alzheimers sjukdom - svenska demensdagarnamedia.svenskademensdagarna.se/2017/05/2_att-se... · att...

Att se Alzheimers sjukdom –hur positronemissionstomografi har förändratvår syn på demenssjukdomen Michael Schöll, med dr Biträdande lektor - Göteborgs universitet Forskare - Lund University

Alzheimers sjukdom

• Vanligaste demenssjukdom

• ~47 miljoner drabbade - snabbt ökande

• Enbart symptomatisk behandling

• Beta-amyloid patologi („Plack“)

• Tau patologi („Neurofibriller“)

• Neuroinflammation

à Neuronal dysfunktion

à Neurodegeneration

à Fortskridande kognitiv svikt

Friskt åldrande och Alzheimers sjukdom (AD)

• AD-relaterad patologi uppträder också vid “vanligt” åldrande(post-mortem studier)

• Utsträckning?

• Temporala / anatomiska förhållanden?

Hypotetisk tidslinje för Alzheimerpatologi

Modifierad Jack et. al 2010 & 2013, Lancet Neurol

• Cerebrospinalvätska (likvor)

• Beta-amyloid (sänkt)

• Fosforylerad och total mängd tau (ökat)

• ingen spatiell information, “sekundära” markörer

• Strukturell bildgivning (MRT)

• Atrofi

• Funktion

• Positronemissionstomografi (PET)

Utvärdering av Alzheimerpatologi med biomarkörer

Modern PET/CT-kamera

PET/MRT-kamera

PET/MRT-kamera

Cyklotron

Isotop

Molekyl/spårämne

Radiokemi

Bild - rekonstruktion

- modellering

Please cite this article in press as: Schöll, M., et al., Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation.Neurobiol. Aging (2009), doi:10.1016/j.neurobiolaging.2009.08.016

ARTICLE IN PRESSNBA-7395; No. of Pages 12

8 M. Schöll et al. / Neurobiology of Aging xxx (2009) xxx–xxx

Fig. 3. CMRglc in carrier 6 at baseline, 2, 10 and 12 years in comparison with the control group (mean ± SD) (ant = anterior; post = posterior; ctx = cortex).

brain, right and left inferior parietal lobules, the superiortemporal gyrus, the left entorhinal and posterior cingulatecortex and the left hippocampus in the brains of sevenasymptomatic PSEN1 mutation carriers in comparison withage-matched controls. Furthermore, comprehensive corticalhypometabolism with a focal parietotemporal deficit in 24members of families with familial AD (Kennedy et al., 1995)and parietotemporal hypometabolism in a 65-year-old sub-ject at risk of developing familial AD (Pietrini et al., 1993)have been reported.

Discrepancies between our findings regarding brainregions and some of the above-mentioned results might beexplained by the fact that the investigated subjects weremostly far closer to their expected age of onset than the sub-jects examined here. Furthermore, some studies had stronga priori hypotheses and did not include brain regions suchas subcortical areas. Several studies involving examination

Fig. 4. Baseline and 12 years FDG scans of carrier 6 showing widespreaddecline in CMRglc over the follow-up period.

of subjects at risk or at prodromal stages of AD, and useof functional neuroimaging revealed thalamic disturbance.In a follow-up study in patients with aging-associated cog-nitive decline (AACD), Hunt et al. (2007) reported glucosehypometabolism in several brain regions including the rightthalamus in AACD patients who converted to AD. An fMRIstudy investigating 95 asymptomatic offspring of familialAD cases showed decreased activation in the cingulate cor-tex and the thalamus in response to a memory paradigmin comparison with a control group (Bassett et al., 2006).In a 18F-fluorodeoxyglucose autoradiographic study of agedtransgenic mice over-expressing a mutant form of APP asso-ciated with a form of early onset AD, CMRglc was foundto be preferentially reduced in several thalamic nuclei aswell as in the posterior cingulate cortex (Reiman et al.,2000).

Hence, the thalamus, with its widespread and complexconnections to cortical association areas that show clear glu-cose hypometabolism in AD is likely to represent an earlyaffected region in AD development. These connections havebeen described in studies showing that lesions in thalamicareas lead to memory impairment, thereby demonstrating theimportance of a network that includes thalamic nuclei, whichinfluence the activity in areas of the cortex responsible formemory processes (Annoni et al., 2003; Parkin et al., 1994;Stenset et al., 2007). A hippocampal thalamic network aspart of Papez’s circuit involved in processes like episodicmemory processing has furthermore been described in sev-eral anatomical and functional studies (Aggleton and Brown,1999; Quirk et al., 1992; Villain et al., 2008). Moreover, char-acterisation of an animal model in studies on discriminativelearning indicated the existence of a circuit linking the tha-lamus, the posterior cingulate cortex and the hippocampalformation (Gabriel and Sparenborg, 1987). However, accu-rate anatomical differentiation of different thalamic nuclei ishard to accomplish given the low spatial resolution of PETimages and the normalisation and projection steps involved

18F ~110min 11C~20 min

Bildanalys

Grundläggande principer för PET


Positron

Gammafoton

+

-

Gammafoton

Elektron

E = mc2


• In vivo-mätning och kvantifiering av fysiologiska och patologiska processer

• Information om biologiska system genom användning av positron-emitterande radiofarmaka (ligand / spårämne)

• Dyrt, relativt dålig tillgänglighet, komplicerat, resurskrävande

• Spatiell upplösning 2-5 mm, tidsupplösning minuter-timmar

• Användningsområden:

• Cancerdiagnostik (98% klinisk rutin)

• Protein (äggvite-) ansamling

• Hjärnans glukosmetabolism (sockeromsättning)

• Receptordensitet

• Enzymaktivitet

• Blodflöde

PET

PET-kamerori Sverige

PET/CT PET/MRT

Lund 3

Malmö 1

Göteborg 2

Stockholm 2 1

Uppsala 2 1

Örebro 1

Umeå 1 1Linköping 1

Växjö 1

Bild- och interventionscentrum (BoIC)vid Sahlgrenska universitetssjukhuset

+

PET i Göteborg

Hammersetal.,HumBrainMapp2003

Bildanalys - Atlas-baserad




Bildanalysis - Voxel-baserad

Fibrilläramyloid-patologi

[11C]-PIB[18F]-Florbetapir[18F]-Florbetaben[18F]-Flutemetamol

...

NeuronaldysfunkDon(Glukos-

metabolism)

[18F]-2-deoxy-D-glucose(FDG)

Neuro-inflammaDon

[11C]-(L)-Deuterodeprenyl

(DED)

[11C]-PK11195[18F]-DPA-714

…

PET inom Alzheimerforskningen

FDG PET (sockeromsättning)

MildkogniDvsvikt(MCI)

EPereQår

Manifesteraddemens(Alzheimer)

Nordberg et al. 2010, Nature Rev Neurol

11C-Pittsburgh Compound B (PiB) PET (Amyloidpatologi)

• OBS!

• 30% av alla kognitivt friska äldre uppvisar “positiva” amyloid PET scans

• Amyloidpatologi är INTE relaterad till kognitiv försämring eller sjukdomsgraden

Amyloidgåtan

Amyloidgåtan

Ossenkoppele et al. 2015, Annals of Neurology

Amyloid-PET [18F]FDG MRIFallstudie – Alzheimervariant

Alzheimers sjukdom

Alzheimer, A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und psychish-gerichtliche Medizin, 1907. (Berlin) 64: 146-148.

Tau (τ)

Taupatologi

• Är associerad med sjukdomsförlopp (Nelson et al. 2012)

• Direkt kopplad till neuronal dysfunktion (Spires-Jones et al. 2014)

djur-, post-mortem-, och likvorstudier Tau-PET: Spridning av taupatologi in vivo

Tau (τ)

Fibrillaramyloidpathology

[11C]-PIB[18F]-Florbetapir[18F]-Florbetaben[18F]-Flutemetamol

...

NeuronaldysfuncDon(Glucose

metabolism)

[18F]-2-deoxy-D-glucose(FDG)

Neuro-inflammaDon

[11C]-(L)-Deuterodeprenyl

(DED)

Tau-patologi

[18F]-AV-1451[11C]-THK523[18F]-THK5351[18F]-PBB3

...

[11C]-PK11195[18F]-DPA-714

…

PET in AD

Fibrilläramyloid-patologi

NeuronaldysfunkDon(Glukos-

metabolism)

Tau (τ) PET spårämnen

18F-AV1451

In vivo utvärdering av taupatologi- [18F]AV-1451 PET

T807 à AV-1451

Xia et al., Alzheimers Dement 2013

Smith et al., Brain 2016

Tau - post mortem vs in vivo

Amyloidgåtan

[11C]PIB [18F]FDG MRI

Case study – AD variant (posterior cortical atrophy)[18F]AV1451

Ossenkoppele et al. 2015, Annals of Neurology

Tau inom Alzheimers sjukdom och åldrande

Acta Neuropathol (1991) 82:239 - 259 Acta H ' pathologica 9 Springer-Verlag 1991

Review

Neuropathological stageing of Alzheimer-related changes H. Braak and E. Braak* Zentrum der Morphologie, Theodor-Stern-Kai 7, W-6000 Frankfurt/Main 70, Federal Republic of Germany

Received March 6, 1991/Revised May 17, 1991/Accepted June 3, 1991

Summary. Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pat tern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibritlary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pat tern permitting the differentiation of six stages. The first two stages were characterized by an ei ther mild or severe alteration of the transentorhinal layer Pre-c~ (transentorhinal stages I-II) . The two forms of limbic stages (stages I I I - IV) were marked by a conspicuous affection of layer Pre-(x in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V - V I ) was the destruction of virtually all isocortical association areas. The investigation showed that recog- nition of the six stages required qualitative evaluation of only a few key preparations.

Key words: Amyloid - Neurofibrillary changes - Dement ia - Alzheimer 's disease - Stageing

The neuropathological hallmark of Alzheimer 's disease (AD) is the progressive accumulation of insoluble fibrous material which is normally not found in the human central nervous system. This material consists of extracellular amyloid [15, 18, 19, 40, 43, 62] and intraneuronal neurofibrillary (NF) changes [4, 8, 39, 53, 55, 56, 59]. Fur thermore , it is not distributed at random

* Supported by the Deutsche Forschungsgemeinschaft Offprint requests to: H. Braak (address see above)

but shows a characteristic pat tern [3, 9, 10, 14, 31, 33, 34, 38, 48, 581.

End-stages of AD are easily recognized at neuropathological examination. Evaluation of cases with mild to moderate affection, in contrast, is fraught with difficul- ties. Currently, quantitative analyses of numerous areas are required for distinction of fully developed AD from cases with insufficiently dense changes [32, 35]. Little effort has as yet been made to fur ther differentiate cases which do not meet the conventional diagnostic criteria [9]. Upon evaluation of a large number of cases with various degrees of involvement the existence of characteristic changes in the distribution pat tern of neurofibrillary tangles (NFT) and neuropil threads (NT) became apparent (Tables 1, 2). It is tempting to assume that this sequence of involvement also reflects - in a still unknown manner - the clinical course of AD. This study, however, is not aimed at correlating morphological changes with clinical symptoms but tries to show differences in the pat tern of NFT and NT rendering morphological stageing of AD-rela ted changes possi- ble.

Materials and methods

A total of 83 brains obtained at autopsy and fixed by immersion into a 4 % aqueous solution of formaldehyde was used for this study. None of the brains had macroscopically detectable infarc- tions. Eight brains were from individuals whose clinical protocols included the diagnosis of dementia (Table 2, nos. 45, 47, 48, 52-54, 56, 59); however, at neuropathological examination these brains did not meet the conventional criteria for diagnosis of fully developed AD [9, 35]. Twenty-one brains were from demented old-aged individuals (nos. 62-83) including four brains from patients who had suffered from Down's syndrome (nos. 70, 71, 74, 75). Brains 62-83 displayed sufficient densities of isocortical NF changes [32, 35] to confirm the clinical diagnosis of AD.

The brains were cut into hemispheres. One hemisphere of each brain was then cut into blocks in the frontal plane with the aid of a macrotome. Fourty brains (marked in Table 2 by an asterisk) were cut into 12-14 blocks. Of the remaining 43 brains only 4 blocks (frontal, anterior central: uncus level, posterior central: CGL level, occipital) were used in the study. The blocks were embedded

“Braak” stadier för taupatologi

Serrano-Pozo et al., Cold Spring Harb Perspect Med 2011 Braak and Braak, Acta Neuropathol 1991 Braak et al., Acta Neuropathol 2006 Alafuzoff et al., Brain Pathol. 2008 Braak et al., J Neuropathol Exp 2011

indirectly attributable to aging (43Y45). Age-related factors thatcan damage postmitotic cells or can exert noxious influenceson them are thought to play a central role in the pathogenesisof AD (13, 46Y48). Yet it should be emphasized in this con-text that, in AD, not all of the known types of postmitotic cellsinside and outside the CNS become involved in the diseaseprocess. Even when the discussion is confined to the brain,it quickly becomes clear that AD does not indiscriminately

involve all neuronal types; the pathologic process is a remark-ably selective one in that it develops in only a minority ofneuronal types while sparing others (49, 50).

It also has been pointed out that the disease process inAD requires an inordinately long prodromal period that lastsfor 5 or more decades (51Y54). Our current findings indi-cate that the AD-associated process may manifest itself inyoung individuals of both sexes as well as in the absence of

Braak et al J Neuropathol Exp Neurol ! Volume 70, Number 11, November 2011

! 2011 American Association of Neuropathologists, Inc.966

Copyright © 2011 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.

Transentorhinal Limbisk Isokortikal

Kognitiv försämring och sjukdomsgrad

“Braak” stadier för taupatologi och ålder

Braak et al., Journal of Neuropathology and Experimental Neurology (2011) Braak and Tredici, Acta Neuropathol (2011)










Braak I/II region FreeSurfer ROIs

Braak 1 Entorhinal ctx

Braak 2 Hippocampus

http://jagustlab.neuro.berkeley.edu/research.html

Braak III/IV region FreeSurfer ROIs

Braak 3 Parahippocampal gyrus Lingual gyrus Amygdala

Braak 4 Inferior temporal ctx Middle temporal ctx Temporal pole Thalamus Caudal, rostral, isthmus posterior cingulate Insula


Braak V/VI region FreeSurfer ROIs

Braak 5 Frontal ctx Parietal ctx Occipital ctx Transverse, superior temporal ctx Precuneus Banks of the superior temporal sulcus Nucleus accumbens Caudate nucleus Putamen

Braak 6 Postcentral gyrus Precentral gyrus Paracentral gyrus Cuneus Pericalcarine


0.8

2

SU

VR

Braak 0 Braak I/II Braak III/IV Braak V/VI

“Braak” stadier med tau PET

Tau and amyloid interaction

Schöll et al., Neuron 2016

Sammanfattning tau I

• Tau kan ansamlas i mediala tinningloben även hos kognitivt friska äldre individer

• Om amyloidpatologi har ansamlats i hjärnbarken, sprider sig taupatologin även till andra delar av hjärnan

Tau och kognition

• Taupatologi anses vara kopplad till neurodegeneration och till kognitiv försämringt ex Mitchell et al., Ann Neurol 2002 Rolstad et al., JAD 2012 Buerger et al., Brain 2007

Schöll et al., Neuron 2016

• Tau PET visar att åldersrelaterad taupatologi (i mediala temporalloben) är kopplad till försämring av episodiskt minne oberoende av amyloidpatologi

• Försämring av global kognition är kopplad till taupatologi och till förekomsten av amyloid i barken

Sammanfattning tau II

Alzheimervarianter

Voxelwise contrasts betweenpatients and control subjects

Next, we performed voxelwise contrasts for 18F-AV1451,11C-PiB and 18F-FDG between patients with posterior cor-tical atrophy and controls. In line with our hypothesis anda previous case study (Ossenkoppele et al., 2015d), pa-tients with PCA showed substantial inverse spatial overlapbetween greater 18F-AV1451 and reduced 18F-FDGuptake, specifically affecting brain regions implicated inhigher-order visual processing, particularly in the righthemisphere (Fig. 2A). This is further illustrated by over-laying the binarized 18F-AV1451 and 18F-FDG significancemaps (Fig. 2D). Additionally, 18F-AV1451 uptake was ele-vated in several brain regions where 18F-FDG uptake didnot differ from controls, including primary visual cortexand posterior cortex in the left hemisphere. Contraryto the regional specificity of 18F-AV1451 and 18F-FDG,11C-PiB retention was distributed throughout the neocor-tex and implicated both clinically affected and relativelyspared regions (e.g. extensive binding in frontal cortex;Fig. 2A).

In line with the clinical presentation, the 18F-AV1451 pat-tern in patients with an amnestic-predominant presentationmost prominently affected the medial temporal lobes and lat-eral temporoparietal cortex (Fig. 2B). When assessing theparametric images and AIs of the five logopenic variantPPA cases individually, three patients showed the predictedleft4 right asymmetry, one was fairly symmetric, and oneshowed right4 left 18F-AV1451 uptake (Table 2 andFig. 2E). Notably, the two patients with most advanced dis-ease severity showed the greatest 18F-AV1451 uptake in theright hemisphere and in anterior brain regions. On group-levelvoxelwise analyses, the 18F-AV1451 pattern in patients withlogopenic variant PPA was rather symmetric, with uptakemainly observed in bilateral temporoparietal regions that aretypically involved in language function (Fig. 2C). Voxelwise11C-PiB and 18F-FDG contrasts between amnestic Alzheimer’sdisease and logopenic variant PPA patients against controlsare shown in Supplementary Fig. 3. In general, the results aresimilar to those seen in patients with PCA (i.e. widespreadneocortical 11C-PiB binding, while 18F-FDG uptake is moreregion-specific), but should be interpreted with caution giventhe smaller sample size due to missing scans.

Figure 1 18F-AV1451 uptake in individuals with distinct phenotypes of Alzheimer’s disease. SUVR 18F-AV1451 images (neurological

orientation) in (A) a 59-year-old female (MMSE: 28) with posterior cortical atrophy [note that this a different patient than presented in

Ossenkoppele et al. (2015d)]; (B) a 77-year-old female (MMSE: 17) with logopenic variant PPA; (C) a 71-year-old female (MMSE: 23) with amnestic

Alzheimer’s disease; (D) a 59-year-old female (MMSE: 27) with non-amnestic Alzheimer’s disease; (E) a 59-year-old male (MMSE: 21) with a

behavioural presentation of Alzheimer’s disease, and (F) a 60-year-old female (MMSE: 16) with a corticobasal syndrome affecting the left

hemibody.

In vivo tau PET in Alzheimer’s disease BRAIN 2016: Page 7 of 17 | 7

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Ossenkoppele, Schonhaut, Schöll et al., Brain 2016

PET biomarkörer för Alzheimer-relaterad patologi erbjuder nu möjligheten att skapa omfattande biomarkörprofiler på individnivå

Sammanfattning

Tidig diagnos

Rekrytering till kliniska studier

“Slutpunkt” för kliniska behandlingsstudier

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