Goals• Increase the knowledge of the Pgp in the pathophysiology of Alzheimer's disease. • Designing an in vivo method, by positron emssion tomography, for measuring Pgp function and Aβ concentration to possibly determine the risk of…
ID
Source
Brief title
Condition
- Encephalopathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study parameters are the Pgp function, Aβ accumalation and their
correlation in Alzheimer's disease and healty controls.
Secondary outcome
Not applicable.
Background summary
Alzheimer's disease (AD) is the most common form of dementia. Since the first
presentation of a presenile dementia by Alois Alzheimer the exact pathogenesis
is not clearified. Today multiple hypothesis exist of which the amyloid
hypothesis receives most support.
The amyloid hypothesis states that beta-amyloid (Aβ) is the core pathogenic
protein. Aβ is a product of proteolytic spliciing of the bigger amyloid
percursor proteine (APP). APP and Aβ is found in every cell, but their function
is not known.
Because Aβ is a normal protein it is highly unlikely that the protein itself
leads tot AD. On the other hand, an enheightened production or diminished
clearance could lead to extracellulair amyloid plaque as found in AD. Genetic
variants of AD are in favor of this theory as in these genetic cases of AD the
production of APP is enheightened.
The Aβ homeostasis is regulated at different levels. There is a peripheral and
central Aβ production, and in absence of any possible degradation or
aggregation there is also transport over the blood-brain-barrier (BBB). The
transport over the BBB is in part via passive *bulk flow* and in another part
via active transporters.
One of these transporters is the P-glycoprotein (P-gp). P-gp protects in
physiological circumstances against foreign substances and functions in
tissues, such as bowel, liver, kidney and BBB, as a transporter with an
excretory and/or barrier function. Recently, it has been pointed out that P-gp
functions as effluxtransporter for Aβ. Furthermore, in a study by Vogelgesang
et al. an inverse correlation between P-gp and cerebral Aβ in non-dementing
elderly has been shown. Therefore, a lowered P-gp concentration could in theory
well be the reason for Aβ accumulation in AD.
P-gp is for two reasons of interest. At first, P-gp expression can vary
according the polymorphism. Interindividual differences of a susceptibility of
lowered P-gp expression and enheightened Aβ can be explained accordingly.
Secondly, Pgp can be modulated pharmacologically. It is known that Pgp function
can be lowered or blocked by cyclosporin A, verapamil, erythromycin, fluoxetin,
HIV protease inhibitors and different statines. Interestingly, Pgp function can
also be enheightened by dexamethason, morfine and riphampicin which could in
theory lower the concentration of Aβ. In a study of Loeb et al. is was pointed
out that adminstrition of a riphampicin and doxycycline has a positive effect
after 6 and 12 months on a cognitive scale. Possibly modulation of Pgp function
can lead to a lesser degree of cognitive decline in AD.
Study objective
Goals
• Increase the knowledge of the Pgp in the pathophysiology of Alzheimer's
disease.
• Designing an in vivo method, by positron emssion tomography, for measuring
Pgp function and Aβ concentration to possibly determine the risk of converting
from mild cognitive impairment to Alzheimer's disease.
Study design
To test our hypothesis we will be using positron emission tomography and the
radiotracers 11C-verapamil and N-methyl-11C-2-(4*-
methylaminophenyl)-6-hydroxybenzothiazole, or simply Pittsburgh Compound B
(PIB) to respectively measure the expression of P-gp and concentration of Aβ.
Furtermore, a H215O PET scan will performe to facillitate anatomical
comparisons and analysis of Pgp function and Aβ concentration. Every patient
undergoes three different PET investigations. At first a H215O PET scan will be
performed. In the same session followed by a 11C-PIB scan. One week later, a
11C-verapamil scan is performed. The scans are made in this order to exclude
any possible Pgp pump modulation by verapamil.
Study burden and risks
The expect mild to negligible risk of a subcutaneous hematoma is further
diminished by working with protocols in the PET center. From experience, it has
been shown that PETscan research in Alzheimer's patients is feasible.
Hanzeplein 1
9713 GZ Groningen
Nederland
Hanzeplein 1
9713 GZ Groningen
Nederland
Listed location countries
Age
Inclusion criteria
- Meet the NINCDS-ADRDA criteria for probable Alzheimer's disease
- Mild form of dementia (MMSE 19-22)
- Older than 50 years
Healthy controls do not meet NINCDS-ADRDA or MCI criteria.
Exclusion criteria
- Use of medication that could influence Pgp function, e.g. digoxin, cyclosporin, amiodarone, steroïds, quinidin, colchicin, etoposide, antiestrogensn and atorvastatin.
- Vasculair braindisease or otherwise braindiseases which could influence cerebral metabolism or perfusion.
- Significant kidney or liverdisase.
- Neurological symptoms not in agreement with a diagnosis of Alzheimer's disease.
- Pregnancy.
- Prior (excessive) radiation exposure in the same year (including radiological assistants or nuclear medicine employees).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
CCMO | NL22165.042.08 |