. Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer's disease. Brain. 2011 Jan;134(Pt 1):301-17. PubMed.

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  1. This case report study of the first Pittsburgh Compound B (PIB) positron emission tomography patient with Alzheimer’s disease (AD) by Kadir et al. provides extensive descriptive information regarding the neuropathological changes found in the brain of a 61-year-old female patient who came to autopsy following an approximate eight-year duration of AD-like clinical symptoms. This thorough investigation provided pathological verification of the clinical diagnosis of AD as well as extensive correlative studies between PIB binding (presumably representing fibrillar Aβ burden) and several cognitive and neuropathological measures.

    Of note was a negative correlation between PIB binding and tissue homogenate assessment of nicotinic acetylcholine receptor binding. Specifically, the authors employed 3H-nicotine and 125I-α-bungarotoxin binding to assess the two major neuronal nicotinic acetylcholine receptor subtypes in the brain (α4β2 and α7) and nicotinic receptor subtypes, respectively. Interestingly, there was a negative correlation between 3H-nicotine binding and PIB retention, particularly in areas with the highest levels of PIB signal, whereas no correlation was found between PIB binding and 125I-α-bungarotoxin binding levels. The authors interpret these results as fibrillar amyloid having a negative drive on the expression of neuronal α4β2 receptors. This certainly may be the case, as there have been reports of decrements of 3H-nicotine binding in cortical tissue in postmortem AD brain, as well as more direct measurements of individual nicotinic receptor subunits via immunocytochemical and genomic-based approaches.

    A caveat to the present approach is that 3H-nicotine is a (well-established) binding assay that is selective, but not specific for α4β2 nicotinic receptors, just as 125I-α-bungarotoxin is selective, but not specific for α7 nicotinic receptors. Furthermore, these assays were performed in tissue homogenates that include admixtures of neuronal and non-neuronal cells, and cannot account for a decrease in 3H-nicotine binding as a function of neuronal loss, which is known to occur in the cortical regions assessed. One might argue that the observation of no changes in 125I-α-bungarotoxin binding in relation to PIB retention obviates the concern of neuronal loss, but this does not take into consideration the abundance of α7 nicotinic receptors on glial cells, particularly astrocytes, which may complicate any interpretation, as gliosis occurs in the cerebral cortex and neuronal loss takes place within the tissue that was used as input material for the assays. A method that our group has used to assess classes of relevant transcripts within vulnerable cell types, without the concern of neuronal cell loss, is single population gene expression profiling in combination with RNA amplification and custom-designed microarray analysis (Ginsberg et al., 2010). Specifically, we have performed expression profiling for acetylcholine receptors on vulnerable cholinergic basal forebrain (CBF) neurons within the nucleus basalis in postmortem AD and mild cognitive impairment (MCI).

    Although not within the cortex, CBF neurons displayed a statistically significant upregulation of α7 nicotinic receptor mRNA in subjects with mild to moderate AD compared with those with no cognitive impairment (NCI) and MCI (Counts et al., 2007). No differences were found for other nicotinic receptor mRNAs (including the α4 and β2 subunits) or muscarinic acetylcholine receptor subtypes across the cohort. Similar to the findings in the present study with PIB binding, expression levels of α7 nicotinic receptor mRNA was inversely associated with cognitive performance (Counts et al., 2007). Thus, expression of individual nicotinic acetylcholine receptor subunits is likely to be cell type-specific, and a correlation between expression levels and PIB binding may require additional studies at the single population level in tissue sections with genomic-based approaches or unbiased estimation techniques, in combination with immunocytochemical methods using subunit-specific antibodies (which is no easy feat in human postmortem brain material when it comes to acetylcholine receptors).

    In summary, this well-written and illustrated case report provides somewhat tantalizing information regarding the power of biomarker assays for fibrillar amyloid and postmortem neuropathological assessments. The research community will have to wait until a full cohort of subjects imaged with PIB comes to autopsy to get a greater understanding of the relationship(s) of amyloid levels with cognitive decline and neuropathology. However, the initial observation of a negative correlation between PIB retention and 3H-nicotine binding is certainly provocative and worth greater follow-up, even though there are many caveats to be considered before coming to a conclusion that fibrillar amyloid (or other neuropathological markers such as neurofibrillary tangles or neuropil threads) drives neurotransmitter-identified system (such as cholinergic and glutamatergic, to name just two) deficiencies that are increasingly becoming hallmarks of AD neuropathology.

    References:

    . Alpha7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease. Arch Neurol. 2007 Dec;64(12):1771-6. PubMed.

    . Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer's disease progression. Biol Psychiatry. 2010 Nov 15;68(10):885-93. PubMed.

  2. This manuscript describes in detail the postmortem assessment of an AD patient studied twice with PIB-PET and three times with FDG-PET during life (last PIB 35 months before death). The subject happens to be the first patient ever studied with PIB-PET, and while this is of historical interest, the main points of the paper are correlation of postmortem measures with in vivo imaging. This sort of correlation remains of interest because, although there are several correlative studies in the literature, few are as detailed and comprehensive as this one. The findings of this study confirm what has been previously reported: 1) in vivo PIB retention is an accurate marker for the total insoluble (i.e., fibrillar) Aβ content of the brain, and 2) there is little progression of PIB retention over two years during the clinical phase of moderate AD—a time during which metabolism progressively decreases in parallel to worsening cognition. One unique aspect of this study is the longitudinal nature of the in vivo data. Another unique aspect is the demonstration of negative correlations between PIB and nicotine binding and positive correlations between PIB binding/retention and a marker of reactive astrocytosis. It will continue to be of value to perform exquisitely detailed postmortem-in vivo correlations such as this in many more brains studied with amyloid tracers in order to determine the limits of sensitivity of the in vivo tracers and to determine if exceptions to the tight in vivo-postmortem correlations can exist in brains with Aβ deposits that may not be primarily fibrillar.