Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment

Abstract

In Alzheimer's disease (AD), loss of cortical and hippocampal choline acetyltransferase (ChAT) activity has been correlated with dementia severity and disease duration, and it forms the basis for current therapies. However, the extent to which reductions in ChAT activity are associated with early cognitive decline has not been well established. We quantified ChAT activity in the hippocampus and four cortical regions (superior frontal, inferior parietal, superior temporal, and anterior cingulate) of 58 individuals diagnosed with no cognitive impairment (NCI; n = 26; mean age 81.4 +/- 7.3 years), mild cognitive impairment (MCI; n = 18; mean age 84.5 +/- 5.7), or mild AD (n =14; mean age 86.3 +/- 6.6). Inferior parietal cortex ChAT activity was also assessed in 12 subjects with end-stage AD (mean age 81.4 +/- 4.3 years) and compared to inferior parietal cortex ChAT levels of the other three groups. Only the end-stage AD group had ChAT levels reduced below normal. In individuals with MCI and mild AD, ChAT activity was unchanged in the inferior parietal, superior temporal, and anterior cingulate cortices compared to NCI. In contrast, ChAT activity in the superior frontal cortex was significantly elevated above normal controls in MCI subjects, whereas the mild AD group was not different from NCI or MCI. Hippocampal ChAT activity was significantly higher in MCI subjects than in either NCI or AD. Our results suggest that cognitive deficits in MCI and early AD are not associated with the loss of ChAT and occur despite regionally specific upregulation. Thus, the earliest cognitive deficits in AD involve brain changes other than simply cholinergic system loss. Of importance, the cholinergic system is capable of compensatory responses during the early stage of dementia. The upregulation in frontal cortex and hippocampal ChAT activity could be an important factor in preventing the transition of MCI subjects to AD.

Increased Anticholinergic Challenge-Induced Memory Impairment Associated with the APOE-ɛ4 Allele in the Elderly: A Controlled Pilot Study

“…Some recent investigations also suggest that cholinergic abnormalities, as measured by reductions in the neocortical activity of the cholinergic marker enzymes, ChAT and AchE, may not be an early pathophysiological event in AD (Davis et al, 1999;Tiraboschi et al, 2000). Additionally, a study in individuals with mild cognitive impairment actually found an upregulation of ChAT activity in the hippocampus and frontal cortex of this population (DeKosky et al, 2002). It should be noted that the findings from these studies are derived from post-mortem observations.…”

Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease

“…75,76 A comparison between these cases and those that have a similar pathological load but a diagnosis of AD may help differentiate factors crucial to cognitive function from those less directly applicable, such as cognitive reserve or neuroplasticity. 79 The pathological variability found in the MCI cases may also have been a reason that the increase in specific tau inclusions did not significantly differ among clinical diagnosis. MCI is characterized by the presence of memory deficits that are not severe enough to curtail activities of daily living or to meet the criteria for dementia, 80 but that are considered to represent a prodromal stage of AD.…”

Auditory brain-stem, middle- and long-latency evoked potentials in mild cognitive impairment

“…Previous studies have shown that acetylcholine can modulate the activity of auditory cortex (Buchwald et al, 1991;Metherate, 2004). There is also an increase in cholinergic enzyme activity in certain cortical regions in MCI (Dekosky et al, 2002). Thus, changes in the cholinergic system may be associated with the modulation of auditory cortical activities in MCI and Alzheimer's disease.…”

“…b-amyloid plaques, neurofibrillary tangles) gradually accumulate in the brain without sufficient neuronal damage to cause clinically detectable dementia (Giannakopoulos et al, 2003;Ohm et al, 1995). Neuropathological studies report that both the extent of neuronal loss (Kordower et al, 2001) and the regional accumulation of b-amyloid plaques and neurofibrillary tangles (Dekosky et al, 2002;Mufson et al, 1999) in MCI are similar to early Alzheimer's disease. Taken together, the greater risk of Alzheimer's disease in MCI and the similarity in neuropathological features to early Alzheimer's disease suggests that MCI can be a transition state between normal aging and Alzheimer's disease.…”