This dissertation is based on the following original publications:
I Haapalinna F, Paajanen T, Penttinen J, Kokki H, Kokki M, Koivisto AM,
Hartikainen P, Solje E, Hänninen T, Remes AM, Herukka SK. Low Cerebrospinal Fluid Amyloid-Beta Concentration Is Associated with Poorer Delayed Memory Recall in Women. Dement Geriatr Cogn Dis Extra 19;6(2):303-12, 2016.
II Haapalinna F, Kokki M, Jääskeläinen O, Hallikainen M, Helisalmi S, Koivisto A, Paajanen T, Penttinen J, Pikkarainen M, Rautiainen M, Soininen H, Remes AM, Herukka S-K. Subtle cognitive impairment and Alzheimer’s disease-type pathological changes in cerebrospinal fluid are common among neurologically healthy subjects. Journal of Alzheimer’s disease 62(1): 165-174, 2018.
III Haapalinna F, Jääskeläinen O, Moilanen V, Tarvainen I, Tuomainen P, Kaipainen A, Poukka E, Nykänen N, Tapiola T, Remes AM, Herukka S-K. The Accuracy of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers in Clinical Practice.
[Submitted]
The publications were adapted with the permission of the copyright owners.
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XV 2.5 Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery ... 13 2.6 Molecular biomarkers for neurodegenerative diseases ... 15 2.6.1 CSF Aβ1-42, tau and p-tau ... 16 4.2.1 Consortium To Establish a Registry for Alzheimer’s Disease Neuropsychological Battery ... 24 4.2.2 TELE phone call cognitive test (study II) ... 24 4.3 CSF samples and biomarker analyses ... 25 4.4 APOE analyses (Study II) ... 26 4.5 Statistical analyses ... 26 4.6 Ethical aspects ... 26 5 RESULTS ... 27 5.1 CSF AD biomarkers and cognition in subjects with AD, MCI and no subjective cognitive symptoms (Studies I and II) ... 27 5.2 AD-type CSF pathology and cognitive impairment among neurologically healthy subjects (Study II) ... 29
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5.3 The effect of APOE-ε4 allele on CSF biomarkers and cognition (Study II) ... 30 5.4 The effects of hypercholesterolemia, cardiovascular diseases, hypertension and diabetes on CSF biomarkers and cognition (study II) ... 31 5.5 There are no significant differences in the accuracy of the CSF AD biomarker measurements between centers in everyday clinical diagnostics (Study III) ... 31
5.5.1 Intercenter variability ... 31 5.5.2 Differences between diagnostic groups ... 33 6 DISCUSSION ... 35 6.1 Associations between the CSF AD biomarkers and cognition (studies I and II) ... 35 6.2 AD-type CSF pathology and cognitive impairment among neurologically healthy subjects (Study II) ... 36
6.2.1 CSF AD biomarkers ... 36 6.2.2 Performance on cognitive tests ... 36 6.2.3 Associations between CSF AD biomarkers and cognition ... 37 6.3 APOE-ε4 allele and CSF biomarkers (Study II) ... 37 6.4 Hypercholesterolemia, cardiovascular diseases and cognition (Study II) ... 38 6.5 Clinical variability of CSF AD biomarker analyses (Study III) ... 38 6.6 Strengths and limitations of the study ... 40 7 CONCLUSIONS ... 42 8 FUTURE PERSPECTIVES ... 43 REFERENCES ... 44
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Abbreviations
AD Alzheimer’s disease
ABCA7 ATP-binding cassette, subfamily A, member 7 AIC Amyloid precursor protein intracellular domain
ALS Amyotrophic lateral sclerosis
ANCOVA Analysis of covariance
ANOVA Analysis of variance
APOE-ε4 Apolipoprotein E ε4 allele
APP Amyloid precursor protein
Aβ Beta-amyloid
BBB Blood-brain-barrier
BIN1 Bridging integrator 1
BIOMARKAPD Biomarkers for Alzheimer’s and Parkinson’s disease
BNT-15 15-item Boston Naming Test
bvFTD Behavioral variant frontotemporal degeneration
CAA Cerebral amyloid angiopathy
CADASIL Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
CERAD-NB Consortium to Establish a Registry for Alzheimer’s Disease-Neuropsychological Battery
CJD Creutzfeld-Jacob’s disease
CLU Clustering/Apolipoprotein J
CR1 Complement receptor 1
CSF Cerebrospinal fluid
CT Computed tomography
C9ORF72 Chromosome 9 open reading frame 72
DLB Dementia with Lewy bodies
DSM-V Diagnostic and Statistical Manual of Mental Disorders fifth edition FDG-PET Fluorodeoxyglucose positron emission tomography
FTLD Frontotemporal lobar degeneration
GRN Progranulin
IWG International Working Group
KUH Kuopio University Hospital
LPA Logopenic progressive aphasia
l-vPPA Logopenic-variant primary progressive aphasia MAPT Microtubule associated protein tau
MCI Mild cognitive impairment
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miRNA Micro ribonucleic acid
MMSE Mini mental state examination
MRI Magnetic resonance imaging
MTA Medial temporal lobe atrophy
MTS Memory Total Score
NINCDS-ADRDA National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association
NFH Neurofilament heavy protein
NFL Neurofilament light protein
NFT Neurofibrillary tangle
nfvPPA Nonfluent variant primary progressive aphasia NOTCH3 A gene coding notch homolog 3 protein
NPH Normal pressure hydrocephalus
NSE Neuron specific enolase
OUH Oulu University Hospital
PCA Posterior cortical atrophy
PD Parkinson’s disease
PiB Pittsburgh compound B
PPA Primary progressive aphasia
PrPC Cellular prion protein
PSEN1+2 Presenilin 1 and 2
p-tau Hyperphosphorylated tau
REM Rapid eye movement
RNA Ribonucleic acid
ROC Receiver Operating Characteristic
SMC Subjective memory complaint
svPPA Semantic variant primary progressive aphasia
TDP-43 TAR DNA-binding protein 43
TDM Transmembrane domain
TLR Toll-like receptor
VaD Vascular dementia
VCI Vascular cognitive impairment
VLP-1 Visinin-like protein 1
1 Introduction
Cognitive impairment and dementing diseases are common, and due to the increase in life expectancy, their prevalence is expected to increase significantly in the future. These illnesses represent a significant social problem from the individual patient and his/hers loved ones as well as a financial burden on the economy (Wimo, Jonsson et al. 2013).
Dementia is a syndrome in which a group of symptoms affect multiple cognitive domains so severely to impair activities of daily functioning (McKeith, Cummings 2005). In 2010, there were 36.6 million people suffering from dementia all around the world, most of them in the developing countries. It has been estimated that the number of sufferers will double every 20 years and accordingly by 2050, as many as 115 million people will be diagnosed with dementia (Prince, Bryce et al. 2013).
The most common cause of dementia is Alzheimer’s disease (AD), accounting for approximately 70% of all cases (Reitz, Mayeux 2014, Mayeux, Stern 2012a). Other common causes include vascular dementia (VaD), dementia with Lewy bodies (DLB) and Frontotemporal lobar degeneration (FTLD). Furthermore, other etiologies such as excessive alcohol consumption and head trauma may lead to cognitive impairment and eventually dementia (Mayeux, Stern 2012b).
There is an overlap between different neurodegenerative diseases in terms of both their genetic background and pathological processes as well as their clinical picture. One common feature is the misfolding and accummulation of fibrillary protein aggregates (Lausted, Lee et al. 2014), such as beta-amyloid (Aβ) in AD (Reitz, Mayeux 2014). It has been proven that the pathological processes in the brain begin already decades prior to the appearence of any clinical symptoms (Price, Morris 1999a, Blennow, Dubois et al. 2015). However, the same kind of neuropathology can be observed also in some individuals who remain cognitively intact (De Meyer, Fred Shapiro et al. 2010, Knopman, Parisi et al. 2003a).
The diagnosis of dementing diseases is typically based on the clinical course of the symptoms, a clinical examination, neuropsychological testing, brain imaging and differential laboratory tests. However, at the present time, a definite diagnosis can be achieved only in a post-mortem neuropathological examination or after a brain biopsy. A number of biomakers have been investigated in order to aid in the diagnosis and differential diagnosis of neurodegenerative diseases, as well as to follow the progression of the diseases and the effects of therapeutic interventions. To date, there are validated disease-specific molecular biomarkers only for AD (Lausted, Lee et al. 2014).
At the present time, there is no curative treatment for neurodegenerative diseases, but it is possible to treat the symptoms of the disease (Carter, Simms et al. 2010). This is most efficiently done in the earlier stages of the pathology. In the future, if one could identify reliable neuropathology-specific cerebrospinal fluid (CSF) biomarkers, then the diagnosis could be achieved already in the disease’s prodromal phase.