"Physiological, Biochemical, and Molecular Alterations in Alzheimer's Disease: What Are the Implications for Clinical Course and Therapeutics?: Presented at AAT"
By Chris Berrie
GENEVA, SWITZERLAND -- April 24, 2006 -- The blurring of the concept of what is a neuroprotective or disease-modifying agent and what is a symptomatic agent is only now beginning to promote a broadening of the approach to treatment of Alzheimer's disease (AD), according to a presentation here at the 9[th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT).
Paul Francis, PhD, reader in neurochemistry, Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, spoke about the implications for treatment of the various physiological, biochemical and molecular alterations seen in patients with AD.
The round-table meeting, titled "Controversies in cholinergic therapy for mild cognitive impairment and Alzheimer's disease," took place April 20th.
Current management of patients with AD is based on a strategy of enhancing acetylcholine-mediated neurotransmission, Dr. Francis said. However, preclinical data have suggested that the multiple biochemical and physiological pathways which underlie the pathology of AD could provide alternative therapeutic targets.
This raises the question, he said: Does the current approach to treatment of Alzheimer's disease fit our current understanding of the physiological, biochemical, and molecular alterations that occur as a result of this disease?
In addition, evidence has shown that treatments might have disease-modifying effects, which could have an impact on clinical management of patients with AD.
As an example, from a basic biochemical level, Dr. Francis pointed to the pyramidal neurone loss that is associated with progression from very low cognitive impairment to severe (Bussiere et al. J Comp Neurol. 2003), might well sound reasonable; however, when considered from the point of view of the use of the cholinesterase inhibitors (ChEIs), although pyramidal neurons are innervated by cholinergic synapses and have cholinergic receptors, they are primarily glutamatergic in nature.
Thus, when considering disease modifying strategies, consideration of the cell and synapse losses seen in the cholinergic systems (nucleus basalis of Meynert, medial septum) should also be applied to the glutamatergic (hippocampus, neocortex), serotonergic (dorsal and median Raphe nucleus), and noradrenergic (locus coeruleus) systems, he said.
To illustrate this point, Dr. Francis outlined previous data showing that pyramidal neurone loss correlates with dementia rating (Neary et al. JNNP. 1986), and both the number of synapses and the neocortical density correlate with the mini-mental state examination (MMSE) scores (Dekosky and Scheff. Ann Neurol. 1990; Terry et al. Ann Neurol. 1991). "These are important correlates of learning and memory and important correlates, by contrast, of dementia," he said.
It is therefore important to understand what causes the neuronal loss, and what kind of strategies can be used to prevent the loss of cell and synapses. However, Dr. Francis indicated, there are numerous factors -- and thus targets -- that can promote cell apoptosis and necrosis in AD.
The effects of some of these factors have been seen in vitro, with cultured cells, as Dr. Francis and colleagues demonstrated that the apoptotic and necrotic effects of beta-amyloid on glutamatergic cell death can be prevented with a neuroprotectant agent.
Although this relatively clean result is very difficult to take from the laboratory to the clinic, results from a recent animal study might provide some further clues (Neuron, 2006). Caccamo et al. studied triple transgenic mice that developed brain beta-amyloid plaques and showed tangle formation and some later cell loss. They found that M1 muscarinic agonist treatment reversed both these pathological changes and the associated cognitive losses.
Thus, Dr. Francis said, this evidence points to a drug that can cross the barriers between what would be considered a symptomatic treatment to neuroprotection, and indeed, to disease modification. However, he added, it remains to be determined what is actually causing these changes, even in this model system.
Therefore, on the basis that he believes that cognition represents potentially the best marker for disease modification in patients with AD, Dr. Francis said, "If we have a situation where we could preserve cognition at the early stages of dementia, and perhaps even in early [mild cognitive impairment], and we could preserve this until [patients] die, we could say that was disease modifying." This thus reflects the beginning of a blurring between the concepts of what is disease modification and what is a symptomatic treatment.
To further blur these concepts, there is indeed a biomarker that can distinguish responders from nonresponders: antibodies to beta-amyloid 42 (Hock et al. Neuron. 2003). Thus, in this beta-amyloid vaccine-based approach, in the 12 months following immunisation with beta-amyloid 42, patients with beta-amyloid antibodies showed significantly more stable MMSE scores that those without these antibodies. Furthermore, the decreases in MMSE score seen in the antibody responders significantly correlated with the level of beta-amyloid antibody response, as seen from their tissue amyloid plaque immunoreactivity scores.
"So again, we are blurring the concept between what is a disease-modifying agent to what is a symptomatic agent, and I think that as we go forward, we need to come up with concepts of how we can look for the things that we see here, in cells in culture, what we can see in animals, and we need to be smarter and think how can we look for this in patients with Alzheimer's disease," he concluded.
Eisai Europe Ltd. and Pfizer Inc. sponsored this meeting. Dr. Francis also acknowledges the receipt of grants/ research support from a number of companies, from UK research councils, from the European Union, and from a number of charities.
This meeting was chaired by Jeffrey Cummings, MD, professor of neurology and director, Alzheimer's Disease Research Centre, department of neurology, David Geffen School of Medicine, University of California, Los Angeles, California, United States.
[Presentation title: Alzheimer's Disease as a Disorder Involving Multiple Physiological, Biochemical and Molecular Alterations: What Are the Implications for Clinical Course and Therapeutics? Combined Abstract 19]
|
