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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Neurochem. Author manuscript; available in PMC 2010 September 3.
Published in final edited form as:
PMCID: PMC2933070
NIHMSID: NIHMS104112

Interaction of the amyloid imaging tracer FDDNP with hallmark Alzheimer's disease pathologies

Abstract

The distinctive cortical uptake of the tracer 18F-FDDNP (2-(1-{6-[(2-fluoroethyl(methyl)amino]-2-naphthyl}ethylidene)malononitrile) in Alzheimer's disease (AD) is believed to be due to its binding to both neurofibrillary tangles (NFTs) and highly fibrillar senile plaques (SPs). We therefore investigated the binding of a tracer concentration of 3H-FDDNP to brain sections containing AD hallmark pathologies. Semi-adjacent sections were labelled with 3H-PIB (Pittsburgh Compound-B, 2-[4'-(methylamino)phenyl]-6-hydroxybenzothiazole) and 14C-SB13 (4-N-methylamino-4'-hydroxystilbene) for comparison. Neocortical sections containing widespread SPs, and cerebrovascular amyloid angiopathy (CAA), produced a sparse and weak labelling following incubation with 3H-FDDNP. Furthermore, in sections containing NFTs there was no overt labelling of the pathology by 3H-FDDNP. In contrast, sections labelled with 3H-PIB displayed extensive labelling of diffuse plaques, classical plaques, CAA, and NFTs. 14C-SB13 produced a broadly similar binding pattern to PIB. Radioligand binding assays employing in vitro generated amyloid-beta peptide fibrils produced a ~10-fold reduced affinity for 3H-FDDNP (85.0±2.0 nM) compared with 3H-PIB (8.5±1.3 nM). These data provide an alternative mechanistic explanation for the observed low cortical uptake of 18F-FDDNP in AD; in that the ligand is only weakly retained by the hallmark neuropathology due to its low affinity for amyloid structures.

Keywords: Alzheimer's disease, amyloid, imaging, amyloid beta, PIB, FDDNP, SB13

Introduction

A range of amyloid PET tracers are currently undergoing extensive trials for the differential diagnosis of dementias and as potential pharmacodynamic endpoints for disease modifying therapeutics in AD (Lockhart, 2006; Nordberg 2008 for recent reviews). Of the five tracers (18F-FDDNP (Shoghi-Jadid et al 2002), 11C-PIB (Klunk et al 2004), 11C-SB13 (Verhoeff et al., 2004), 18F-BF227 (Kudo et al 2007) and 18F-AV1-BAY94-9172 (Rowe et al 2008)) that have so far progressed into humans only PIB has received an extensive and robust biochemical profiling of its binding to a range of in vitro amyloid filaments (Klunk et al 2003; Lockhart et al 2004; Fodero-Tavoletti et al 2007; Ye et al 2008) and, more importantly, neuropathological lesions (Lockhart et al 2007; Fodero-Tavoletti et al 2007; Ye et al 2008; Ikonomovic et al 2008). Such studies are critical to understanding not only the molecular basis of tracer binding to amyloid but also interpreting the disease specific patterns of retention and potential changes associated with drug intervention (Kadir et al 2008).

The tracer FDDNP is distinct from the other amyloid probes in terms of its chemotype, in vitro binding properties and in vivo cortical uptake, the latter in terms of both the magnitude of the signal and its neuroanatomical pattern (Shoghi-Jadid et al 2002; Small et al 2006; Shin et al 2008; Braskie et al 2008; Small et al 2009). Data from these imaging studies indicates that the maximal cortical uptake of the tracer in AD cases is at most ~20 % higher when compared with non-demented control cases; in contrast 11C-PIB demonstrates a 100-200 % higher cortical uptake in AD cases relative to non-demented controls (Klunk et al 2004; Pike et al 2007; ). Importantly the differences in both the pattern and magnitude of cortical uptake were confirmed in a recent study in which subjects were sequentially scanned with 18F-FDDNP and 11C-PIB (Shin et al 2008).

Critically, the highest relative area of FDDNP uptake is associated with the medial temporal lobe, an area prone to NFT pathology and conversely, consistently associated with a lower uptake of PIB (Ikonomovic et al 2008). This difference has provided circumstantial evidence that in vivo FDDNP binds to NFTs as well as highly fibrillar forms of SPs (i.e. classical plaques, CPs) (Shoghi-Jadid et al 2002; Small et al 2006). In vitro evidence supporting this pattern of interaction is sparse and based on studies either employing high μM concentrations of unlabelled FDDNP (Agdeppa et al 2001; Bresjanac et al 2003; Smid et al 2006) or low-magnification tissue autoradiography employing 18F-FDDNP with no supporting high-magnification histology to definitively identify SPs and/or NFTs (Agdeppa et al 2001). Additionally, there is data (Ye at al 2005; Suemoto, et al 2004) contradicting the reported high (i.e. low nM) affinity of FDDNP for Aβ fibrils (Agdeppa et al 2001).

The cerebral concentrations of ligand attained in imaging studies is typically in the low nM range (Mathis et al., 2004; Rowe et al., 2007) and the aim of the present study was to determine the histologic structures labelled by FDDNP at these tracer concentrations. An autoradiography study employing tritium labelled preparations of FDDNP (3H-FDDNP) and PIB (3H-PIB) was performed which permitted the comparative analysis of near adjacent sections for ligand binding to key amyloid containing neuropathological lesions. A third amyloid tracer, the stilbene derivative SB13 (labelled with carbon-14, 14C-SB13), was also evaluated on a subset of the sections providing additional corroborative data.

Experimental Procedures

Materials

Radiolabelled preparations of 3H-PIB (71 Ci/mmol, 2.63 TBq/mmol), 3H-FDDNP (13 Ci/mmol, 0.48 TBq/mmol) and 14C-SB13 (53mCi/mmol, 1.96 GBq/mmol) were prepared as custom syntheses by GE Healthcare Life Sciences (Little Chalfont, UK). Hyperfilm-3H (RPN535B: early availability batch) was obtained from GE Healthcare Life Sciences. Thioflavin T (Sigma, Poole, UK) was prepared as an aqueous 10 mM stock and stored at -20oC. Aβ (1-40) peptide was obtained from California Peptide Research (Napa, California, USA).

Serial cryosections were obtained from the Brain Donation Program at Sun Health Research Institute (Beach et al 2008) as described (Lockhart et al 2007). Commercial sections were obtained from AMS Biotechnology (Europe) Ltd (Abingdon, UK).

Radiolabelling of sections and analysis of films

All sections were treated in the same manner using the methods described in Lockhart et al 2007. Non-displaceable binding was performed using 50 μM Thioflavin T as the cold competitor ligand. Films were developed and digitised as described in Lockhart et al 2007. No manipulations other than optimization of lighting conditions (for image capture), image cropping and re-sizing were performed except for Figure 2B where the brightness and contrast levels were altered to provide increased image contrast.

Figure 2
Hippocampal region sections labelled with 3H-FDDNP (A and D), 3H-PIB (B and E) and Gallyas stain (C and F). A to C are ECX sections from case D1 and D to F are HIP sections from case H1. Insets to pictures (A, B and D) represent sections labelled for ...

Nomenclature and classification of pathological features

The identification of SPs, CAA and NFTs were based on data from two separate staining techniques, combined with morphological appearance, as detailed in Lockhart et al 2007. SP is used as a generic term to encompass both diffuse plaques (DPs) and CPs. CPs were not further differentiated into neuritic plaques and cored plaques. Briefly SPs and CAA were identified using 6E10 antibody (CHEMICON International, Temecula, USA) and Thioflavin S (Sigma, Poole, UK). NFTs were identified using Gallyas stain and Thioflavin S.

Radioligand binding assays

Amyloid beta (Aβ1-40) peptide fibrils were prepared as described previously (Lockhart et al, 2004). Radioligand binding assays were performed as described (Lockhart et al, 2004) using a fixed concentration of Aβ fibrils (500 nM) and a range of 3H-FDDNP or 3H-PIB concentrations as detailed in the Results section. The specific binding signals for both radioligands were determined in the presence of 50 μM Thioflavin T. Initial attempts to define the specific binding signal for 3H-FDDNP using the non-steroidal anti-inflammatory drug, naproxen (Agdeppa et al 2003), were unsuccessful due to its poor ability to displace bound radiotracer and are discussed further in the Results section. Data were analyzed using Grafit (Erithacus Software Limited, Horley, Surrey, UK) to obtain the apparent dissociation constant (Kd) and the maximum number of binding sites (Bmax) using the single-site ligand binding module.

Results

Comparative autoradiography studies: FDDNP and PIB

The majority of the tissues selected for characterisation were the subject of an earlier autoradiography study using 3H-PIB (Lockhart et al 2007). For the current study, adjacent cryosections were obtained from the same blocks of tissue used in Lockhart et al 2007. Consequently the underlying amyloid neuropathologies of these sections were well characterised and identical case numbers are used (Table 1). The following categories of pathology were examined: Mixed amyloid pathology (SPs, NFTs and CAA) using superior parietal lobe (SPL) from Case B2; CAA predominant pathology using occipital lobe (OCL) from Case C2; and, NFT predominant pathology using entorhinal cortex (ECX) from Case D1. Additionally, we investigated the binding of 3H-FDDNP and 3H-PIB to hippocampal (HIP) sections obtained from a commercial supplier. Only one of these sections, H1, demonstrated a significant radiolabelling and was the subject of further neuropathological investigation which demonstrated the presence of extensive NFT and SP pathologies (Table 1).

Table 1
Neuropathological characteristics of sections. Pathology scores:+++, frequent. ++, moderate. +, sparse. -, absent. Note that the neuropathological diagnosis for each case was based on a full pathological examination according to Consortium to Establish ...

In contrast to the cortical and hippocampal formation sections labelled with 3H-PIB those incubated with 3H-FDDNP did not display an overt macroscopic, punctate labelling pattern (Figures 1 and and2).2). However, higher magnification views of contrast-enhanced images from the case B2 SPL section (Figure 3) revealed intermittent patches of punctate FDDNP-labelling associated with the outer cortical layers. An analogous labelling pattern was present on similarly contrast-enhanced images from FDDNP-labelled OCL section (data not shown). This is consistent with the radiotracer only weakly labelling the largely Aβ related neuropathology present on these sections.

Figure 1
Neocortical sections labelled with 3H-FDDNP (A and D), 3H-PIB (B and E) and 14C-SB13 (C and F). SPL sections from case B2 (A-C) and OCL sections from case C2 (D-F). Insets to pictures represent sections labelled for NDB. Boxed area I is discussed further ...
Figure 3
Higher magnification images of SPL section from case B2 labelled with 3H-FDDNP corresponding to boxed area I (on Figure 1A). A Non-contrast enhanced image demonstrating the sparse labelling of section by the radiotracer. B and C Enhanced, higher magnification ...

Case B2 (SPL) was characterised with a predominantly Aβ peptide-related neuropathology with extensive DPs and CPs, and moderate CAA (Table 1). In particular the outer portion of the cortical surface was characterised by a more or less continuous band of DPs characteristic of subpial diffuse amyloid deposits (Lockhart et al 2007). The absence of 3H-FDDNP labelling of this ribbon-like Aβ band indicated that the radiotracer did not significantly label this diffuse form of amyloid. Analysis of the higher magnification, contrast-enhanced images (Figure 3 B and C) allowed some tentative assignment of radiolabelled features with both DPs and CPs, however, this is not absolute given the low level of contrast associated with the autoradiographic images. Higher resolution microautoradiography techniques may be required to address these possibilities further; however, in terms of the significance of these findings for in vivo imaging the present study indicates that at tracer concentration FDDNP interacts weakly with Aβ peptide related neuropathology.

Case D1 (ECX), containing extensive NFT pathology and no Aβ related pathologies (Lockhart et al 2007), also displayed no overt labelling with tracer concentrations of 3H-FDDNP (Figure 2A). An enhanced image, similar to that generated for case B2 (Figure 3B), failed to demonstrate evidence of specifically labelled structures (data not shown). In contrast, the semi-adjacent sections from this case displayed discrete patches of labelling with 3H-PIB (Figure 2B), replicating the findings from our previous study, where we found that the PIB binding was selectively increased over the NFT clusters of the layer II “stellate cell islands” of the ECX (Lockhart et al 2007).

The hippocampal formation section, associated with Case H1, was also negative for labelling with 3H-FDDNP (Figure 2D). Although, in contrast-enhanced images a weak labelling was associated with regions containing extensive SP pathologies (as noted above). In contrast, the 3H-PIB labelled section displayed an extensive labelling which was particularly pronounced in the parahippocampal gyrus and subiculum, although this extended, in finer detail, through the hippocampus and into the adjoining dentate gyrus (Figure 2E). Histological analysis of adjacent sections indicated the presence of extensive DP pathology associated with the presubiculum and parasubiculum as well as the entorhinal and transentorhinal areas. Additionally, there was a lightly-labelled band in the hippocampus CA1 region, associated with numerous NFTs in the same distribution on a semi-adjacent section (Figure 2F).

The areas labelled with 3H-PIB showed a robust correspondence with the underlying neuropathologies and unequivocally confirms our previous findings that this tracer binds NFTs in addition to Aβ lesions (Lockhart et al 2007). However, as noted previously and clearly demonstrated with case H1, the intensity of the PIB associated with the NFT pathology is greatly reduced relative to its labelling of Aβ deposits. The pattern of 3H-PIB labelling associated with the parasubiculum and presubiculum closely matches earlier studies identifying these patches of Aβ deposits as being largely diffuse in nature (Akiyama et al 1990; Mufson et al 1999) and closely associated with the parvopyramidal cell islands of these regions (Kalus et al 1989).

Comparative autoradiography studies: PIB and SB13

The autoradiographic images of the semi-adjacent neocortical sections labelled with 14C-SB13 underscores the detection sensitivity of this method (Figure 1 C and F). Due to the limiting numbers of ECX and HIP sections available for analysis the interaction of SB13 with NFT pathology was not investigated. The data demonstrated that 14C-SB13 macroscopically labelled the sections in a more or less equivalent manner to the 3H-PIB labelled sections (Figure 1 B and C, E and F). SB13 therefore seems to target identical pools of Aβ lesions (DPs, CPs and CAA) as PIB which is consistent with their broadly analogous in vivo cortical uptake patterns (Verhoeff et al., 2004).

A further facet that appears to be shared by these two tracers is their behaviour with CAA associated with apoliprotein E-ε4 (ApoE4) positive cases. Previous studies indicated that 3H-PIB associated with this specific Aβ pool was only partially displaceable in labelling reactions containing excess unlabelled ligand (Lockhart et al 2007). Although not as extensively examined in this study both the sections treated with SB13 are from ApoE4 positive cases and these both display areas where there is an incomplete displacement of the radiotracer (see insets to Figures 1C and F), although clearly this is most pronounced on the CAA enriched OCL sections. A non-ApoE4 positive OCL case, containing extensive CAA pathology, labelled with 14C-SB13 displayed complete displacement of the radiotracer (data not shown).

In vitro characteristion of the 3H-FDDNP preparation using Aβ fibrils

In an effort to further understand the weak labelling of the 3H-FDDNP treated sections (relative to both 3H-PIB and 14C-SB13) we investigated the binding properties of the radioligand preparation for in vitro generated Aβ fibrils, using a previously developed radioligand binding assay (Lockhart et al 2004; Ye et al 2005). The non-steroidal anti-inflammatory drug, naproxen, was reported to bind with high affinity to the same binding on Aβ fibrils as FDDNP (Ki ~ 6 nM, Agdeppa et al 2003) and we initially attempted to use this drug to define the non-specific binding signal. However, in our hands, naproxen did not display a strong dose dependent competition with 3H-FDDNP and displaced <20 % of the filter bound 3H-FDDNP when used at a very high concentration (500 μM, data not shown). These findings are in keeping with our previous investigations of FDDNP binding using a fluorescence assay format (Ye et al 2005). Replacing naproxen with Thioflavin T (50 μM) resulted in a specific binding signal of ~60-70 %, which we have found typical for this Aβ binding assay format (Lockhart et al 2004; Ye et al 2005).

The binding of 3H-FDDNP (concentration range 300 to 0.0125 nM) was determined using a fixed concentration of Aβ fibrils (500 nM). The resultant binding isotherm was consistent with a single class of ligand binding sites and a Kd value of 85.0±2.1 nM (Figure 4). The Bmax value associated with the batch of fibrils was 3.8±0.04 nM, which is equivalent to 1 ligand binding site per ~130 Aβ peptide monomers. Efforts to detect the two affinity sites reported by Agdeppa et al (2001) were unsuccessful as a two-site fit of the data produced binding constants that were incompatible with the range of ligand concentrations under investigation (data not shown). Characterisation of the same batch of Aβ fibrils using 3H-PIB, under identical assay conditions, produced a Kd value of 8.5±1.3 nM (data not shown), which is ~10-fold lower (i.e. higher affinity) than that observed for the 3H-FDDNP preparation. Consistent with our previous investigations (Ye et al 2005), these data indicate that FDDNP binds with a relatively weak affinity to in vitro generated Aβ fibrils.

Figure 4
Binding isotherm for the ligand 3H-FDDNP with in vitro generated Aβ(1-40) fibrils. Data was fitted by non-linear regression to derive Kd and Bmax values of 85.0±2.1 nM and 3.8±0.04 nM, respectively. The inset figure shows FDDNP ...

Discussion

The data associated with this study indicate that FDDNP, when utilised at the tracer concentrations associated with in vivo imaging studies, has a low sensitivity for amyloid-containing structures such as SPs and NFTs. This provides an alternative, data driven, mechanism for the observed low cortical uptake of the tracer in AD patient populations. Our conclusions are based in two strands of analysis.

Firstly, there was strong evidence from the tissue autoradiography that 3H-FDDNP did not label to any significant extent cortical sections heavily burdened with amyloid containing pathologies. In comparison near-adjacent sections reacted with either 3H-PIB or 14C-SB13 demonstrated an extensive and essentially equivalent labelling pattern (at least with respect to labelling Aβ lesions). These latter findings demonstrate the robustness of the technique in detecting ligand binding irrespective of the radioisotope and associated specific activity. Evidence from the contrast enhanced images from case B2 (Figure 3) indicated that 3H-FDDNP may be labelling a subset of Aβ peptide related pathologies which are most likely to be highly fibrillar CPs and CAA as these contain the highest densities of ligand binding sites. Further investigation using higher resolution emulsion autoradiography techniques will be required to address this outstanding issue.

The current data do not contradict the findings from earlier studies which reported the binding of FDDNP to a wide range of amyloid containing neuropathological lesions including senile plaques (both diffuse and classical), neurofibrillary tangles, Lewy bodies and prion deposits (Agdeppa et al 2001; Bresjanac et al 2003; Smid et al 2006), as these studies were performed using high μM concentrations of FDDNP which are >1000-fold in excess of those achieved during imaging scans and associated with the current study. It is difficult to gauge whether the current data conflicts with the single previous tissue autoradiography study, which used an 18F-labelled ligand preparation, as no detailed microscopic analyses of the treated section or supporting neuropathology from adjacent sections were reported (Agdeppa et al 2001).

Secondly, further support for our conclusions was obtained from the in vitro analysis of 3H-FDDNP binding to Aβ1-40 fibrils. These studies demonstrated that the binding affinity of ~85 nM was around 10-fold less than of 3H-PIB for the same preparation of fibrils, and ~80-fold lower than that reported originally for the ligand (Agdeppa et al 2001). PET tracers characteristically have a low nM affinity for their in vivo target(s) and the current finding of a relatively low affinity interaction of FDDNP with Aβ fibrils, supported by similar findings in two earlier studies (Ye et al 2005; Suemoto et al 2004), may in part explain the low signal-to-noise associated with FDDNP. Importantly, each of these latter studies used different assay formats and methods to prepare the Aβ fibrils. Although the reason(s) for these discrepancies are still unclear they may revolve around the method used to derive the binding data (Agdeppa et al 2001) and is discussed further in Ye et al (2005). It is of course also conceivable that the differences in the in vitro binding constants observed between the groups are due to subtle variations in the quaternary folding of the assembled fibrils. If this is the case FDDNP must be uniquely sensitive to these potential conformational differences as it has not been observed to any significant degree for the other amyloid tracers. We have not attempted to further dissect the nature of the FDDNP binding site on Aβ fibrils in this study, but its density and compound selectivity appear similar to those described in our earlier study (Ye et al 2005) and are consistent with the 3H-FDDNP radioligand assays detecting the low density site, termed BS3, in our previous studies (Lockhart et al 2004; Ye et al 2005).

Given the consistently small (~20 %) maximal increases in cortical uptake of 18F-FDDNP (Shoghi-Jadid et al 2002; Small et al 2006; Shin et al 2008; Braskie et al 2008) it is worth considering what factors, others than those relating to the present study findings, could explain this phenotypic effect. Although, not addressed by this study concerns have been expressed over the validity of the Logan analysis method (van Berckel and Scheltens, 2007) and the unknown role of polar metabolites in defining plasma input functions (Luurtsema et al 2008). The lack of a fully validated model emphasises that differences in the non-specific binding component in either the reference tissue (pons, Shoghi-Jadid et al 2002 or cerebellum, Small et al 2006) or the region of interest could make significant contributions to the derived cortical uptake values. The medial temporal lobes, which are associated with the highest 18F-FDDNP binding values (Shoghi-Jadid et al 2002; Small et al 2006), display not only extensive NFT and SP pathologies but are also subject to significant volumetric reductions as dementia progresses (reviewed in Ries et al 2008). Disease related pathology could also potentially contribute to alterations in brain uptake and removal and could include subtle changes to blood brain barrier integrity (Zlokovic 2008), although this latter point may equally affect other amyloid tracers.

Of further interest is the data associated with 14C-SB13, which represents the first detailed description of the tissue binding characteristics of a stilbene derivative, and indicates that the ligand has a broadly similar sensitivity for the different pools of Aβ-related pathologies (e.g. DPs, CPs and CAA). The cortical uptake of 11C-SB13 in vivo appears analogous to that of 11C-PIB (Verhoeff et al., 2004) and this data supports the view that both ligands are markers of Aβ-related cerebral amyloidosis. Given the high degree of structural homology between SB13 and AV1-BAY94-9172 (Rowe et al 2008) it seems probable that the data apply equally to the latter tracer as well.

Finally, the labelling of the hippocampal formation section (HIP1) with PIB illustrates on a single section the differential sensitivity of the tracer for the hallmark AD pathologies and complements two recent studies, which in part, addressed this issue (Lockhart et al 2007 and Ikonomovic et al 2008). It is clear from all of these studies that whilst PIB is able to bind to NFTs, or possibly a subset of extracellular (`ghost') tangles (Ikonomovic et al 2008), that this labelling is not as intense as that observed for SPs and CAA, and that in vivo the tracer is a highly specific marker of Aβ associated lesions (Lockhart et al 2007).

In summary, the primary data associated with this study provide prima facia evidence that the PET imaging agent, FDDNP, when used at tracer concentrations fails to significantly label the hallmark pathologies of AD, namely SPs and NFTs. The findings provide a robust, data focused, explanation for the unique cortical uptake associated with FDDNP and provide a rational basis for the further development of tracers associated with this chemotype class.

Acknowledgements

We are grateful to the Sun Health Research Institute Brain Donation Program of Sun City, Arizona for the provision of human brain tissue. The Brain Donation Program is supported by the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05-901 to the Arizona Parkinson's Disease Consortium) and the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson's Research.

Abbreviations

amyloid-beta peptide
AD
Alzheimer's disease
ApoE
apolipoprotein E
AV1-BAY94-9172
4-(N-methylamino)-4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)stilbene
BF227
2-(2-[2-Dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxybenzoxazole
CAA
cerebrovascular amyloid angiopathy
CPs
classical plaques
DPs
diffuse plaques
ECX
entorhinal cortex
FDDNP
2-(1-{6-[(2-fluoroethyl(methyl)amino]-2-naphthyl}ethylidene)malononitrile
HIP
hippocampal
NFTs
neurofibrillary tangles
NDB
non-displaceable binding
OCL
occipital lobe
PET
positron emission tomography
PIB
Pittsburgh Compound-B (2-[4'-(methylamino)phenyl]-6-hydroxybenzothiazole)
SB13
4-N-methylamino-4'-hydroxystilbene
SPs
senile plaques
SPL
superior parietal lobe

Footnotes

Disclosure Statement. The authors declare that they have no actual or potential conflicts of interest.

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