Neurology advanced dementia r lavayssiere


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Neurology advanced dementia r lavayssiere

  1. 1. Multi-modality Imaging of dementia Robert Lavayssière (IPN Sarcelles) Anne-Elizabeth Cabée (RMX-Paris XV, CIMH Neuilly) JFIM 2013 HK 8 november 2013
  2. 2. 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
  3. 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. 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. 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. 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
  7. 7. MRI & Multiples tools Ü  Standard MRI 1,5 T/ 3T Ü  3D T1 and/or STIR: Ü  Advanced MRI Ü  ASL - Commissuro-mammillary plane Ü  Volume calculation - Oblique coronal Ü  Diffusion/Fiber Tracking « visual » quantification Ü  FLAIR: parenchyma/WM Ü  T2*: haemorrhage ? Ü  Diffusion: ischemia ? Ü  1,5 T Blade © or Propeller © Ü  Functional MRI Ü  Spectroscopy Ü  (3 T vs 1,5 T) Ü  Very high field 3T
  8. 8. Normal brain aging
  9. 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. 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. 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. 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. 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. 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 +++
  15. 15. 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 ?
  16. 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. 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. 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
  19. 19. Atrophy: classification ? Kipps: f-temporal atrophy 0 to 5 Barkhof: parietal atrophy 0 to 4
  20. 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. 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. 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. 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. 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. 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. 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
  27. 27. AD MCI Choroïdal fissure width Hippocampus height Temporal horn width Healthy
  28. 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. 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
  30. 30. « Automatic » analysis Volumetry/Morphometry Morphometric Analysis Gerardin et al. NeuroImage 2009 Segmentation Automatique Compétitive de l’Hippocampe et de l’Amygdale Chupin et al, ISMRM 2009 à 7T Cortex thickness measurement (Mc Gill, Harvard)
  31. 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
  32. 32. Enthorinal cortex atrophy (not easy to measure!) Normal Early stage Advanced MR in dementia, Jaap Valk, Springer ed AD
  33. 33. Association
  34. 34. « Bleeds » Ü  T2* 3T 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
  35. 35. 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 :
  36. 36. Advanced…
  37. 37. Other methods/advanced DTI ASL F MRI RBF Perfusion Healthy NM Alzheimer Lewy’s body 123I-FP-CIT SPECT (DAT scan) Spectroscopy Pit compound
  38. 38. ASL Local perfusion decrease Johnson NA et al. Radiology. 2005 Mar;234(3):851-9.
  39. 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. 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. 41. Diffusion Ü  Diminution of apparent diffusion coefficient predominant in hippocampus, gyrus cingularis, parietal cortex. Kejal Kantarci Radiology 2001; 219:101–107
  42. 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. 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.
  44. 44. High resolution Neurospin
  45. 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. 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. 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. 48. AD Perfusion decrease: - Diffuse: posterior associative cortex (parieto-temporal+++) - Local: medial temporal area Normal Hypoperfusion Medial Temporal lobe AD Hypoperfusion Associative post cortex
  49. 49. Fronto-temporal dementia •  Decreased perfusion of frontotemporal cortex •  Normal posterior cortex : Antero-posterior gradient = FTD 99mTc-ECD
  50. 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
  51. 51. Question ??? Advanced imaging techniques in MCI & Alzheimer's disease: how much imaging is enough?
  52. 52. From early phase to dementia Aisen PS, Petersen RC, Donohue MC et al. Alzheimers Dement. 2010;6:239-246
  53. 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. 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. 55. Mentally Challenging Activities Improve Memory as Baby Boomers Age Study participants who spent time learning digital photography showed gains in memory.