The objectives of the project is to validate the precision of the AD Detect & Prevent AD detection tool for detecting subtle cognitive changes in asymptomatic AD at-risk individuals. The AD detection tool will be validated by AD hallmarks (amyloid build-up and tau protein plaques) using PET and hippocampal volume using MRI. The integrity of brain connectivity will be measured with diffusion-weighted MRI (DW-MRI).
Methods and ethics
We aim to apply the AD detection tool (consisting of the tasks on working memory, executive planning and visuomotor functions) to a total of 60 elderly APOE4 gene carrying participants (40 amyloid negative and 20 amyloid positive healthy controls without overt cognitive decline along with diagnosed AD patients). We hypothesize that there will be a positive correlation between covert impaired cognitive functions measured by the AD Detect & Prevent, detection tool and the presence/quantity of amyloid and tau proteins, as well as a pathological reduction of hippocampal volume in the preclinical Alzheimer group. Ethics approval will be sought according to standard regulations for healthy and patient studies.
Positron emission tomography (PET)
Pittsburgh compound B (PiB) is a neutral analogue of thioflavin T, an accepted histological stain for detecting fibrillar Aβ allowing visual and quantitative measurement of Aβ deposition. 11C-PiB is a PET tracer designed to cross the blood-brain barrier, bind to fibrillar Aβ with high nanomolar affinity, and clear over 90 minutes from normal brain tissue. The degree of 11C-PiB uptake in the cerebral cortex in vivo measured with PET correlates with fibrillar Aβ levels in brain tissue measured subsequently at postmortem, as demonstrated through histochemistry and immuno-histochemistry analyses of brain tissue samples. Tau is a protein that binds to and stabilizes the microtubules in neurons that help transport nutrients. Tau is abundant in neurons of the central nervous system (CNS) but expressed in low levels in CNS astrocytes and oligodendrocytes. In neurodegenerative diseases, tau becomes excessively phosphorylated and abnormally aggregates to form fibrils. Post-mortem Alzheimer brains show extracellular deposits (plaques) of Aβ peptide and intracellular neurofibrillary tangles (NFT) of abnormally aggregated tau protein. The tau aggregates in NFTs take the form of paired helical filaments (PHFs) and express either three or four repeat binding sites for tubulin. In AD the density of cortical tau neurofibrillary tangles found at human post-mortem correlates well with the premortem cognitive deficit, unlike amyloid load (Maccioni, Farias, Morales, & Navarrete). The formation of intracellular tau tangles is, therefore, more relevant than extracellular Aβ plaque deposition to the genesis of cognitive symptoms in at-risk subjects. PHFs are seen first in the parahippocampal region (entorhinal cortex), then the hippocampus, and later the posterior and finally the frontal association cortex.
In recent years several novel small molecule agents for in vivo tau PET imaging have been developed. In 2017, a new tau tracer called MK-6240 was developed by Merck/MSD, which showed massive brain uptake in longitudinal preclinical studies involving AD patients. This preliminary data is promising because with lower doses compared to previous tracers, MK-6240 was able to show no off-target binding in interested brain regions and offers clearer PET tau data. Merck/MSD will sponsor this state-of-the-art, new generation tau tracer in the proposed project. Therefore, research team at the PET centre will apply MK-6240 for measuring accumulation of tau in the brain parenchyma of the cohorts mentioned above. These PET imaging biormarkers enables detection of the pathological hallmarks of disease even at asymptomatic preclinical stages.
Magnetic resonance imaging (MRI)
Although macroscopic changes in brain morphology seemly occur downstream of Aβ retention, the accumulation of Aβ has already reached a plateau at the time of symptom onset (Jack et al., 2010). At the time of the patients’ first contact with the health care system, cerebral atrophy may have already started, and changes in brain structure detected by MRI are sensitive to disease progression in the period where therapy may be initiated and monitored (Frisoni, Fox, Jack, Scheltens, & Thompson, 2010; Jack et al., 2010). The first signs of AD related atrophy are found in the entorhinal cortex (EC) and the hippocampus (Braak & Braak, 1995). Morphological MRI, primarily T1- and T2-weighted images, is used to assess EC and hippocampal atrophy. Methods for measuring hippocampal subfields (HCSF) are now sufficiently accurate and reliable to be used as highly senssitive markers for neurodegeneration with potential improvement in diagnosis and prediction (Romero, Coupe, & Manjon, 2017). Recently, CFIN scientists and their collaborators proposed robust and accurate methods for HC segmentation (Coupe, Eskildsen, Manjon, Fonov, & Collins, 2012) and cortical thickness estimation (Eskildsen et al., 2013). It was demonstrated that improvements in segmentation methods lead to significant improvement of diagnosis and prediction (Eskildsen, Coupe, Fonov, Pruessner, & Collins, 2015). Diffusion-weighted MRI (DWI) is utilized for the detection of changes in water diffusion caused by damage to the brain’s microstructural integrity, such as cell loss and myelin damage. A recent breakthrough in the biophysical understanding of water diffusion in brain tissue has enabled CFIN scientists to link kurtosis of the diffusion signal to the density of neurites - and hence a cellular feature closely related to neurodegeneration (Jespersen, Kroenke, Ostergaard, Ackerman, & Yablonskiy, 2007). So far this sophisticated imaging technique has only been applicable in animals due to a very time-consuming (several hours) MRI protocol. However, another recent breakthrough by CFIN scientists in the data acquisition design has made it possible to obtain this new diffusion metric on a clinical MRI system within two minutes (Hansen, Lund, Sangill, & Jespersen, 2013). This has the potential to detect neurodegenerative changes that precede neuronal loss and changes in brain morphology.
The proposed project will acquire high resolution MRI on a state-of-the-art MRI system (3 Tesla MAGNETOM Prisma, Siemens) applying pulse sequences sensitive to macrostructural (T1 and T2) and microstructural (diffusion kurtosis) changes. The project will apply the above-mentioned current state-of-the-art quantification methods for estimation of atrophy, neurodegeneration and tissue integrity enabling disease staging and disease progression tracking.