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Redefining Alzheimer’s Disease Hakan Gürvit Istanbul University Istanbul Faculty of Medicine Department of Neurology Behavioral Neurology and Movement.

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... konulu sunumlar: "Redefining Alzheimer’s Disease Hakan Gürvit Istanbul University Istanbul Faculty of Medicine Department of Neurology Behavioral Neurology and Movement."— Sunum transkripti:

1 Redefining Alzheimer’s Disease Hakan Gürvit Istanbul University Istanbul Faculty of Medicine Department of Neurology Behavioral Neurology and Movement Disorders Unit

2 Auguste Deter Alzheimer A. Allgem Z Psychiatr Psych- Gerich Med 1907

3 Alzheimer’s Disease is a Rare Mental Disorder Emil Kraepelin. Psychiatrie: ein Lehrbuch für Studierente und Ärzte. (Leipzig, 1910) –Alzheimer’s disease is a presenile dementia

4 AD is the Most Prevalent Dementia B.E. Tomlinson, G. Blessed and M. Roth –Observations on the brains of non-demented old people. Journal of Neurological Sciences (1968) 7, –Observations on the brains of demented old people. Journal of the Neurological Sciences (1970) 11, “Senile dementia is not arteriosclerotic but is associated with AD-like changes.” R. Katzman –The prevalence and malignancy of Alzheimer’s disease. A major killer. Arch Neurol 1976;33:217–8. “Senile dementia is identical with Alzheimer’s disease.”

5 Alzheimer Type Dementia Multiple cognitive deficits with an amnestic core, disrupting ADL’s NINCDS-ADRDA (1984) – Probable AD (PRAD) DSM-IV (1994) – AD-type dementia (DAT) The clinician is excluded from the definite diagnosis of AD, which is granted to the pathologist as the exclusive right.

6 Pre-Dementia Memory Impairment – BSF: Forgetful elderly, who do not progress into dementia MCD (ICD-10), MNCD (DSM-IV), AACD (IPA), CIND (CSHA) – Age-associated Memory Impairment (AAMI) 2 A person aged over 50 with subjective memory complaints and a formal memory performance which is 1SD lower than that of the normative mean of the young adults 2 – Mild cognitive impairment (MCI) 3 Objective evidence of memory impairment as compared to age norms, no functional impairment 3 1 Kral NIA Petersen et al. 2001

7 Healthy Aging Age- Associated Memory Impairment (AAMI) Mild Cognitive Impairment (MCI) Mild Dementia Moderate Dementia Severe Dementia Memory Impairment Continuum None As compared to young adults Isolated, no functional impairment Prominent among multiple cognitive deficits, with functional impact Severe with intact basic ADL’s Severe, totally dependent

8 Spatio-Temporal Distribution of NFT Pathology in AD High Neocortical (severe AD) Low Neocortical (variable AD) High Limbic (MCI) Low Limbic (Normal/ AAMI) Time Entorhinal Limbic Paralimbic Prefrontal STS, iPL Unimodal Ass Primary S-M Space M-M Mesulam 2000 Braak-Braak. NeurAging 1995 I-IIIII-IV VVI Tauoism: High clinical correlation with NFT distribution

9 Familial Alzheimer’s Disease Chr 21. APP (Goate, Hardy, Nature 1991) Chr 14. PSEN1 (Sherrington, St. George-Hyslop, Nature 1995) Chr 1. PSEN2 (Levy-Lahad, Schellenberg, Science 1995) Chr 19. APOE polymorphism (Strittmatter, Lancet 1996)

10 Baptism : Amyloid Cascade Hypothesis The prime mover of AD neuropathology is Aβ peptide. – All the genetic causes of AD, whether Mendelian mutations or susceptibility polymorphisms, affect either by increasing Aβ levels or decreasing its clearence from the brain parenchyma – Tau gene (MAPT) mutations cause FTD, but never AD Hardy & Allsop, Trends Pharmacol Sci 1991

11 İntrasitoplazmik inklüzyon (NFY’ler, Lewy cisimcikleri, TDP-43, FUS) Fagozom /lizozomlar

12 Nörofibriler Yumak İntraselüler birikim NFY’ler ilk kez 1977’de izole edilmiş (Cleveland et al.) olan tau proteinine immünoreaktif (Brion et al. 1985) NFY’nin temel bileşeni fosforillenmiş  proteinidir (Grundke- İqbal et al. 1986) 17.kromozomda kodlanan mikrotübül asosiye proteinlerden (MAPT) biri (Hutton et al. 1998) İşlevi aksonal transport (kargo vezikülleri: yenilenme ve sinaptik aktivite için gerekli enzimler) ve sitoskeletal bütünlük

13 MAP-τ’nun NFY’ye Evrimi

14 Amiloid Plaklar AP’ler ekstraselüler birikim Amiloid yükü hastalık şiddetiyle korele değil Amiloid maddelere yüksek affiniteli Kongo kırmızısı ile boyanırlar (Divry 1927) Temel bileşenleri A  peptidi (Glenner ve Wong 1984) A  21. kromozomda kodlanan bir transmembran protein APP’nin çözülemeyen fragmanı (Hardy 1991) Gevşek plaklarda non-fibriler (granüler) Aβ42 Sert plaklarda fibriler Aβ42 ve Aβ40 birlikte

15 Çözülebilir Oligomerik vs. Çözülemeyen Fibriler Aβ Fibrilizasyon amiloid yapısının ilk elektron mikroskopik belirlenimlerinden beri nörodejenerasyonla ilişkilendirilmiştir (Cohen and Calkins, 1959; Kidd, 1964; Terry et al.,1964). Yakınlarda çözülebilir, oligomerik yapıların güçlü nörotoksik aktiviteleri gösterildi. Ekstraselüler amiloid depozitleri, intraselüler aggregatlar, (örn, aggresomlar) (Kopito, 2000) hastalık seyrinde geç evre özellikleri olabilir; çözülebilir asambleler nöronal disfonksiyona yolaçacak şekilde daha erken dönemde etki ediyor olabilirler (Bucciantini et al., 2002). Aβ fibrillerinin i n vitro analizi bir dizi oligomerik ara yapılar ortaya koymuştur: – Özellikle, protofibriller ve Aβ’dan türeyen çözülebilir ligandlar ( ADDL’ler).

16 p3 sAPPα N C C N sAPPβ Aβ Membran AICD α-sekretaz β-sekretaz γ-sekretaz kompleksi 711/ Nukleus Gen ifadesi 720/721 AICD /50 Amiloidojenik Proteoliz Non-amiloidojenik Proteoliz Gen ifadesi NICD NOTCH Psen 1/2 Pen-2 Nicastrin Aph1 A/B 717/718 ε ζ γ Aβ 1 40/42 DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA 142 DAEFRHDSGYE…………A 1 42 QC ADDL LMW- Aβ 4kDa Aβ(pE)3-42 Aβ(pE)11-42 Dimer Tetramer 8-20kDa Aβ protofibrilleri kDa Aβ*56 - Dodekamer Globulomer Sferoid Fibriler Aβ >100 kDa Sert AP Toksik Lizozomal Mikroglial fagositoz Proteozoma l Astrositik otofaji APO E α2M Nep IDE Plasmin Nöronal proteoliz Gevşek AP Jacobsen et al. PNAS 2008 İntranöronal agrezomlar İntranöronal agrezomlar α→β

17

18 A Decade of Glory – Tacrin 1993 – Donepezil 1996 – Rivastigmine 1997 – Galantamine 2001 – Memantin 2003

19 A Decade of ACH-based Disappointments Phase III Failures – AN 1792 (2002) – Phase II, Active immunisation – Alzhemed (2007) – Phase III, Aβ anti-oligomerisator – Flurizan (2009) – Phase III, GSM – Dimebon (2010) – Faz III, Mitochondrial stabilisator – Semagacestate (2010) – Phase III, GSI – TTP488 (PF ) (2011) – Phase II, RAGE iinhibitor – Ponezumab (2011) – Phase II, Passive immunisation – Bapineuzumab (2012) – Phase III, Passive immunisation Despite the total clearence of AP’s in 7/8 autopsy cases from AN1792, their last recorded MMSE scores before death were 0.

20 Rinne et al. Lancet Neurol 2010 Bapineuzumab Phase II – PIB-PET

21 Klunk, Engler, Nordberg et al. Ann Neurol 2004 In-vivo Amyloid Load: PIB-PET

22 2-year Follow-up of the Original Study Engler H et al. Brain 2006 Re-scanning of the 16 AD subjects Despite 20% decrease in the glucose metabolism with FDG-PET, no substantial increse in amyloid load with PIB-PET Klunk et al. Brain 2006

23 PIB-PET in Healthy Aging, MCI and AD 31 AD, 33 MCI, 32HA. PIB retention in 97% of AD, 61% of MCI, 22% of HA subjects. Pike et al. Brain 2007

24 Longitudinal Studies with Amyloid Imaging in MCI 21 MCI; Karolinska (Forsberg et al., Neurobiol Aging 2008) – 10/21 PIB+ aMCI; conversion to AD in 8 months 7/10 in PIB+ and 0/11 in PIB- groups 26 MCI; Pittsburgh (Wolk et al, Ann Neurol 2009) – 13/26 PIB+; 5/13 PIB+ and 0/13 PIB- convert to AD in 21.2±16 mo. 31 aMCI; London (Okello et al., Neurology 2009) – 14/17 PIB+ (1/14 PIB-) convert to AD in 3 years – 8/14 in 1 year: all of whom are ε4 carriers with higher PIB load 65 MCI; Heidelberg, Australia (Villemagne et al., Ann Neurol 2011) – 35/45 PIB+ convert in 2 years (1/20 PIB- [4/20 to non-AD])

25 Longitudinal Studies with Amyloid Imaging in Healthy Control Subjects 106 HS; Heidelberg, Australia (Villemagne et al., Ann Neurol 2011) – 33/106 PIB+; 5/33 in 20 mo., 11/33 in 36 mo. convert to MCI/AD (1/73 PIB-) – Binding is predominantly prefrontal and precuenus 146 HS; Wash Uni, St. Louis (Vlassenko et al., Ann Neurol 2011) – In 2.5 years 17/21 PIB+ subjects become high load- carriers (8%/year increase) – No reversion into PIB- state – 10/125 PIB- become PIB+ (%3.1/year conversion rate) – 7%/year in ε4 carriers

26 PIB Load in HS Villemagne et al., Ann Neurol 2011

27 Beynin Olağan (“Default”) İşlevi Hipotezi Nicel PET ile PCC ve vACC’yi de içeren bir dizi beyin bölgesinde gözleri kapalı, istirahat halindeki bireylerde süregiden harici ipuçlu görevlerin performansı sırasında askıya alınan aktivite “These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.” Raichle et al. PNAS 2001

28 DMN Aktivitesi AH’yi Sağlıklı Yaşlanmadan Ayırır A: Sağlıklı yaşlanma B: Erken AH Duyarlılık: %85 Özgüllük: %77 Grecius et al. PNAS 2004

29 Amiloid Yükü ve DMN Aktivitesi AH’liler ve PIB+ normal kognisyonlu bireyler PIB- normal kognisyonlu bireylere göre benzer şekilde anlamlı düzeyde DMN hipoaktivitesi gösterirler. AH: 35 PIB+: 20 PIB-: 48 Sheline et al. Biol Psychiatry 2010

30 APOE Polimorfizm ve DMN DMN aktivitesi ε4+/PIB- normal bireylerde, ε4-/PIB- bireylere kıyasla, PIB+ bireyler ve AH’lilere benzer tarzda değişir. Sheline et al. J Neurosci 2010

31 Clinical Progression is Driven by Tau but not by Amyloid Deposition 21 HS, 32 aMCI, 8 AD, 2 years; Mayo, USA (Jack et al., Brain 2009) – Increase in PIB load: HS>MCI>AD – Ventriculer enlargement: HSLC

32 Amyloidosis and Neurodegeneration are Separate Processes 819 HS, MCI and AD, 59 ADNI centers, 2 years (Lo et al., Arch Neurol 2011) – CSF-Aβ42 decrease: HC>MCI>AD – FDG-PET metabolism and Hipp Atrophy: HC< MCI < AD – Amyloid load is an earlier event as compared to hypometabolism and atrophy 110 MCI, low CSF-Aβ 42 ; Amsterdam (van Rossum et al., Neurology 2012) – 63/110 AD converters in 2.2 years. – Conversion HR’s: CSF-t-Tau 2.3, CSF-pTau 3.5, MRI-Hipp atrophy 2.5, t-Tau+HA 7.3 – Neuronal damage markers in cerebral amyloidosis are the predictors of conversion

33 Interim Conclusions Aβ plaque accumulation is a slow process and seems to terminate before cerebral atrophy and cognitive impairment It is age-related – >64 years: %20; >85 years: %85 Amyloid imaging: 2/3 MCI and 1/3 HS positive Amyloid positivity is the predictor of conversion from HS to MCI and from MCI to AD Amyloid positivity is diagnostic in atypical AD presentations Amiloid negativity is a marker of non-AD dementia

34 NIA-AA Instead of NINCDS-ADRDA Biomarkers (BM) – Molecular CSF Aβ and tau PET amyloid imaging – Structural imaging Hippokampal volumetry Cortical thickness – Metabolic imaging FDG-PET Aβ accumulation markers – CSF Aβ and amyloid imaging Neurodegeneration markers – CSF tau and structural/metabolic imaging Pre-clinical AD (PC-AD) – Normal cognition + BM MCI-AD – MCI + BM AD dementia (AD-Dem) – Dementia + BM Sperling et al., Albert et al., McKhann et al., ADAD 2011

35 Aβ Leaves the Stage to Tau as AD Progresses from Pre-Clininical to Clinical Stages Jack et al. Lancet Neurol 2010 BOS-Tau FDG-PET MRG NPGYA

36 PC-AD = Cerebral Amyloidosis Phase I – Evidence of Aβ accumulation – Normal cognition (COG ∅ ) Phase II – Phase I – Positivity of neurodegeneration (ND) markers Phase III – Phase II – Subjective memory problems (COG +) Phase 0 – Aβ ∅, ND ∅, COG ∅ SNAP (suspected non-Alzheimer pathology) – Aβ ∅, ND +, COG +/- Unclassified (Phase X) – Aβ +, ND -, COG + – Aβ ∅, ND ∅, COG + Sperling et al., Alzheimer Dement 2011

37 PC-AD Outcomes Mayo Series 529 HS aged between years MRI, FDG-PET, PIB-PET – Phase 0: 44% – Phase I: 16% – Phase II: 12% – Phase III: 2% – SNAP: 23% – Phase X: 3% 1-year follow-up of 296 cases: 31 MCI/Dem cases – Phase 0: 5% – Phase I: %11% – Phase II: 21% – Phase III: 43% – SNAP: 10 % – Evre X: 10% Knopman et al., Neurology 2012

38 PC-AD Outcomes Washington Uni Series 65 years +, 311 HS BOS Aβ, τ; – Phase 0: 41% – Phase I: 15% – Phase II: 12% – Phase III: 4% – SNAP: 23% – Phase X: 5% CDR 0.5 in 5 years – Phase 0: 2% – Phase I: 11% – Phase II: 26% – Phase III: 56% – SNAP: 5 % – Evre X: 29% Vos et al., Lancet Neurol 2013

39 Subjective Memory Complaints and Amyloid Deposition 131 HS, 73.5±6 years of age; Boston, ABD (Amariglio et al., Neuropsychologia 2012) – Amyloid load as detected by PIB-PET Correlates with subjective memory complaints Does not correlate with objective memory and executive scores.

40 Age-Associated Memory Impairment (AAMI) AAMI: Poor memory performance of >50 year-old subjects as compared to young (<30) individuals (NIA 1985) Individuals with AAMI cannot acquire the contextual details of the recently learned information (Zacks et al. 2000) Contextual similarity increases the memory difficulty (Henkel et al. 1998) Responding to novelty weakens – The ability to discriminate novel and familiar items decreases (Friedman 2000) – Eelectrophysiologically the latencies and amplitudes of the novelty P3a responses in ERP recording prolongs and decreases respectfully (Daffner et al. 2005)

41 AAMI: Compensation of Novelty Detection Failure by Familiarity EC II EC III EC IV-VI Multimodal Association Cortices Multimodal Association Cortices Dentate gyrus CA3 CA1 Subiculum Perforant pathway Mossy fibres Schaffer collaterals Oto-associative fibres Wilson et al. TINS 2006 Pattern discrimination vs. Pattern completion

42 Variation on the Theme of NIA-AA Alzheimer’s cerebral amyloidosis (Pre-clinical AD) – Biomarker positivity with normal cognition Anti-amyloid + other prevention Alzheimer’s neurodegeneration (Clinical AD) – Mild (AD-AAMI) Biomarkers + novelty detection failure (familiarity compensation) – Anti-amyloid (?) + anti-tau + glutamate modulation – Moderate (AD-MCI) Biomarkers + isolated episodic memory impairment – Anti-amyloid + anti-tau + Glu modulation ± Cholinergic replacement (AChEIs) – Severe (AD-dementia) Biomarkers + multiple cognitive deficits – Anti-tau + glutamate modulation ± Cholinergic replacement (AChEIs)

43 Possible Benefits of Discriminating Between Alzheimer’s Amyloidosis and Neurodegeneration CA-ND relationship is probably not a linear sequential inevitability (Lazarczyk et al., BMC Med 2012) – Progression from CA to ND is preventable either by natural defence mechanisms and/ or pharmacologically. – Analogies with atherosclerosis and MI/stroke, osteoporosis and pathological fracture The treatment of AD-CA and AD-ND will probably be different, if with some overlaps in the future. – CA: anti-amyloid + other prevention – ND: : anti-amyloid (?early stage) + anti-Tau + established AD treatment


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