Cerebrovascular effects of galantamine treatment in patients with Alzheimer's disease.

Rationale: Cholinesterase-inhibitors (ChEI*s) are drugs used to treat symptoms
of Alzheimer*s disease, which is characterized by a progressive cholinergic
deficit. The central hypothesis of this study is that ChEI*s directly act to
augment cerebral perfusion. Consequently, we hypothesize that a vascular
mechanism is responsible for most of the observed clinical effects of ChEI*s in
patients with Alzheimer*s disease (AD). This hypothesis is closely related to
recent insights in the contribution of cerebral vascular disease to the
pathogenesis of Alzheimer*s disease, known as the vascular hypothesis of AD.
Central to both our new hypothesis and the vascular hypothesis of AD are the
common findings of cerebrovascular lesions in the brains of Alzheimer patients,
and the high prevalence of cardiovascular risk factors in these patients. In
our hypothesis, the cholinergically-mediated vascular effects include a global
increase in perfusion, prevention of ischemia in areas of the brain at risk for
hypoperfusion, and improvement of cerebral autoregulation. More precisely,
treatment with ChEI*s may reduce the incidence of new cerebrovascular lesions
as well as slow down the neurodegenerative process in AD.

To provide an answer to the following questions: 1. In patients with AD, does
treatment with a ChEI improve cerebral hemodynamics? 2. Is there less
progression of cerebrovascular lesions on follow-up of AD patients receiving
ChEI*s? 3. Does this improvement of cerebral hemodynamics translate in a
clinically relevant benefit for patients? 4. Can an early-dose-effect of ChEI*s
on cerebral perfusion be identified, and if so, is this early effect predictive
of the future clinical response to treatment?

a double-blind, randomized placebo-controlled clinical trial. Patients will be
evaluated at baseline, at early dose, after six months and after one year of
treatment.

Methods: Effects on cerebral perfusion, autoregulation, and cerebrovascular
damage will be evaluated using state-of-the-art techniques for this field:
Trans-cranial Doppler (TCD), Near Infrared Spectroscopy (NIRS), phase-contrast
and diffusion tensor imaging MRI, and beat-to-beat arterial pressure by
Finapres. Cognitive outcome will be assessed by neuropsychological testing,
which will also include assessment of attention and executive function.

This study includes diagnostic tests that are included in, or closely resemble,
the standard diagnostic and therapeutic approach to patients with Alzheimer*s
disease at our institution. Extra burden for patients consists of repeated site
visits (total: 4), repeated MRI evaluation (2 visits), repeated assessment of
cerebral autoregulation (4 visits) and one repeated CSF analysis. All tests are
non-invasisve and pose few health risks. The study drug is approved for use in
Alzheimer*s disease.