This study has shown decreased 123
I‐5IA‐85380 uptake, presumably reflecting α4β2 receptor loss, in patients with AD compared to controls bilaterally in frontal and striatal regions as well as in the right medial temporal and pons. Reductions in the frontal cortex seem to be consistent with previous in vitro postmortem and in vivo PET imaging studies in patients with AD,5,12
where 52% of nicotine and 55% of acetylcholine‐binding sites were found in patients with AD. Reduced 123
I‐5IA‐85380 uptake in striatum in patients with AD is in agreement with most, though not all,24
autopsy studies showing significant reductions in nicotinic binding sites in caudate,2,10
and whole striatum,26
and may reflect loss of corticostriatal projections. Interestingly, marked amyloid deposits, particularly in frontal and striatal regions, were observed in patients with mild AD relative to controls using an amyloid‐binding PET tracer termed Pittsburgh Compound‐B.27
Temporal lobe deficits in nAChR, especially in the hippocampus and entorhinal cortex, have been identified in AD in numerous postmortem studies3,7,8,10,28,29
and with 11
C‐Nicotine PET imaging.12
We found only modest reductions on the right side. It is possible that the reduction in nAChR in the temporal cortex may indicate either end‐stage or severe AD and the relative preservation in this region observed may reflect the inclusion of earlier, milder cases. A previous study reported no significant differences between controls and subjects with mild AD in insular cortex, suggesting nicotinic receptor density in temporal areas may be relatively preserved early in the disease process, perhaps because of receptor upregulation.10
Alternatively, previous demonstrations of nicotinic receptor loss in the temporal cortex may reflect reductions in another subtype, with relative preservation of the α4β2 receptor.
SPECT measures of rCBF and receptor availability are both influenced by atrophy and partial volume effects, and so both nicotinic and rCBF scans should be equally affected by neural degeneration. Thus, where there is overlap between the results of nicotinic α4β2 receptor and rCBF loss—that is, in frontal, striatal and temporal regions—this could be a result of atrophy. Overall, our results suggest that there is some selective loss of nicotinic receptors in patients with AD that was greater than the general functional deficits shown on rCBF scans.
Demographical and neuropsychological measures (age, MMSE, CAMCOG and NPItotal
) did not correlate with 5IA uptake in patients with AD. Several possible explanations could include small sample size, cognitive and clinical or SPECT measures lacking sensitivity, or that α4β2 receptor loss occurred early in the disease process, even before symptoms appeared. Another reason could lie in that most of our patients with AD were in the mild–moderate stages of illness; inclusion of a larger heterogeneous group ranging from very early to more severe disease may improve sensitivity in detecting a significant correlation between imaging and cognitive scores. However, results appear to support previous studies showing that treatment of AD with nicotine and nicotinic agonists have limited effects on cognitive functioning—that is, only in attention, but not in memory30,31,32
—while an autopsy report revealed that the decline in cognitive function does not correlate with loss of nicotine acetylcholine receptors in either AD or DLB.33
Also, patients tended to lack behavioural and psychiatric disturbances—for example, NPI scores were low and insufficient numbers had psychotic features for correlates to be examined. Autopsy studies have revealed possible links between delusions and the muscarinic receptor, although the α7 nicotinic receptor has been associated with visual hallucinations in DLB,34
and the α4β2 subtype has also been shown to be linked with fluctuations in this group.35,36
However, fluctuations are prominent in DLB rather than in AD, and it will be important for future studies to examine associations with 123
I‐5IA‐85380 uptake in vivo in DLB.
The group with AD was slightly older than the control group (p
0.01), therefore statistical analyses were used in an attempt to adjust for such age differences despite no significant relationship between nicotinic uptake and age in either group for any brain region. Seven patients with AD were being treated with cholinesterase inhibitors at the time of their 123
I‐5IA‐85380 scan. Those patients not on medication showed the same differences from controls as the whole group. However, although the use of cholinergic medication could not have accounted for our results, it is still possible that cholinergic treatment produces small changes in the α4β2 receptor, as has been demonstrated after long‐term use of tacrine.37
Serial studies before and after treatment is required to address this issue.
A difference in pattern of uptake was demonstrated between 123
I‐5IA‐85380 and 99m
Tc‐HMPAO scans in both study groups. Nicotinic‐binding patterns in pons, occipital, thalamic and striatal regions significantly differed from rCBF patterns in controls and patients with AD (fig 1). The pons and thalamus are cholinergic‐rich brain regions with high concentrations of α4β2‐nAChR. Uptake was consistent with the known distribution of nAChR in humans, providing validation of this ligand as being specific for the cholinergic system and not simply a distribution reflecting perfusion. The uptake pattern observed in controls also resembled the pattern of uptake reported from previous SPECT studies using 123
I‐5IA‐85380 in healthy volunteers.14,15
The difference in uptake between 123
I‐5IA‐85380 and 99m
Tc‐HMPAO were generally in regions with a greater density of nicotinic binding sites, but other reasons that explain the distribution of these radiotracers in the current dataset may exist.
I‐5IA‐85380 and 99m
Tc‐HMPAO SPECT imaging demonstrated comparable ability in this dataset to correctly classify controls and patients with AD. The discriminant functions accounted for 44% of the variance between groups using nicotinic SPECT and 36% using HMPAO SPECT. The unexplained variance was probably due to the other ROI variables not entered into the models as well as random experimental and physiological variations between subjects. Sensitivity in identifying patients with AD was 73% for nicotinic SPECT and 80% for HMPAO SPECT whereas specificity was 88% and 81%, respectively. These values are in keeping with previous 99m
Tc‐HMPAO SPECT imaging studies on AD.38,39
Eleven controls (11/16; 69%) were correctly and mutually classified with nicotinic or HMPAO SPECT and this was lower for patients with AD (8/15; 53%), but clearly much larger studies are needed to investigate diagnostic utility.
In summary, we have demonstrated significant reductions using 5IA SPECT in patients with AD in cortical and striatal regions, with a pattern distinct from that obtained using perfusion (rCBF) SPECT. Together with previous studies in healthy volunteers and autopsy studies in patients with AD, this validates 123I‐5IA‐85380 SPECT as an in vivo marker of the α4β2 receptor subtype. Further studies, including those in very early disease (mild cognitive impairment), other dementias and serial imaging are required to further assess its role in diagnosis, progression of disease and response to treatment.