Details

Autor(en) / Beteiligte

• Thordardottir, Steinunn

Titel

Biomarkers in Preclinical Familial Alzheimer Disease

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2018

Beschreibungen/Notizen

• Background: Alzheimer disease (AD) is a neurodegenerative disorder, characterized by the accumulation of b-amyloid (Ab) plaques and tangles consisting of hyper phosphorylated tauprotein in the brain. It accounts for 60-70% of dementia cases, making it the most common cause of dementia. In rare cases the disease is inherited in autosomal dominant early onset form caused by mutations in APP, PSEN1 or PSEN2. These familial forms of AD (FAD) allow for studies of the long preclinical stage of the disease and may thereby address un answered questions about the natural history of AD which can be used to develop optimal tools for early diagnos is and for monitoring treatment response, as well as finding new possible treatment targets. To this end we conducted a prospective study, involving repeated clinical evaluations and collection of biomarkers from asymptomatic carriers of mutations leading to FAD with in on-carriers (NC) from the same families as controls. The asymptomatic mutation carriers(MC) are good representatives of the preclinical stage of AD as they will develop symptoms of the disease in the future at an age which can be estimated based on the age at symptom on setin their family members who have already become symptomatic.Aims: To map biomarker changes in preclinical AD, as well as their temporal trajectories and sequence, through repeated collection and analysis of biomarkers in asymptomatic FAD MC and NC.Results: There were significant differences in the levels of the cerebrospinal fluid (CSF)biomarkers Ab42, total-tau protein (t-tau) and phosphorylated tau-protein (p-tau), as well as in the Ab42/p-tau ratio when comparing MC to NC, more than 7 years before the expected on set of symptoms in the MC. Ab42 and the Ab42/p-tau ratio were lower in MC than NC, while tau and p-tau were higher in MC than NC. There was a trend of Ab42 and the Ab42/p-tau ratio decreasing as the onset of symptoms approached in MC, while t-tau and p-tau showed a trend of increasing with approaching symptom onset. On structural magnetic resonance imaging(MRI) of the brain, the MC had reduced volume of the left precuneus, left superior temporal gyrus and left fusiform gyrus, 9 years before the expected symptom onset. However, there was no observable decline in grey matter thickness or volume as the onset of symptoms approached, making the temporality of these changes difficult to assess. In the same group of subjects there was no significant difference on neuropsychological assessments between MC and NC, but a trend of poorer results was observed in the MC regarding immediate memory, episodic memory and attention/executive function. The CSF biomarkers YKL-40, reflecting glial activation, and neurogranin, a synaptic marker, were compared between asymptomatic MC and NC and found not to differ between the groups. A longitudinal study of changes in YKL-40 and neurogranin with approaching symptom onset was also conducted, revealing an increase in YKL-40 in both MC and NC as the age of symptom onset drew nearer, with a steeper increase in MC than NC. No such correlation to years to symptom onset was found for neurogranin. The APP processing products sAPPa, sAPPb, Ab42, Ab40 and Ab38 were compared both between the MC group as a whole and the NC and between subgroups of MC carrying specific mutations and the NC. The whole MC group had lower levels of Ab42, Ab40 and Ab38, as well as a lowerAb42/Ab40 ratio than NC. No significant correlation was observed between any of the aforementioned APP processing products and years to symptom onset in MC. When comparing different MC subgroups to each other, the whole MC group and the NC group, some mutation specific differences in the levels of the APP processing products and their temporality emerged. During the biomarker studies presented above the presence of a statistical outlier came to our attention, an MC carrying the PSEN1 H163Y mutation who had passed the age at symptom onset in his family but displayed no cognitive decline and no abnormalities in CSF biomarkers.