Laura Ekblad: INSULIN RESISTANCE, COGNITION, AND BRAIN AMYLOID ACCUMULATION

107 Pages·2017·3.23 MB·English

by  Laura Ekblad

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INSULIN RESISTANCE, COGNITION,
AND BRAIN AMYLOID ACCUMULATION
An Epidemiological and a Positron Emission Tomography Study
Laura Ekblad
Oy, Turku , Finland 2018
ma
Painosala
ISBN 978-951-29-7103-9 (PRINT)
TURUN YLIOPISTON JULKAISUJA – ANNALES UNIVERSITATIS TURKUENSIS
ISBN 978-951-29-7104-6 (PDF)
Sarja - ser. D osa - tom. 1331 | Medica - Odontologica | Turku 2017
ISSN 0355-9483 (Print) | ISSN 2343-3213 (Online)
INSULIN RESISTANCE, COGNITION,
AND BRAIN AMYLOID ACCUMULATION
An Epidemiological and a Positron Emission Tomography Study
Laura Ekblad
TURUN YLIOPISTON JULKAISUJA – ANNALES UNIVERSITATIS TURKUENSIS
Sarja - ser. D osa - tom. 1331 | Medica - Odontologica | Turku 2018
University of Turku
Faculty of Medicine
Department of Geriatrics
Doctoral Program in Clinical Research
Turku PET Centre
Supervised by
Professor Juha O. Rinne MD, PhD Professor Matti Viitanen, MD, PhD
Turku PET Centre Department of Geriatrics
Turku University Hospital and University of
University of Turku
Turku, Finland
Turku, Finland
Professor Antti Jula, MD, PhD
National Institute for Health and Welfare
Turku, Finland
Reviewed by
Adjunct Professor Jouko Laurila, MD, PhD Adjunct Professor Seppo Lehto, MD, PhD
University of Helsinki University of Eastern Finland
Helsinki, Finland Kuopio, Finland
Opponent
Adjunct Professor Auli Verkkoniemi-Ahola, MD, PhD
Department of Neurology
Helsinki University Central Hospital
Helsinki, Finland
Cover photo/image by Laura Ekblad
The originality of this thesis has been checked in accordance with the University of Turku quality
assurance system using the Turnitin OriginalityCheck service.
ISBN 978-951-29-7103-9 (PRINT)
ISBN 978-951-29-7104-6 (PDF)
ISSN 0355-9483 (Print)
ISSN 2343-3213 (Online)
Painosalama Oy – Turku, Finland 2018
To Arttu, Otso and Sisu
Abstract
ABSTRACT
Laura Ekblad
INSULIN RESISTANCE, COGNITION, AND BRAIN AMYLOID ACCU-
MULATION
University of Turku
Faculty of Medicine
Department of Geriatrics
Doctoral Program in Clinical Research
Turku PET Centre
Insulin resistance is a common phenomenon, closely associated with obesity, and
defined as the inability of target tissues to respond normally to insulin. Insulin
resistance typically precedes the onset of type 2 diabetes by several years. Type 2
diabetes is a risk factor for dementia and for Alzheimer´s disease (AD), the most
common type of dementia. Some epidemiological studies suggest that insulin re-
sistance increases the risk for dementia and AD, even in non-diabetic populations.
In vitro and animal studies indicate that insulin resistance can contribute to the
pathogenesis of AD through multiple different pathways.
This thesis was set out to explore the cross-sectional and longitudinal associations
between insulin resistance and cognitive functioning in the Finnish large, nation-
wide Health 2000 survey, and its follow-up, Health 2011. The possible modulating
effects of sex and apolipoprotein E ε4 genotype (APOEε4), the most significant
genetic risk factor for sporadic AD, were of specific interest. The aim of this thesis
was also to investigate whether midlife insulin resistance increases the risk for
brain amyloid accumulation, which is considered an early sign of AD.
Insulin resistance was associated with poorer verbal fluency in women and in non-
carriers of APOEε4 cross-sectionally (n=5935). Insulin resistance was an inde-
pendent predictor of poorer verbal fluency performance after 11 years, and of a
steeper decline in verbal fluency during the follow-up in both men and women,
and in carriers and non-carriers of APOEε4 (n=3695). Midlife insulin resistance
increased the risk for brain amyloid accumulation, measured with positron emis-
sion tomography (PET), after a 15-year follow-up (n=60). The risk was similar in
both carriers and non-carriers of APOEε4.
These results indicate that midlife insulin resistance is an independent risk factor
for cognitive decline, and for late-onset AD.
Keywords: Alzheimer’s disease, APOEε4, cognition, HOMA-IR, insulin re-
sistance, [11C]PIB, positron emission tomography, PET, verbal fluency.
Tiivistelmä
TIIVISTELMÄ
Laura Ekblad
INSULIINIRESISTENSSI, KOGNITIO JA AIVOJEN AMYLOIDIKER-
TYMÄ
Turun yliopisto
Lääketieteellinen tiedekunta
Geriatria
Turun yliopiston kliininen tohtoriohjelma
Valtakunnallinen PET-keskus
Insuliiniresistenssi on tavallinen, keskivartalolihavuuteen liittyvä ilmiö, jolla tar-
koitetaan eri kudosten heikentynyttä vastetta insuliinille. Insuliiniresistenssi edel-
tää tyypillisesti tyypin 2 diabeteksen puhkeamista vuosien ajan. Tyypin 2 diabetes
lisää riskiä sairastua vanhuusiän muistisairauteen ja sen yleisimpään muotoon,
Alzheimerin tautiin (AT). Joidenkin seurantatutkimusten perusteella insuliiniresis-
tenssi lisäisi riskiä sairastua muistisairauteen myös henkilöillä, joille ei vielä ole
kehittynyt tyypin 2 diabetesta. Insuliiniresistenssi voi vaikuttaa AT:lle tyypillisten
aivomuutosten kehittymiseen useiden eri mekanismien kautta.
Tämän tutkimuksen tarkoituksena oli selvittää, onko insuliiniresistenssin ja muis-
tin tai muiden tiedonkäsittelytoimintojen välillä yhteyttä väestötasolla, perustuen
laajoihin Terveys 2000 ja 2011 -tutkimuksiin. Lisäksi selvitettiin, säätelevätkö su-
kupuoli ja/tai AT:n tavallisin geneettinen riskitekijä eli apolipoproteiini E -geenin
ε4-geenimuoto (APOEε4) insuliiniresistenssin ja tiedonkäsittelytoimintojen vä-
listä yhteyttä. Positroniemissiotomografia (PET)-kuvausten avulla tutkittiin, li-
sääkö keski-iän insuliiniresistenssi riskiä aivojen amyloidikertymälle, jota pide-
tään AT:n varhaisena merkkinä.
Tutkimuksessa osoitettiin, että insuliiniresistenssi oli yhteydessä heikompaan suo-
riutumiseen kielellistä sujuvuutta mittaavassa testissä poikkileikkausaineistossa
(n=5935). Tämä yhteys havaittiin vain naisilla, ja vain niillä, jotka eivät kantaneet
APOEε4-geenimuotoa. Sen sijaan 11 vuoden seurannassa insuliiniresistenssi en-
nusti heikompaa suoriutumista ko. testissä sekä naisilla että miehillä, APOEε4-
geenimuodosta riippumatta (n=3695). Keski-iän insuliiniresistenssi lisäsi myös
riskiä aivojen amyloidikertymälle 15 vuoden seurannassa APOEε4-geenimuodosta
riippumatta (n=60).
Löydösten perusteella näyttää siltä, että keski-iän insuliiniresistenssi on itsenäinen
tiedonkäsittelytoimintojen heikentymisen ja AT:n riskitekijä.
Avainsanat: Alzheimerin tauti, APOEε4, HOMA-IR, insuliiniresistenssi, kielelli-
nen sujuvuus, [11C]PIB, positroniemissiotomografia, PET.
Table of contents
TABLE OF CONTENTS
ABSTRACT ........................................................................................................... 4
TIIVISTELMÄ ....................................................................................................... 5
ABBREVIATIONS ................................................................................................ 8
LIST OF ORIGINAL PUBLICATIONS ............................................................. 10
1 INTRODUCTION ....................................................................................... 11
2 REVIEW OF THE LITERATURE ............................................................. 13
2.1 Cognitive decline, dementia, and mild cognitive impairment ............ 13
2.1.1 Definitions and diagnostic criteria .......................................... 13
2.2 Alzheimer´s disease ............................................................................ 17
2.2.1 Pathogenesis ............................................................................ 17
2.2.2 Diagnostic criteria ................................................................... 18
2.2.3 PET imaging in Alzheimer´s Disease ..................................... 20
2.3 Risk factors for cognitive decline, dementia, and Alzheimer´s
disease ................................................................................................. 26
2.3.1 Genetic risk factors .................................................................. 26
2.3.2 Metabolic and vascular risk factors ......................................... 27
2.4 Insulin resistance ................................................................................. 29
2.4.1 Definition and measurements .................................................. 29
2.4.2 Insulin, insulin resistance, and the central nervous system ..... 31
2.4.3 Insulin resistance and the risk for cognitive decline and
dementia .................................................................................. 32
2.5 Summary of the literature ................................................................... 45
3 OBJECTIVES OF THE STUDY ................................................................ 46
4 MATERIALS AND METHODS ................................................................ 47
4.1 Overall study design ........................................................................... 47
4.2 Study populations ............................................................................... 49
4.3 Methods............................................................................................... 52
4.3.1 Demographic data .................................................................... 52
4.3.2 Laboratory assessments and APOE genotyping ...................... 52
4.3.3 Cognitive tests ......................................................................... 53
4.3.4 [11C]PIB PET (Study III) ......................................................... 55
4.4 Statistical analysis ............................................................................... 55
4.4.1 Demographic data (Studies I–III) ............................................ 56
4.4.2 Cross-sectional associations between insulin resistance and
cognitive test scores (Study I) ................................................. 56
Table of contents
4.4.3 Longitudinal associations between insulin resistance and
cognitive test scores (Study II) ................................................ 57
4.4.4 [11C]PIB analysis (Study III) ................................................... 58
4.4.5 Association between midlife insulin resistance and [11C]PIB
uptake 15 years later (Study III) .............................................. 59
5 RESULTS .................................................................................................... 60
5.1 Demographic data (Studies I–III) ........................................................ 60
5.2 Cognitive test scores in 2000 and 2011 ............................................... 61
5.3 Cross-sectional associations between insulin resistance and cognitive
test scores (Study I) ............................................................................. 62
5.4 Longitudinal associations between insulin resistance and cognitive test
scores (Study II) .................................................................................. 65
5.5 Association between midlife insulin resistance and [11C]PIB uptake 15
years later (Study III) .......................................................................... 68
6 DISCUSSION .............................................................................................. 73
6.1 Insulin resistance and cognitive functioning ....................................... 73
6.1.1. Cross-sectional findings ........................................................... 73
6.1.2. Longitudinal findings ............................................................... 74
6.2 Insulin resistance as a risk factor for brain amyloid accumulation ..... 75
6.3 Methodological considerations ........................................................... 76
6.3.1 Study populations..................................................................... 76
6.3.2 Cognitive tests .......................................................................... 77
6.3.3 Definition of insulin resistance ................................................ 78
6.3.4 PET imaging and data analysis ................................................ 80
6.4 Clinical implications ........................................................................... 81
6.5 Future prospects .................................................................................. 84
7 CONCLUSIONS .......................................................................................... 86
ACKNOWLEDGEMENTS .................................................................................. 87
REFERENCES ..................................................................................................... 90
ORIGINAL PUBLICATIONS ........................................................................... 107
Abbreviations
ABBREVIATIONS
Aβ beta-amyloid
AD Alzheimer’s disease
AIBL Australian Imaging Biomarker and Lifestyle study
APOEε4 Apolipoprotein E ε4 genotype
ARIC Atherosclerosis Risk in Communities study
BBB Blood-brain barrier
BDI Beck´s Depression Inventory
BMI Body Mass Index
CERAD Consortium to Establish a Registry for Alzheimer´s Disease
CNS Central nervous system
CSF Cerebrospinal fluid
FDG [18F]fluorodeoxyglucose
hs-CRP High sensitive C-reactive protein
HOMA-IR Homeostatic Model Assessment of Insulin Resistance
IDE Insulin degrading enzyme
IR- HOMA-IR in the lowest tertile of the Health 2000 study population
IR+ HOMA-IR in the highest tertile of the Health 2000 study population
IWG International Working Group
MCI Mild cognitive impairment
MetS Metabolic syndrome
MMSE Mini-mental State Examination
MRI Magnetic resonance imaging
NIA-AA National Institute on Aging-Alzheimer's Association
Abbreviations
OGTT Oral glucose-tolerance test
OR Odds ratio
PIB Pittsburgh compound-B
PIB+ Amyloid positive PIB-PET scan
PET Positron emission tomography
QUICKI Quantitative Insulin Sensitivity Check Index
ROI Region of interest
RT Reaction time
SUVR Standard uptake value ratio
VaD Vascular dementia
VC Visual choice reaction time
VF Verbal fluency
WHO World Health Organization
WLDR Word-list delayed recall
WLL Word-list learning
WMH White matter hyperintensity