Pathologic and Nicotinic Receptor Binding Differences Between Mild Cognitive Impairment, Alzheimer Disease, and Normal Aging

Abstract

Background: Neurochemical and pathologic studies show that mild cognitive impairment (MCI) is frequently a transitional state between normal aging and Alzheimer disease (AD). Neuropathologic sample sizes have been limited because relatively few individuals with MCI die before dementia develops. Decreased neocortical nicotinic receptor binding is characteristic of AD but has not been investigated in subjects with MCI.Objective: To assess nicotinic receptor binding and pathologic differences in control subjects with no dementia (ND) and in subjects with clinically and pathologically described MCI or Alzheimer disease.Design: This was a clinicopathologic analysis. Subjects with ND had no demonstrable cognitive or functional impairment. Subjects with MCI met Petersen clinical criteria for single-or multiple-domain amnestic MCI and died before the disorder progressed to AD. Subjects with AD met National Institute for Neurological Diseases and Stroke/Alzheimer's Disease and Related Disorders Association clinical criteria for AD. All subjects underwent a complete diagnostic and semiquantitative neuropathologic examination. Data were examined after both clinical and histopathologic classification of subjects.Setting: Sun Health Research Institute Brain Donation Program, and Arizona Alzheimer Disease Center.Participants: Twenty-one control subjects with ND, 8 subjects with MCI, and 70 subjects with AD, prospectively followed up to autopsy. Main Outcome Measures:Nicotinic acetylcholine receptor binding value, total tangle density, total plaque density, and Braak stage.Results: At the last examination before death, subjects with AD were significantly younger, less educated, and more cognitively and globally impaired compared with subjects with ND. When categorized by clinical diagnosis, MCI was always intermediate between ND and AD. On the whole, MCI was pathologically intermediate between ND and AD for senile plaque density, neurofibrillary tangle density, and Braak stage, but some subjects with MCI lacked neuritic plaques entirely. Binding for nicotinic acetylcholine receptors did not differ between the ND and MCI groups, but it was significantly less in the AD group.Conclusions: Most MCI may be considered a transitional state between ND and AD clinically and neuropathologically, but in some MCI cases there is lack of neuritic plaques, and, therefore, it cannot be considered early AD. Nicotinic receptor binding seems to be lost during the transition from MCI to AD.

Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection

“…Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and ␣4␤2 nAChRs in AD (Cook et al, 2004(Cook et al, , 2005Vasto et al, 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the ␣7 subunit (D'Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al, 1999;Gotti et al, 2006;Sabbagh et al, 2006). In addition, not only have ␣7 nAChRs been found colocalized with plaques (Wang et al, 2000b) but ␣7 and ␣4 subunits are also positively correlated with neurons that accumulate A␤ (Wevers et al, 1999).…”

“…The loss of nAChR subunits, as determined by [ 3 H]-epibatidine binding, seems to take place after the transition from mild cognitive impairment (MCI) to AD (Sabbagh et al, 2006), although the loss of epibatidine binding did not correlate with decline in memory, cognitive performance, or with the development of neurofibrillary tangles or plaques (Sabbagh et al, 2001).…”

123I-5-IA-85380 SPECT Imaging of Nicotinic Receptors in Alzheimer Disease and Mild Cognitive Impairment

“…Postmortem binding studies have indicated that a 4 b 2 -nAChR is the nicotinic receptor subtype that is most profoundly affected by AD (reviewed in (9)), with reductions of up to 50% in the neocortex, entorhinal cortex, and hippocampus (2,(6)(7)(8)(9)(10)(11). Decreases in regional nAChR expression have been shown to correlate with declines in cognitive function (7).…”

“…Decreases in regional nAChR expression have been shown to correlate with declines in cognitive function (7). Evidence has accumulated that cholinergic changes, including reductions in nAChR (7,11), may be a late-stage phenomenon in AD (3,4,12). However, it remains uncertain whether the nAChR deficits occur at an early or a preclinical stage of the disease.…”

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

“…These changes include reduction of nicotine and nicotinic agonist binding sites and changes in brain expression of nicotinic acetylcholine receptor (nAChR) subunits (Picciotto and Zoli 2002;Rogers et al 1998;Sabbagh et al 2006). The involvement of nAChRs in aging is also supported by multiple epidemiological studies showing the protective effect of smoking against the development of aging-associated diseases such as Alzheimer's and Parkinson's diseases (AD and PD, respectively;Elbaz and Moisan 2008;Fratiglioni and Wang 2000).…”