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

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]
D2/3	[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-HT2A	[18F]setoperone [18F]altanserin	Decreased Decreased	Decreased 5-HT2A receptor densityDecreased 5-HT2A receptor density	[41,42]
5-HT1A	[18F]MPPF	Decreased	Decreased 5-HT1A 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.

Authors and Disclosures

Lucas Porcello Schilling^1,2,3, Antoine Leuzy^1,2, Eduardo Rigon Zimmer^1,2,4, Serge Gauthier² & Pedro Rosa-Neto*^,1,2

¹Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging (MCSA), Douglas Mental Health Research Institute, Montreal, Canada
²Alzheimer's Disease Research Unit, McGill Center for Studies in Aging (MCSA), Douglas Mental Health Research Institute, Montreal, Canada
³Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
⁴Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

*Author for correspondence
pedro.rosa@mcgill.ca

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.