. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol. 2002 Feb;51(2):145-55. PubMed.

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  1. This study is important as it shows that at least at the level of the enzyme choline acetyltransferase, that there is not a decrease in this cholinergic marker until relatively late in the clinical course of Alzheimer's disease. While there may still be dysfunction in the cholinergic system (e.g. atrophy of cholinergic neurons, sprouting, abnormal firing, etc.), there is not a gross loss of the enzyme used to synthesize acetylcholine. It has been known for some time that cholinergic neurons are only one subset of neurons affected in Alzheimer's disease. Many other neurons are dysfunctional and ultimately degenerate in many areas of the limbic system and other areas of neocortex. Most of these neurons utilize glutamate as their major neurotransmitter.

    Given these results, it is not surprising that cholinesterase inhibitors have only modest effects in patients with Alzheimer's disease. On the up side, this study suggests that development of new drugs that influence other neurotransmitter systems may have the ability to have much more profound effects on symptoms and signs of dementia than drugs which affect the cholinergic system. - David Holtzman.

  2. The study by DeKosky does not allow for conclusions about whether or not the cholinergic deficit is present at early stages of AD. The data show that there are differences in ChAT activity between a "no cognitive impairment" (NCI) group and a "mild cognitive impairment" group (MCI) but these groups should not be equated with "no Alzheimer's disease" and "mild Alzheimer's disease" since in both groups, about 60% of the cases had CERAD diagnoses of possible AD. Since even in the MCI group 40% of the cases do not have significant AD pathology, the study is really about the clinical groups (NCI and MCI), not about AD stages. This error was also made by Davis et al [3] in a 1999 paper.

    To examine the question of whether or not the cortical cholinergic deficit is present at early stages in AD, we have divided cases on histopathologic grounds into a "normal" group (no plaques, with low Braak stage) and a "mild AD" group (diffuse plaques and/or sparse neuritic plaques, also with low Braak stage). Our published results [1;2] showed that the mild AD group had significantly lower cortical ChAT activities and cholinergic fiber densities. Katzman et al had similar findings in 1988 [4]. - Tom Beach

    References:

    . Cholinergic fibre loss associated with diffuse plaques in the non-demented elderly: the preclinical stage of Alzheimer's disease?. Acta Neuropathol. 1997 Feb;93(2):146-53. PubMed.

    . The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease. J Neuropathol Exp Neurol. 2000 Apr;59(4):308-13. PubMed.

    . Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA. 1999 Apr 21;281(15):1401-6. PubMed.

    . Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988 Feb;23(2):138-44. PubMed.

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