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5. TREATMENT AND PREVENTION OF ALZHEIMER'S DISEASE

EFFICACY OF CHOLINESTERASE INHIBITORS IN THE TREATMENT OF NEUROPSYCHIATRIC SYMPTOMS AND FUNCTIONAL IMPAIRMENT IN ALZHEIMER DISEASE

The following points are made by N-H. Trinh et al (J. Am. Med. Assoc. 2003 289:210):

1) Alzheimer disease (AD) is the most common form of dementia, accounting for more than 50% of all dementia cases, and the number of affected individuals will likely quadruple over the next several decades.(1) Research in the treatment of AD has focused on reducing cognitive decline with cholinesterase inhibitors (ChIs), the primary class of medications currently available for this purpose. However, neuropsychiatric symptoms and functional deficits also contribute greatly to the disability associated with AD. As many as 80% of patients with AD will experience neuropsychiatric symptoms such as hallucinations, paranoia, agitation, and affective disturbances during the course of their illness.(2-3) Functional impairment occurs in all patients with AD, first appearing as impairment in instrumental activities of daily living (IADL) tasks, including using the telephone and taking medications. As the disease progresses, alterations in basic activities of daily living (ADLs), such as feeding and dressing, become evident.(4) Both neuropsychiatric symptoms and functional impairment contribute to an increase in caregiver burden, poor patient quality of life, and institutionalization.(5)

2) Cognitive deficits are linked to cholinergic dysfunction. More recently, neuropsychiatric and functional deficits have also been associated with cholinergic dysfunction, with growing interest in ChIs for treatment of these symptoms in AD. Several clinical trials have included neuropsychiatric and functional measures, but have had conflicting results. In addition, these trials varied in numbers of subjects (ranging from 16 to 978) and used a variety of different measures of behavior and function. The authors therefore conducted a systematic review and meta-analysis to quantify the efficacy of ChIs on neuropsychiatric and functional outcomes in patients with mild to moderate AD and living in the community.

3) The authors conclude that their results indicate that cholinesterase inhibitors have a modest beneficial impact on neuropsychiatric and functional outcomes for patients with AD. Future research should focus on how such improvements translate into long-term outcomes such as patient quality of life, institutionalization, and caregiver burden.

References (abridged):

1. Fratiglioni L, Launer LJ, Andersen K, et al for the Neurologic Diseases in the Elderly Research Group. Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology. 2000;54:S10-S15

2. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA. 2002;288:1475-1483

3. Mega M, Cummings JL. The spectrum of behavioral changes in Alzheimer's disease. Neurology. 1996;46:130-135

4. Gauthier L, Gauthier S. Assessment of functional changes in Alzheimer's disease. Neuroepidemiology. 1990;9:183-188

5. Coen RF, Swanwick GRJ, O'Boyle CA, Coakley D. Behaviour disturbance and other predictors of carer burden in Alzheimer's disease. Int J Geriatr Psychiatry. 1997;12:331-336

Related Material:

ON ALZHEIMER'S DISEASE AND LITHIUM

The following points are made by Bart De Strooper and James Woodgett (Nature 2003 423:392):

1) Studies of people with Alzheimer's disease have revealed several notable changes in the brain, including the build-up of protein deposits known as amyloid plaques outside nerve cells, and the accumulation of so-called neurofibrillary tangles inside the cells. Should treatments for this disease target the plaques or the tangles? Phiel et al (1) propose the idea of tackling both with a single drug -- one that inhibits the enzyme glycogen synthase kinase-3 (GSK-3).

2) This enzyme is an evolutionarily conserved serine/threonine kinase that in response to cellular signaling events modifies the functions of a variety of proteins by specifically adding phosphate groups to the amino acids serine or threonine(2). It is one of the candidates for producing excessive phosphorylation of the tau protein -- and "hyperphosphorylated" tau is the main component of the neuronal tangles seen in patients with Alzheimer's disease. The precise effects of these tangles are unknown, and indeed it remains a matter of debate whether the phosphorylation of tau by GSK-3 in vivo harms(3) or protects(4) neurons. Nonetheless, the accumulation of tangles does correlate with progression of the disease.

3) So, too, does the build-up of amyloid plaques. One of the major components of these plaques is a small peptide known as amyloid-beta (A-beta) peptide, which is produced from a longer protein -- the amyloid precursor protein (APP) -- that sits in neuronal membranes. APP is precisely snipped in two places to generate A-beta. The first cleavage is carried out by an enzyme called beta-secretase, or by metalloprotease enzymes(5). This cleavage generates a membrane-bound fragment of APP (the carboxy-terminal fragment), which is then severed by the gamma-secretase complex. The A-beta peptide is thereby produced, and is shed from the neuronal surface. The prevalent hypothesis is that A-beta peptides, congregating outside nerve cells in the brain, are the main trigger for the neuronal degeneration characteristic of Alzheimer's disease.

4) The past decade has seen strong investment in the development of drugs that tackle the deposition of amyloid plaques, using various approaches. On the other side of the coin, the idea of using GSK-3 inhibitors to prevent the build-up of tangles has been around for some time (although validation of this strategy has been problematic, mainly because there are still no good animal models of tangle accumulation, but also because of the question marks over the importance of the in vivo phosphorylation of tau by GSK-3). Phiel et al.(1) now add another aspect to the issue. They find that lithium and kenpaullone -- two structurally unrelated inhibitors of GSK-3 -- interfere with the production of A-beta peptides in cell culture. This has been found previously for lithium and with different cells, but Phiel et al. go further and show that the inhibitors have the same effect in vivo in a mouse model of Alzheimer's disease. So GSK-3 inhibitors could be an attractive addition to the list of candidate drugs for preventing amyloid plaques -- with the potential benefit of also inhibiting the formation of tangles.

References (abridged):

1. Phiel, C. J., Wilson, C. A., Lee, V. M.-Y & Klein, P. S. Nature 423, 435-439 (2003)

2. Doble, B. W. & Woodgett, J. R. J. Cell Sci. 116, 1175-1186 (2003)

3. Lucas, J. J. et al. EMBO J. 20, 27-39 (2001)

4. Spittaels, K. et al. J. Biol. Chem. 275, 41340-41349 (2000)

5. Annaert, W. & De Strooper, B. Annu. Rev. Cell. Dev. Biol. 18, 25-51 (2002)

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