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- Hertze, Joakim
(author)
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Pathophysiological Mechanisms and Diagnostic Markers in Alzheimer’s Disease
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Alzheimer’s disease (AD), the most common cause of dementia, is a growing concern. As the life expectancy increases across the globe, the number of affected people is estimated to reach 100 million by 2050. Efforts to develop effective treatments for humans have mostly been based on the assumption that a faulty homeostasis of beta amyloid (Aβ) is the triggering or the driving factor behind this condition. So far these efforts have failed, making a better understanding of other pathophysiological mechanisms behind this disease necessary in order to find new therapeutic approaches. The aim for this thesis was to explore such mechanisms. Besides changes typical of AD, these patients often show signs of vascular disease. In order to explore how white matter changes (WMLs) affects the course of disease, we analyzed CSF levels of phosphorylated tau (P-tau) and assessed WMLs on brain scans in healthy controls and patients with mild cognitive impairment. We found that a pathological level of P-tau and WMLs in the parietal lobes independently increased the risk of developing AD dementia, but that the risk was considerably higher for patients that had both. Next, we analyzed the CSF/plasma ratio of albumin, as a proxy for blood-brain barrier integrity, and found it to be increased in AD and other common dementias. This ratio was not associated with the APOE genotype, as had previously been suggested, or markers of Aβ load. Instead, we found it to be associated with diabetes mellitus and markers of microvascular damage in the brain. We then moved on from vascular factors to other mechanisms suggested in AD.The insulin-like growth factor (IGF) related system is implicated in regulating life-span and in growth-promotion and neuroprotection in the human nervous system. There are reports of changes to the IGF-related system in cognitive disorders. When we analyzed components of this system in healthy controls and patients with AD we found differences in CSF and blood plasma levels of IGF-II and some of its associated binding proteins, possibly reflecting an activated general response to neuronal damage. Lastly, we analyzed CSF biomarkers of synaptic degeneration (neurogranin) and microglial activation (YKL-40) in healthy controls, patients with mild cognitive impairment and patients with common dementias. We found the former to be selectively increased in AD dementia, whereas the latter was increased in both AD and frontotemporal dementia. However, these biomarkers did not improve the diagnostic accuracy of either prodromal AD or AD dementia when compared to established CSF biomarkers of AD. Nevertheless, we think they are useful, since they reflect other processes in AD than Aβ deposition and axonal damage. We hope that the results from this thesis has provided new insights into the pathophysiological mechanisms in AD and that they might suggest novel routes for exploring this complex condition.
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| 2. |
- Janelidze, Shorena, et al.
(author)
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Cerebrospinal fluid neurogranin and YKL-40 as biomarkers of Alzheimer's disease.
- 2016
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In: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 3:1, s. 12-20
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Journal article (peer-reviewed)abstract
- Widespread implementation of cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) in clinical settings requires improved accuracy for diagnosis of prodromal disease and for distinguishing AD from non-AD dementias. Novel and promising CSF biomarkers include neurogranin, a marker of synaptic degeneration, and YKL-40, a marker of neuroinflammation.
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| 3. |
- Janelidze, Shorena, et al.
(author)
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Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype
- 2017
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 51, s. 104-112
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Journal article (peer-reviewed)abstract
- Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF bio-markers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage. (C) 2016 The Authors. Published by Elsevier Inc.
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