo: Putamen
24 yo 1,5 T
Calcifications
82 yo 1,5 T
27 yo
56 yo
Neurospin (7T)
14. 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 +++
16. 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 cardiovascular risk factors exploration »
FLAIR MRI
17. Quantification/classification ?
Fazekas
Walhund
Ü Periventricular (PVH)
Ü 0: none
Ü 1: horns
Ü 2: halo
Ü 3: irregular, extensive
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
Ü Deep (DWMH)
Ü 0: none
Ü 1: focal
Ü 2: confluence
Ü 3: large confluence
Ü Sub-cortical (SC)
Ü 0: none
HS vascular
Ü 1: patchy
DWMH > 2 ou SC > 2
Ü 2: multiple
HS non vascular
DWMH < 2 et SC < 2
Ü 3: diffuse
1 = normal > 35 y
2 = normal > 70 y
3 = abnormal (any age)
18. 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
Association fibers
Pericallous fibers
Projection fibers
81
Stadlauer
Radiology 2008
20. 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
21. 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
Misbehaviour ?
Yes/No
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)
Two sub-types :
- Onset ≤ 65
- Onset ≥ 65
22. 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.
7 T/NRI, Gachon, South Korea (Siemens)
3T
IR
23. Alzheimer disease (AD)
« in the centre of an apparently normal cell (…) one or a more fibrillar structures
caracterized by their thickness and particular staining »
Extra cellular senile plaques
Amyloïd deposit: peptide αβ
Accumulation
Fibrillar degeneration,
within neurons: Tau protein
= Tubule associated unit (gene 17p21)
24. Lesion
Progression
1
Ü AD lesions are similar to lesion
encountered in normal aging
(JJ Hauw)
1
1
Ü Progressive increase
(« hierarchical »)
Ü Over a certain topographic
and quantitative threshold,
evolution toward AD.
Ü Genetic and environment
factors
Delacourte A et al. Neurology 2000/ Niagara O JFR
25. 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).
26. 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
28. At a glance ???
Grade 3
Grade 1
Sensitivity : 95 %
Specificity : 96 %
2
AD/healthy
1
3
Hippocampe
Cortex
entorhinal
Corne
Temporale
Grade 2
Grade 4
Scheltens P et al. J Neurol 1999
Wahlund LO et al. JNNP 2000
Wahlund LO et al. Psych Resarch 1999
29. Hippocampus atrophy
non specific
Ü
Normal: 1,5% per year
Ü
Other dementia
Ü
Ü
Parkinson, with or without dementia
Ü
Ü
Vascular
Lewy’s body dementia
Atrophy rate is increased in
Ü
Alzheimer disease :
Ü
Normal/MCI before conversion = 3/3.5%
Ü
Association
AD = 3/3.5 %
Ü
Vascular dementia
Ü
Ü
FT D
Lewy’s body dementia
Follow–up +++
2009
2012
Semantic D
Lewy’s body
F. Bonneville Neuro-Imagerie des démences
31. 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
39. 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
40. 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
41. Diffusion
Ü Diminution of apparent diffusion coefficient
predominant in hippocampus, gyrus cingularis, parietal
cortex.
Kejal Kantarci Radiology 2001; 219:101–107
42. DTI
Ü Diminution in anisotropy
fraction of association fibres
(wallerian degeneration ?)
Normal
Ü Early stage, before atrophy ?
DTA
MCI
Alzheimer
Blue : isotropy
Red : anisotropy
Naggara O. JFR 2008
43. 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.
45. Amyloïd plaques imaging
7T Clinical Scanner
Siemens
23.4 x 23.4 x 90 μm3
Tacq = 13 hours 50 min
Sequence: GRE
Neurospin
46. NM & Molecular Imaging
2000
2013
Metabolism
FDG PET
1990
PET MRI
2001-2006
Amyloid Plaques
Florbetapir
Florbetaben
Flutemetamol
Perfusion
SPECT
HMPAO/Neurolite
HAS 2008
Dopamine Transporter
DaT Scan
123I-FP-CIT SPECT
Atypical dementia:
Perfusion
Metabolism
Lewy’s body:
DaTSCAN
47. 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
48. AD
Perfusion decrease:
- Diffuse: posterior associative cortex (parieto-temporal+++)
- Local: medial temporal area
Normal
Hypoperfusion
Medial
Temporal lobe
AD
Hypoperfusion
Associative post cortex
50. AD or Lewy’s body dementia ???
Normal Dopamine uptake
123I-FP-CIT SPECT (DAT scan)
Perfusion decrease
-
Associative cortex (temp et occip)
-
Inner prefrontal and dorsolat D
-
Right hippocampus
52. From early phase to dementia
Aisen PS, Petersen RC, Donohue MC et al. Alzheimers Dement. 2010;6:239-246
53. Conclusion/Take Home
Ü Dialogue: patient, family, other MDs
General radiologist should be familiar
Ü Basic imaging = MRI (HAS)
Ü Treatable disease…
Ü Diagnosis orientation
Ü Early detection
Ü Follow-up
Ü Evolution
Ü Occurrence ?
Ü With normal brain aging
Ü Numerous works
Ü Quantification
Ü Advanced MRI
Ü Functional
Ü Nuclear Medicine
Ü With abnormal brain aging
Report
Ü Structured
Ü Practical: strategy, recommendation
Ü Beware of words: « atrophy », etc…
DWI
54. 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
55. Mentally Challenging Activities Improve Memory
as Baby Boomers Age
Study participants
who spent time
learning digital
photography showed
gains in memory.
