The role of neuroimaging

in dementia of the

working age

Nick Fox Dementia Research Centre

Institute of Neurology, UCL

Queen Square, London

Overview

• Changing role of imaging

• “Working age” dementia

• Guidelines and consensus criteria

• Imaging features of the dementias

• What a scan can tell you – adding value

• A practical approach …

…..and a look to the future

Early-onset dementia. Jefferies & Agrawal APT 2009;15:380-388

The diagnosis of young-onset dementia. Rossor, Fox et al Lancet Neurology 2010;9:793-806.

Changing roles of imaging

• From excluding treatable causes

– Neoplasm, hydrocephalus, subdural

– “Yield” – 1% ?

• To making a positive diagnosis

– moving from “dementia” to a specific diagnosis

• Supporting an earlier diagnosis

– adding specificity to “MCI”

• Adding molecular information

• Research and Trials

Improving diagnosis

• National priority: “Dementia Strategy”

• Patient and carers: Alzheimer’s Society

“…it is crucial to highlight the value of

early diagnosis and intervention …”

Structural imaging for diagnosis

•Structural imaging should be used to assist in the diagnosis of dementia, to aid in the differentiation of type of dementia and to exclude other cerebral pathology

•Magnetic resonance imaging (MRI) is the preferred modality to assist with early diagnosis and detect subcortical vascular changes, although computed tomography (CT) scanning could be used

• CT and MRI may be used to exclude treatable causes of dementia.

• Multislice CT and coronal MRI may be used to assess hippocampal atrophy to support a clinical diagnosis of AD (Level B).

• FDG PET and perfusion SPECT are useful adjuncts when diagnosis remains in doubt (level B).

• Dopaminergic SPECT is useful to differentiate AD from DLB (level A).

• Follow up with serial MRI is useful in a clinical setting to document disease progression (good practice point).

Establishing the subtype diagnosis

• Diagnosis is based on clinical criteria

Imaging supportive but not required

• Alzheimer’s disease

• Dementia with Lewy bodies

• Frontotemporal dementia

• CJD

Imaging needed for vascular dementia

• Extent

• Topography

• Severity

How is imaging different in

people of working age?

“working age” is ?

Working age dementia in

the UK

• 40,000 cases (20-60K) vs 700,000 total

• Unusual causes relatively more common –

not so dominated by AD and VaD

• And so are atypical presentations of AD

• Higher proportion of

– “treatable” causes

– Genetic causes

• Some characteristic imaging features

Working age dementia

• AD 30-35%

• Vascular 10-15%

• FTD ~10-15%

• Alcohol ~10%

• DLB ~5%

• Other ~20-25%

• Other .. – HD

– PSP, CBD

– Head injury

– MS

– Epilepsy

– CJD

– Familial AD & trisomy 21

– Antibody mediated

Unusual & “treatable” causes are more common

in younger than older onset dementia

Early-onset dementia. Jefferies, and Agrawal APT 2009;15:380-388

©2009 by The Royal College of Psychiatrists

Structural imaging to assess: space occupying

lesions, vascular damage and pattern of atrophy

Gait disturbance

Cognitive impairment

Urinary difficulties

Normal pressure hydrocephalus Tight convexity CSF spaces

Changing roles of imaging

• From excluding treatable causes

• To making a positive diagnosis

– moving from “dementia” to a specific diagnosis

“No space occupying lesion. There

is involutional change likely related

to ageing and there are some

scattered white matter

hyperintensities…”

A scan is only as useful as its

interpretation …

What can you ask (look for)

beyond a surgical cause?

• Is the scan normal for age?

• Signal change?

– VaD?

• Look at basal ganglia & brain stem

• Extent of white matter change

– Other?

• Atrophy?

– Is there focal (lobar) or generalised atrophy?

– Disproportionate hippocampal atrophy?

Vascular dementia

• Stepwise progression of dementia may be a feature

but… many cases of VaD have gradual deterioration

• Focal neurological signs (e.g. aphasia, hemiparesis)

may be present but are often not

• Frontal subcortical cognitive profile with gait

abnormalities, brisk reflexes, pout

• Small vessel disease may mimic AD/DLB - insidious

onset and progression including “memory”

Large vessel (multi-infarct)

dementia

Cortico-

subcortical

occipito-temporal

infarct

Strategic infarct(s)

• THALAMIC

DEMENTIA

Subcortical VaD

• White matter predominant

• Lacunar

predominant

1 = Punctate 2 = Early Confluent 3 = Confluent

NEVER normal “Normal” Abnormal < 70

White matter lesions – Fazekas scale

Pattern of microbleeds

Not all signal change is

vascular

Baseline 6 months later

VGKC associated Limbic Encephalitis

DWI FLAIR

Prion – CJD

C

J

D

Atrophy

• Generalised? Symmetrical?

• Hippocampal atrophy > global?

• Progressive?

In AD tangles first appear in

Entorhinal Cortex and then

Hippocampus

Transentorhinal

Stages I-II

Limbic

Stages III-IV

Braak & Braak 1991

H

A

E

C

Medial temporal lobe regions

atrophy early in AD

AD

• Symmetrical atrophy with posterior

greater than anterior loss (cf FTLD)

• The medial temporal lobe and posterior

cingulate are sites of early change

In “mild” AD the hippocampus is

10-20% smaller than in controls

Seab ’88, De Leon ’89, Scheltens ’92, Soininen ’94, Jack ’99, Du ’01, Killiany ’02

Proposed criteria for AD

Time 0 18months 36months

H

Serial coronal MRI of an individual with initially mild AD

MMSE ~20/30

H/c 25% down

Sens & spec ~85%

Less sensitive in younger and milder patients

Arch Neurol 2007

Duara Neurology 2008

Visual assessment of atrophy

Spiral CT – now able to get

high resolution - atrophy

pattern similar to MRI

Wattjes M P et al. Radiology 2009

MRI CT

55 yr AD CDR =1

+ 18 mths

+ 36 mths

+ 42 mths

3%/yr loss

58 year old – c/o problems with vision and reading, memory not

a problem

Biparietal Alzheimer’s disease (PCA)

Symmetrical hippocampal atrophy is

characteristic of AD but also seen in

Dementia with Lewy Bodies

DLB AD PM proven

Low dopamine transporter uptake in

basal ganglia

AD DLB/PDD

Control PD

A “suggestive

feature” in

consensus criteria

for DLB (2005)

McKeith et al, 2005

O’Brien et al, 2004

Walker et al, 2002-8

Atrophy

• Focal?

• Pattern?

• Progressive?

FTD patterns…

• Behavioural variant FTD:

– Orbitofrontal or dorsolateral atrophy

• Changes in personality and social behaviour

– Right temporal (+frontal)

• Semantic dementia (svPPA):

– Ant>post; fusiform, pole

• Left: anomia, impaired comprehension & loss of word knowledge

• Right: behaviour

• Progressive nonfluent aphasia:

– Perisylvian – inf frontal

• Disrupted speech output, phonological deficits

• Cf Logopenic aphasia (AD)

Frontal

Semantic

dementia

Prosopagnosia

R L

PNFA

nfPPA

R L

Control

AD

FTLD

Jagust et al, Neurology 2007

Functional imaging: metabolic

patterns differ between diseases

FDG-PET

From

“Neuroimaging in

Dementia” - 2010

Research? Or the future of

clinical practice?

- an increasing range of

imaging modalities are

available

Structural imaging now can be accelerated –

retaining resolution and contrast

PM-proven AD: 1.5T MRI

Imaging amyloid with PET

PIB: Klunk Ann Neurol ’04; FDDNP: Barrio ’99; F-BAY: Rowe

Lancet Neurol ’08;

[11C] PIB, [18F] FDDNP, [18F] BAY94, [18F] AV 45 & others

MCI non-converter MCI subject who

subsequently

converted to AD

Amyloid binding increases several

years before clinical AD

David Brooks, Hilary Archer, Aren Okello

Maruyama et al.

Neuron 2013

Tau-PET imaging with 11C-PBB3

In vitro binding to

Neurofibrillary tangles, neuropil threads and neurites in AD

How do the different

modalities associate with

each other?

Imaging posterior cortical

atrophy

Slattery CF et al Phenotypical variation in AD: insights from posterior cortical atrophy. Pract

Neurol 2014.

Profiles of atrophy, glucose metabolism and amyloid deposition in a patient with atypical AD

Ossenkoppele R, et al Annals of Neurology 2014

Tau, amyloid, and hypometabolism in a patient with posterior cortical atrophy.

Profiles of atrophy, glucose metabolism and tau deposition in a patient with atypical AD

In practice

• All patients should have structural imaging –

in working age dementia this should be MRI

• Positive predictive value for AD of

hippocampal atrophy – and

posterior>anterior gradient

• Focal atrophy syndromes and heavy

vascular burden suggest non-AD diagnoses

• Consider diffusion imaging in rapid dementia

Conclusion

• Imaging in dementia of working age is an essential part of

diagnosis

– NICE guideline

– Diagnostic criteria for AD, vascular dementia and other dementias

• Only as good as the assessment – a structured approach

can be usefully applied by a non-radiologist

• Positive contribution to the diagnosis of dementia is

possible with imaging and is even more relevant in working

age dementia

Thank you