MEG in Alzheimer's Disease: unravelling the underlying network to explain the stereotypical spread of Tau protein

Alzheimer*s Disease (AD) is pathologically characterized by the accumulation of
amyloid- ß and hyperphosphorylated tau in the brain. Most of the AD research
has focused on amyloid- ß as the major cause of AD, because a widely accepted
view is that amyloid- ß, which is deposited many decades before the first
symptoms occur, induces abnormal tau formation, neuronal death and clinical
dementia. However, the field has been disappointed by numerous negative study
results. Most strikingly, none of the numerous amyloid-targeting drug trials
has as yet yielded convincing positive effects on cognitive functioning.
Additionally, several studies have suggested that tau - and not amyloid-ß- is
the first neuropathological sign of AD. Interest has therefore not only shifted
towards earlier pre-dementia stages of the disease, but also towards
alternative disease mechanisms.
Recent in vitro and in vivo studies have presented an increasing amount of
clues that tau protein spreads through the brain via anatomical connections of
the brain network, leading to disrupted network activity, synaptic
insufficiency and eventual cognitive decline. However, which factors and
network characteristics promote the spread of tau remains as of yet unknown.
In AD, functional brain networks, based on magnetoencephalography (MEG),
electroencephalography (EEG) or functional MRI, seem to display mostly
hypoconnectivity and disrupted network topology. This seems to affect the most
strongly connected and active network hubs in particular, suggesting a
mechanism of 'activity dependent degeneration'. Additionally, in vitro and in
vivo enhancement of neuronal activity has been shown to accelerate tau
deposition in the brain.
Because of the recent discovery of specific tracers for PET imaging of
tau-deposition enabling the visualisation of tau in living patients, we can now
investigate the relationship between functional network characteristics (such
as hyperactivity and topology), and the spread of tau in AD. We will also
simulate several hypothesized damage mechanisms using a computational model, as
an attempt to identify vulnerability factors for the progression of AD. This
could not only lead to deeper knowledge about the etiology and risk factors
associated with AD, but also to novel targets for future interventions.

The primary objective of the MANTA-study is to investigate MEG-based network
topology and 'activity dependent degeneration' as mechanisms in the
stereotypical spread of tau pathology (18F-AV1451 retention) in preclinical and
clinical stages of AD.

Specific research questions that will be addressed include:

1. to compare MEG-based oscillatory activity, functional / directed
connectivity and network topology measures across preclinical and clinical
stages of AD in order to find evidence for the *activity dependent
degeneration*- hypothesis

2. to investigate which changes in functional network characteristics and
oscillatoryactivity mirror regional 18F-AV1451 retention in each disease stage

3a. to assess which characteristics of a healthy network predict the spread of
18F-AV1451 retention in each stage of AD
3b. to assess whether MEG-predictors of the previous disease stage improves the
prediction of the spread of 18F-AV1451 retention in the subsequent disease
stage (e.g. for tau-spread in AD, MEG-measures of MCI patients are used as
predictors) compared to MEG-predictors of the healthy network, in order to
evaluate whether tau-deposition reciprocally damages the network

4. to investigate damage and spread mechanisms in a dynamic neural network to
predict pathological effects on large-scale network and compare the modeled
outcome to the observed tau and hyperactivity patterns in patient data.

MANTA is a cross-sectional observational cohort study. It includes Alzheimer's
Disease patients in different stages of the disease (SCD, MCI and dementia with
abnormal amyloid biomarkers). It also includes a group of young healthy
controls and elderly controls (patients with SCD with normal Alzheimer-specific
biomarkers).

After completing a written informed consent, all patients fulfilling the
inclusion criteria as described in the next chapter will undergo an MEG
measurement at the MEG centre of the VU medical centre in Amsterdam. The young
controls will also undergo an MRI scan in order to determine the placements of
the MEG electrodes during co-registration (patients and elderly controls will
have previously been submitted to an MRI scan in preparation for the PET scan
for the TITAN, TRT AV-1451 and LUNAR study). Patients will be requested to
complete questionnaires about physical and mental health, quality of life and
use of care.

Previously acquired data from the TITAN, TRT AV-1451 and LUNAR studies will be
used in this project.

Participation consists of one 1.5-2 hour (2-2.5 for controls) visit to the VUmc
MEG centre, during which patients will undergo an MEG measurement and fill in
a questionnaire. Controls will additionally undergo an MRI scan.

There is no direct therapeutic effect or other benefit of this study; clinical
decision making will not be based on the results. The test is non-invasive,
short of duration, and pain free. Risks associated with participation are
negligible, and the burden is minimal. Unexpected findings which could lead to
medical treatment will always be discussed with patients.