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 Neuroinflammation

Imaging Microglial Activation

AD is associated with neuroinflammatory processes, with the key cellular event signaling its presence the accumulation of reactive microglia in areas affected by neurodegeneration.[91] Observed in both sporadic and familial forms of AD, significant microglial activation appears to occur early on in the disease course, with a significant increase in the fractional area of reactive microglia accompanying the formation of neuritic plaques comprising fibrillary Aβ.[21,22,92,93] In vivo quantification of microglial activation has been achieved using [11C]PK11195, a specific ligand for TSPO, formerly called the peripheral benzodiazepine receptor.[23] While early work using racemic [11C]PK11195 was negative[94] – likely due to the relatively high level of nonspecific binding – more recent studies using the R-isomer have shown increased binding of [11C]-(R)-PK11195 in the entorhinal, temporoparietal and cingulate cortices of AD patients in comparison to healthy control subjects.[21] Moreover, high microglial activation has been observed in [11C]PIB+ AD patients, with an inverse correlation found between cortical microglial activation and cognition.[95] Novel approaches aiming to augment the sensitivity of [11C]-(R)-PK11195 signal modelling may be required; in this respect, a recent study has shown that the inclusion of a vascular component results in an amplified signal in patients with AD.[96]

Additional ligands targeting TSPO have been developed aiming for improved pharmacokinetics and specificity. For example, PET imaging with [11C]DAA1106 showed robust binding in AD patients, compared with healthy controls,[97] with [18F]FEDAA1106 or [11C]AC5216 showing promising results in preclinical PET studies in AD-like transgenic models.[98,99] Further, a recent clinical study showed that while increasing binding of [18F]FEDAA1106 was not seen in AD, widespread increases were noted in MCI, when compared with healthy controls, with these values predictive of conversion to AD dementia within a 5-year follow-up period.[24] These findings contrast with those obtained using [18F]FEDAA1106 – a novel TSPO ligand with in vitro affinity superior to that of [11C]DAA1106[100] – with no statistically significant differences in binding between healthy controls and AD patients, possibly due to the inability to separate specific and nonspecific signals in vivo.[101] Though not yet tested in AD patients, [11C]AC5216 has shown promising pharmacokinetic properties and higher affinity than [11C]PK11195 in healthy subjects.[102] However, potential clinical utility of TSPO ligands is undermined by the rs6971 polymorphism in the TSPO gene, which confers lower uptake in carriers (˜30%) in comparison to noncarriers.[25] Finally, growing interest in the endocannabinoid system has identified the cannabinoid receptor type 2 (Cref-2) as a marker of microglial activation.[103] Specifically, preclinical studies show upregulation of Cref-2 – as indexed by [11C]A-836339-in a transgenic model displaying cerebral amyloidosis.[26]

Imaging Reactive Astrocytosis

Increased expression of glial fibrillary acidic and astroglial S100B proteins are typically observed in AD postmortem tissue, indicating an increased number of reactive astrocytes.[104] PET studies using [11C]DED – a ligand with high affinity/specificity for monoamine oxidase B, an enzyme expressed primarily on the mitochondrial membrane of reactive astrocytes[105,106] – have shown elevated binding in patients with MCI, pointing to astrocytosis as an early event in AD.[107]

Imaging Phospholipase Activity

Microglia-derived inflammatory cytokines are capable of binding to astrocytic cytokine receptors coupled to cPLA2, and sPLA2,[108] Ca2+-dependent enzymes whose activation initiates the hydrolysis of esterified arachidonic acid (AA) from membrane phospholipids.[109] Release of nitric oxide can likewise promote membrane-based AA hydrolysis via the role of cPLA2vis à vis ionotropic glutamate receptor mediated increases in intracellular Ca2+ concentrations.[110–112] Indeed, increased cytokine levels have been noted in AD,[113] as have increased expression levels of both cPLA2 and sPLA2, CSF levels of AA metabolites-isoprostane and isoflurane-,[114] and glutamatergic markers,[27,28,115] suggesting that AD is associated with increased AA metabolism. Preliminary results obtained using 1-[11C]-AA support this hypothesis, showing elevated incorporation coefficients in neocortical areas shown to have high densities of senile (neuritic) plaques with activated microglia. To the extent that the elevated binding of 1-[11C]-AA represents the upregulation of AA metabolism secondary to neuroinflammation, PET with 1-[11C]-AA may be used to examine neuroinflammation in patients with AD.[109]

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