Neuro degenerative PET image from FDG, amyloid to Tau Kun Ju Lin ( ) MD, Ph.D Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital ( ) Department of Medical Imaging and Radiological Sciences and Healthy Aging Research Center, Chang Gung University ( ) 2017 10 14
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Biomarkers to improve the diagnostic accuracy Clinical degenerativ e dementia diagnosis Memory domain AD NIA AA criteria Behavior/Language domain FTLD FTLD criteria Parkinsonism/Visual hallucination DLB DLB criteria Biomarkers support clinical diagnosis Biomarkers (use NIA AA criteria as example): Aβ deposition: CSF Aβ 42, amyloid PET imaging Neuronal injury: CSF tau, hippocampus volume or medial temporal atrophy by MR, FDG PET imaging Gold standard Neuropathological diagnosis for degenerative dementia AD: A β plaque, neurofibrillary tangle FTLD: TDP 43, tau, etc DLB: lewy body
MIC @ CGMH Prog. Neurol. Psychiatry, 20: 16 20
MIC @ CGMH Prog. Neurol. Psychiatry, 20: 16 20
MIC @ CGMH
MIC @ CGMH Prog. Neurol. Psychiatry, 20: 16 20
FDG PET pattern in MCI/AD Probable Alzheimer s disease (pad) :characteristic and progressive CMRgl reductions in posterior cingulate (PC), temporal (TE), parietal (PA), precuneus (PCu), occipital (OC). A meta analysis including 27 studies evaluating FDG PET in the diagnosis of AD resulted in a pooled sensitivity (SN) of 91% and specificity (SP) of 86%. AD v.s Control: SN and SP of 99% and 98%. AD v.s. DLB: SN and SP of 99% and 71%. AD v.s. FTD: SN and SP of 99% and 65%. Clinical Nuclear Medicine & Volume 39, Number 10, October 2014 Journal of Neuroscience Methods 192 (2010) 277 285
MIC @ CGMH FDG PET imaging Original transverse image (raw image) L 3D-SSP analysis (lesion pattern) L SPM-like analysis (T-score) L
FDG PET in DLB DLB criteria: dementia, parkinsonism, visual hallucination, fluctuation. FDG PET in DLB: reduced uptake in the occipital lobe. cingulate island sign (preserved posterior cingulate activity relative to the precuneus). J Nucl Med 2014; 55:1959 1965
Cingulate island sign transverse image (raw image) 3D-SSP analysis (image pattern) SPM-like analysis (T-score) 12
Dementia Visual hallucinations, Parkinsonsim Cognitive fluctuations, Dysautonomia, Sleep disorders, Neuroleptic sensitivity (not seen in patients with AD, but occurs in 27% of patients with PD, 39% with PDD, and is most frequent in patients with DLB (53%)) DLB
FDG and TRODAT Abnormalities Associated With Clinical Stage Specific DLB Clin Nucl Med 2015;40: 26 31
Hsiao et al., Correlation of Parkinson Disease Severity and 18F- FP-(+)-DTBZ PET. JAMA Neurology, June 2014 3D Distribution patterns of 18 F AV 133 PD images at different stages
FDG PET in FTLD (1) Behavioral variant of FTD Clinical: behavior abnormality predominant. Metabolic pattern: frontal and anterior temporal glucose metabolism is decreased, though the medial temporal region and the subcortical structures, including the striatum and thalamus, are also affected. http://dx.doi.org/10.3174/ajnr.a3695
FDG PET in FTLD (2) Language variant of FTLD Progressive nonfluent aphasia Left posterior frontal and insular region atrophy. Tau positive pathology. Semantic aphasia Anterior temporal region atrophy. Ubiquitin positive TDP 43 positive pathology. Logopanic aphasia Left temporo parietal region atrophy. AD pathology., 2015,48(08): 681-686.
Management Impact of FDG PET in Dementia: Results from a Tertiary Center Memory Clinic FDG PET had moderate to high impact on the diagnosis and management in 44% participants. PET changed the type of dementia in 15% participants and prescription of cholinesterase inhibitors in 17% patients. Number of uncertain diagnoses reduced 11%, decreased differential diagnosis 37% and increase very probable diagnose 19%. FTD AD AD FTD Alzheimer s & Dementia 9 (2013) 414 421 Journal of Alzheimer s Disease 42 (2014) 885 892
Self propagation of pathogenic protein aggregates in neurodegenerative diseases Amyloid: AD Tau: AD & others a Synuclein inclusion: DLB, PD TDP 43 inclusion: MND N AT U R E VO L 5 0 1 5 S E P T E M B E R 2 0 1 3
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2009 First Amyloid PET case in CGMH 2009 First Amyloid PET case in CGMH
Regional Amyloid Deposition in Amnestic Mild Cognitive Impairment and Alzheimer's Disease PLoS One. 2013;8(3):e58974
Amyloid PET abnormality AD > LMCI AD > EMCI AD > NC P<0.05, extent voxels = 100, with FDR correction
Dynamic F18 AV 45 brain PET Nucl Med Biol. 2010;37:497-508
Correlation of early phase F 18 Florbetapir PET images to FDG Normal control AD subject 1.5 AV45 R1 image FDG PET 0 1.5 0 Eur J Nucl Med Mol Imaging. 2012;39(4):613 20.
Perfusion abnormality NC > AD NC > LMCI P<0.01, extent voxels = 100, with FDR correction
Dual phase 18F florbetapir PET for the concomitant detection of perfusion deficits and beta amyloid deposition Eur J Nucl Med Mol Imaging. 2016 Jul;43(7):1304 14.
Add perfusion like image for DDx 2 1 0 SUR MRI pav45 PET Amyloid PET
Alzheimers Res Ther. 2011 Nov 10;3(6):31.
Tentative clinical algorithm for the utility of amyloid imaging http://dx.doi.org/10.1016/j.nicl.2013.03.014
Suspected non-alzheimer MIC @ CGMH pathophysiology (SNAP) Suspected non-alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. SNAP is present in ~23% of clinically normal individuals aged >65 years and in ~25% of mildly cognitively impaired individuals. Nat Rev Neurol. 2016 Feb; 12(2): 117 124.
Clinical, genetic, and pathological spectrum of misfolded proteins in neurodegenerative disease Lancet Neurol 2015; 14: 114 24
N Engl J Med. 2012;367:795 804.
MIC @ CGMH This new tau PET tracer shows low uptake in controls, and intense tau pathology spreading across the frontal and temporal cortex in Alzheimer s disease Coronal images (75 mm thick) of sequential whole body PET images (10, 60, 120, and 240 min after injection of 18 F-THK-5351) from one subject. Images are displayed on SUV scale. Preparing
Tau distribution in AD
MIC @ CGMH
In vivo cortical spreading pattern of tau and amyloid in the Alzheimer's disease spectrum 1. Tau accumulation was most frequently observed in the medial temporal regions and stepwise spread to the basal and lateral temporal, inferior parietal, posterior cingulate, and the other association cortices, and then ultimately to the primary cortical regions 2. The image-based tau stage correlated with the general cognitive status, while cortical thinning was found only in the advanced tau stages Hanna Cho et al. Annals of neurology
Landscape of PET tracer development for Alzheimer s Disease PET tracers for Abeta plaques: 3 FDA approved Tracer Avid Radiopharm/Eli Lilly Amyvid (Florbetapir; 18 F AV 45) FDA approval April 6, 2012 Piramal Healthcare Neuraceq (BAY 94 9172) FDA approval March 20, 2014 GE Healthcare Flutemetamol (GE 067) FDA approval Oct 25, 2013 Navidea BioPharm. 18 F NAV4694 Phase 1/2 PET tracers for tau tangles : need to be developed Tracer NIRS 11 C PBB3 Phase 1/2 Eli Lilly/Avid 18 F T807, 18 F T808 Phase 1/2 GE Healthcare 18 F THK 5351 Phase 1/2 Hoffmann La Roche RO6931643, RO6924963, and RO6958948 Phase 1 Piramal/AC Immune N/A N/A
Mangialasche et al, 2010 Dementia Strategies of AD Treatment BIIB047 Tau therapeutics BMS 708163 MK0752 Rasiglitzaone EVP0334; EVP6124 Bapineuzumab Solaneuzumab; Semagacestat Pioglitazone RO1459; MABT5102A Aß therapeutics Currently, there is no Phase III success to develop disease modifying therapies; novel approaches are urgently needed Systematic treatment
Elegiline reduces brain 18 F THK5351 standardized uptake value Interpretation of 18 F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain Alzheimer s Research & Therapy 20179:25
Next Generation Tau PET Tracers APRINOIA Therapeutics Inc.
Andrew Stephens, MD, PhD Piramal Imaging and AC Immune April 3, 2017
Thanks your attention Acknowledgement: Team members of Department of Nuclear Medicine and Department of Neurology at Chang Gang Memorial Hospital.