Nonamyloid PET Biomarkers and Alzheimer's Disease: Current and Future Perspectives

Lucas Porcello Schilling; Antoine Leuzy; Eduardo Rigon Zimmer; Serge Gauthier; Pedro Rosa-Neto

Disclosures

Future Neurology. 2014;9(6):597-613. 

In This Article

PET Biomarkers for Neurotransmission

Imaging Cholinergic Neurotransmission

Degeneration of the cholinergic system is a well-established biochemical and histopathological feature of AD,[116] with reduction in levels of acetylcholine (ACh) and AChE – the most important enzyme mediating hydrolysis of ACh in the human brain – consistently described.[117,118] Indeed, radiolabeled analogs of ACh – such as [11C]PMP and [11C]MP4A, themselves substrates for AChE – can be used for measuring and imaging its activity in vivo.[119,120]

PET studies using [11C]PMP and [11C]MP4A have consistently found reduced cortical activity in AD, with the severity of such reductions greatest in the temporal cortex.[121–124] In a study examining the association between [11C]MP4A imaging and APOE ε4 genotype in patients with AD, AChE was found to be lower in ε4 noncarriers,[29] with the relative preservation of cortical AChE activity in β4 carriers possibly due to its preserved cellular expression or as a result of AChE activity in amyloid plaques.[30] In AD, AChE activity, as indexed by [11C]PMP, has been shown to associate significantly with performance on executive measures, as opposed to tests reflecting episodic memory.[31] Reduced AChE activity has also been reported in MCI,[124] particularly in those subjects who later convert to AD,[32] suggesting that low AChE activity may be a marker of prodromal AD. [11C]PMP and [11C]MP4A have likewise been used to examine the effects of currently available cholinesterase inhibitors[118] in AD, with standard clinical doses producing a 30–40% inhibition of AChE.[31,125,126]

ACh exerts its effects on the CNS via binding at the ligand-gated nicotinic ACh receptors (nAChRs) – consisting of five subunits, variously comprising α2–α10 and β2-β4 and the G-protein coupled muscarinic receptors (mAChRs), proteins known to play an important role in the neuronal circuitry underlying attention, learning and memory. To date, there have been few PET studies targeting mAChRs in AD. Using [11C]NMPB, a nonselective mAChR ligand, no changes were observed in patients with AD.[127] Higher binding was, however, shown in AD APOE ε4 carriers using [18F]FP-TZTP, a tracer selective for the mAChR type 2.[128] In the case of nAChRs, studies have been more numerous, with three general compound classes of radiopharmaceuticals developed for use with PET: nicotine and its derivatives, 3-pyridyl ether derivatives-including 2-[18F]A-85380 – and derivatives of epibatidine.[129]

PET studies using [11C]nicotine have shown decreased availability of nAChRs in AD,[33] with such reductions shown to correlate significantly with performance decrements on measures of executive functioning, in particular, attention.[130] When measured before and after treatment with rivastigmine – an AChE inhibitor – [11C]nicotine binding sites were found to be significantly increased, with this increase found to correlate with improved performance on an attentional task at 12-month follow-up.[126,131] However [11C]nicotine results are contaminated by cerebral blood flow effects (see review,[34]). In the case of 2-[18F]A-85380, a tracer specific to the α4β2 nAChR subtype, results have proven inconsistent, with reports of no differences between patients with AD and age-matched healthy controls[132] and reduced availability of α4β2 receptors in both MCI and AD.[35] Owing to the lengthy acquisition time required for studies using 2-[18F]A-85380 (7–8 h), additional α4β2 nAChRs radioligands have been developed, including [18F]NCFHEB. Preclinical work in a porcine model has established that in comparison to 2-[18F]A-85380, [18F]NCFHEB enantiomers possess superior kinetics and shorter acquisition times.[133]

A recent approach has involved the development of PET tracers selective for the α7 nAChR subtype. Along with α4β2, the α7 subtype is the most abundant nAChR in the human brain and, is known to occupy a key role in neuronal plasticity, sensory gating and memory. In contrast to α4β2, however – whose numbers are decreased in AD – the α7 receptor population has been shown to remain largely intact in AD, and as such, stands as a potential target for novel therapeutics.[134] An interesting approach is to develop PET tracers selective for α7 nAChRs, as this receptor subtype may have broad interactions with several neurotransmitter systems and pathologic processes in AD.[135] Recently, the results of PET studies have suggested that [11C]CHIBA-1001 may be a suitable radioligand for imaging α7 nAChRs in the human brain, possessing desirable prerequisites for being considered adequate for PET imaging.[36] Finally, several in vitro/in vivo studies[37–40] using the vesamicol derivative [18F]FEOBV – which binds VAChT – suggest this tracer to be a promising marker of brain VAChT, sensitive to subtle disruptions of the cholinergic system.[38]

Imaging Dopaminergic Neurotransmission

Various aspects of the dopaminergic system can be assessed using PET, including synthesis, receptor densities, uptake system, vesicular transporter and neurotransmission release. In contrast to other neurodegenerative diseases, studies using [18F]fluorodopa in AD have shown dopamine synthesis to be preserved, even in the presence of mild 'parkinsonian' rigidity.[136] Relative to controls, reduced striatal uptake of the dopamine D1 receptor antagonist [11C]NNC756 has been show in AD patients, in contrast to the absence of significant declines in striatal dopamine D2 receptors, as assessed using [11C]raclopride. Moreover, findings with either tracer were not found to correlate with MMSE or extrapyramidal symptoms, measured using the Unified Parkinson's Disease Rating Scale.[137] Use of [11C]raclopride in patients with more advanced AD, however, has shown a correlation between decreased binding and scores obtained on the Behavioral Pathology in AD Frequency Weighted Severity Scale.[138] Using the dopamine D2/D3 receptor antagonist [11C]FLref-457, declines in hippocampal and temporal cortex D2 receptors have been observed in AD, with reductions in the right hippocampus shown to associate significantly with verbal memory performance and declarative naming.[139] Further, using [11C]β-CFT, a cocaine analog, striatal dopamine reuptake was found to be reduced in AD patients, with the severity of such reductions found to correlate with extrapyramidal symptom severity.[140] Finally, several PET studies using [11C]DTBZ – a reliable marker of dopaminergic presynaptic integrity owing to its affinity for the vesicular monoamine transporter 2 – support its use to facilitate in the differential diagnosis of AD, dementia with Lewy Bodies and Parkinson's disease,[141,142] with decreased binding of [11C]DTBZ in patients with AD a potential marker for coexisting subclinical dementia with Lewy bodies pathology.[143]

Imaging Serotoninergic Neurotransmission

Widely involved on pathophysiology of mood and anxiety, disruption of the serotonergic system has been reported to closely parallel the occurrence of neuropsychiatric features in AD.[144] While the loss of serotonergic neurons within the raphe nuclei,[145] as well as dysfunction of isocortical and allocortical serotonin nerve terminals[146–148] have been reported in AD, results have proven contradictory with respect to the correlation between such findings and neuropsychiatric symptoms.[149,150] Despite numerous lines of evidence supporting this serotonin (5-HT) deficiency theory,[41–44,151] in vivo studies using PET have largely focused on the link between 5-HT receptors and cognitive impairment in AD.[152]

Using [18F]setoperone, a PET ligand specific to the 5HT2A receptor, significant declines were noted in the cortical 5-HT2A population, with maxima in the frontal, parietal, temporal and occipital cortices, as well as in the parieto-temporal carrefour.[153] In a similar study using [18F]altanserin, likewise a ligand for the 5HT2A receptor, decreased binding was noted in several brain regions, including the prefrontal and sensorimotor cortices, as well as the in anterior cingulate. Moreover, no correlation was seen between ligand binding and dementia severity,[154] indexed using the MMSE.[45] In a study measuring 5HT1A receptor densities using [18F]MPPF and PET in patients with AD significantly decreased receptor densities were noted in the hippocampus and the raphe nuclei.[155] Reduction in hippocampal binding was significantly greater when hippocampal volume loss was accounted for, with a strong correlation found between such declines and clinical severity, measured with the MMSE.[155] Finally, a recent study using [11C]Sref-207145, a novel radioligand selective for the 5-HT4 receptor, showed that while no differences existed between patients with AD and healthy controls when AD was defined on clinical grounds, increased binding was noted in amyloid positive individuals. The authors suggest that upregulation of 5-HT4 may begin in preclinical AD, possibly in an attempt to counteract the accumulation of Aβ.[156]

Imaging Other Neurotransmitters

Numerous postmortem studies indicate that cell numbers within the locus coeruleus (LC) – the primary source of norepinephrine (NE) in the brain – are significantly decreased in AD, as are levels of NET.[46,157,158] In a series of autoradiographic experiments using (S,S)-[18F]FMeNER-D, a novel PET ligand selective for NET, significant declines in NET densities were noted in the LC and thalamus of AD tissue sections, as compared with healthy controls.[159] These results suggest that NET levels stand as a potential biomarker for AD, and that the thalamus – as opposed to the LC, whose small size is problematic given the spatial resolution of current diagnostic PET scanners – may prove a suitable target for future in vivo PET studies using (S,S)-[18F]FMeNER-D.

Histaminergic receptors have been shown a role an important role in the modulation of learning, memory[160] and attention,[161] and are implicated in antiapoptopic pathyways[161] as well as in the mediation of neuroprotective effects at the level of the hippocampus.[162] In this respect, a PET study using [11C]doxepine, an H1 receptor ligand, showed reduced binding in temporal and frontal brain areas in AD patients, with receptor binding correlating with clinical severity, as measured using the MMSE.[47] These findings suggest that histaminergic disruption may contribute to the cognitive deficits seen in AD.

Interest likewise exists in the use of PET for studying the opioidergic system in AD given the putative modulatory role of the endogenous opioid system in behavior and cognition,[163] the observation that high doses of the opiate receptor antagonist naloxone produce cognitive impairment in normal subjects[164,165] and postmortem studies showing declines in opiate receptors in AD.[166,167] In vivo work aiming to further clarify the role of the opioidergic system in AD has shown declines in μ and -k receptor subtypes using [18F]fluoronaltrexone, a μ and -k receptor antagonist, with significant declines noted in the parietal, frontal and limbic cortices, but not in the temporal cortex.[168]

Finally, decreased density of the adenosine A1 receptor has been noted in postmortem autoradiographic and pathological studies using hippocampal AD tissue.[48,169–171] Citing the observation that despite considerable neuronal loss within the medial temporal cortex, patients with AD do no invariably exhibit medial temporal cortex hypometabolism following [18F]FDG PET,[64,172,173] Fukumitsu et al.[174] argued that [11C]MPDX, a tracer with affinity for the adenosine A1 receptor, may prove of use as a diagnostic biomarker in AD. An in vivo study using [18F]FDG PET and [11C]MPDX in a small sample of AD patients and healthy controls showed that while decreased retention of [11C]MPDX was observed in the temporal and medial temporal cortices, declines in [18F]FDG were noted only in the temporal cortex. As such, the authors proposed that [11C]MPDX, but not [18F]FDG, may prove sensitive to disrupted neuronal integrity within the performant path and its terminal, owing to it being a site characterized by high density of adenosine A1 receptors.[175]

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