Blood-Brain Barrier function: The key to successful cognitive aging?

The brain is vulnerable to age-related pathologies, which can result in
cognitive decline. Nevertheless, some people age successfully, while others
suffer substantially from this cognitive decline. To date, the exact mechanism
of cognitive aging remains unclear.
A potential initiating mechanism is Blood-Brain Barrier breakdown. Blood-Brain
Barrier breakdown can cause a suboptimal environment for neuronal cells and
results in several brain pathologies, which may eventually lead to neuronal
damage and cognitive decline. Most techniques to detect Blood-Brain Barrier
breakdown are not sensitive enough to detect the subtle leakage that
characterises normal aging, so that previous Blood-Brain Barrier studies did
not focus on normal cognitive aging.
A promising method to detect subtle Blood-Brain Barrier leakage in vivo in
humans is Dynamic Contrast-Enhanced Magnetic Resonance Imaging. Recently, we
developed a new Dynamic Contrast-Enhanced Magnetic Resonance Imaging scan
sequence, making our Dynamic Contrast-Enhanced Magnetic Resonance Imaging scan
sensitive enough to detect subtle globally distributed leakage spots.

The present study will investigate the association between Blood-Brain Barrier
leakage and cognitive aging.
Primary research question:
1. a. Is stronger BBB leakage associated with greater decline in episodic
memory?
b. Post-hoc explorative analyses investigating the connection between
learning/processing speed/complex information processing/compound score/global
cognition and Blood-Brain Barrier leakage
Secondary research question:
2. a. Is stronger BBB leakage associated with smaller hippocampal volume?
b. Post-hoc explorative analyses investigating the association of Blood-Brain
Barrier leakage with cortical thickness/ WMHs/ markers of SVD/ white matter
integrity

The present study is an observational Magnetic Resonance Imaging study.
Participants will be subjected to blood sampling, neuropsychological assessment
(approximately 60 minutes with 5 cognitive tests) and Magnetic Resonance
Imaging scanning (approximately 60 minutes in total, first without, then with
the gadolinium-containing contrast agent).
For the first hypothesis, information on cognitive decline over the past 23
years, obtained from the MAastricht Aging Study and our own baseline
measurements, will be used to investigate the association between Blood-Brain
Barrier leakage and cognitive aging. The hypothesis will be investigated using
our follow-up measurements of radiologically visible brain tissue abnormalities.
Potential participants will be selected from the MAastricht Aging Study
database, based upon whether they have completed all testing sessions of the
MAastricht Aging Study and are not deceased or have obtained a psychiatric or
neurological diagnosis in the mean time. For those who meet these criteria
according to the MAastricht Aging Study database, the Registration Network of
Family Practices database will be checked right before the inclusion to see
whether they are not deceased or have obtained any diagnosis in the meantime.
The Registration Network of Family Practices works by a strictly anonymous
procedure and will only convey the registration numbers of the participants we
can approach. All MAastricht Aging Study participants have formally agreed that
they may be approached for future studies. Potential participants will receive
a short letter announcing a new part of the MAastricht Aging Study with a brief
description. A week after receiving this letter, they will be contacted by
phone by the principal investigator and asked if they would be interested.
Those who are interested will then receive more elaborate information on the
present study by mail (including the informed consent form). A week after
receiving this information, they will be contacted by phone by the principal
investigator again. Over the phone, the principal investigator will record
medical history and fill out a questionnaire to check the inclusion and
exclusion criteria. The principal investigator will then make an individual
appointment for the first testing session with each suitable candidate. At the
beginning of the first testing session, participant and principal investigator
will sign the informed consent form. Participants will be reminded that they
can ask questions the whole time before, during and after the present study.
Participants will be invited to come to the Maastricht University Medical
Center for blood sampling to measure their blood Haematocrit and creatinine
level and determine their cardiovascular risk profile. The blood Haematocrit
level will be used to calculate the red blood cell volume, which may influence
the amount of leakage from the blood to the brain. The blood creatinine level
will be used to calculate the estimated Glomerular Filtration Rate, which
indicates renal function or the rate at which the kidneys filtrate blood.
Through this filtrate mechanism, substances such as our contrast agent leave
the body through the urine. Estimated Glomerular Filtration Rate thus
influences how long the gadolinium-containing contrast agent is present in the
bloodstream and may therefore influence the amount of leakage. Moreover, very
few cases of Nephrogenic Systemic Fibrosis, a serious syndrome characterized by
an excess of connective tissue on the skin and internal organs, have been
related to the use of the gadolinium-containing contrast agent. Nephrogenic
Systemic Fibrosis only occurs in patients with severe acute or chronic renal
insufficiency (estimated Glomerular Filtration Rate < 30 mL/min), so that
scanning will take place only in case estimated Glomerular Filtration Rate > 30
mL/min. Afterwards, neuropsychological assessment will be performed. If
estimated Glomerular Filtration Rate and Mini-Mental State Examination and
Disability Assessment for Dementia scores are sufficient, participants will be
invited to return the next week for Magnetic Resonance Imaging scanning.

Participants will be subjected to blood sampling, neuropsychological assessment
(approximately 60 minutes with 5 cognitive tests) and Magnetic Resonance
Imaging scanning (approximately 60 minutes in total, first without, then with
the gadolinium-containing contrast agent).
The gadolinium-containing contrast agent is used by the department Radiology on
a daily basis in a broad patient population. Moreover, the administration
protocol is well established and the laboratory technicians well experienced in
administration and handling of possible side effects. All necessary
administration equipment, and medication and equipment in the rare case a
severe side effect occurs that requires treatment, are standard available on
every clinical Magnetic Resonance Imaging scanner.
Participants will be subjected to the risk of positioning an infusion line
(bruise; bleeding; infection) and side effects of the gadolinium-containing
contrast agent, of which the most severe may be an allergic reaction. The
latter is very rare (from >= 1/1000 to < 1/100 cases) and all necessary
precautions are taken at the Magnetic Resonance Imaging scanner that such a
condition can be identified and treated properly. The gadolinium-containing
contrast agent can incidentally cause mild to moderate side effects, although
not in all individuals who receive this contrast agent. The most frequent
observed side effects are headache, nausea, injection site reactions, disturbed
sense of taste and feeling hot (from >= 1/1000 to < 1/100 cases).
Participants will be informed about unexpected medical findings. In case
participants do not wish to be informed, they are not allowed to participate in
the present study.
Very few cases of Nephrogenic Systemic Fibrosis, a serious syndrome
characterized by an excess of connective tissue on the skin and internal
organs, have been related to the use of the gadolinium-containing contrast
agent. Nephrogenic Systemic Fibrosis only occurs in patients with severe acute
or chronic renal insufficiency (estimated Glomerular Filtration Rate < 30
mL/min), so that all participants will be tested on renal function by a blood
creatinine test. Scanning will take place only in case estimated Glomerular
Filtration Rate > 30 mL/min.