Daniela Perani

Vita-Salute San Raffaele University,

Nuclear Medicine Department and Division of Neuroscience

San Raffaele Scientific Institute, Milano

AIP 15° Congresso Nazionale

Firenze 16-18 aprile 2015

Simposio

Il punto sulle più recenti evoluzioni dell’imaging nelle

demenze

HIGHLIGTHS SUI CONTRIBUTI della PET

• investigating underline

pathophysiological mechanisms

• providing disease evidence in early

and preclinical phase

• supporting clinical diagnosis and

differential diagnosis

• evaluating prognosis and risk

progression

• monitoring therapy

PET molecular neuroimaging

in neurology research

This patient demonstrates a significant correlation

between severe decreased cognitive functions and

diffuse functional reduction more severe in the

temporo/parietal associative cortex

Probable AD

Perani et al. JNM, 1988

FDG PET imaging in dementia

20 years

Post mortem autoradiograms In vivo PET imaging

Klunk et al. 2004

AMYLOID-PET imaging in dementia

10 years

Current diagnostic neuroimaging

biomarkers fall into two categories:

biomarkers of disease stage (neuronal injury):

FDG-PET

biomarkers of disease state (Ab amyloid burden): AMY-PET

These PET biomarkers are sufficiently validated to have been incorporated into research diagnostic criteria and commonly used in therapeutic trials

Jack CR, Holtzman DM, Neuron 2013

RESEARCH DIAGNOSTIC CRITERIA

including FDG PET or/and amyloid PET

ALZHEIMER DISEASE

• McKhann, G.M., Knopman, D.S., Chertkow, H., Hyman, B.T., Jack Jr, C.R., Kawas, C.H., et al.,2011. The diagnosis of dementia due to Alzheimer’s disease: recommendations fromthe National Institute on Aging- Alzheimer3s Association workgroups on diagnostic guidelines for Alzheimer3s disease. Alzheimers Dement. 7 (3), 263–269

• Albert, M.S., DeKosky, S.T., Dickson, D., Dubois, B., Feldman, H.H., Fox, N.C., et al., 2011. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer3s Association workgroups on diagnostic guidelines for Alzheimer3s disease. Alzheimers Dement. 7 (3), 270–279

• Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., et al., 2011. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer3s Association workgroups on diagnostic guidelines for Alzheimer3s disease. Alzheimers Dement. 7 (3), 280–292

• Dubois, B., Feldman, H.H., Jacova, C., Cummings, J.L., Dekosky, S.T., Barberger-Gateau, P., et al., 2010. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 9 (11), 1118–1127

• Dubois, B., Feldman, H.H., Jacova, C., Hampel, H., Molinuevo, J.L., Blennow, K., et al., 2014. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria.Lancet Neurol. 13 (6), 614–629

• Crutch, S.J., Lehmann, M., Schott, J.M., Rabinovici, G.D., Rossor, M.N., Fox, N.C., 2012. Posterior cortical atrophy. Lancet Neurol. 11 (2), 170–178.

LEWY BODY DISEASE

• McKeith, I.G., Dickson, D.W., Lowe, J., Emre, M., O3Brien, J.T., Feldman, H., et al., 2005.Diagnosis and management of dementia with Lewy bodies: third report of the DLB. Consortium. Neurology 65 (12), 1863–1872

FRONTOTEMPORAL DEGENERATION SPECTRUM

• bvFTD Rascovsky, K., Hodges, J.R., Knopman, D., Mendez, M.F., Kramer, J.H., Neuhaus, J., et al.,2011. Sensitivity of revised diagnostic criteria for the behavioural variant of Frontotemporal dementia. Brain 134 (9), 2456–2477

• PPA Gorno-Tempini, M.L., Hillis, A.E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S.F., et al.,2011. Classification of primary progressive aphasia and its variants. Neurology 76 (11), 1006–1014

• CBD Armstrong, M.J., Litvan, I., Lang, A.E., Bak, T.H., Bhatia, K.P., Borroni, B., et al., 2013. Criteria for the diagnosis of corticobasal degeneration. Neurology 80 (5), 496–503

RESEARCH DIAGNOSTIC CRITERIA

including FDG PET or/and amyloid PET

Summary sensitivity effect measures: 0.86 for FDG-early diagnosis 0.90 for FDG-differential diagnosis

0.91 for amyloid-early sensitivity

• FDG PET = detect specific topographical

patterns

• AMY PET = measure the amount of

amyloid burden

Statistical Parametric Mapping SPM [18F]FDG-PET

VOXEL-BASED ANALYSIS at a GROUP and SINGLE SUBJECT

LEVEL

Probable AD

Logopenic vPPA

Lewy-Body Dementia (DLB) ♀ 71 years old

Behavioral Variant FTD (bvFTD) ♀ 69 years old

Higher sensitivity and specificity values for SPM Maps (96% and

84%),

Improved diagnostic accuracy with SPM Maps

Additional value to clinical information

Importance of metrics in the clinical setting!

NEUROIMAGE CLIN: 2014

no

conversion 8 AD

conversion

5 FTD

conversion

2 DBL

conversion

FDG PET

• Recent memory impairment, sustained attention disorder, anxiety and depression;

• Mild long-term memory impairment at NPS evaluation (Rey word list borderline performance) • 4 years of disease duration;

• BADL 6/6; IADL 8/8; MMSE 29/30;

• Normal brain MRI;

♀ 56 years old

aMCI?

aMCI ♀ 62 years old

NO Neurodegenerative

disease

“the high specificity of FDG-PET in AD, FTLD and DLB implies that a negative, or normal scan in the presence of the suspicion of dementia makes a diagnosis of a neurodegenerative disease very unlikely “.

“in the context of initial diagnosis, the exclusionary role of FDG-PET, is especially important in younger subjects with a suspicion of neurodegenerative disease”.

(Jagust et al. 2007)

25 years of research in

neurodegenerative diseases

using FDG PET imaging

FDG PET metabolic patterns

clinical application

BIOLOGICAL PROCESS

[

[11

C]PIB-PET

[18F]NeuroCeq

[18F]AV-45

[18F]GE

Amyloid plaques

Mo

le

cu

la

r Im

ag

in

g

In

divid

ua

l leve

l

The strong direct correlation of in vivo PiB retention with

region-matched quantitative analyses of Ab plaques in the

same subject supports the validity of PiB-PET imaging as a

method for in vivo evaluation of Ab plaque burden

Villemagne and Rowe JAD 2013

AMYLOID PET

[11C]PIB

the more diffuse and clinically tested

amyloid ligand

• Short half life

• Low cost, few production centres

[18F] fluorbetaben

[18F] fluorbetapir

[18F] flutemetamol

in clinical trials sponsored by the industries

• Long half life, commercializzabile

• High cost for public health system

Amy-PET analysis

methods

• Standardized Uptake Value (SUVr)

[Kepe et al. 2004]

• Distribution Volume Ratio (DVR)

[Logan et al. 2006]

• Simplified reference tissue-based

methods [Wong et al. 2006 ]

• Voxel-based analysis (Statistical

Parametric Mapping-SPM)

Why quantification

or semi-quantification in amyloid

PET?

1. Multicentric studies

2. Between group variability

3. Intersubject variability

4. DISEASE variability

5. Therapy monitoring

TERMINATED 2.8%

RECRUITING 34.7% ACTIVE

ENROLLING 18%

UNKNOWN 1.4%

SUSPENDED 1.4%

COMPLETED 37.5%

NOT YET

RECRUITED 4.2%

PET AMYLOID CLINICAL TRIALS

Exclusion of amyloid pathology should allow a more accurate

prognosis to be given and ensure appropriate recruitment into

clinical trials testing the efficacy of new putative antiamyloid

agents at an earlier disease stage.

Villemagne et al. 2008

• Alzheimer’s disease and AD subtypes

• MCI subjects (amnestic type) and converters

• Lewy Body Dementia

• PD, PD dementia

• Amyloid angiopathy

• Traumatic injuries

Variable or high amyloid load

(SUVr >1.1-1.5 up to 2.5……)

Amy-PET positivity in:

Lewy Diseases

Gomperts et al. Mov Dis 2012

Viswanathan,and Greenberg

Ann Neurol 2011

TRAUMATIC BRAIN INJURY

Hong YT et al. JAMA Neurol 2014

Aß amyloid in

Alzheimer Disease

risk of progression

to dementia

DIMI Eu Project 7° FWP

EJNM 2012

11

C-PIB PET imaging

102 AD patients (51 male, 51 females, 69±8

yrs, MMSE 23.9±3)

73 MCI patients (38 males, 35 females,

67±8 yrs, MMSE 27.1±2.0) 4 yrs follow up

52 healthy controls (22 males, 30 females,

67±6, MMSE 29.1±1.1)

65%

RESULTS

• Significantly higher PIB uptake in cortical regions in

AD patients compared to HC

• Low, intermediate or high PIB uptake in MCI

None of the 21 PIB- MCI

converted to AD

67,4 % of the PIB+ MCI

converted to AD at 28 ±

15 month follow-up

PIB+ MCI patients

progressed to AD at an

estimated rate of 25%

per year

Neurodegenerative diseases are complex disorders

with multiple and overlapping pathophysiological

processes, multitracer imaging may be helpful in

combining metabolic with those labelling typical protein

aggregations seen in the progression of MCI to

Alzheimer’s disease.

Combination of biomarker modalities, such as AMY-

PET, FDG-PET, and structural MR, is likely to provide

the best additional neuroimaging information over that

of single imaging (Jack 2008; Trzepacz 2014)

Moreover, the combined use of 11C-PIB and 18F-FDG

PET provided beneficial information for MCI due to

non-AD (Banzo 2014).

Fig. 1 . Classification abilities of single and

combined Imaging biomarkers in predicting MCI

conversion to AD dementia (F-up > 2yrs to 5)

1. FDG PET SPM Hypometabolism Pattern

was the best single predictor of

conversion to AD dementia

Sens: 1; Spec: 0.954; Acc: 0.974

2. Amyloid PET positivity above the cut-

off thresholds showed high

sensitivity but low specificity

Sens: 1; Spec: 0.65; Acc: 0.80

3. Adding Amyloid PET to FDG PET did

not incresed sensitivity and

specificity

Sens: 1; Spec: 0.954; Acc: 0.974

The role of SPM FDG-PET and Amyloid-PET in predicting MCI conversion to AD dementia

IIaccarino, Chiotis et al., submitted

1. 16/17 Amy+/FDG+ converted to

AD

2. 14/14 Amy-/FDG- did not convert

3. 7/7 Amy+/FDG- did not convert

(incident amyloid positivity)

4. 1/17 Amy+/FDG+ did not convert

Longer follow-up needed

7

14

1

16

The role of SPM FDG-PET and Amyloid-PET in predicting MCI conversion to AD dementia

Iaccarino, Chiotis et al., submitted

DIFFERENT PET MARKERS

= DIFFERENT MOLECULAR

MEASURES

Voxel-Based Comparisons of Amyloid PET, FDG PET Differences between Subjects with AD and Cognitively Normal

Elderly

Jack et al., Neuron, 2013

AMYLOID-PET FDG-PET

Diverging patterns of amyloid deposition and

hypometabolism in clinical AD variants

Lehmann et al. Brain 2013

no associations between regional PIB and FDG

uptake in AD dementia

Furst et al. Neurobiol Aging 2012

No FDG- AMY PET

brain regional correlations

in MCI converters

Alongi, Iaccarino et al. submitted

Furst et al. Neurobiol Aging 2012

Spatial convergence between Aβ, DMN,

heteromodal cortex and cortical hubs

PIB-PET

amy load

cortical HUBs

Heteromodal

Cortex

DMN

Aerobic

Glycolysis

Jagust and Mormino Trends Cogn Sci. 2011

AD sbj NC high PIB

Brain Reserve

in diseases

Amyloid deposition is associated with lower

cognitive performance both in AD patients and in the

normal elderly, but the association is modified by

CR, suggesting that CR may be protective against

amyloid related cognitive impairment.

temporal cortex

parietal cortex and precuneus

pAD

Garibotto et al, Neurology 2008

1. synthesis 2. release 3. binding potentials 4.neurotransmission 5. re-uptake

POSITRON EMISSION TOMOGRAPHY

Education/Occupation and BPs

positive correlation

Garibotto et al. NBD 2013

POSITRON EMISSION TOMOGRAPHY

Tau-mediated neuronal injury

and dysfunction

FDG-PET HYPOMETABOLISM IN EARLY AD

Tau pathology

tau PET ligands FDG-PET

[18F]FDDNP signal was associated with

lower cognitive Z scores at each cortical voxel

Ossenkoppele et al. Ann Neurol 2015

FDG/AMYLOID/TAU relationship

PCA AD case

Tangle stage, and not amyloid

phase, significantly explained

age of onset, disease duration

and MMSE final score

N=3618 autopsy cases with neurodegenerative history

N=1375 High AD likelihood (abeta and tau)

Aging and Aß amyloid

The presence of brain Aß does not necessarily imply pathology, but may even be a physiological age-related phenomenon

• post mortem studies have revealed that Aß plaque prevalence increases in an exponential fashion with age

• 20-30-40% of elderly healthy subjects have increased brain Aß amyloid upon amyloid PET

Sugihara et al. 1995 Rowe et al. 2007,2010, Pike et al.

2007,Villemagne et al.2013, Nordberg et al 2013,

Chetelat et al. 2013, Lopez et al. 2014 ………………

Nordberg et al. 2013

Arch Neurol. 2008;65(11):1509-1517

• amyloid deposition was not associated with worse cognitive function

• elderly person with a significant amyloid burden can remain cognitively normal

• Once amyloid reaches AD levels, deposition reaches a plateau.

Future Directions: Biomarker temporal modeling

The rate of amy deposition per year

is indendependent by amy burden

at baseline in HC, MCI and AD

Different rates of amy deposition

independent by the MMSE

in HC, MCI and AD

Findings suggest that the major growth in

Ab burden occurs during a preclinical stage

of Alzheimer disease (AD), prior to the onset

of AD-related symptoms

Future Directions: When amyloid turns toxic

• Results show that toxic oligormers may form after a critical concentration of amyloid has been reached • The oligomers are formed from monomeric peptide molecules through a secondary nucleation reaction involving also amyloid fibrils

Future Directions: When amyloid turns toxic

•Amyloid plaques are not toxic by themselves in vivo, but facilitate the generation of toxic oligomers after a critical concentration of amyloid by a surface catalysis

•This is in contrast to the theory that Ab oligomers form first and then form fibrils. We can hypothesize from these data and our PET imaging data that a pathologic threshold of amyloid fibril accumulation, sufficient to catalyze formation of toxic oligomeric Ab, is occurring at a PiB SUVR of at least 1.5.

•Left open to question is whether minimal levels of amyloid lower than 1.5 exert any neurotoxic effect seen as hypometabolism or otherwise it requires more longitudinal and serial individual data to resolve

Lowe et al. Neurology, 2014

THANK YOU

FOR YOUR ATTENTION