08/11/2019

Normal aging and brain atrophy

Meike Vernooij, MD PhD
Professor of Population Imaging
Radiology & Nuclear Medicine; Epidemiology
Erasmus University Medical Center
Rotterdam, The Netherlands

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Example of report The Radiologist’s perspective

Request: 77‐yr old male, subjective memory 
complaints. Q: pathology? 
Phrase from brain MRI report:
“There is loss of brain volume normal for age”
• We are used to assess abnormality, not normality.
• Age‐related changes are non‐acute…
…and thus not of interest.
• Usually no clinical question addressing ageing.
• Lack of proper frame of reference.
• Aging is a dynamic process.

What is ‘normal for age’?
“ atrophy unremarkable for age”
“ nonspecific leukoaraiosis”
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The Epidemiologist’s perspective The Neuroscientist’s perspective
• Characteristic changes of brain aging are also strongly 
linked to neurodegeneration.
• ‘Normal ageing’ may form a spectrum with 
neurodegeneration.
• Succesful versus less successful ageing likely influenced 
by genetic, lifestyle and environmental factors.

• Populations are ageing, so is age‐related brain pathology!

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What happens in the brain in aging?  Age‐related brain changes

MICROSCOPY IMAGING
• amyloid plaques • atrophy
• neurofibrillary tangles • white matter disease
• Lewy bodies
• neuronal loss • cerebral microbleeds
• ependymal loss NEURODEGENERATION • silent brain infarcts
• iron deposition CEREBROVASCULAR DISEASE • enlarged perivascular spaces
• subependymal gliosis • iron deposition
• myelin loss
• axonal degeneration
• microvascular pathology
• …..
NORMAL PATHOLOGICAL
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Brain atrophy: normal? Atrophy: clinical assessment
• symmetric > asymmetric
• Loss of brain tissue occurs after age of 30: 0.2%/year. • generalized > focal
• Acceleration after age 70: 0.5%/year. • severity: visual assessment: global cortical atrophy (GCA)
• At age 75: 10% loss of brain tissue compared to age 30.

What is abnormal?
o > 1‐2% tissue loss/ yr
o Regional atrophy/asymmetry

GCA 0 GCA 1 GCA 2 GCA 3

Vinke et al.; Neurobiology of Aging 2018 (none) (mild) (moderate) (severe)
based on >4,000 Rotterdam Study subjects 
9 no atrophy          widening sulci       volume loss gyri        ‘knife‐blade’

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Atrophy: clinical assessment Hippocampus: what is normal?

• symmetric > asymmetric Medial temporal atrophy (MTA) scale
• generalized > focal
• severity: visual assessment: global cortical atrophy (GCA)
Pasquier F, Eur Neurol 1997
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Severity

abnormal < 75 yr no atrophy 

always abnormal widening choroid fissure 
widening temporal horn
↓ hippocampal volume
GCA 0 GCA 1 GCA 2 GCA 3 ↓↓  hippocampal volume 
(none) (mild) (moderate) (severe)

no atrophy          widening sulci       volume loss gyri        ‘knife‐blade’ Scheltens et al. 1992

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Hippocampus: what is normal? Atrophy: change over time?

0 1 2 3 4

Severity 11% 10% 9%

124 ml 111 ml 100 ml
no atrophy 
What is abnormal?
widening choroid fissure 
o Up to 75 yr: MTA ≥ 2 on one
widening temporal horn side 2009 2010 2011
↓ hippocampal
o Over 75 yr: MTA ≥ 2 on both sides volume
↓↓  hippocampal volume 

Scheltens et al. 1992

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t=0

What is normal? What is normal ?

t=5
90
References values derived from normal aging population
Brain volume (% ICV)

80
95%

75%
50%
70
25%

5%

60
Ikram et al., Neurobiol of Aging 2008 Vrooman et al., NeuroImage 2006 50 60 70 80 90 100
Age

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White matter hyperintensities White matter disease: terminology

50
45 ‐ 59 y
40 60 ‐ 74 y
74 ‐ 97 y

30
% “WMH OF PRESUMED VASCULAR ORIGIN”
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0
0 1 2 3 4 5 6 7 8 9

white matter lesion severity (categories)

De Leeuw et al., JNNP 2001 Wardlaw Lancet Neurology 2013

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White matter lesions and cognition

dementia risk
Fazekas 1

Fazekas 2

cognitive decline

de Groot et al., Annals of Neurology 2002 Prins et al., Archives of Neurology 2004
Fazekas 3

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WMH: MRI versus CT
I II III

Fazekas 1

What is abnormal?
Fazekas 2
o Diffuse confluent lesions (Fazekas 3)
o Rapid progression

Wattjes, Radiology 2009

Fazekas 3
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2005 2008 2005 2008

FA MD De Groot et al.; Stroke 2013

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Normal ageing? Microbleeds

T2 FLAIR T2* GRE amyloid angiopathy (CAA) hypertension

male, 72 years Greenberg et al., Lancet Neurology  2009
Vernooij et al.; Neurology 2008

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Microbleeds: what is normal? Microbleeds: what is normal?

• prevalence > 20% in general population > 60 yrs. • Boston criteria: ≥ 2 lobar (micro)bleeds = probable CAA1.

• single microbleed in person considered not relevant. • multiple: relate to worse cognitive function.
• caveat: strong dependency on technology. • multiple: increased risk of stroke and dementia.
1Knudsen; Stroke 2001.

o Multiple CMBs: suggest
SVD.
o Lobar: CAA.
o Deep: hypertension.
o Note imaging technique
used. 
GRE SWI 1.5 T 3.0 T 2013 2014
Yamada; J Stroke 2015. Akoudad; Circulation 2015.

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Silent brain infarcts Silent?
lacunes

• prevalence up to 30%
• size 3‐15 mm
• rim of gliosis

o Lacune: suggest small vessel
disease
o Doubles risk of stroke and
dementia

Vermeer; Stroke 2002

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Newly recognized subtypes Ischemic lacune?

cortical
microinfarcts
(6%)

small cerebellar
infarcts (11%)

31 2011 2012

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Enlarged perivascular spaces Enlarged perivascular spaces
• Typical locations:
– Mesencephalon
– Lenticulostriatal
– Subinsular
– CSO

• Relate to markers of small 
vessel disease.
• Worse cognition.
• Correlations with 
parenchymal amyloid 
deposition.
Zhu; Stroke 2010.
Adams; Stroke 2013.
Maclullich; JNP 2004.
Charimidou; Stroke 2015.

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Enlarged perivascular spaces État criblé

blockage atrophy
hypertension inflammation

Zhu; Stroke 2010. Satizabal; JAD 2012. Kress; Ann. Neurol. 2014. Weller; Brain path. 2008.
Charimidou; Stroke 2015. Roher; Mol Med 2003. Zlokovic; Neuron 2008. Patankar AJNR 2005. 36

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Iron deposition in brain ageing

• essential element (ATP synthesis, myelin) • normal: globus

• accumulation in aging (> 20‐30 yrs): homeostatic VARIABILITY:  pallidus, dentate
disturbance nucleus
* TECHNIQUE (FIELD STRENGTH)
• risk factors: age, smoking, hypertension, obesity
* INTER‐INDIVIDUAL
• accumulation  oxidation, inflammation  QUANTIFICATION NEEDED • abnormal: excessive
neurodegeneration hypointensity, 
abnormal locations
(pulvinar)  

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Iron versus calcification Checklist for normal brain aging

• Brain atrophy: report MTA, GCA, lobar pattern, asymmetries. 
• GCA: score of 3 (‘knife‐blading’) always abnormal.
• GCA: score of 2 abnormal in persons < 75 years.
• MTA: score of 2 or higher on one side is abnormal in < 75 yrs
• MTA: score of 2 or higher on both sides is abnormal in ≥ 75 yrs
• WMH: report Fazekas scale, normal up to 1.  
• Fazekas: score of 2 or 3 suggests underlying small vessel disease.
T2 FSE T2*
• Report presence of lacunar infarcts, cortical (micro)infarct, small 
cerebellar infarcts.
• Report enlarged perivascular spaces (basal ganglia, centrum 
semiovale, mesencephalon, subinsular region). 
• Etat criblé is always abnormal.
• Microbleeds: number and location (lobar versus deep). Mention 
field strength and pulse sequence.
SWI-magnitude SWI-phase SWI-mIP
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Example of report Take home points

77‐yr old male, subjective memory complaints. Abnormal patterns of 
atrophy or vascular lesions? • Age‐related brain changes can no longer be ignored.
Interpretation: • Understand that aging is a dynamic process.
• Mild generalised brain volume loss (GCA 1) in accordance with patient’s  • Use of reference values will become increasingly 
age, no lobar preference, no asymmetry. important for clinical interpretation.
• Mild hippocampal atrophy, MTA 1 on right, MTA 2 on left side, normal 
for age. • Many visible changes are only tip of the iceberg.
• Punctate WMH in periventricular and subcortical locations, Fazekas 1. • Use checklist for reading and reporting brain scans in 
• No lacunar or cortical infarcts. Single small cerebellar infarct on left aging.
side.
• Single lobar microbleed in right frontal lobe.

Conclusion:
Mild degenerative and vascular brain changes, consistent with normal 
brain aging, no evidence for a neurodegenerative disorder. Today’s radiologist is prepared for tomorrow’s patients
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Thank you for your attention

m.vernooij@erasmusmc.nl

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