The APOE-epsilon 4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and... Show moreThe APOE-epsilon 4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE-epsilon 4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1 beta, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau(181) and amyloid-beta(1-42) (AD pathology markers) of 97 participants (aged 38-83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-epsilon 4 genotype. This suggests that APOE-epsilon 4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD. (C) 2019 The Author(s). Published by Elsevier Inc. Show less
Rooden, S. van; Berg-Huysmans, A.A. van den; Croll, P.H.; Labadie, G.; Hayes, J.M.; Viviano, R.; ... ; Damoiseaux, J.S. 2018
Background:Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer’s disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel... Show moreBackground:Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer’s disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD.Objective:The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume).Methods:67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints.Results:We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD.Conclusion:SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD. Show less
Rooden, S. van; Doan, N.T.; Versluis, M.J.; Goos, J.D.C.; Webb, A.G.; Oleksik, A.M.; ... ; Grond, J. van der 2015
In this research heavy chain antibody fragments (VHHs) are developed as potential tools for non-invasive in vivo imaging of Alzheimer__s disease (AD) and Cerebral Amyloid Angiopathy (CAA). First... Show moreIn this research heavy chain antibody fragments (VHHs) are developed as potential tools for non-invasive in vivo imaging of Alzheimer__s disease (AD) and Cerebral Amyloid Angiopathy (CAA). First the generation of antibody fragments, directed against A_ is described. VHHs that were selected from different libraries showed differential affinity for different A_ epitopes when used for immunohistochemistry. These observations indicate that the VHHs are the first immunologic probes with the capacity to differentiate between parenchymal and vascular beta amyloid aggregates. Next, in chapter three the VHH are assessed on their ability to cross the blood-brain barrier using an established in vitro blood brain barrier co-culture system. VHH ni3A showed the highest transmigration efficiency of all tested VHHs. This transport is, in part, facilitated by a 3 amino acid substitution in its N-terminal domain. Additional studies indicated that the mechanism of transcellular passage of ni3A is by active transport. The data described in chapter four provides preliminary proof that these VHHs have the capacity to target A_ depositions in vivo. Consequently, the VHHs are promising tools for further development as imaging agents for the differential diagnosis of A_-related neurodegenerative diseases like CAA and AD. Show less
Sabayan, B.; Jansen, S.; Oleksik, A.M.; Osch, M.J.P. van; Buchem, M.A. van; Vliet, P. van; ... ; Westendorp, R.G.J. 2012
Magnetic resonance imaging (MRI) is sensitive to structural and functional changes in the brain caused by Alzheimer's disease (AD), and can therefore be used to help in diagnosing the disease.... Show moreMagnetic resonance imaging (MRI) is sensitive to structural and functional changes in the brain caused by Alzheimer's disease (AD), and can therefore be used to help in diagnosing the disease. Improving classification of AD patients based on MRI scans might help to identify AD earlier in the disease's progress, which may be key in developing treatments for AD. In this study we used an elastic net classifier based on several measures derived from the MRI scans of mild to moderate AD patients (N = 77) from the prospective registry on dementia study and controls (N = 173) from the Austrian Stroke Prevention Family Study. We based our classification on measures from anatomical MRI, diffusion weighted MRI and resting state functional MRI. Our unimodal classification performance ranged from an area under the curve (AUC) of 0.760 (full correlations between functional networks) to 0.909 (grey matter density). When combining measures from multiple modalities in a stepwise manner, the classification performance improved to an AUC of 0.952. This optimal combination consisted of grey matter density, white matter density, fractional anisotropy, mean diffusivity, and sparse partial correlations between functional networks. Classification performance for mild AD as well as moderate AD also improved when using this multimodal combination. We conclude that different MRI modalities provide complementary information for classifying AD. Moreover, combining multiple modalities can substantially improve classification performance over unimodal classification. (C) 2016 The Authors. Published by Elsevier Inc. Show less
Dementie is een verwoestende ziekte waar wereldwijd miljoenen mensen aan leiden. De meest voorkomende oorzaak van dementie is de ziekte van Alzheimer. Voor het ontwikkelen van effectieve... Show moreDementie is een verwoestende ziekte waar wereldwijd miljoenen mensen aan leiden. De meest voorkomende oorzaak van dementie is de ziekte van Alzheimer. Voor het ontwikkelen van effectieve behandelingen is het belangrijk om dementie in een vroeg stadium te detecteren. Traditioneel alzheimeronderzoek is voornamelijk gericht op groepsverschillen tussen patiënten en controles. Recent onderzoek is deels verschoven naar individuele classificatie met machine learning. In dit proefschrift onderzoeken we het gebruik van magnetic resonance imaging (MRI) voor automatische detectie van de ziekte van Alzheimer, en vroege detectie van cognitieve achteruitgang. In dit proefschrift laten we zien dat het combineren van MRI modaliteiten de classificatie kan verbeteren. Ook laten we zien dat diffusie MRI een goede maat is om alzheimer te diagnosticeren. Bij toepassing van dezelfde methoden op een groep presymptomatische gendragers die amyloïdangiopathie zullen ontwikkelen vonden we geen verschillen tussen de gendragers en controles. Tevens waren we niet in staat om cognitieve achteruitgang na 4 jaar te voorspellen in een groep ouderen met verhoogd risico op achteruitgang. Met MRI kunnen betrouwbare individuele uitspraken gedaan kan worden over patiënten, maar het is met de huidige methoden niet gevoelig voor vroege detectie van cognitieve achteruitgang. Show less
Shamonin, D.P.; Bron, E.E.; Lelieveldt, B.P.F.; Smits, M.; Klein, S.; Staring, M.; Alzheimer's Dis Neuroimaging In 2014
Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently... Show moreIncreasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved. Show less
The vascular and neurodegenerative processes related to clinical dementia cause cell loss which induces, amongst others, an increase in interstitial fluid (ISF).We assessed microvascular,... Show moreThe vascular and neurodegenerative processes related to clinical dementia cause cell loss which induces, amongst others, an increase in interstitial fluid (ISF).We assessed microvascular, parenchymal integrity, and a proxy of ISF volume alterations with intravoxel incoherent motion imaging in 21 healthy controls and 53 memory clinic patients - mainly affected by neurodegeneration (mild cognitive impairment, Alzheimer's disease dementia), vascular pathology (vascular cognitive impairment), and presumed to be without significant pathology (subjective cognitive decline).The microstructural components were quantified with spectral analysis using a non-negative least squares method. Linear regression was employed to investigate associations of these components with hippocampal and white matter hyperintensity (WMH) volumes. In the normal appearing white matter, a large f(int )(a proxy of ISF volume) was associated with a large WMH volume and low hippocampal volume. Likewise, a large f(int) value was associated with a lower hippocampal volume in the hippocampi.Large ISF volume (f(int)) was shown to be a prominent factor associated with both WMHs and neurodegenerative abnormalities in memory clinic patients and is argued to play a potential role in impaired glymphatic functioning. (C) 2021 The Author(s). Published by Elsevier Inc. Show less
Toledo, J.B.; Arnold, M.; Kastenmüller, G.; Chang, R.; Baillie, R.A.; Han, X.; ... ; Kaddurah-Daouk, R. 2017
IntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our... Show moreIntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.MethodsFasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1–42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.DiscussionMetabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. Show less
