Disclosures Advisor / Director Grants The Tau Consortium, Scientific Advisor National Institute of Health/National Institute of Aging grants: P50 AG023501, P01 AG019724, The John Douglas French Foundation, Medical P50 AG1657303, and T32 AG023481 Advisor Centers for Medicare & Medicaid Services The Larry L. Hillblom Foundation, Medical Advisory Dementia Care Ecosystem 1C1CMS331346-01-00 Board The Use of Biomarkers to UCSF / Quest Diagnostics Dementia Pathway National Institute for Health Research, Director Collaboration Research Grant Classify Dementia Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia Royalties (UK) American Brain Foundation, Board Member Bruce L. Miller, MD Cambridge University Press University of Washington ADRC, External Advisor A.W. and Mary Margaret Clausen Distinguished Professor in Neurology Guilford Publications, Inc. Stanford University ADRC, External Advisor Director, Memory and Aging Center Oxford University Press Joint Appointment in Psychiatry Arizona ADC, External Advisor Neurocase UCSF School of Medicine International Society of FTD, USA-President, Elsevier, Inc. Executive Committee 2/9/2017 UCSF Memory and Aging Center 2016 “A public health approach to dementia could prevent up to 30 percent of the dementia cases projected around the world in the next two decades. Norton, Matthews, Barnes, et al. 2014 UCSF Mission Bay Campus, Sculpture by Mark di Suvero 1 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Neurodegenerative Overview Causes Alzheimer’s disease • Neurodegeneration caused by protein frontotemporal dementia Lewy body disease aggregation in specific circuits and more • Research criteria for AD and FTD • FTD genes – towards precision medicine • Molecular markers in AD • Molecular markers in FTD • Drug development Dementia cognitive decline that interferes with everyday functioning memory, executive, behavioral, and/or motor symptoms Models of Degenerative Dementia Neuropathology & Chemistry of Inclusions All degenerative dementias have: • CJD: prions (1982) – Genetic and sporadic form • AD: plaque (A β -42, 1984), tangle (tau, 1986) – Cell culture and animal model • PD/DLB: Lewy body ( α -synuclein, 1998) • FTLD: Pick body (tau, 1990), ubiquitin positive – Preclinical, early symptomatic and tau negative inclusions (TDP43, 2006), (FUS, symptomatic phase 2009), dipeptides from C9 mutations (2013) – Abnormal protein aggregation – Proteins spread from cell to cell 2 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
FTLD-tau Pick 3R PSP 4R CBD 4R FTLD-FUS Molecular Changes Underlying AD TDP-A TDP-B TDP-C Dipeptides (C9ORF72) FTLD-TDP NFL Player: Amygdala/Tau Idiopathic Parkinson’s Disease Parkinson (1817): f Lewy (1913): concentric hyaline inclusions. Trétiakoff (1919): Substantia nigra degeneration Lewy body McKee AC et al. J Neuropathol Exp Neurol . 2009 3 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Differing Anatomy Defines Dementias Research Criteria for Alzheimer’s Disease • At least two of the following: Disease Imaging Anatomy 1st Symptom Spared • Impairment in ability to remember new information • Impaired reasoning ability to manage complex Social behavior tasks Hippocampus posterior Memory, naming, AD temporal-parietal visuospatial Movement • Impaired visuospatial abilities • Impaired language functions (speaking, reading, writing) Frontal (emotional > Navigation, FTD • Changes in behavior, personality or comportment cognitive neocortex) Apathy, behavior memory • Insidious onset of decline and progressive worsening of symptoms and function Movement, hallucinations • Evidence of a causative genetic mutation Amygdala temporal- Behavior, DLB visuospatial occipital memory • Biomarkers for amyloid deposition sleep International Research Criteria for Preclinical AD – Staging Behavioral Variant FTD • Stage I: Asymptomatic 1. Early (2–3 yrs) behavioral disinhibition – Elevated amyloid PET/low CSF A β 42 • Stage II: Early synaptic dysfunction 2. Early (2–3 yrs) apathy or inertia – Positive amyloid biomarker 3. Early (2–3 yrs) loss of emotional – Abnormal CSF tau or MRI or FDG-PET reactivity/sympathy and empathy • Stage III: Symptomatic 4. Perseverative, stereotyped or – Positive amyloid biomarker compulsive/ritualistic behavior – Abnormal CSF tau or MRI or FDG-PET 5. Hyperorality and dietary changes – Abnormal cognitive testing 6. FTD neuropsychological profile 4 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
3 Types Frontotemporal Dementia VBM of FTD & AD vs Controls Behavioral Variant Language Variants Semantic Nonfluent Variant Variant R L Often genetic Tau, TDP, FUS Rarely genetic Some genetic 2/3 TDP 83% TDP-C 85% Tau, TDP-A Concept from Delay, Brion Escourolle 1950s, Thibodeau MP, Miller BL. Neurocase. 2013 Voxel-wise Comparisons of How Classify C9ORF72 Carriers? Grey Matter Volumes Other PSP n=41 CBS svPPA nfvPPA bvFTD ALS Parkinsonism R Ossenkoppele et al. Brain. 2015 5 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
How Classify GRN Carriers? How Classify MAPT Carriers? PSP Other PSP Other n=41 n=41 CBS CBS svPPA svPPA bvFTD bvFTD nfvPPA nfvPPA ALS Parkinsonism Parkinsonism ALS Rare Variants with FTD-ALS bvFTD, high confidence, n = 68 Gene Variant Phenotype Publication aFTLD-U TARDBP P112H FTD Moreno et al 2015 AD, (FUS), 7 Pick’s, 8 CBD, 3 4 FUS Q140H tauopathy Ferrer et al 2015 ALS-TDP, 1 PSP, 2 LRRK2 C2154F tauopathy Chen-Plotkin et al 2008 FTDP-17, 2 TDP-U, Tau TBK-1 FTD-ALS Le Ber et al 2015 Nonsense variant MND, 7 unclassifiable, 3 PRNP TDP-A, 6 Q160X dementia Fong et al 2016 TDP-U, 1 deletion, nonsense & TDP-C, 3 OPTN ALS Maruyama et al 2010 TDP-B, missense mutation TDP-A, MND, 15 MND, 1 UBQLN2 TDP-B, 5 PXX ALS Deng et al 2011 6 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Role of Biomarker Tablet-based Cognitive Assessments • Capture early disease (sensitive) • Separate healthy aging from neurodegeneration (specific) • Determine molecular determinants of neurodegeneration (AD vs. FTD due to tau, TDP, FUS, and PDD or DLB (specific) • Help with staging of disease Executive FTD vs. AD: Executive Control Control in • AD & bvFTD are similar: bvFTD & AD – Working memory: Spatial 1-Back, Dot count Performance on – Category fluency: Animal generation executive tasks, – Attention: Set shift, Flanker emotion • bvFTD worse than AD recognition – Letter fluency increasing – Antisaccade accuracy disease severity AD (n= 678) vs – Social decision making: Social norms bvFTD (n=206) – Social behavior: Behavior checklist • Discriminant function classify 73% bvFTD vs AD Possin et al. Neurology 2014 Ranasinghe & Rankin Neurol 2016 7 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
PSP Disease Severity Circadian Activity Rest-activity Rhythm Disruption PSP Walsh et al, Sleep Medicine, 2016 Walsh et al, Sleep Medicine, 2016 Automated Classification Analysis of sMRI Scans Network-based Neurodegeneration • Averaging across patient maps can be very insensitive • Machine-learning algorithms (e.g., using support vector machines) more effectively discriminate when atrophy patterns heterogeneous within same clinical class patient Time (sec) Single subject Seeley et al Neuron 2009 8 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Plasma Neurofilament PSP vs. Controls Neurofilament Level Cognitive Decline Rojas et al., Ann Clin Transl Neurol. 2016 Rojas et al, Ann Clin Transl Neurol. 2016 18 F-florbetapir (Amyvid TM ) Amyloid Deposition in Autosomal Dominant AD FDA approved April 2012 18 F O O O Carriers N NHCH 3 18 F-flutemetamol (Vizamyl TM ) FDA approved October 2013 Non-carriers 18 F-florbetaben (Neuraceq TM ) FDA approved March 2014 Years from symptom onset Bateman et al., NEJM 2012 9 2/9/2017 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
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