01 rabinovici imaging neurodegenerative diseases
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1
Imaging Neurodegenerative Diseases: When Should We Get Fancy?
Gil Rabinovici, MDEdward Fein & Pearl Landrith
Distinguished ProfessorUCSF Memory and Aging Center
UCSF Recent Advances in NeurologyFebruary 14, 2018
Disclosures
• Consulting/research relationships with Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Merck
• Presentation includes the amyloid tracer [11C]PIB and tau tracer [18F]AV1451 which are not FDA-approved for clinical use
• All case vignettes are based on UCSF Memory & Aging Center patients, identifying features have been modified
ARS Question #1Which of the following is TRUE about amyloid PET?A. It is investigational only and not yet FDA
approved for clinical use
B. It is a definitive diagnostic test for Alzheimer’s disease
C. Can be clinically useful in patients with cognitive impairment of uncertain etiology
D. Amyloid PET ligands bind to soluble more than fibrillar forms of Aβ
It is i
nvesti
gatio
nal only
...
It is a
definiti
ve diag
nosti...
Can be cl
inically
useful in
...
Amyloid PET lig
ands bind ..
23%
13%
60%
3%
ARS Question #2Which of the following patients would be highest priority for clinical molecular imaging?
A. Tau PET in an 84 year-old retired attorney with clinically typical Alzheimer’s disease
B. Amyloid PET in a 53 year-old commercial airline pilot with early-onset dementia
C. FDG-PET in a 45 year-old with subjective memory complaints, normal cognitive testing, and a family history of Alzheimer’s disease
D. DaTscan in a 75 year-old with cognitive decline, parkinsonism, and recurrent visual hallucinations
Tau PET
in an 84
year-o
ld...
Amyloid PET in
a 53 year..
.
FDG-PET in
a 45 year-o
ld...
DaTscan in
a 75 year-o
ld ...
0%9%
25%
66%
2
Outline
• Limitations of purely clinical diagnosis
• MRI: more than just a “rule out” test
• FDG-PET, DaTscan
• Amyloid PET– Accuracy vs. neuropathology
– Clinical applications
– Appropriate Use Criteria
– IDEAS: national study on clinical utility
• Preview of Tau imaging
Clinical Diagnosis of AD Circa 1984
McKhann et al., Neurology 1984
“Clinical criteria for AD include insidious onset and progressive impairment in memory and other cognitive functions.The diagnosis cannot be determined by laboratory tests – these tests are important primarily in identifying other causes of dementia”
1984 – 2018: Evolution of AD Biomarkers
FDGPET
StructuralMRI
AmyloidPET
CSF Aβ42, Tau, p-Tau
In 2018, diagnosis of AD is still based on clinical symptoms and cognitive testing.Laboratory tests are still used primarily to exclude other causes of dementia.
Accuracy of Clinical Diagnosis of ADU.S. Alzheimer’s Disease Centers 2005-10
• Probable AD (NINCDS-ADRDA) vs. autopsy* (n=526)– Sensitivity 71%, specificity 71%
• Clinical diagnosis of non-AD dementia vs. autopsy* (n=271)– 39% found to have primary AD post-mortem
* Based on pathologic criteria of intermediate or high-likelihood AD (NIA-Reagan: CERAD-mod or freq; Braak III-VI)
Beach et al., J Neuropathol Exp Neurol 2012
3
Limitations of Clinical Diagnosis
• Same clinical phenotype can be due to multiple pathologies
• Same pathology can lead to multiple clinical phenotypes
• Clinical manifestations occur late in disease course– Long pre-clinical phase offers a therapeutic
window for early intervention
MRI: Not Just a “Rule Out” Test
• Atrophy patterns– Cortex, medial temporal,
basal ganglia, brainstem, cerebellum
• Cerebrovascular– Infarcts; white matter
hyperintensities
• Diffusion abnormalities– Cortical and subcortical
DWI in CJD
• “Pathognomonic” features– “Hummingbird” – PSP
– “Hot cross buns” - MSA
AD FTDFTD mentioned in radiology report in only 10% of patients(Suarez et al., Neurology 2009)
Desikan et al. AJNRAm J Neuroradiol. 2013
Clinical Quantitative MRI FDG-PET in Dementia Syndromes
Bohnen et al. J Nucl Med 2012
4
Diagnostic Accuracy of FDG“AD” vs. “Non-AD”
Sensitivity Specificity
Silverman et al. 2001(mixed, n=138) 94% 73%
Jagust et al. 2007(mixed, n=44) 84% 74%
Minoshima et al. 2001(AD vs. DLB, n=53) 90% 80%
Foster et al. 2007(AD vs. FTD, n=45) 97% 86%
Lost in Translation?
• Comparison of FDG reads in the community to expert clinical diagnosis (Shipley et al., Neurol Clin Pract 2013)
– FDG performed in 49/1580 (3.1%)
– PET reads discordant with final expert dx in 65%
• Sources of error
– Ambiguous metabolic patterns• Very little use of SSP or other statistical displays
– Limited radiologist experience with brain PET
• 89% read by general radiologists or non-radiologists
– Non-specific or inappropriate clinical question
• 7% ordered for AD vs. FTD
Dopamine Imaging: 123I-FP-CIT SPECT (DaTscan)
• FDA approved for Parkinson’s disease vs. essential tremor
• Some studies support utility in DLB vs. AD
• More sensitive than clinical exam for dopaminergic deficit
• Not useful in identifying cause of degenerative parkinsonism (e.g. PD vs. MSA or PSP)
Normal AbnormalMcKeith et al. Lancet Neurol 2007
Pittsburgh Compound B (PIB)Amyloid plaques
Imaging Amyloid Plaques (11C-PIB PET)
Klunk et al., Ann Neurol 2004
5
NHCH3NO
OO
18F
18F-florbetapir (AmyvidTM)FDA approved April 2012
18F-flutemetamol (VizamylTM)FDA approved October 2013
18F-florbetaben (NeuraceqTM)FDA approved March 2014
Clark et al. JAMA 2011
Pathology Validation: Florbetapir PET
Amyloid PET Visual ReadsPET vs. Autopsy Studies
Gold standard: moderate- frequent neuritic plauques (CERAD)
1 – Clark et al., Lancet Neurol 20122 – Curtis et al., JAMA Neurol 20153 – http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204677s000lbl.pdf
Tracer N Report Sensitivity Specificity
Florbetapir (Amyvid)1 59 Median 92% 95%
Flutemetamol (Vizamyl)2 68 Median 88% 88%
Florbetaben (Neuraceq)3 82 Median 98% 80%
At a Loss for Words
• 57 year-old RH practicing internist with 2 years of progressive word-finding difficulties– Struggles to come up with words that
should be familiar
– Embarrassing socially and professionally
– Feels less efficient at accomplishing tasks
– No other cognitive or physical symptoms
– Has not impacted daily function
6
• General physical and neurological exams wnl
• MMSE 30/30
• Fluent speech with occasional pauses; poor repetition; comprehension/reading/writing wnl
• Boston Naming Test 12/15 (normal≥14)
• Average performance for age on tests of executive functions
• Above average on verbal memory, superior visual memory
At a Loss for Words
• Basic laboratory work-up normal
• MRI: “age-appropriate global volume loss, mild periventricular white matter changes”
• Patient’s questions:– Is this normal aging?
– If not, what is the diagnosis?
• I’m worried about Alzheimer’s but my memory is fine
– Can I keep working and if so for how long?
– Should I take a cholinesterase inhibitor?
At a Loss for Words
At a loss for Words: PET Results
• Diagnosis: MCI – High likelihood due to AD (NIA-AA)
Logopenic-variant primary progressive aphasia
• Treatment– Cholinesterase inhibitor
– Referral to anti-A clinical trial
– Early retirement due to medical disability
[11C]PIB-PET[18F]FDG-PETL R L R
Amyloid Positivity in Normal Older Adults:Concept of Preclinical AD
Mintun 2006; Pike 2007; Mormino 2009 & 2011; Sperling 2011; Chételat 2012; Petersen 2015
15%-30% of cognitively normal older adults are Aβ+• More common in
ApoE4+ and older age
Aβ+ “controls” • AD-like structural
and functional brain changes
• Longitudinal cognitive decline
• Elevated risk of incident cognitive impairment
7
Aβ PET+ Predicts Cognitive Decline in Aging
Donohue et al., et al., JAMA 2017
Ain’t Misbehavin’
A forgetful veteran61 yo RHM, 6 years of cognitive and behavioral changes
• First symptoms: misplacing personal items
• Increasingly repetitive; lost in familiar environments
• Disinhibited, impulsive, prone to outbursts
• Overeating, 35 lb weight gain
• h/o PTSD, EtOH abuse
Riding blind55 yo LHM, 9 yrs of personality and behavioral changes
• First symptoms: disinhibited comments to strangers
• New compulsive behaviors (sorting neighbor’s garbage)
• Skinny dipping at family beach picnic
• Pretended to be blind so that dog could ride public transit
Ain’t Misbehavin’
A forgetful veteranExam• Apathetic, slow, perseverative
• Mild limb rigidity
Neuropsych• MMSE 26/30
• Impaired executive function, episodic memory, visuospatial
• NPI 52
Differential diagnosis• Frontal-variant AD vs.
behavioral-variant FTD
Riding blindExam• Jocular, disinhibited
• Mild limb rigidity
Neuropsych• MMSE 20/30
• Impaired executive function, episodic memory, visuospatial
• NPI 46
Differential diagnosis• Frontal-variant AD vs.
behavioral-variant FTD
Differential Diagnosis: AD vs. FTD
• Ideal scenario for amyloid imaging– Clinical diagnosis is challenging
– Aβ a core feature of AD but not part of FTD pathologic spectrum (Tau or TDP-43)
– Accurate diagnosis has implications
– Early-onset dementia patients less likely to have “age-related” amyloid
– Amyloid PET outperforms FDG-PET in this scenario (Rabinovici et al., Neurology 2011)
8
ARS Question #3Which patient/s do you think will be
amyloid PET positive?
A. Forgetful veteran
B. “Blind” bus rider
C. Both
D. Neither
Forge
tful v
eteran
“Blin
d” bus r
iderBoth
Neither
52%
12%
24%
12%
A forgetful veteran Riding blind
FDG FDG
PIB PIB
Follow-up
Autopsy:CBD
Follow-up
Autopsy:AD
L R L R
L R L R
Am
ylo
id p
reva
len
ce
(%
)
100
90
80
70
8080
60
50
40
30
20
10
0
AD PCA LPA FTD SD PNFA bvFTD VaD DLB PDD CBS
Clinical diagnosis
AD=Alzheimer’s disease; PCA=Posterior cortical atrophy; LPA=Logopenic aphasia; (bv)FTD= (behavioral variant) Frontotemporal dementia; SD=Semantic dementia; PNFA= Progressive non-fluent
aphasia; VaD=Vascular dementia; DLB=Dementia with Lewy bodies; PDD=Parkinson’s disease dementia; CBS=Corticobasal syndrome.
N= 1358 54 70 287 62 59 24 138 51 22 56
Ossenkoppele et al., JAMA 2015
Prevalence of Amyloid PET+in Dementia Syndromes
Positive Predictive Value of Amyloid PET Decreases with Age
Ossenkoppele et al. JAMA 2015
9
Core Criteria:• Cognitive complaint with
objectively confirmed impairment
• Uncertain diagnosis (with AD as a possibility) after comprehensive evaluation by a dementia expert
• Knowledge of Aβ status expected to increase diagnostic certainty and alter management
33
Top Clinical Scenarios:• Persistent/progressive
unexplained MCI
• “Possible” AD– Atypical or mixed course
– Significant co-morbidities (e.g. vascular, psychiatric, substance abuse)
• Atypically early age-of-onset (<65 years)
Johnson et al., Alzheimers Dement/J Nuc Med 2013
Inappropriate Clinical Uses
• Initial evaluation of cognitive complaints– Scan not a substitute for clinical evaluation
• Screening of cognitively normal individuals– Pre-clinical AD is a research concept only!
– Non-medical use (disability, employment)
• Differentiate AD from other Aβ diseases– Dementia with Lewy bodies; amyloid angiopathy
• Less added value in straightforward clinical cases
Johnson et al., Alzheimers Dement/J Nuc Med 2013
• National, open-label study on utility of amyloid PET in ~18,500 Medicare beneficiaries meeting AUC
• Eligible patients referred for PET by dementia experts
• Scans covered by CMS, performed and interpreted locally
• Aim 1: Impact of scan on management plan at 3 months
• Aim 2: Impact on major medical outcomes at 12 months
• The primary hypothesis is that, in diagnostically uncertain cases, amyloid PET will lead to significant changes in patient management, and this will translate into improved medical outcomes
• Secondary objectives include impact on resource utilization
IDEAS-Study@acr.orgIDEAS-Study.org
IDEAS-Study.org
18,295 scans completedMedian age 75 (65-105)
60.4% MCI39.6% dementia
PET Aβ+: MCI 55.2%Dementia 69.6%
Study closed Jan ’18Aim 1 results: early 2018Aim 2 results: mid 2019
592 dementia practices1,163 dementia experts343 PET facilities
10
IDEAS-Study.org
Amyloid PET Changes Patient Management (N=3,979)
Chan
ge in
man
agem
ent c
ompo
site
(%)
0
25
50
75
Overall MCI Dementia
67.6% 67.8% 65.9%
30% goal
Rabinovici et al., AAIC 2017
Composite change in: AD medications, non-AD medications, counseling about safety and future planning
Amyloid PET vs. CSF Aβ42
Florbetapir cortical retention ratio
κ = 0.72
Both positive
Both negative Normal κ = 0.76
EMCI κ = 0.65LMCI κ = 0.71AD κ = 0.70
a
bn
orm
al
CS
F A
β1
-42
no
rma
l
Landau et al, Ann Neurol 2013
Nakamura et al., Nature 2018
Amyloid PET in Drug Development
Sevigny et al., Nature 2016
Aducanumab (humanized monoclonal Anti-Aβ antibody)Phase Ib RCT
11
Landscape of Tau TracersTau PET Across Aging-AD Continuum
Scholl et al., Neuron 2016; Ossenkoppele et al., Brain 2016
Jack et al., Neurology 2016 Schonhaut et al., Ann Neurol 2017
PSP (N=33) vs. NC (46) and PD (26)
12
68 yo retired NFL player with neurobehavioral decline, Aβ-neg
0.0 2.3
AV1451 SUVR
McKee CTE Stage III
Rabinovici et al., HAI 2015
ARS Question #1Which of the following is TRUE about amyloid PET?A. It is investigational only and not yet FDA
approved for clinical use
B. It is a definitive diagnostic test for Alzheimer’s disease
C. Can be clinically useful in patients with cognitive impairment of uncertain etiology
D. Amyloid PET ligands bind to soluble more than fibrillar forms of Aβ
It is i
nvesti
gatio
nal only
...
It is a
definiti
ve diag
nosti...
Can be cl
inically
useful in
...
Amyloid PET lig
ands bind ..
11%3%
82%
4%
ARS Question #2Which of the following patients would be highest priority for clinical molecular imaging?
A. Tau PET in an 84 year-old retired attorney with clinically typical Alzheimer’s disease
B. Amyloid PET in a 53 year-old commercial airline pilot with early-onset dementia
C. FDG-PET in a 45 year-old with subjective memory complaints, normal cognitive testing, and a family history of Alzheimer’s disease
D. DaTscan in a 75 year-old with cognitive decline, parkinsonism, and recurrent visual hallucinations
Tau PET
in an 84
year-o
ld...
Amyloid PE
T in a 53 yea
r...
FDG-PET in
a 45 year-o
ld...
DaTscan in
a 75 year-o
ld ...
1% 0%10%
89%
Take Home Points
• MRI can be highly informative in expert hands
• When should we get fancy in 2018?– When we are diagnostically uncertain
– When stakes of diagnosis are high
– When test likely to change management
– MAY: Mild, Atypical, Young
• Use the right test to answer your clinical question– Know the limitations of each technique
• Towards era of precision care in neurodegeneration– From clinical syndromes to molecular phenotyping
– From symptomatic therapy to early detection and prevention
13
UCSF-MACBruce MillerJalayne AriasNagehan AyaktaAlexandre BejaninViktoriya BourakovaJungho ChaKiran ChaudharyLeonardo IaccarinoRenaud La JoieManja LehmannOrit Lesman-SegevRik OssenkoppeleJulie PhamDaniel SchonhautSalvatore SpinaRichard TsaiAdrienne VisaniAdam BoxerLea GrinbergMarilu Gorno-TempiniAnna KarydasJoel KramerZach MillerHowie RosenBill Seeley
FundingNIA R01-AG045611, P01-AG1972403, P50-AG023501NINDS U54NS092089Tau ConsortiumMichael J. Fox FoundationAFTDAlzheimer’s Association Avid RadiopharmaceuticalsAmerican College of RadiologyFrench Foundation
AcknowledgmentsUC Berkeley/LBNLBill JagustSuzanne BakerMustafa JanabiSam LockhartAnne MaassKris NortonJim O’NeillMichael Scholl
IDEAS Study TeamCharlie ApgarMaria CarrilloC GatsonisIlana GareenLucy HannaBruce HillnerCynthia OlsonBarry SiegelRachel Whitmer
Extra Slides
Alzheimer's & Dementia 2015
Aggregated Aβ Lesions
Diffuse Plaques Neuritic Plaques Cerebral AmyloidAngiopathy (CAA)
Slide credit: UCSF Neurodegenerative Disease Brain Bank
14
Thal Phase: spatial extent of Aβ plaques
CERAD: density of neuritic plaques
Misdiagnosis Impedes Drug Development
Liu et al. Neurology 2015
Amyloid vs. FDG-PET in Differential Diagnosis of AD vs. FTD
Rabinovici et al. Neurology 2011
AD (N=62, age 65, MMSE 22)
FTD (N=45, age 65, MMSE 22)
Amyloid (PIB) PET visual reads
90% sensitivity, 83% specificity
Inter-rater agreement κ=0.96
FDG-PET visual reads
78% sensitivity*, 84% specificity
Inter-rater agreement κ=0.72*
95 autopsy-proven dementia casesPIB: Sensitivity 95%, Specificity 85%
FDG: Sensitivity 76%, Specificity 81%
* - p<0.05 vs. PIB
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