PREVENTION OF DEMENTIA BY INTENSIVE VASCULAR CARE - OBSERVATIONAL EXTENSION STUDY

The prevalence of dementia is about 180.000 in the Netherlands. In addition to
the burden for patients and caregivers associated with this devastating
condition, the estimated increase in dementia prevalence will have an important
impact on the health care system and on society at large. Despite tremendous
research efforts, there are currently no options for effective prevention or
treatment of Alzheimer's disease or dementia in general.
Vascular risk factors during life are associated with increased risk of
dementia. A crucial question is whether these disease mechanisms can be
influenced during life. If vascular changes play such an important role in the
pathophysiology of AD, can treatment of vascular risk factors during life
prevent cognitive decline and dementia? Several observations, suggest that
intensive vascular care can reduce the incidence of dementia. Since
neuropathological changes precede the occurrence of dementia by years or even
decades, interventions should probably take place long before the clinical
onset of cognitive impairment. Therefore, targeting modifiable vascular risk
factors in a population aged 70-78 years, was the main focus of the recently
conducted *prevention of dementia by intensive vascular care* (preDIVA) trial.
In this trial, vascular risk factors associated with dementia that are directly
amenable to intervention were addressed, such as hypertension,
hypercholesterolaemia, obesity, smoking, lack of physical exercise and diabetes
mellitus, in this trial. In total, 3526 participants were randomized to either
intensive vascular care or standard care and 6-8 year follow up was completed.
This trial provides a unique and well-defined cohort with valuable data in
relation to dementia and vascular risk. The incidence of dementia during the
trial was around 7%. Observational extension will increase the number of
incident cases which will allow for additional analyses on factors that
contributed to the development of dementia and aspects of the intervention that
were most successful for the prevention of dementia.
Most patients clinically diagnosed as Alzheimer*s Disease (AD) have multiple
cerebral pathologies at autopsy, including prominent cerebrovascular pathology.
Vascular changes contribute in a synergistic way to cognitive impairment by
lowering the threshold for plaque and tangle load to give rise to cognitive
decline. Cerebral ischemia may even be an important process at the origin of
the cascade of events leading to the development of Aβ and tau depositions.
Abnormalities in vessel architecture, diminished cerebral blood flow, and
altered oxygen utilization resulting in dysfunction of the cerebral
microcirculation, may all lead to neuronal cell loss in AD. Additional
interaction of vascular and neurodegenerative changes with systemic and
neuro-inflammation might play a role in the final occurrence of clinical
symptoms of AD. Chronic inflammation associated with atherosclerosis has been
shown to precede Aβ deposition and Aβ in turn induces an array of
pro-inflammatory responses24. Animal experiments have strongly suggested a
causal relationship of hypertension and hypercholesterolemia with Aβ
depositions, further fueling hypotheses about direct interaction between
vascular factors and neurodegenerative changes. However, the interaction
between cerebrovascular lesions, neuroinflammation and neurodegeneration is
complex and exact mechanisms by which they contribute to cognitive decline and
dementia are not yet fully understood.
The clinical implications of these pathophysiological mechanisms are largely
unknown. Can the neuropathological changes that underlie AD be slowed or even
prevented? And if so, which neuropathological mechanisms are influenced?
Several post-mortem studies have tried to address these questions.
Hypertension, being one of the most important vascular risk factors, is
associated with increased presence and severity of Aβ and tau neuropathology in
older individuals without dementia. Treatment of hypertension has been
associated with less severe neurodegenerative changes. This knowledge is,
however, derived from cohort studies, precluding causal inference.
Neuropathological outcomes in randomized controlled trials (RCTs) are generally
not possible. Although clinical outcomes are the basis of most RCTs, knowing
whether an intervention to prevent cognitive decline affects neuropathological
changes would substantially increase our understanding of the etiology of AD.
This could also guide in the design of new interventions to prevent cognitive
decline and dementia. Such *interventional neuropathology studies* are rare,
and we will, for the first time, obtain neuropathological outcomes of a
long-lasting dementia prevention RCT.
PreDIVA offers an excellent opportunity to study the effect of the intervention
on neuropathological changes. In other words, can longstanding vascular care
protect against neuropathological changes associated with dementia, including
microvascular changes, neurodegenerative changes and neuroinflammation? Due to
the high age at recruitment, resulting in a cohort aged 79-89 in 2016, a
relatively high mortality rate can be expected which can result in a
considerable autopsy cohort in a relatively short period.
In most Western countries, including the Netherlands, autopsy rates have been
declining for decades. Especially in old age autopsy rates are low. The reasons
for this are probably multifactorial, but an important contributor may be
changes in patients* or their relatives attitude towards post-mortem
examination. Understanding barriers and facilitators to participate in a brain
donation program can lead to adjustment of recruitment strategies to improve
the participation rate. This will decrease inclusion bias and increase the
external validity of future autopsy-cohorts. By Integrating 1) evaluating the
effect of a clinical intervention to prevent dementia with 2) the building of a
new autopsy cohort from an RCT and 3)qualitative research on brain donation, we
aim for a comprehensive approach to improve clinic-pathological research into
Alzheimer*s Disease.

Primary Objectives:
• To continue observational data collection for the main clinical outcomes of
the research subjects who participated in the preDIVA trial between 2006-2015.
• To assess the effects of long-term vascular risk factor modification on the
extent and severity of (micro)vascular changes, neurodegenerative changes,
neuroinflammation and the interaction between them, by setting up a unique
autopsy cohort derived from a large long-term dementia-prevention trial.

Secondary Objectives:
• To build a state of the art brain bank from a well-defined/characterized
older population.
• To use this cohort for association studies on specific participant
characteristics in relation to neuropathological changes to further advance the
understanding of the relation between vascular risk factors and dementia in
order to guide the development of better-targeted interventions to prevent
dementia
• To relate the neuropathological findings to changes on MRI during life, to
improve understanding of brain changes as can be visualized on MRI during life.
• To explore barriers and facilitators for participation in a brain donation
program.

This current study is designed as a single-centre, multi-site, prospectively
observational cohort study and will be an extension of the randomized
controlled preDIVA trial12 (METC MEC 05/093 # 06.17.0420 ; ISRCTN29711771 ), a
single-centre, multi-site, open, randomized, parallel group trial, conducted in
the Netherlands from 2006-2015. In this trial it was investigated whether
intensive vascular care could lead to the prevention of dementia. Participants
in the control group received care as usual. Participants in the intervention
group consulted a practice nurse every 4-months, who addressed all vascular
risk factors and unhealthy lifestyles. Participants were between 70 and 78
years at baseline and were not demented when the study started in 2006. All
individuals in this age-range in 116 general practitioner (GP) practices were
invited, of whom 53.3% agreed to participate.
In the current observational follow up study, all participants from the preDIVA
trial, now between 79-89 years of age, will be asked to participate in the
preDIVA-extension study, through a new informed consent procedure. Those
preDIVA participants who indicated they were willing to consider participation
in future research or extended follow-up, are deemed eligible. At the final
follow-up visit of the preDIVA in 2015, 578 participants had died, leaving 2948
participants alive at that moment. Considering the high age, we expect that
approximately 200 more participants have died since mid-2015, leaving around
2700 preDIVA participants still alive in mid-2016. Of all preDIVA participants
we will carefully check whether they are still alive using the Dutch death
registry, before contacting them. Those participants still alive will be
informed about the outcome of the preDIVA trial by a newsletter. In this
newsletter the possibility for participation in the extended data collection
and brain donation will be raised. Participants will be contacted by phone and
a visit will be scheduled (at their own home or at an easily accessible
location in the area, provided by the researchers) during which the
participants will be further informed about the observational extension and the
possibility for brain donation. Participants will be contacted based on age,
starting with the oldest participants and the possibility of participation in
various components of the current study will be discussed (figure 1):
1. Two yearly clinical data collection (component 1).
2. Post-mortem brain autopsy with optional MRI-scan (component 2).
3. Participation in a qualitative sub-study on fears and expectations on the
subject of brain autopsy (component 3).

Figure. Overview of the project. In the preDIVA RCT clinical data have been
collected since 2006. This is all considered preliminary work. During the
current project, subjects can agree to multiple components of participation:
Component 1; two yearly clinical data collection in all participants will start
in 2016 and will continue until the subject has passed away. Component 2;
registration for post-mortem brain donation. Component 3; qualitative study on
barriers and thoughts on brain donation will start in 2016 and will continue
until the study has reached saturation. Neuropathological analyses in relation
to clinical information will start when the first brain tissue is available and
will be continued in the future.

In case home visits are not feasible for informing eligible participants about
the preDIVA extension, information on the observational data collection
(component 1) can be provided by phone and informed consent can be send by mail
using a return envelope.

Component 1
All participants agreeing to exclusively participate in the data collection
part (component 1) of this study will be subjected to questionnaires until
death or request to end participation. This is preferably conducted during home
visits (or at a site easily accessible provided by the researchers). However,
if home visits are deemed not feasible, these may be replaced by telephone
calls. To be able to identify any potential registration bias, reasons for
decline of brain autopsy (component 2) will be recorded in all eligible
subjects. When communication (or other) difficulties occur during telephone
call, a visit (at their own home or at site provided by the researchers) will
be suggested to overcome these problems.

Component 2/3
When subjects express interest in component 2 and/or 3 of the study, a visit at
their own home or at a site provided by the researchers (e.g. at the AMC or at
their primary care practice if feasible) will be scheduled. During this visit
the subject will be informed about the current study and the possibility for
brain donation. A careful, step-wise approach will be used to thoroughly
address all the potential barriers and provide comprehensive information on the
procedures leading to registration as a brain donor. We will build upon the
experience of the Netherlands Brain Bank (NBB) for psychiatry (www.nhb-psy.nl)
and the Cognitive Functioning an Ageing Study (CFAS) in Cambridge in the
personal approach of potential donors. The consultants conducting the visits
will be extensively trained using the CFAS experience and familiarized with all
brain donation logistics of the NBB.
Participants agreeing to participate in both clinical data collection and
post-mortem brain autopsy (component 2) will be subjected to two yearly visits
(at their own home or at site provided by the researchers) to undergo more
extensive questioning including a limited set of cognitive tests, until death.
If participation in the brain donation program is higher than the anticipated
10-15%, the two yearly visits for data collection may be replaced by telephone
calls for data collection. Subjecting large numbers of participants to home
visits may not be feasible, since home visits are logistically challenging,
time consuming and costly. Even so, home visits are preferred, since data
collection via such visits can yield to the close contact that is considered
necessary to sustain a donation program, and can therefore be of great value.
In a subset (N ~ 20) of all participants interested in participating in
component 2 and/or 3 who are informed about brain donation, an interview to
address fears and expectations concerning brain donation will be planned. This
interview will be semi-structured using a topic-list and will be conducted by a
trained researcher in the subject*s own home. Participants will be encouraged
to address perceived barriers (i.e. fears, preoccupations) and facilitators
(i.e. altruistic motives) to participate in such a program. The topic list will
be modified when new themes emerge from the data. Once data saturation is
achieved (i.e. no new themes emerge during subsequent interviews), generally
after 15 to 25 interviews, no further participants will be recruited.

Brain donation program
Post-mortem brain autopsy will be performed by the Netherlands Brain Bank
(NBB). The existing infrastructure of the NBB will be used to allow for optimal
expertise and efficiency. The current prospective cohort study among
psychiatric patients (NBB-psy) will serve as an example for the current
project. We will base ourselves on the best practices available at the NBB. The
NBB is accessible 24/7. Whenever a donor has passed away, family members or the
general practitioner will contact the NBB, who will initiate the logistics for
autopsy. The existing rapid autopsy protocols of the NBB will be used
(www.hersenbank.nl and www.brainbank.nl and appendix A), guaranteeing adequate
tissue handling and storage. The donor is retrieved form their own home and
transported to the VU medical centre, where brain autopsy will take place. The
donor will be returned to the family or mortician/undertaker within 24 hours.
Annually the NBB performs 90-130 autopsies and since its start the NBB has
performed more than 3700 autopsies. In the current proposal, the
neuropathological data will be linked to the data in the Case Report Form (CRF)
of PreDIVA, containing prospectively and systematically collected clinical
data, including vascular risk factors, medical history, medication use,
cognition, depression daily and functioning.
Based on the literature we estimate that 10-15% will potentially consent to
brain donation. It is expected that most participants have deceased after a
decade considering the high age at the start of this project, resulting in a
foreseen horizon of around 2026 for completion of this study, but a fixed date
cannot be set at this moment.

General practitioners will receive notice of participation of their patient in
the current preDIVA extension study. Medical records of participants may be
requested via the general practitioner for additional information on medical
status and primary/secondary outcome measures.

An independent and blinded outcome adjudication committee will be consulted to
evaluate the primary outcome i.e. dementia. This committee will consist of
neurologists, old age psychiatrists, geriatricians, general practitioners and
cardiologists, who will evaluate all cases using available clinical
information. The procedure for independent outcome adjudication used in preDIVA
will be used in the current study.

The burden of participation in either one of the three levels of the study is
low and the risks are negligible. There are no direct benefits for the
individual participants.

Clinical data collection
Participants will be subjected to data collection once every two years either
by a phone call, or by a visit at their own home or at a site provided by the
researchers if preferred and feasible. This phone call or visit can be
relatively short and will be conducted by trained researchers and will be
planned whenever suitable for the participant.

Qualitative study
For inclusion in the qualitative study, participation may be somewhat more
demanding since an interview on thoughts and fears regarding brain donation may
initiate a topic participants do not wish to think or talk about. We consider
it therefore important to specifically ask informed consent for this substudy
and train interviewers. For this component 3 of the study, no incapacitated
subjects will be included.