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Frdjupad demensutredning Nenad Bogdanovic nenad.bogdanovic@ki.se - PowerPoint PPT Presentation

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Frdjupad demensutredning Nenad Bogdanovic nenad.bogdanovic@ki.se nenad.bogdanovic@sll.se Professor L Geriatriska Kliniken Minnesmottagningen KUS Huddinge Currently: Chair of the external safety Committee Orion Pharma co-chair of the

  1. Use of biomarkers at the prodromal stage of AD Memory CSF MRI FDG-PET PET- Amyloid not not NINCDS-ADRDA 1 exclusion exclusion unknown specified specified amnestic A beta MTL P – T hypo PiB New criteria H type T- P tau atrophy metabolism retention >90% >90% >73% >80% >95% Specificity for Sarazin Hansson Colliot Mosconi Ng Prodromal AD 2007 2 2006 3 2008 4 2008 5 2007 6 CSF: cerebrospinal fluid; MRI: magnetic resonance imaging; MTL: medial temporal lobe; NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; PET: positron emission tomo graphy; FDG-PET: 18 F-2-fluoro-deoxy-D-glucose positron emission tomography; T-P tau: threonine-proline tau 1. Criteria for AD dementia, June 11 2010, available at: http://www.alz.org/research/diagnostic_criteria/dementia_recommendations.pdf. Last accessed 30 March 2011. 2. Sarazin M, et al. Neurology. 2007;69:1859-1867. 3. Hansson O, et al. Lancet Neurol. 2006;5:228-234. 4. Colliot O, et al. Radiology. 2008;248:194-201. 5. Mosconi L, et al. Neurobiol Aging. 2008;29:676-692. 6. Ng S, et al. J Nucl Med. 2007;48:547-552.

  2. 54 Petersen 2014

  3. How do amyloid PET and CSF A β 42 compare ? Study design: 118 patients with cognitive complaint examined for both CSF biomarkers - as part of clinical routine – 2 years and amyloid 18 F-flutemetamol PET Cut-offs: CSF A β42 < 647 pg/mL 18 F-flutemetamol PET > 1.42 Validation cohort n= 38 Original cohort n= 118 Positive PET+CSF or Negative PET+CSF 97 % Positive PET+CSF or Negative PET+CSF 92 % Palmquist S, et al, JAMA Neurol 2014

  4. 1350 1300 1250 1200 1150 1100 1050 1000 950 900 New cut off ? 850 760 800  -Amyloid 1-42 750 LBD Depression PTSS Oskar Hanson’s 700 FTLD FTLD PDD PCA 650 600 550 500 Current Cut-off 450 550 400 350 300 250 PET -ve 200 PET +ve 150 100 50 0 0 10 20 30 40 50 60 No of cases

  5. Biomarker signature Neurodegeneration N+ Amyloidosis A+ CSF PET-FDG MRI PET Amyloid CSF Amyloid Tau, pTau H +/- Cx PET Amyloid MRI PET - FDG CSF Amyloid CSF Tau A-/N- A+/N- + + A-/N+ + + + A+/N+ + + + + + Bogdanovic 2016

  6. SCI/MCI MRI NP, MRI , Lab Memory Impairment Non-Memory Impairment Vizamyl CSF agnosia speech behaviour executive PET – FDG + - Vizamyl A+T+ A+T- A-T- A-T+ AD LBD Park + 4A Hallucination Agnosia Fluctuation Apraxia Aphasia Amnesia FLD, CBS, PSP MSA PDD, VD, ADL - Dementia LBD Bogdanovic 2016

  7. MCI: NP MRIq CSF CSF* NP MRIq T+ A+ NP-A NP-nA MRI-H MRI-C* NP – nA & MRI+ & T- / A+ NP-nA & MRI + & CSF - NP-A & MRI + & CSF - PET - FDG Frontal / Temp Pariet- / Temp PCA,CBS,LBD bvFLD, nfPPA, SD PET – Flute NP : neuropsychology: A-amnestic , nA-nonamnestic - MRIq : quantitative H-hippocampal, C-Cortical + * cortical specification CSF: T tau /pTau -ve, +ve A – amylod +ve , – ve * Amyloid cut off ? AChE I Amyloid 42 positive < 550 current cut off < 760 suggested cut off ?? Follow Up, (NP, PET-FDG) Symptomatic Th Bogdanovic 2016

  8. SCI MRIq CSF MRI - CSF - MRIq+ and T- A- MRIq+ and T- A+ MRIq+ and T+ A+ CSF + (A 550 - 760) CSF - (A > 760) T- PET – Flute PET – FDG - - + + Follow Up 2-3 y 1 y 1-2 y 1 y 1 y RE-testing Symptomatic Th NP progression NP no-progression Biomarkers assessment Follow up Bogdanovic 2016

  9. Summary Biomarkers for A  are widely available and are sensitive and specific compared to pathological detection of neuritic plaques Models of preclinical AD include a prolonged period of asymptomatic A  accumulation Amyloid biomarkers have revolutionized clinical trials Tau deposition is seen in normal aging in the medial temporal lobe Tau deposition in the neocortex is associated with cognitive decline and the presence of A 

  10. DIAGNOSTIC NOISE

  11. Prevalence of four major types of dementia > 75 y Tangle Only Dementia 2-5% Other 5% Primary Age-Related Tauopathy (PART) FLD Pure DLBD 3% 5% 5% AD AD 15% DLBD with VaD AD 12% 60% DLBD 15% Mixed VaD and AD 10% FLD Pure VaD 5% Other ”Argyrophilic Grain Disease” Primary Age-Related Tauopathy (PART) 5-9% Gearing, 1995; Kosunen, 1996, Nagy, 1998, mod Bogdanovic 2015.

  13. Crary 2014

  14. Neurofibrillary changes – not amyloid L D

  16. POSTERIOR Retrieval control ANTERIOR posterior Encoding Hippocampus anterior AD presymptomatic aMCI /PART

  18. Crary 2014

  19. Crary 2014

  20. PART (definite) N+ A- - rapid decline on tasks involving - episodic memory - semantic memory - processing speed - attention - Age of death > 80 - MMSE 24 – 28 - APOE e4<e3<e2

  21. MCI / DEMENTIA TAU AMYLOID TAU AD PART

  22. THERAPY

  23. / PART

  24. - Intraneuronal amyloid-  accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life - Increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer’s disease . - Selective intraneuronal amyloid-  accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer’s disease.

  25. • Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. • Basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.

  27. APOE AND BChE GENOTYPES AND AChEI RESPONSE APOE 4- /BChE wt APOE 4+ /BChE K+ APOE 4- /BChE wt APOE 4+ /BChE K+ Age, gender Female >75y Female <75y Male <75y Male <75y genotyper Relative loss Hippocampus Whole brain A minimal loss Volume loss of of > Whole brain > Hippocampus of volume all brain regions brain volume Symptomatic Yes Yes/None Slight None response Respone to Donepezil Donepezil Mixed effect Donepezil Specific AChEI Beneficial Detrimental from Might ? Donepezil Beneficial Rivastigmine Rivastigmine Rivastigmine Detrimental Beneficial Rivastigmine Detrimental Lane RM 2015

  28. 12 Rivastigmin 4,5 patch Donepezil 10 mg 3 9 6

  29. Alzheimer’s disease pathologies A concept treatment: SHIFT TO THE LEFT Symptomatic therapy Disease Modification • Amyloid-modulating agents • Acetylcholinesterase Inhibitors • Serotonin TH6 antagonist ANTIBODIES • Mitochondrial enhancement beta- , gamma- secretase inhibitors) • Synapses enhancement • Tau modulating agents • Neuroprotective agents • Neurorestorative agents Bogdanovic N. Author‘s own slide

  30. Anti-amyloid antibodies – Treatment principle

  31. Anti-A β Antibodies Solanezumab 2, Bapineuzumab Aducanumab 8, Gantenerumab 10,1 Crenezumab 1 BAN2401 5 – 7 3 4 9 1 Roche/ Biogen/ Roche/ Eisai/Biogen Company Eli Lilly Pfizer/J&J Neurimmune Genentech Genentech Mid-domain Mid-domain N-Terminus N-Terminus N-Terminus N-Term & Mid Epitope Humanized Humanized Humanized Humanized Human Human Origin IgG4 IgG1 IgG1 IgG1 IgG1 IgG1 Isotype Fibrillar & Fibrillar & All forms of All forms of A β Soluble A β oligomeric oligomeric Target A β A β protofibrils forms of A β forms of A β Microglia- Microglia- mediated mediated Sequestration clearance; clearance; Microglia- Microglia- Microglia- of soluble Sequestratio Sequestration mediated mediated mediated MoA monomeric n of soluble of soluble clearance clearance clearance A β monomeric monomeric A β A β Adapted from Neurimmune/Biogen presentation at AD/PD 2015, Nice, FR. 1. Adolfsson O, et al. J Neurosci 2012;32:9677-9689; 2. Doody RS, et al. NEJM; 2014:370:311-321; 3. Yamada K, et al. J Neurosci 2009;29:11393-11398; 4. Kerchner GA, Boxer AL. Expert Opin Biol Ther 2010;10:1121-1130; 5. Kaplow JM, et al. Alz Demen 2013;9:807-808; 6. Lai R, et al. Alz Demen 2014;10:689; 7. Lannfelt L, et al. Alz Res Ther 2014;6:16 8. Hang Y, et al. Neurodegener Dis 2015;15:800; 9. Sevigny J, et al . Neurodegener Dis 2015;15:311; 10. Ostrowitzki S, et al. Arch Neurol 2012;69:198-207; 11. Bohnmann B, et al. J Alz Dis 2012;28:49-69.

  32. One Year treatment with Aducanumab Placebo (n=36, 36, 22) Aducanumab 1 mg/kg (n=28, 28, Adjusted mean change in CDR-SB from Aducanumab 3 mg/kg (n=30, 30, 27) 23) Aducanumab 6 mg/kg (n=27, 27, 2.50 Difference from Aducanumab 10 mg/kg (n=28, 28, 23) NA) Placebo at Week 54 2.00 baseline ( ± SE) -0.33 1.50 -0.71 1.00 -1.44 * 0.50 0.00 * P <0.05 vs placebo 0 26 54 Analysis visit (weeks) Placebo (n=34, 34, 21) Aducanumab 1 mg/kg (n=26, 26, 21) Aducanumab 3 mg/kg (n=26, 26, 21) Aducanumab 6 mg/kg (n=23, 23, NA) 1.50 Aducanumab 10 mg/kg (n=28, 27, 21) Mean composite SUVR ( ± SE) 1.40 1.30 1.20 SUVR cut-point for florbetapir = 1.13* 1.10 0 26 54 Analysis visit (weeks)

  33. FEW CASES

  34. Top Clinical Scenarios: Core Criteria: Persistent/progressive Cognitive complaint with P unexplained MCI objectively confirmed impairment “Possible” AD Uncertain diagnosis (with AD as a Atypical or mixed course possibility) after comprehensive P Significant co-morbidities (e.g. evaluation by a dementia expert vascular, psychiatric, substance abuse) Knowledge of A β status expected Atypically early age-of-onset (<65 to increase diagnostic certainty P years) and alter management Scans on asymptomatic people are not appropriate

  35. Patient 1 56 y man Music teacher Problem to read musical notation MMT = 29/30 Memory Clinic - Mild Cognitive Impairment

  36. Aperceptual visual agnosia Direct copy Delay recall after 30 min

  37. Neurodegeneration N+ PET-FDG MRI T2

  38. Atrophy of the parietal cortex Neurodegeneration N+

  39. PCA (posterior cortical atrophy) Lewy Body AD CBS-CBD dementia Corticobasal SYNDROM CSF PET - AMYLOID

  40. CSF PET – 18F-Flutemetamol

  41. Alzheimer Disease – atypical form – Posterior Cortical Atrophy PET – Amyloid ( A+) PET-FDG ( N+) MRI T2 ( N+) A+/N+

  42. 5/15 10/15 11/14 Galantamin 24 mg

  43. Alzheimer Disease - atypical form Posterior Cortical Atrophy Atypically early age-of-onset (<65 years)

  44. Patient 2 Female 1942 2009 concern for developing a dementia condition – Memory Clinic - Mild cognitive impairment of amnestic type - 2013. subdural hematoma - misperception / delusion about her husband. - Capgras syndrom

  45. 2013

  46. 2014 A A = amygdala

  47. A 2015 A

  49. Lumbal Puncture (06/14)  -Amyloid 571 ng/L (>550) Total Tau 433 ng/L (0-500) Fosfo-tau 46 ng/L (<80)

  50. PET – AMYLOID (+) 2015

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