Dementia Conference Highlights
Editor's note: In this article Professor Serge Gauthier, one of the world's leading authorities on dementia and a member of the CNSforum Editorial Board, presents the clinical highlights from two recent scientific meetings. Articles presenting highlights from other events will follow.
"Targeting the Glutamatergic System in the Management of Alzheimer’s Disease", CINP Congress symposium, Paris, 24 June 2004
Throughout the course of AD a pattern of impairments in mood/behavior, cognition and functional autonomy can be identified. Validated scales accurately measure these changes and have been used as outcome measures in randomized clinical trials comparing memantine to placebo at different stages of disease severity.
Glutamate plays a major role in long term potentiation. On the other hand excessive amounts of glutamate can have excitotoxic effects. There is evidence for anatomical and functional dysruption of gluatamatergic neurons and pathways in AD.
Memantine as a moderate antagonist of NMDA receptors is considered to act in AD by blocking the effects of pathologically elevated levels of glutamate while preserving physiological activation required for learning and memory.
Clinical evidence for the efficacy of memantine include clinical trials in patients with moderate to severe AD in nursing homes or in the community. There is benefit in global measures of changes as well as cognitive and functional outcomes. Of note is the reducted incidence of agitation in memantine-treated patients compared to placebo, which was documented through adverse events reporting as well as questioning using the NeuroPsychiatric Inventory.
This anti-agitation effect of memantine may be of great clinical significance since it likely reduces the need for atypical neuroleptics.
Memantine has also been tested successfully in patients already taking donepezil, and there are no reasons to believe that it would not work equally well with the other cholinesterase inhibitors. This combination approach is well in keeping with the long term goal of disease stabilization with antioxidants and other potemtially acrtive agents such as statins and amyloid-suppressing drugs under development such as Alzhemed.
Website of the CINP Congress 2004
9th International Conference on Alzheimer’s Disease and Related Disorders, Philadelphia, 17-22 July 2004
Reports presented during this meeting led to the conclusion that cholinesterase inhibitors (CI) had symptomatic effects of modest size in mild to moderate stages of AD but of limited duration, in the order of 18 months: evidence for benefit in amnestic Mild Cognitive Impairment (MCI) was borderline, with the 2-year study comparing galantamine to placebo being negative for conversion from CDR 0.5 to CDR 1, and the 3-year study comparing donepezil to tocopherol and to placebo being negative for delay of conversion to AD over three years, although there was a significant difference between donepezil and placebo from 6 to 18 months for all subjects, and from 6 to 36 months for patients carrying one or two copies of the apoE4 gene.
Results from a 4-year study comparing rivastigmine to placebo will be available later in 2004, but the evidence so far does not indicate that CI will be widely used in MCI.
The results of the 3-year study AD2000 (Lancet 2004; 363, 2105-15) comparing donepezil to placebo were discussed and although there was no delay in institutionalization or in disability over three years, there was significant improvement on the cognitive measure MMSE and the functional measure Bristol ADL for the first two years of treatment.
Positive results were presented on a study comparing rivastigmine to placebo in Parkinson-associated dementia, opening the way to treatment with CI in this common condition.
In terms of non-cholinergic therapies, results of the phase II study comparing the GAG mimetic agent Alzhemed to placebo were reviewed and generated a lot of interest; this drug is now in Phase III in North America.
A 12-month follow-up after immunotherapy using AN1792 showed some improvement in cognitive measures and a reduction in brain volume using MRI in the 19.5% of patients who developed the predetermined antibody response compared to placebo, which may be due to amyloid plaque removal.
Analysis of behavioral outcomes in memantine studies for moderate to severe AD showed a significant effect on agitation.
Website of the 9th International Conference on Alzheimer’s Disease and Related Disorders
Published on CNSforum 29 Jul 2004