5 Brain Scans & Biomarkers Jagust

Brain Scans and Biomarkers William Jagust Helen Wills Neuroscience Institute and School of Public Health University of California, Berkeley and Molecular Biophysics and Integrated Bioimaging Lawrence Berkeley National Laboratory 1980s onward 1970s onward Functional Imaging Structural Imaging (CTÞMRI) Metabolism (FDG-PET) Atrophy Hypometabolism 1990s onward 2000s onward Functional Imaging Molecular Imaging fMRI, resting BOLD (Amyloid/tau PET) Activation Protein aggregates and network changes Structural, functional, and molecular imaging are all crucial components of research evaluations of dementia patients today 1984: Publication of widely accepted clinical diagnostic criteria for Alzheimer’s disease 2018: Publication of a novel research framework – Alzheimer’s disease as a biological disorder 34 years to move from a clinical diagnosis to a biological model of AD Alzheimer’s Disease: Neuropathology b-amyloid (Ab) Plaque pathology Brain atrophy is a sign of neurodegeneration Tau Neurofibrillary Tangles Positron Emission Tomography Central Radiopharmacy for F18 Injection into Cyclotron for Fast participant production of short- Radiochemical lived radionuclides synthesis of PET (C11, F18) tracers PET Scan Image reconstruction and data analysis Fluorodeoxyglucose (FDG) – PET Reduced glucose metabolism in Alzheimer’s Disease likely reflects synaptic dysfunction Normal Alzheimer’s Disease FDG-PET in Alzheimers and FTLD FTLD AD F = frontal cortex, TP = Temporoparietal cortex, PC = posterior cingulate/precuneus Glucose Metabolism Declines in AD Characteristic brain regions affected in Alzheimer’s disease: Medial parietal lobe, lateral Cortical Thinning in AD temporal/parietal cortex, medial temporal lobe Similar regional vulnerability in structure and function Wirth et al J Neuroscience 2013 In vivo Amyloid Imaging with Pittsburgh Compound B (PIB) H3C S CH3 N N + CH3 Fibrillar Ab CH3 Histology - Thioflavin T Amyloid Plaques PET Imaging - [11C]6-OH-BTA-1 (PIB) HO S 11 NH CH3 N Chet Mathis and Bill Klunk, University of Pittsburgh Control AD Control AD 18F-Flutemetamol 18F-Florbetaben AD AD Control Control 18F-Florbetapir 18F-NAV4698 FDG (glucose metabolism) vs PIB (b-amyloid) Neurodegeneration vs Molecular Pathology FDG PIB Normal Alzheimer’s Disease Molecular Biomarkers vs Neurodegeneration Biomarkers Neurodegeneration Molecular Indicative of brain damage Indicative of pathology Non-specific (as to cause) Specific May be complex to interpret Relatively straightforward Correlation with symptoms May or may not correlate Questionable utility for with symptoms therapeutic testing Should be useful for therapeutic testing Multiple tau radiopharmaceuticals are now available for PET imaging Villemagne et al, Nat Rev Neurol 2018 Tau Imaging with Flortaucipir Young Adults PIB- Older Adults PIB+ Older Adults Alzheimer’s Disease N=5 N=17 N=16 N=15 Key regional paUern of tracer reten&on Braak staging (t-tests) Supra-threshold voxels AD-vulnerable regions (t-tests) Schöll, Lockhart et al, Neuron 2016 Topography of tau deposition in the AD continuum reflects Braak Pathological staging } Key regions of tau accumula&on: } medial temporal lobe (MTL) and inferior/middle temporal regions, retrosplenial cortex/posterior cingulate, precuneus, inferior parietal Utility of Tau PET in Differential Diagnosis 719 participants from Lund, Seoul, SF Tau PET 90% sensitivity & specificity discriminating AD from other disorders Ossenkoppele et al JAMA 2018 Biomarker Patterns: Similarities and Differences Biomarker Measurement in Autosomal Dominant AD Supports the Amyloid Hypothesis Dominantly Inherited Alzheimer’s Disease The Dominantly Inherited Cross-sectional data on Biomarkers from Alzheimer’s Disease (DIAN) Study tected in mutation carriers 15 years before expect- autosomal dominant, symptomatic and ed symptom onset (Table 2). As expected, there 2 Aβ deposition asymptomatic family memBers was an age-dependent decrease in hippocampal volumes in noncarriers (Fig. 1D).22 CSF tau 1 CSF Aβ42 CEREBRAL GLUCOSE METABOLISM CDR–SOB Because age-at-onset is preserved across FDG-PET measures of cerebral glucose use in the Difference precuneus were compared with the use of an a 0 generations, biomarker values in relation to priori hypothesis of decreased metabolism in age-at-onset can be calculated mutation carriers to determine regional metabolic Hippocampal −1 volume defects. The precuneus region, which is known Standardized to be an area of early deposition in both sporadic Results show that the earliest Biomarker Alz heimer’s disease and autosomal dominant Alz- Glucose −2 metabolism heimer’s disease,4,23,24 was chosen for analysis of b −30 −20 −10 0 10 change is elevation of A in Brain, about amyloid deposition. A significant decrease in cere- Estimated Yr from Expected Symptom Onset 20 years Before expected onset bral metabolism in the precuneus was detected in mutation carriers 10 years before expected symp- Figure 2. Comparison of Clinical, Cognitive, BatemanStructural, etMetabolic, al, NEJM and 2012 tom onset (Fig. 1E and Table 2). Biochemical Changes as a Function of Estimated Years from Expected Symptom Onset. Aβ DEPOSITION TheThe normalized Amyloid differences betweenHypothesis mutation carriers and: noncarriersAmyloid are deposition is the initiating event in PIB-PET measures of fibrillar Aβ deposition25 in shown versus estimated years from expected symptom onset and plotted with a fitted curve. The order of differences suggests decreasing Aβ in the precuneus were compared with the use of an 42 AD,the CSF leading (CSF Aβ42), followed to by NFTsfibrillar Aβ deposition,-tau, then Brain increased taudegeneration, and dementia a priori hypothesis of increased regional amounts in the CSF (CSF tau), followed by hippocampal atrophy and hypometabo- of amyloid deposition in mutation carriers. There lism, with cognitive and clinical changes (as measured by the Clinical De- was no detectable amyloid deposition in noncar- mentia Rating–Sum of Boxes [CDR-SOB]) occurring later. Mild dementia riers. All noncarriers had PIB-PET SUVR values of (CDR 1) occurred an average of 3.3 years before expected symptom onset. 95% confidence interval bands are shown in Figure S2 in the Supplementary less than 0.88. As compared with noncarriers, Appendix. mutation carriers had significant amyloid deposition in the precuneus 15 years before expected symptom onset (Fig. 1F and Table 2). The amount of amyloid deposition in mutation carriers in- COMBINED MODEL creased as a function of estimated years from ex- The order and rate of pathophysiological changes pected symptom onset at least until clinical symp- in autosomal dominant Alz hei mer’s disease were tom onset. estimated with the use of an analysis of the rela- tionship among clinical, cognitive, imaging, and BIOCHEMICAL MEASURES biochemical measures in the DIAN cohort (Fig. 2). In mutation carriers, levels of tau in the CSF were Beginning 25 years before expected symptom on- increased 15 years before expected symptom onset set, Aβ42 concentrations in the CSF in mutation (Fig. 1G and Table 2). Concentrations of Aβ42 in carriers appeared to decline, as compared with A video showing the CSF decreased as a function of estimated years those in noncarriers. Aβ deposition as measured Aβ deposition over from expected symptom onset and were pseudo- by PIB-PET (Fig. 3; and see Video 1, available at time is available at NEJM.org normal at approximately 20 years before expected NEJM.org) was detected at least 15 years before symptom onset, reaching low levels 10 years be- expected symptom onset (Table 2). Increases in fore expected symptom onset (Fig. 1H). The de- levels of tau in the CSF and in brain atrophy were crease by half in Aβ42 in the CSF and the increase detected approximately 15 years before expected in tau in the CSF were similar in magnitude to symptom onset, followed by cerebral hypometab- those typically observed in late-onset sporadic Alz- olism and impaired episodic memory approximate- 26 heimer’s disease. Plasma Aβ42 levels were elevat- ly 10 years before expected symptom onset and ed in mutation carriers, as compared with non- global cognitive impairment starting at 5 years carriers (Fig. 1I). before expected symptom onset. n engl j med 367;9 nejm.org august 30, 2012 801 The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on September 30, 2012. For personal use only. No other uses without permission. Copyright © 2012 Massachusetts Medical Society. All rights reserved. NIA-AA Research Framework 540 Alzheimer’s diseaseC.R. Jack defined Jr. et al. / Alzheimer’s& by Dementia 3 pathological 14 (2018) 535-562 processes: b-amyloid Table 2 deposition (A), tau deposition (T), and neurodegeneration (N) Biomarker proﬁles and categories AT(N) profiles Biomarker category A-T-(N)- Normal AD biomarkers Alzheimer’s Continuum: A+T-(N)- Alzheimer’s pathologic change Amyloid Positivity (A+) A+T+(N)- Alzheimer’s disease Alzheimer’s A+T+(N)+ Alzheimer’s disease continuum Alzheimer’s Disease: A+T-(N)+ Alzheimer’s and concomitant suspected Amyloid and tau non Alzheimer’s pathologic change positivity (A+T+) A-T+(N)- Non-AD pathologic change A-T-(N)+ Non-AD pathologic change A-T+(N)+ Non-AD pathologic change This is currently a framework meant only for research, not clinical care Abbreviation: AD, Alzheimer’s disease. Jack et al Alz & Dementia 2018 NOTE. See text for explanation of (N) notation. NOTE. Binarizing the three AT(N) biomarker types leads to eight different biomarker “proﬁles”. Every individual can

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