Diagnosis before NIA AA The impact of FDG PET in. Diagnosis after NIA AA Neuropathology and PET image 2015/10/16

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1 The impact of FDG PET in degenerative dementia diagnosis Jung Lung, Hsu MD, Ph.D (Utrecht) Section of dementia and cognitive impairment Department of Neurology Chang Gung Memorial Hospital, Linkou, Taipei 台灣臨床失智症學會 2015 年會 13:30 14:20 Diagnosis before NIA AA 2011 Degenerative dementia Alzheimer s dementia Fronto temporal lobar degeneration: behavior variant FTD Dementia with Lewy bodies (DLB) MCI concept, CIND, etc Diagnosis after NIA AA 2011 Degenerative dementia Alzheimer s disease dementia Amnestic variant Visuospatial variant (PCA) Frontal variant (fv AD) Fronto temporal lobar degeneration: behavior variant FTD Primary progressive aphasia Semantic variant, Progressive nonfluent variant, logopenic variant Dementia with Lewy bodies (DLB) MCI: early and late MCI due to Alzheimer s disease Preclinical s of Alzheimer s disease. Clinical degenerativ e dementia diagnosis Biomarkers support clinical diagnosis Gold standard Biomarkers improve the diagnostic accuracy Memory domain AD NIA AA criteria Behavior/Language domain FTLD FTLD criteria Parkinsonism/Visual hallucination DLB DLB criteria 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 Neuropathological diagnosis for degenerative dementia AD: A β plaque, neurofibrillary tangle FTLD: TDP 43, tau, etc DLB: lewy body Neuropathology and PET image Disease Positive pathology Negative pathology Alzheimer s disease dementia Lewy body dementia (DLB, PDD) Synaptic loss, neuronal loss, spongiosis. Synaptic loss, neuronal loss, spongiosis. Main neurotransmitter deficit Acetylcholine (Nu. Meynert) Dopamine (dorsal motor X nucleus), Acetylcholine Metabolic dysfunction early than anatomical changes FDG MRI Fronto temporal lobar degeneration (bv FTD, PPA) Synaptic loss, neuronal loss, spongiosis. Serotonin? von Economo neurons Current PET image marker Amyloid tracer, tau tracer FDG Different hypometabolism pattern 11C MP4A, VMAT2(AV 133), R.A. Sperling et al. / Alzheimer s & Dementia 7 (2011)

2 PET imaging in neurodegenerative disease PET imaging agents for neurodegenerative diseases have a significant impact on clinical diagnosis and patient care. PET radionuclides and imaging agents: Radionuclides: 11 C: (T 18 1/2 : 20 min), F: (T 1/2 : 110 min). Imaging agents: Metabolism: 2 [ 18 F]fluoro 2 deoxy D glucose (FDG). Amyloid: flutemetamol (FPIB), florbetapir (AV 45), florbetaben (AV 1). Tau: non selective tau PET tracer (FDDNP) and selective tau PET tracer (e.g THK523, THK5105 and THK5117). Dopamine neuron: 6 fluoro [ 18 F]DOPA (FDOPA), 9 Fluoropropyl (+) DTBZ (AV 133, VMAT2 marker). Neuronal degeneration/injury Non specific marker, based on the pattern distribution. Decreased uptake in temporo parietal cortex on FDG PET. Elevated CSF tau. Disproportional atrophy of med/basal and lateral temporal lobe and medial parietal cortex on MRI. Chem. Soc. Rev., 2014, 43, 6683 Anatomical landmark and use pons region as reference Align AC PC line Occipital lobe PCC Precuneus Parietal occipital lobe FDG PET measures It represents resting state synaptic function and density. Decrease uptake (synaptic dysfunction) may due to: Altered intracellular signalling cascades. Altered mitochondria bioenergetics. Impaired neurotransmitter release. Long distance disconnection effects. In AD: local and specific brain circuit (hippocampus, entorhinal region and in the neocortex) disrupt/alter mitochondria bioenergetics cause uptake decreased. FDG decrease uptake maybe a partly amyloid independent process contribute to neuronal dysfunction. Curr Opin Neurol 2014, 27: AD case: 77 y/o male, a farmer, 6 years education. Progressive memory loss for 6 months, repeat questions. More irritable mood. MMSE 17, CDR 0.5 AD hypometabolism pattern in PET Normal: (MMSE > 28) 98% did not show cortical hypometabolism. 1% hypometabolism restricted to the PCC. AD patients: % showed a pattern of prominent parietotemporal itt and PCC hypometabolism. 1% patient showed hypometabolism restricted to the PCC. 84% AD symmetric, 10% showed more severe hypometabolism in the left hemisphere, 6% showed more severe hypometabolism in the right hemisphere. 13 % additional frontal hypometabolism, 5% occipital hypometabolism. J Nucl Med 2008; 49:

3 Plaque and tangle distribution at different s of Alzheimer s disease progression (Braak staging) Spread of tau pathology follows a distinct neuroanatomical path that suggests network connectivity Braak & Tredici Acta Neuropath 2011 FDG PET in MCI Mild Moderate Severe FDG PET showed posterior cingulate region is the most prominent changes in AD and the earliest changes seen in MCI. Individuals with MCI may also present patterns of hypometabolism resembling AD, frontotemporal dementia, or dementia with Lewy bodies, and approximately 10% of MCI subjects are reported to have normal FDG PET scan. There are no established FDG PET criteria for preclinical dementia at the MCI. A. Zimny et al. / FDG PET and MR Neuroimaging in amci Different hypometabolism maps in MCI predict future outcome DLB case: 76 y/o male, progressive memory loss for 2 years, fluctuation cognition, visual hallucination. MMSE16 C. Cerami et al. / NeuroImage: Clinical 7 (2015)

4 DLB hypometabolism pattern in PET DLB pattern: 14 patients 71% showed hypometabolism in the posterior brain regions preferentially involving the OCC, parietal cortex in 21% and of the PCC in 7%. 29% parietotemporal and PCC hypometabolism more severe than the OCC, and were misclassified as AD. bilateral in 71% of the patients, more severe in the left hemisphere in 7%, and more severe in the right hemisphere in 21% of the patients. 67% mild and 75% moderate to severe DLB patients showing occipitoparietal hypometabolism. Pathological basis of cingulate island sign (CIS) In FDG PET, median value in the posterior cingulate gyrus ROI was divided by the median value in the precuneus plus cuneus ROI to derive the CIS ratio. CIS on FDG PET is not associated with fibrillar β amyloid deposition but indicates lower Braak NFT in patients t with DLB. J Nucl Med 2008; 49: J Nucl Med 2009; 50: ; Neurology 83 August 26, 2014 Lewy body dementia (LBD) Dementia with lewy bodies (DLB) Parkinson s disease dementia (PDD) Scheme of the progression pathways and s of Lewy body (LB) disorders The pathway for PD seems likely to proceed through Stage IIa (brainstem predominant) while that for ADLB passes through Stage IIb. The pathway followed by DLB is uncertain as thecurrent definition of DLB largely excludes all but the neocortical. There may be two types of ILBD, one that leads to PD and another that leads to ADLB and possibly DLB. Only PD and DLB progress to the neocortical. Acta Neuropathol Jun;117(6):

5 Braak Staging and clinical symptoms Mild Moderate Severe Brainstem substantia nigra DA (parkinsonism) n. basalis ACh (cognitive fluctuations) locus coerleus NE (agitation) dorsal raphe 5HT (depression /anxiety) Neocortical Occipital hypometabolism visual hallucinations, parkinsonism Temporal lobe hypometabolism delusions /psychosis Orbitofrontal hypometabolism depression /anxiety Kobayashi et al., Int. J. Geriatric Psychiatry, 2009 Bv FTD case: 55 y/o male with progressive behavior disturbance, apathy, disinhibition, hyperorality, MMSE 26. FDG PET in FTLD FTLD: behavioral variant and language variant. bv FTD: behavior abnormality predominant. Language variant: semantic dementia, progressive aphasia. bv FTD: prevalent involvement of the anterior cingulate cortex, ventromedial and/or dorsolateral frontal cortex, and orbito frontal cortex as typical of the behavioral variant of frontotemporal dementia (bvftd). Bv FTD hypometabolism pattern in PET von Economo neurons in fronto insular and anterior cingulate cortex FTD pattern: 49 patients 65% patients showed a pattern of prominent frontal or temporal hypometabolism. 35 % eitherparietotemporal and PCC hypometabolism with no frontal hypometabolism or parietotemporal and PCC hypometabolism with frontal hypometabolism that was not more severe than that in the parietotemporal and PCC regions, and were misclassified as AD. J Nucl Med 2008; 49:

6 Severity of atrophy for identifying the different s of FTLD Mild Moderate Severe J Mol Neurosci (2011) 45: SN/SP in different FDG PET pattern AD Sen: 99% Spe: 98% Normal AD DLB DLB Sen: 99% Spe: 71% FTD Sen: 99% Spe: 65% Sen: 71% Spe: 65% Management Impact of FDG PET in Dementia: Results from a Tertiary Center Memory Clinic FTD AD FDG PET had moderate to high impact on the diagnosis and management in 44% participants. AD PET changed the type of dementia in 15% participants p and prescription of Clinical cholinesterase inhibitors in 17% patients. Number of uncertain diagnoses reduced 11%, decreased differential diagnosis 37% and increase very probable diagnose FTD 19%. Alzheimer s & Dementia 9 (2013) Journal of Alzheimer s Disease 42 (2014) PET Conclusion THM FDG PET topographical uptake pattern represents different type/ degenerative dementia. Typical AD reduced uptake in the bilateral symmetric parieto temporal, posterior cingulate, precuneus areas. DLB: reduced occipital and parieto temporal p but cingulate island sign noted. Amyloid PET (AV 45): provide evidence of amyloid deposition (cerebral amyloidosis). Dopamine system (VMAT2, AV 133): provide monoamine system activity. Tau tracer: specific THK5117 for neuronal injury marker. Thanks your attention Acknowledgement: Team members of Department of Nuclear Medicine and Department of Neurology at Chang Gang Memorial Hospital. 6