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

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

Future Neurology. 2014;9(6):597-613.

Future Perspective

On the basis of recent biomarker studies, AD pathophysiology is thought to precede the onset of clinical symptoms by up to a decade or more. As such the field has begun to shift toward the early diagnosis of AD, recognizing that a relatively broad window of opportunity exists, potentially, for intervention with novel disease modifying therapies. Though none have yet to demonstrate efficacy in Phase III studies, various strategies targeting primarily amyloid and tau are under development. As such, multitracer approaches utilizing, for instance, [¹⁸F]FDG and tau ligands, will be required in both symptomatic and disease-modifying trials in order to determine tau engagement and treatment response. Similarly, neuroinflammatory molecular imaging can similarly contribute to anti-inflammatory interventions. Finally, on the basis of the vast literature reporting the effects of psychiatric drug, tracers for neurotransmission may contribute to the development of improved therapeutic prospects addressing neuropsychiatric features in AD as well as the refinement of current treatment protocols and improved study designs.

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Financial & competing interests disclosure
This work was supported by the Canadian Institutes of Health Research (CIHR; MOP-11-51-31 and MOP 10-27-52), Alzheimer's Association (NIRG-12-259245), Fonds de Recherche du Quebec – Santé (FRQS; Chercheur Boursier), the Allan Tiffin Trust (Infrastructure), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Fundacao de Amparo a Pesquisa do Rio Grande do Sul (Fapergs, Brazil), and INCT for Excitotoxicity and Neuroprotection/CNPq. This research was also partially supported by Fonds d'innovation Pfizer-FRQS sur la maladie d'Alzheimer et les maladies apparentées – Volet 2 to P Rosa-Neto. S Gauthier and P Rosa-Neto are members of the CIHR Canadian Consortium of Neurodegeneration in Ageing. The authors have no other relevant affiliations or financialinvolvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Table 1. Potential nonamyloid PET biomarkers for Alzheimer's disease.
Biological target	Radiopharmaceuticals	Findings	Interpretation	Ref.
*Neurodegeneration*
Tau pathology	[¹⁸F]T807 [¹⁸F]T808 [¹⁸F]THK523 [¹⁸F]THK5105 [¹⁸F]THK5117 [¹¹C]PBB3	Increased Increased Increased Increased Increased Increased Increased	Increased formation of tau aggregates	[14] [15] [16] [17] [17] [18]
Hexokinase activity	[¹⁸F]FDG	Decreased	Decreased glucose metabolism	[19]
*Neuroinflammation*
TSPO	[¹¹C]PK11195 [¹¹C]DAA1106 [¹⁸F]FEDAA1106 [¹¹C]AC5216	Increased Increased Increased Increased	Increased microglial activation Increased microglial activation Increased microglial activation Increased microglial activation	[20] [21] [22] [23]
CB2	[¹¹C]A836339	Increased	Increased microglial activation	[24]
MAO-B	[¹¹C]_L-deprenyl	Increased	Increased reactive astrocytosis	[25]
Phospholipase	1-[¹¹C]-AA	Increased	Increased phospholipase activity	[26]
*Neurotransmission*
AChE activity	[¹¹C]PMP [¹¹C]MP4A	Decreased Decreased	Decreased AChE activity	[27] [28]
mAChR	[¹¹C] NMPB	Decreased	Decreased mAChR density	[29]
mAChR₂	[¹⁸F]FP-TZTP	Decreased	Decreased mAChR₂ density	[30]
nAChRs	2-[¹⁸F]A-85380 [¹¹C]nicotine	Decreased Decreased	Decreased nAChR density Decreased nAChR density	[31] [32]
nAChRs type α₄β₂	[¹⁸F]NCFHEB	Decreased	Decreased nAChRs type α₄β₂ density	[33]
nAChRs type α₇	[¹¹C]CHIBA-1001	Decreased	Decreased nAChRs type α₇ density	[34]
VAChT	[¹⁸F]FEOBV	Decreased	Decreased VAChT activity	[35]
D₁	[¹¹C]NNC756	Decreased	Decreased D₁ density	[36]
D₂	[¹¹C]raclopride	Decreased	Decreased D₂ density	[37]
D_2/3	[¹¹C]FLB457	Decreased	Decreased D₂/D₃ density	[38]
DAT	[¹¹C]β-CFT	Decreased	Decreased dopamine reuptake	[39]
VMAT2	[¹¹C]DTBZ	Decreased	Decreased VMAT2 activity	[40]
5-HT_2A	[¹⁸F]setoperone [¹⁸F]altanserin	Decreased Decreased	Decreased 5-HT_2A receptor densityDecreased 5-HT_2A receptor density	[41,42]
5-HT_1A	[¹⁸F]MPPF	Decreased	Decreased 5-HT_1A receptor density	[43]
5-HT₄	[¹¹C]SB207145	Increased	Increased 5-HT₄ receptor density	[44]
NET	[¹⁸F]FMeNER-D2	Decreased	Decreased NET density	[45]
H₁	[¹¹C]doxepine	Decreased	Decreased H₁ density	[46]
μ and κ opioid receptors	[¹⁸F]fluoronaltrexone	Decreased	Decreased μ and κ opioid receptors densities	[47]
A₁	[¹¹C]MPDX	Decreased	Decreased A₁ density	[48]

5-HT: Serotonin receptor; A: Adenosine receptor; D: Dopamine receptor; DAT: Dopamine transporter; H: Histamine receptor; mAChR: mACh receptor; nAChR: Nicotinic acetylcholine receptor; NET: Norepinephrine transporter.

Sidebar

Executive Summary

PET biomarkers of neurodegeneration

Imaging tau pathology:
- PET studies and related in vitro findings highlight the suitable kinetics and high affinity/selectivity for tau fibrils of novel tau radiotracers; however, validation studies are necessary.
Imaging brain glucose metabolism:
- Though declines in [¹⁸ F]FDG adhere to a specific topographic distribution in Alzheimer's disease (AD), focal [¹⁸ F]FDG patterns have been noted in atypical presentations. Greater hypometabolism has likewise been noted in patients with early onset AD;
- [¹⁸ F]FDG hypometabolism has been noted in patients at various points along the AD continuum and in those at risk for AD. [¹⁸ F]FDG may likewise prove of use in terms of characterizing patients with suspected non-AD pathophysiology (SNAP).

PET biomarkers for neuroinflammation

Imaging microglial activation:
- The clinical utility of TSPO PET ligands are potentially limited owing to a polymorphism in the TSPO gene conferring low uptake in carriers.
Imaging reactive astrocytosis:
- Increased binding of [¹¹ C]DED has been noted in patients with AD and mild cognitive impairment.
Imaging phospholipase activity:
- Elevated metabolism of arachidonic acid (AA)-indexed by 1-[¹¹ C]-A- has been noted in AD.

PET biomarkers for neurotransmission

Imaging cholinergic neurotransmission:
- Reduced uptake of radiolabeled acetylcholine analogues, nicotine and its derivatives and 3-pyridyl ether/epibatidine derivatives are seen in patients with mild cognitive impairment and AD.
Imaging dopaminergic neurotransmission:
- [¹⁸ F]fluorodopa PET show that the synthesis and storage of dopamine (DA) is preserved in AD. [¹¹ C]NNC756 shows declines in DA D1 receptor availability. DA, as indexed using [¹¹ C]β-CFT, is reduced in the striatum;
- Hippocampal and temporal cortex DA D2 receptors have been shown to be reduced using [¹¹ C]FLref-457, in the right hippocampal findings associated with memory scores;
- In AD patients, decreased binding of [¹¹ C]DTBZ, a ligand with affinity for the vesicular monoamine transporter 2, may be a marker of Lewy Body pathology.
Imaging serotoninergic neurotransmission:
- PET studies using [¹⁸ F]setoperone and [¹⁸ F]altanserin show declines in neocortical 5HT _2A receptors;
- Using [¹⁸ F]MPPF, decreased 5HT _1A receptor densities were noted in the hippocampus and raphe nuclei of patients with AD, with hippocampal binding correlating with clinical severity;
- Findings with the 5-HT ₄ ligand [¹¹ C]Sref-207145 suggest that upregulation of 5-HT ₄ may characterize preclinical AD.
Imaging other neurotransmitters:
- Autoradiographic studies using (S,S)-[¹⁸ F]FMeNER-D, a PET ligand selective for the norepinephrine transporter, have shown declines in norepinephrine transporter densities in the locus coeruleus and thalamus of AD tissue;
- Binding of [¹¹ C]doxepine, a histamine H1 receptor PET ligand, has been found to be reduced in temporal and the frontal brain areas in AD patients, with receptor binding correlating with clinical severity;
Imaging other neurotransmitters:
- In vivo studies in AD using [¹⁸ F]fluoronaltrexone, a μ and -k opioid receptor antagonist, have shown declines in parietal, frontal and limbic cortices;
- Decreased density of the adenosine A ₁ receptor has been noted in postmortem studies using hippocampal AD tissue. [¹¹ C]MPDX, a tracer with affinity for the adenosine A ₁ receptor, may prove sensitive to the integrity of the perforant path and its terminal zone.