In this thesis, the monitoring of the immune system in balance and during active responses (by flow cytometry) plays a central role. In chapter 2.1 and 2.2, we investigated the optimal sample... Show moreIn this thesis, the monitoring of the immune system in balance and during active responses (by flow cytometry) plays a central role. In chapter 2.1 and 2.2, we investigated the optimal sample logistics for high-dimensional flow cytometry in clinical trials. In chapter 3.1-3.4, we monitored the longitidinal kinetics of circulating immune cells in humans after vaccination or bacterial challenge against Bordetella pertussis. Lastly, in chapter 4, we investigated the immune system in humans carrying a genetic variant of PLCG2 'p.P522R', which is associated with increased longevity and reduced chance of developing dementia. Show less
Wubben, N.; Haaksma, M.; Ramakers, I.H.G.B.; Flier, W.M. van der; Verhey, F.R.J.; Rikkert, M.G.M.O.; Melis, R.J.F. 2022
Objectives: To explain the heterogeneity in dementia disease trajectory, we studied the influence of changing patient characteristics on disease course by comparing the association of dementia... Show moreObjectives: To explain the heterogeneity in dementia disease trajectory, we studied the influence of changing patient characteristics on disease course by comparing the association of dementia progression with baseline comorbidity and frailty, and with time-varying comorbidity and frailty.Methods: We used individual growth models to study baseline and time-varying associations in newly diagnosed dementia patients (n = 331) followed for 3 years. We measured cognition using the Mini-Mental State Examination (MMSE), daily functioning using the Disability Assessment for Dementia (DAD), frailty using the Fried criteria and comorbidity using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G).Results: Although baseline comorbidity and frailty were associated with decreased daily functioning at diagnosis, their effects clearly diminished over time. In contrast, when incorporating comorbidity and frailty as time-varying covariates, comorbidity was associated with lower daily functioning, and frailty with both lower cognition and daily functioning. Being frail was associated with a 0.9-point lower MMSE score (p = 0.03) and a 14.9-point lower DAD score (p < 0.01). A 1-point increase in CIRS-G score was associated with a 1.1-point lower DAD score (p < 0.01).Conclusions: Time-varying comorbidity and frailty were more consistently associated with dementia disease course than baseline comorbidity and frailty. Therefore, modeling only baseline predictors is insufficient for understanding the course of dementia in a changing patient context. Show less
Kenkhuis, B.; Somarakis, A.; Haan, L. de; Dzyubachyk, O.; IJsselsteijn, M.E.; Miranda, N.F.C.C. de; ... ; Weerd, L. van der 2021
Brain iron accumulation has been found to accelerate disease progression in amyloid-beta(A beta) positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified... Show moreBrain iron accumulation has been found to accelerate disease progression in amyloid-beta(A beta) positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL(+)Iba1(+)-microglia, which were found to be the predominant A beta-plaque infiltrating microglia. Finally, an increase of FTL(+)Iba1(+)-microglia was seen in patients with high A beta load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with A beta. Show less
This thesis focuses on amyloid proteins, a class of proteins that convert into amyloid fibrils. Such proteins are of high interest because they are related to many of the neurodegenerative diseases... Show moreThis thesis focuses on amyloid proteins, a class of proteins that convert into amyloid fibrils. Such proteins are of high interest because they are related to many of the neurodegenerative diseases. In the brains of patients with neurodegenerative diseases, plaques of β-sheet amyloid aggregates are found, but the mechanism of their formation and their role vis-à-vis the disease are unknown. Aggregation is difficult to study because amyloids are intrinsically disordered proteins that lack an ordered structure in solution. Here we apply electron paramagnetic resonance (EPR) as a new technique to better understand the properties of amyloid oligomers and their formation. Show less
Rausch, A.; Caljouw, M.A.A.; Ploeg, E.S. van der 2017
This thesis describes neuroimaging techniques to investigate brain networks in healthy aging and dementia. Functional and structural brain networks change with healthy and pathological... Show more This thesis describes neuroimaging techniques to investigate brain networks in healthy aging and dementia. Functional and structural brain networks change with healthy and pathological aging, with differences in network degeneration between different types of dementia. These disease-specific network differences suggest the potential of brain networks to improve diagnostic accuracy. However, at this moment, our findings are only applicable for groups of patients and not yet suitable as a diagnostic tool on an individual basis. Show less
The general aim of this thesis was to explore the possibility to detect changes related to amyloid deposition in vivo using ultra-high field MRI. The central finding of the work presented in this... Show moreThe general aim of this thesis was to explore the possibility to detect changes related to amyloid deposition in vivo using ultra-high field MRI. The central finding of the work presented in this thesis is the cortical phase change on T2*-weighted sequences that we observed in AD patients using this novel ultra-high field imaging approach at 7T. It has been demonstrated that such phase measurements are a reliable indicator of iron content in the brain. It is known that amyloid depositions co-localize with iron accumulations. However, in autopsy material of AD patients, in addition to amyloid deposition, neurofibrillary tangles as well as tau deficiency were also found to co-localize with neuronal iron accumulation. In addition to iron, myelin and deoxy-hemoglobin can also contribute to phase changes. Although the exact origin of the observed phase changes in AD is not completely clear, these changes could have value for diagnostic purposes and as a biomarker. Show less
Alzheimer's disease is manifested in amyloid fibril but caused by protofibril oligomers of A_ peptide and tau protein. I discovered a molecular mechanism which involves a new globular state of the... Show moreAlzheimer's disease is manifested in amyloid fibril but caused by protofibril oligomers of A_ peptide and tau protein. I discovered a molecular mechanism which involves a new globular state of the A_ peptide formed by protofibril oligomers, and from which fibrils can nucleate. Another striking finding in my thesis is to present new concept to inhibit amyloid fibrillation. For instance, natural factors found in vivo, such as ,lysozyme, insulin and spermine, and non-natural factors found in vitro, like gramicidin S, can interfere with the toxicity and fibrillation of A_. Show less
Stargardt, A.; Gillis, J.; Kamphuis, W.; Wiemhoefer, A.; Kooijman, L.; Raspe, M.; ... ; Reits, E. 2013
