NEUROIMAGING OF VASCULAR COGNITIVE IMPAIRMENT VCI

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NEUROIMAGING OF VASCULAR COGNITIVE IMPAIRMENT
(VCI)

• Timo Erkinjuntti M.D., Ph.D., FAAN, FAHA
• Professor of Neurology
• Department of Neurology
• Helsinki, Finland
• 7th ANNUAL MCI SYMPOSIUM, 2009
• FOCUS ON NON-ALZHEIMERS PRODORMAL DEMENTIAS
• Miami, March 28, 2009

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VASCULAR COGNITIVE IMPAIRMENT CONCEPT
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VASCULAR COGNITIVE IMPAIRMENT(VCI)

• SPECTRUM OF ETIOLOGIES
• Vascular risk-factors (HT, Kol, DM, Obesity)
• CVD (TIA, Stroke) Cortico-subcortical infarcts
  Strategic infarcts Lacunar infarcts Small
  vessel disease (WMLs and lacues) WMLs Silent
  infarcts AD CVD
• SPECTRUM OF SEVERITY
• Cognitive impairment no dementia (CIND) mild
  cognitive impairment (MCI), different degrees of
  dementia

Bowler 1998, 2002 Rockwood 1999,
2000 Erkinjuntti, Gauthier 2002
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VASCULAR COGNITIVE IMPAIRMENT - VCI

• Is the latest modification of nosological
  terminology that aims to encompass all the
  effects of vascular disease or lesions on
  cognition
• (Erkinjuntti T. Psychiatry 2008715-20)
• Any cognitive impairment associated or caused
• by a vascular factor
• (Hachinski V. et. al. Stroke
  2006372220-2241.)

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The Lancet Neurology2003289-98. Vascular
Cognitive Impairment  

• JT OBrien, T. Erkinjuntti,
• B. Reisberg et al.

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The Lancet Neurology20087246-255. Vascular
Cognitive Impairment current concepts and
clinical developments  

• P. Moorhouse and K. Rockwood

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VCI PATHOLOGIES

• A) VASCULAR
• B) DEGENERATIVE

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VCI VASCULAR PATHOLOGIES

• Large vessel diease
• Cardiac embolic events
• Small vessel disease (lacunae, WMLs)
• Haemodynamic factors
• Haemorrhages
• Venous collagenosis
• CAA Cerebral Amyloid Angiopathy
• CADASIL Cerebral Autosomal Dominant
  Arteriopathy with Subcortical Infarcts and
  Leucoenecephalopathy .....

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VCI DEGENERATIVE PATHOLOGIES

• Alzheimers disease
• Lewy-dody disease
• Parkinsons disease
• Lobar degenerations
• -Frontal lobe dementia
• -Progressive aphasia
• -Semantic dementia
• Agyophilic grain disease ....

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VCI INCLUDE COGNITIVE IMPAIRMENT RELATED TO

• Vascular risk-factors (e.g. HT, Kol, DM, Obesity)
• CVD (TIA, Stroke)
• Cortico-subcortical infarcts
• Strategic infarcts
• Small vessel disease Lacunar infarcts, WMLs
• Silent infarcts
• AD (and other degenerative pathologies) CVD

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VCI - CHANGES IN THE BRAIN

• Arterial territorial infarct
• Distal field (watershed) infarct
• Lacunar infarct
• Etat crible widening of perivascular spaces
• Ischemic white-matter lesions
• Cortical microinfacts
• Haemorrhages incl. microbleeds
• Specific pathologies AD, PD, LBD, CAA ....

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VCI BRAIN MECHANISMS

• Volume of brain infacts (size reeaching critical
  threshold)
• Number of infarcts (additive, synergistic)
• Site of infarcts (bilateral, strategic cortical
  or subcortical site)
• White-matter lesions (type, density, extent,
  site)
• Other incoplete ischemic injury, delayed
  neuronal death, functional changes
• Atrophy (location, exent)
• Additive effects of other pathologies (AD, LBD ..)

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HOST FACTORS
brain infarcts
e.g. age education genetics
VASCULAR ETIOLOGIES
cognitive impairment dementia
white matter changes
cerebrovascular disorders vascular risk factors
brain atrophy
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HOST FACTORS
brain AD pathology
e.g. age education genetics
VASCULAR ETIOLOGIES
cognitive impairment dementia
infarcts white matter changes
cerebrovascular disorders vascular risk factors
brain atrophy
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VASCULAR COGNITIVE IMPAIRMENT GENERAL
CHALLENGES
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Workshop Vascular Cognitive Impairment
Harmonization CriteriaWashington, DC, April
24-27, 2005.
Stroke 2006372220-241.
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CURRENT CHALLENGE IN VCI (1)

• Adopt a common metric system
• Test several provisional criteria simultaneosly
• Indentify and treat
• the vascular component / burden
• and
• the degenerative component/burden

Hachinski et al. Stroke2006372220-2241
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CURRENT CHALLENGE IN VCI (2)

• A solution for comparative studies
• and co-operation
• use of a common minimal research
• data set with standardized terminology

Hachinski et al. Stroke2006372220-2241
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VASCULAR COGNITIVE IMPAIRMENT NEUROIMAGING
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NEUROIMAGING IN VCI

• The main role neuroimaging in the study of VCI
• so far has been to describe the brain, not
  diagnose it
• as
• (1) vascular and degenerative pathology frequent
  coexist and
• (2) there are no pathognomic radiological fetures
• of VCI (TE but are those of VCI subtypes)

Hachinski et al. Stroke2006372220-2241
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NEUROIMAGING TOOLS IN VCI

• Magnetic Resonance Imaging MRI
• -the ideal imaging tool
• -most sensitive, greatest amount of reliable data
• -minimally acceptable field strength is 1.0 T,
  but 1.5 or greater is preferred

• Computed Tomography
• CT
• -limited use
• -measures only severe disease
• -difficult to quantify
• -significant radiation exposure

Hachinski et al. Stroke2006372220-2241
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VASCULAR COGNITIVE IMPAIRMENT NEUROIMAGING -
CT
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IMAGING CT MEASURES

• Ventricular size (validated scale needed)
• Hippocampus medial temporal atrophy (-30
  orbitomental, N15)
• Diffuse white matter ARWMC
• Discrete hypodensities
• (CSF density consistent with infarction or old
  hemorrhage)
• gt 3 mm 1 cm small
• gt 1 cm large
• No, volume, location same as MRI
• Acute hemorrhage

Hachinski et al. Stroke2006372220-2241
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WHITE MATTER LESIONS - CT

• ill-defined areas of low attenuation in the
  white matter
• usually bilateral
• periventricular area, centrum semiovale
• WMLA e.g. Erkinjuntti et al. 1987
• leuko-araiosis Hachinski el al 1987
• ARWMC Wahlund et al. 2001

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WHITE MATTER CHANGE ON CT
without CE
with CE
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WHITE MATTER CHANGE ON CT
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RATING SCALES FOR WHITE MATTER CHANGE ON CT

• ERKINJUNTTI et al 1987
• REZEK et al 1987
• AHARON-PERETZ et al 1988
• BLENNOW et al 1991
• VAN SWIETEN et al 1992
• TARVONEN-SCHRÖDER et al 1995
• CHARLETTA et al 1995
• LOPEZ et al 1995
• WAHLUND et al 2001

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VISUAL RATING OF AGE RELATED WHITE MATTER CHANGES
OF CT AND MRI the European Task Force on
Age Related White Matter Changes
Wahlund et al, Stroke, 2001
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Rating score 1
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Rating score 2
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Rating score 3
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VASCULAR COGNITIVE IMPAIRMENT NEUROIMAGING -
MRI
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BASIC MRI SEQUENCES

• 3D T1-weighted
• (e.g. sagittal whole brain, hippocampal
  reformates)
• FLAIR Fluid attenuated invesrion recovery,
  e.g. Axial
• T2 weighted, e.g. Axial
• T 2 - Gradient echo, e.g. Axial

Hachinski et al. Stroke2006372220-2241
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BASIC MRI SEQUENCES

• Atrophy T 1-w (3D T1-w.)
• WMLs FLAIR
• Infarct FLAIR, T2-w., T1-w.
• Perivascular spaces - -
• Microbleeds T 2

Hachinski et al. Stroke2006372220-2241
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T2
T1
FLAIR
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T2
T2
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IMAGING MRI MEASURES

• Brain atrophy
• White matter hyperintensities (WMHs)
• Infarction
• Haemorrhage
• Discrete chronic hypodensities
• old infarcts and hemorrhages
• Other

Hachinski et al. Stroke2006372220-2241
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MRI MEASURES BRAIN ATROPHY

• RECOMMENDED
• -Quantitative measurement of brain volume
  normalized for head size

• ACCEPTABLE
• -Esitimates of atrophy and ventricular size using
  the CHS (Cardiovascular Health Study) Scale
• -Estimates of medial temporal lobe atrophy using
  Scheltens Scale

Hachinski et al. Stroke2006372220-2241
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QUANTITATIVE BRAIN VOLUME NORMALIZED FOR HEAD
SIZE FOLLOW UP STUDY
SIENAX ?baseline normalized whole brain volume
(NBV) SIENA ? volume loss ? annualized
examples
Dx subj. compl. MCI (stable) MCI (progr) AD Age
74 y 80y 67 y 63 y NBV 1471mL 1607mL
1548 mL 1286mL rate -0.7/y -0.6/y -1.9
/y -4.2/y
Courtesy Wiesje M. van der Flier 2008
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www.adni-info.org, www.loni.ucla.edu/ADNI/
ADNI
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MRI MEASURES BRAIN ATROPHY

• RECOMMENDED
• -Quantitative measurement of brain volume
  normalized for head size

• ACCEPTABLE
• -Esitimates of atrophy and ventricular size using
  the CHS (Cardiovascular Health Study) Scale
• -Estimates of medial temporal lobe atrophy using
  Scheltens Scale

Hachinski et al. Stroke2006372220-2241
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MTL ATROPHY VISUAL RATING
Scheltens, Leys, Barkhof, et al. JNNP
199255967-72
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MTL ATROPHY VISUAL RATING
1
0
2
3
4
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MRI MEASURES WHITE MATTER CHANGES

• RECOMMENDED
• -Quantitative measurement of WMH volume
  normalized for head size
• -Anatomical mapping also encouraged

• ACCEPTABLE
• -Preferred ARWMC Scale
• -Also acceptable CHS WMH Scale

Hachinski et al. Stroke2006372220-2241
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THE EXECUTIVE SMALL VESSEL NETWORKBRAIN
THE LARGEST ENDOTHELIAL ORGAN OF THE HUMAN
ECONOMY
Roman GC ADAD 2008221-3.
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Medullary veins
Penetrating arteries


Okudera et al, Neuropathology 1999
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WHITE MATTER CHANGES - MRI

• hyperintense areas on T2-, PD-, FLAIR- sequences
  
• without or with only minor hypointensity on
  T1-WI
• focal or confluent
• periventricular, subcortical/deep
• WHIs, WMLs, ARWMCs

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PERIVENTRICULAR HYPERINTENSITIES

• Around frontal and occipital horns
• Small caps ? 5mm
• Large caps 6-10 mm
• Extending caps gt10 mm
• Along the bodies of lateral ventricles
• Thin lining ? 5mm
• Smooth halo 6-10 mm
• Irregular halo gt10 mm

Mäntylä et al. Stroke 1997281614-1623
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HYPERINTENSITIES IN OTHER WHITE MATTER AREAS

• Small focal ? 5 mm
• Large focal 6-10 mm
• Focal confluent 11-25 mm
• Diffusely confluent gt25 mm
• Extensive white matter change

Mäntylä et al. Stroke 1997281614-1623
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PERIVENTRISCULAR WMHIs H
Around frontal and occipital horns A. Small
caps B. Large caps C. Extending caps Along the
bodies of lateral ventricles D. Thin lining E.
Smooth halo F. Irregular halo
Mäntylä R, Aronen HJ, Salonen O, et al. (1999).
Neuroradiology 41657-65.
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OTHER WMHIs
Deep WM (centrum semiovale), subcortical WM and
watershed areas

• Small focal, Large focal
• Focal confluent
• Diffusely confluent
• Extensive WMC

Mäntylä R, Aronen HJ, Salonen O, et al. (1999).
Neuroradiology 41657-65.
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RATING SCALES FOR WHITE MATTER CHANGES ON MRI

• AWAD et al 1986 MIRSEN et al 1991
• ZIMMERMAN et al 1986 COFFEY et al 1991
• GERARD and WEISBERG 1986 LIU et al 1992
• ERKINJUNTTI et al 1987 DAVIS et al 1992
• FAZEKAS et al 1987 SCHMIDT et al 1992
• KERTESZ et al 1988 SCHELTENS et al 1993
• HUNT et al 1989 YLIKOSKI et al 1993
• VAN SWIETEN et al 1990 BRETELER et al 1994
• SHIMADA et al 1990 ERKINJUNTTI et al 1994
• HERHOLZ et al 1990 VICTOROFF et al 1994
• WAHLUND et al 1990 FUKUDA et al 1995
• HARRELL et al 1991 LOPEZ et al 1995
• FIGIEL et al 1991 LONGSTRETH et al 1996
• WAHLUND et al 2001, FAZEKAS 2005

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VISUAL RATING OF AGE RELATED WHITE MATTER CHANGES
ON MRI

• Mäntylä R, Erkinjuntti T, Salonen O, Aronen HJ,
  Peltonen T, Pohjasvaara T et al.
• Variable agreement between visual rating scales
  for white matter hyperintensities on MRI.
  Comparison of 13 rating scales in a poststroke
  cohort.
• Stroke 1997, 281614-1623.

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NEW FAZEKAS RATING SCALE - LADIS ARWMC -Scale
Mild - grade 1 WMH single lesions must
be below 10mm,
areas of grouped
lesions must be smaller than 20mm in
any diameter
Moderate - grade 2 WMH single lesions between 10
to 20 mm,
areas of grouped lesions more than 20 mm
in any diameter, no more than connecting
bridges between individual lesions
Severe - grade 3 WMH Single lesions or
confluent areas of hyperintensity 20mm or
more in any diameter
The basis for rating is always the most
severe abnormality, even when seen only on
one slice
Pantoni L et al. Neuroepidemiology 20052451-62.
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Pantoni
L et al. Neuroepidemiology 20052451-62.
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Pantoni L et al. Neuroepidemiology 20052451-62.
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Pantoni L et al. Neuroepidemiology 20052451-62.
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MRI MEASURES INFARCTION

• RECOMMENDED
• -All infarcts should be localized using a
  standard approach to generate quantitative
  measures of volume and location. Ideally,
  identified infarcts would also be mapped to a
  common stereotactic space

• ACCEPTABLE
• -No. and size at specified location
• -Size (largest diameter) Large gt 1.0cm, Small
  3-10 mm
• -Location. Anatomical locations Supratentorial,
  Hemisphere, Cortical (may include subcortical),
  Exlusively subcortical GM or WM, Infratentorial
• -Encourage use of Talairach atlas for precise
  anatomical localization

Hachinski et al. Stroke2006372220-2241
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ADDITIVE IMAGING MODALITIES

• STATUS OF THE CEREBRAL VASCULATURE
• WHITE MATTER
• Diffusion Tensor Imaging (DTI) for measures of
  mean diffusity (MD) and fractional anisotrophy
  (FA). Tractography
• FOR THE EXCLUSION / INCLUSION OF AD
• FDG PET , Perfusion SPECT, Amyloid PET

Hachinski et al. Stroke2006372220-2241
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VCI NEUROIMAGING

• DAIGNOSING TYPES OF VCI
• GENERAL VaD

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GENERAL VaD CRITERIA
Neurology 199343250-260
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NINDS-AIREN CRITERIA

• Dementia syndrome
• Ceberovasular disease on CT/MRI
• large vessel stroke, small vessel disease
• A (temporal) relationship
• onset lt 3 months of stroke
• abrupt deterioration
• fluctating/stepwise progression
• Topography AND severity criteria

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NINDS NEUROIMAGING CRITERIA FOR VAD

• Topography
• Large vessel strokes
• Extensive white matter change
• Lacunes (frontal/basal ganglia)
• Bilateral thalamic lesions
• Severity
• Large vessel lesion of dominant hemisphere
• Bilateral strokes
• WML affecting gt25 white matter

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NINDS-AIREN CRITERIA CLINICOPTAHOLOGICAL
VALIDATION

• Gold et al. Am J Psychiatry 200215982-87
• Sensitivity Specifity
• POSSIBLE 0.55 0.84
• PROBABLE 0.20 0.94
• Erkinjuntti et. al. JNNP 1988511037-1044
• PROBABLE 23 of 27 (85) no AD changes

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VCI NEUROIMAGING

• DIAGNOSING TYPES OF VCI
• SIVD

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SMALL-VESSEL PHENOTYPE

Lancet
Neurology 20021426-36.
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THE SMALL VESSEL PROTOTYPE

J
Neural Transm 2000 59 23-30
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SIVD - SUBCORTICAL VASCULAR DISEASE AND DEMENTIA

• MRI criteria (panel)
• extending caps ( gt10 mm or irregular halo (gt10 mm
  broad, irregular margins and extending into deep
  white matter)
• and diffusely confluent hyperintensities (gt25 mm,
  irregular shape) or extensive white matter change
  (diffuse hyperintensity without focal lesions),
  and lacune(s) in the deep grey or white matter.

J Neural Transm 2000 59 23-30
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SIVD -SUBCORTICAL VASCULAR DISEASE ANDE DEMENTIA

• MRI criteria (2)
• lacunes (lacunar state) multiple lacunes ( ? 5)
  in the deep gray matter
• and
• at least moderate white matter lesions extending
  caps or irregular halo or diffusely confluent
  hyperintensities or extensive white matter
  changes.

J Neural Transm 2000 59 23-30
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SUBCORTICAL ISCHEMIC VD- MRI
P. Scheltens 2001
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VCI NEUROIMAGING

• DIAGNOSING TYPES OF VCI
• CADASIL

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(No Transcript)
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VCI NEUROIMAGING

• DEMONSTRATING
• CHOLINERGIC TRACTS

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Cholinergic deficit in VCI is related to
involvement of ascending cholinergic pathways

With permission from Oxford University Press.
Selden NR, et al. Brain. 19981212249-2257.
Swartz RH, Black SE. J Neurol Sci.
2002203-204(C)281.
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CHOLINERGIC HYPERINTENSITY PATHWAY SCALE (CHIPS)
Correlation of CHIPS and Dementia Rating Scale(
r2.12, p.02)
Swartz et al, JStr CVD, 2002 Bocti et al,
Stroke, 2008
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VCI NEUROIMAGING

• AS PART OF POST-MORTEM DIAGNOSTICS

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HISTOPATHOLOGY OF WMLs (P Ince 2005)
Proton density MRI
HE
T2w MRI
Herovici
Microglia/macrophages
Myelin stain
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VCI NEUROIMAGING

• SMALL VESSEL DISEASE SURROGATE
• CONFLUENT WMLs

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11 Centres in Europe Florence (D.
Inzitari) Helsinki (T. Erkinjuntti) Graz (F.
Fazekas) Lisboa (J. Ferro) Amsterdam (P.
Scheltens) Goteborg (A. Wallin) Huddinge (L.O.
Wahlund) Paris (H. Chabriat) Mannheim (M.
Hennerici) Copenhagen (G. Waldemar) Newcastle (J.
OBrien)
The LADIS Project a European Union Concerted
Action
Search LADIS
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RESULTS
Mean follow-up 2.42 0.97 years (median 2.94
years)
639 non-demented and - disablled patients
enrolled (mean age 74.1 5.0 yrs, 45males)
633 (96.9) with information on vital and IADL
status (mean age 74.0 5.1 yrs, 45males)
TRANSITION TO DISABILITY OR DEATH 242 (38.2)
patients
Inzitari et al. BMJ 2009 (in press)
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MRI ASSESSMENT

• Baseline (visual scales)
• Modified Fazekas scale (scores 0-3)

Mild Grade 1 ARWMC
Moderate Grade 2 ARWMC
Severe Grade 3 ARWMC
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Annual rate of transition to disability or death
according to ARWMC severity (Fazekas)
Kaplan-Meier Log-Rank Test plt0.001
ARWMC
29.5
15.1
Annual rate of transition to disability or death

10.5
Inzitari et al. BMJ 2009 (in press)
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Kaplan-Meier probability of transition to
disability or death according to ARWMC severity
grades
Inzitari et al. BMJ 2009 (in press)
84
SIVD EXTENSIVE WMLs LADIS EXPERIENCE

• EXTENSIVE (GR 3) WMLs RELATE TO BAD OUTCOMES
• TRANSITION TO DISABILITY
• COGNITIVE DECLINE
• DEMENTIA
• DEPRESSION
• IMPAIRED ADLs
• IMPAIRED GAIT, STABILITY
• URINARY PROBLEMS
• STROKE

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The effect of ARWMC on MRI on overall post
stroke survival in SAM-cohort. Kaplan-Meier log
rank analysis.
p0.001 K-M (10 years)
mild-moderate severe
Plt.001 (12 years)
Patients at risk 182 166 139
112 83
12 mild-moderate ARWMC
214 172 120 91
66 10 severe ARWMC
Oksala et al JNNP 2009 Feb 23 Epub