In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD
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Although the pathogenesis underlying behavioral variant frontotemporal dementia (bvFTD) has yet to be fully understood, glutamatergic abnormalities have been hypothesized to play an important role. The aim of the present study was to determine the availability of the metabotropic glutamate receptor type 5 (mGluR5) using a novel positron emission tomography (PET) radiopharmaceutical with high selectivity for mGluR5 ([11C]ABP688) in a sample of bvFTD patients. In addition, we sought to determine the overlap between availability of mGluR5 and neurodegeneration, as measured using [18F]FDG-PET and voxel-based morphometry (VBM). Availability of mGluR5 and glucose metabolism ([18F]FDG) were measured in bvFTD (n = 5) and cognitively normal (CN) subjects (n = 10). [11C]ABP688 binding potential maps (BPND) were calculated using the cerebellum as a reference region, with [18F]FDG standardized uptake ratio maps (SUVR) normalized to the pons. Grey matter (GM) concentrations were determined using VBM. Voxel-based group differences were obtained using RMINC. BvFTD patients showed widespread decrements in [11C]ABP688 BPND throughout frontal, temporal and subcortical areas. These areas were likewise characterized by significant hypometabolism and GM loss, with overlap between reduced [11C]ABP688 BPND and hypometabolism superior to that for GM atrophy. Several regions were characterized only by decreased binding of [11C]ABP688. The present findings represent the first in vivo report of decreased availability of mGluR5 in bvFTD. This study suggests that glutamate excitotoxicity may play a role in the pathogenesis of bvFTD and that [11C]ABP688 may prove a suitable marker of glutamatergic neurotransmission in vivo.
KeywordsBehavioral variant frontotemporal dementia Frontotemporal lobar degeneration Positron emission tomography 11C-ABP688 Metabotropic glutamate receptor type 5 Excitotoxicity
Behavioral variant frontotemporal dementia (bvFTD) is a progressive neurodegenerative syndrome characterized by change in personality, impaired social cognition, and executive dysfunction (Mendez et al. 2008; Swartz et al. 1997). Approaching Alzheimer’s disease (AD) as the leading cause of early-onset (before 65 years of age) dementia (Ratnavalli et al. 2002; Rosso et al. 2003), bvFTD arises from a heterogeneous range of pathologies—referred to collectively as frontotemporal lobar degeneration (FTLD)—resulting in degenerative changes within frontal paralimbic, temporal and subcortical brain regions. In most cases, patients show either deposition of the microtubule associated protein tau (tau) or the TAR DNA-binding protein of 43 kDa (TDP) (Mackenzie et al. 2010). A minority, however, show a defect in metabolism of the tumor-associated protein fused in sarcoma (FUS). The majority of FTLDs can therefore be classified into FTLD-tau, FTLD-TDP, or FTLD-FUS, with further subclassification based predominantly on inclusion morphology and lesion distribution (Mackenzie et al. 2010).
Although the pathogenic mechanisms underlying bvFTD have yet to be fully elucidated, aberrant glutamatergic neurotransmission has been hypothesized to play a role. The primary excitatory neurotransmitter in the mammalian brain, glutamate acts via ionotropic and metabotropic receptors (Schaeffer and Duplantier 2010). Whereas ionotropic receptors mediate fast excitatory neurotransmission, metabotropic glutamate receptors (mGluRs) play an important role in synaptic modulation via regulation of neuronal excitability, transmitter release, synaptic plasticity and glial function. In the case of bvFTD, FTLD has been found to accumulate preferentially within paralimbic and homotypical heteromodal brain regions, areas rich in excitatory glutamatergic pyramidal cells. Indeed, several autoradiographic and immunohistochemical studies in post-mortem bvFTD tissue have provided evidence supporting this hypothesis (Dalfo et al. 2005; Ferrer 1999; Procter et al. 1999), highlighting reduced expression of the N-methyl-d-aspartate (NMDA) ionotropic glutamate receptor. Importantly, activation of mGluR5 was shown to regulate glutamatergic neurotransmission via modulation of NMDA receptor functionality (Llansola and Felipo 2010; Niswender and Conn 2010; Perroy et al. 2008). Moreover, mGluR5 signaling has been shown to be critically involved in the normal cognitive functioning of various neuronal populations (Schaeffer and Duplantier 2010), including those within FTLD predilection sites (Ferraguti and Shigemoto 2006).
Despite a strong in vitro evidence base, glutamatergic abnormalities in bvFTD have yet to be systematically characterized in vivo owing to the lack of suitable molecular probes. Using [11C]ABP688—a novel positron emission tomography (PET) radiopharmaceutical with high selectivity for mGluR5 (Ametamey et al. 2006, 2007)—we sought to measure mGluR5 availability and to determine the topographic overlap with neurodegeneration within frontotemporal and subcortical brain regions, as indexed using [18F]fluorodeoxyglucose ([18F]FDG)-PET and voxel-based morphometry (VBM).
Five patients meeting research criteria for probable bvFTD (Rascovsky et al. 2011) were recruited from the McGill Centre for Studies in Aging (MCSA) Alzheimer’s Disease Research Unit. Exclusion criteria were (1) past or present use of memantine; (2) presence of other neurological diseases; (3) premorbid psychiatric disease or intellectual disability; (4) history of head injuries and loss of consciousness following head trauma; (5) current (within 1 month) use of psychoactive substances; (6) parkinsonism—as identified using the United Parkinson’s Disease Rating Scale (Goetz et al. 2007)—and (7) the presence of any major structural anomaly or signs of major vascular pathology on magnetic resonance imaging (MRI) evaluation (Roman et al. 1993). All patients underwent neuropsychological assessment and behavioral testing. Global cognition was assessed using the Mini-Mental State Examination (MMSE) (Folstein et al. 1975), with language and visuospatial function measured using the Wechsler Abbreviated Scale of Intelligence, second edition (McCrimmon and Smith 2013). The Cogstate Research test battery was used to assess executive function, episodic memory, and social cognition (http://cogstate.com/tag/cogstate-brief-battery/). The choice of measures included in the overall assessment battery took into consideration test availability in both English and French. Behavioral measures included the Neuropsychiatric Inventory (NPI) (Cummings et al. 1994), and the Frontal Behavioral Inventory (FBI) (Kertesz et al. 1997). In addition, given that bvFTD and the frontal variant of AD are often difficult to differentiate on clinical grounds alone (Alladi et al. 2007), all patients underwent carbon-11 Pittsburgh Compound B ([11C]PiB) PET to rule out the presence of amyloid pathology. The diagnosis of bvFTD was determined during a multidisciplinary conference taking into consideration available medical, clinical, imaging, neuropsychological, and complementary laboratory information.
The bvFTD patients were matched by age and gender to a group of 10 cognitively normal (CN) controls, recruited via advertisements in a local newspaper. CN subjects were identified as individuals who (1) were independently functioning community dwellers; (2) did not have a personal or first degree relative history of psychiatric disorders; (3) had no cognitive complaints; (4) had a normal neurological and psychometric examination; (5) were not taking any psychoactive medications; (6) had no history of head trauma; (7) showed no signs of vascular pathology on MRI evaluation (Roman et al. 1993) and (8) had an MMSE score ≥29, an NPI score of 0, and an FBI score of 0.
Demographic and clinical data for all subjects
BvFTD (n = 5)
CN (n = 10)
Age at scan, Med (IQR), years
Education, Med (IQR), years
MMSE, Med (IQR), max = 30
FBI, Med (IQR), max = 72
NPI Total, Med (IQR), max = 144
Ratings of hypometabolism and lobar atrophy in patients with bvFTD
Anterior temporal lobe
3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime ([11C]ABP688) was synthesized as described previously (Elmenhorst et al. 2010), with a radiochemical purity >99 %. The study was performed using a high-resolution research tomograph (HRRT) PET scanner (CTI/Siemens, Knoxville, Tennessee), a brain-dedicated tomograph combining high spatial image resolution with high sensitivity. Prior to radiopharmaceutical administration, a 6-min transmission scan was acquired for scatter and attenuation correction using a [137Cs] rotating point source. A 60-min dynamic list-mode emission scan was started concomitantly with the venous injection of 370 MBq (mean specific activity >500 Ci/μmol) of [11C]ABP688, with emission data acquired in list-mode format, and binned into 26 time frames. For each and every time frame, sets of fully 3D sinograms were generated from the list-mode data (2,209 sinograms, span 9, with 256 radial bins and 288 azimuthal angle samples). A time-series of 26 3D images (frame duration: 6 × 30 s, 4 × 60 s, 8 × 120 s, 3 × 240 s, 5 × 300 s) were then reconstructed from these sinograms, each 3D image being composed of 256 × 256 × 207 cubic voxels (voxel side-length of 1.21875 mm), using an expectation maximization image reconstruction algorithm with an ordinary Poisson model of the acquired PET data. The reconstruction included full accounting for the normalization, attenuation, and time-dependent scatter of random events. To reduce the partial volume effect, resolution modeling with point-spread function was implemented in the reconstruction (Comtat et al. 2008). Subject head-motion correction was implemented using a data-driven motion estimation and correction method (Costes et al. 2009).
All patients underwent an [18F]FDG-PET scan using a Siemens ECAT EXACT HR+ PET device (CTI/Siemens, Knoxville, TN, USA) as part of their clinical evaluation. In keeping with the ALARA radiation safety principle (Natarajan et al. 2013), data were not recollected on the HRRT. After fasting overnight, patients received a venous bolus injection of 185 MBq of 18F-fluorodeoxyglucose ([18F]FDG) in a quiet environment. A dynamic scan was performed in 3-dimensional mode for 10 min under standard resting-state conditions with eyes open, recording 63 transaxial slices simultaneously with an axial resolution of 5 mm full width at half maximum (FWHM) and an in-plane resolution of 4.6 mm. Each collected slice had a thickness of 2.45 mm and a matrix size of 128 × 128 voxels. After correction for attenuation, scatter, decay and scanner-specific dead time, the PET data were reconstructed by filtered back-projection using a Hann filter (4.9 mm FWHM).
CN subjects had their acquisition conducted on the HRRT, with acquisition parameters identical to those for [11C]ABP688, as described above. Images were reconstructed taking into consideration data acquired between 45 and 60 min only, with reconstruction matching that used for the HR+ data. In order to compare data from the HRRT and HR+ PET scanners, the resolution of the HRRT was matched to the partial volume effect of the HR+. To do so, an anisotropic Gaussian kernel of 5.7 × 5.7 × 6.7 mm FWHM was used, which was found to be the best match of scanner resolutions through an internal phantom study (unpublished data). In the case of [18F]FDG, two CN subjects were excluded owing to movement with one patient unable to return for the scan, reducing the sample size for [18F]FDG to 4 bvFTD and 8 CN.
Magnetic resonance imaging
For anatomical co-registration and identification of the volumes of interest (VOI), all subjects underwent a high-resolution T-1 weighted MRI using a Siemens TRIO 3T scanner (Siemens Medical Solutions, Erlangen, Germany). Images were acquired in 3-D (voxel size = 1 mm3; FOV = 256 × 256 mm; TR = 22 ms; TE = 9.2 ms; flip angle = 30°), with the scan performed on either on the same day or less than 2 weeks apart from the PET acquisitions, depending on the availability of the research slots.
[11C]ABP688 binding potential, non-displaceable (BPND) values were obtained using the simplified reference tissue method (SRTM) (Gunn et al. 1997), using the cerebellum as a reference region (Elmenhorst et al. 2009; Minuzzi et al. 2009). [18F]FDG-PET frames were summed and standardized uptake value ratio (SUVR) maps calculated by normalizing the summed image to mean pontine activity for each subject. In order to correct for partial volume error (PVE), a modified version (Greve et al. 2014; Rousset et al. 2007) of the Muller-Gartner method (Muller-Gartner et al. 1992; Rousset et al. 1998) was implemented using the PVElab software package (https://nru.dk/downloads/software/pveout/pveout.html) (Quarantelli et al. 2004).
Following correction for field inhomogeneities (Sled and Evans 1998), native MRI volumes were nonlinearly resampled into standardized stereotaxic space, using the high-resolution ICBM template as reference (Fonov et al. 2009). Subsequently, normalized images were classified into grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) using an automatic algorithm (INSECT) (Zijdenbos and Evans 1998). Voxel-based morphometry (VBM) (Ashburner and Friston 2000) was carried out on the structural segmented GM images nonlinearly resampled to the standard stereotaxic space after blurring with an isotropic Gaussian kernel of 10 mm FWHM. Finally, classified images were resampled to an anatomical template and automatically labeled using a probabilistic atlas-based approach (ANIMAL) (Collins et al. 1999; Collins and Evans 1997). VOIs yielded by this procedure were subsequently applied to PET BPND (cerebellum) and SUVR maps (pons).
Voxel-wise analysis maps of [11C]ABP688 BPND, [18F]FDG SUVR, and VBM values were estimated using a basis functions approach (Gunn et al. 1997), with PET images convolved using an isotropic Gaussian kernel of 6 mm FWHM. Parametric maps created in native space were then normalized into MNI space in order to allow for group comparisons. The resulting t-maps, calculated using RMINC (Lerch 2006), show the areas with a significant difference in BPND, SUVR, and relative concentration of GM between groups. Those areas were subsequently adjusted for a statistical cluster-wise threshold of p < 0.05, and corrected for multiple comparisons using random field theory (Worsley et al. 1998). [11C]ABP688 BPND local maxima coordinates were used to extract [18F]FDG SUVR, and VBM values, in order to compare the magnitude of decline.
Brain regions where all patients differed significantly from controls on the basis of Z scores ≥2—calculated using the formula [(individual patient value) − (control mean)/(control standard deviation)]—were calculated for [11C]ABP688 BPND, [18F]FDG SUVR, and VBM t-maps. These areas were then used to extract raw [11C]ABP688 BPND, [18F]FDG SUVR, and VBM values, which, after reconversion to Z scores, were plotted using GraphPad Prism 5 software. Overlap maps—[11C]ABP688 BPND and [18F]FDG SUVR, [11C]ABP688 BPND and VBM, [18F]FDG SUVR and VBM—as well as areas showing only reduced [11C]ABP688 BPND, [18F]FDG SUVR, and VBM—were created using MINC tools (http://www.bic.mni.mcgill.ca/ServicesSoftware/MINC). For overlap maps, binary masks were generated by applying the cluster-corrected t-map thresholds to each individual t-map—[11C]ABP688 BPND, [18F]FDG SUVR, and VBM—setting voxels less than the given threshold to 0 and voxels greater than the threshold to 1. Binary masks were then summed, with voxels having a value of 2 indicating overlap. In order to show areas exhibiting only reductions (e.g., in availability of mGluR5) binary masks were subtracted (e.g., [11C]ABP688 BPND − [18F]FDG SUVR − VBM), with the range of values in the resulting volume restricted to lie between 0 and 1, removing negative values generated as a result of the subtraction. Finally, volumes were visualized and color-coded using the software DISPLAY (http://www.bic.mni.mcgill.ca/software/Display/Display.html).
Groups differed significantly in terms of MMSE, FBI and NPI (see Table 1). No differences were observed for age at scan, education, sex, or handedness. Since only two patients were capable of completing the entire neuropsychological assessment battery, quantitative assessment proved uninformative. Qualitative assessment based on the expert judgement of neuropsychologists (JP and CC) indicated clear deficits in executive and social cognitive measures in all bvFTD patients. Two patients displayed abnormal performance on measures of abstract and concrete language, with three showing deficits in visuospatial processing. While all patients showed moderate hypometabolism within frontotemporal regions, atrophy ranged from very mild to moderate (see Table 2).
Location and Talairach coordinates of local maxima for areas of reduced [11C]ABP688 BPND in patients with bvFTD, along with t values for [18F]FDG SUVR and VBM findings, using [11C]ABP688 BPND maxima coordinates
Gyrus rectus L
Gyrus rectus R
Medial orbitofrontal cortex L
Medial orbitofrontal cortex R
Lateral orbitofrontal cortex L
Lateral orbitofrontal cortex R
Ventromedial prefrontal cortex L
Ventromedial prefrontal cortex R
Dorsomedial prefrontal cortex L
Dorsomedial prefrontal cortex R
Anterior cingulate L
Anterior cingulate R
Frontal pole L
Frontal pole R
Dorsolateral prefrontal cortex L
Dorsolateral prefrontal cortex R
Ventrolateral prefrontal cortex L
Ventrolateral prefrontal cortex R
Paracentral lobule L
Paracentral lobule R
Temporal pole L
Temporal pole R
Superior temporal gyrus L
Superior temporal gyrus R
Middle temporal gyrus L
Middle temporal gyrus R
Inferior temporal gyrus L
Inferior temporal gyrus R
Hippocampal formation L
Hippocampal formation R
Lingual gyrus L
Lingual gyrus R
The present findings represent the first in vivo report of decreased availability of mGluR5 in bvFTD. In line with recent studies showing reduced binding of [11C]ABP688 in disorders characterized by glutamate excitotoxicity—such as major depressive disorder and temporal lobe epilepsy (Choi et al. 2014; Deschwanden et al. 2011)—our findings may indicate altered glutamatergic neurotransmission in bvFTD, or conformational changes specific to the mGluR5 allosteric site. Further, we reproduced previous [18F]FDG and VBM findings in terms of both the topography of neurodegeneration and its partially asymmetric distribution (Diehl-Schmid et al. 2007; Hornberger et al. 2012; Jeong et al. 2005; Pan et al. 2012). In addition, we showed that the volume of decreased mGluR5 availability was inferior to that for hypometabolism and GM atrophy, and that the overlap between reduced [11C]ABP688 BPND and hypometabolism was superior to that for GM atrophy. Moreover, we showed that declines in mGluR5 availability were unique to several isocortical, limbic, and paralimbic areas, possibly representing an early sign of pyramidal cell dysfunction. In this respect, the focality of [11C]ABP688 BPND reductions in the present study is striking given the widespread distribution of mGluR5. In addition, several frontotemporal areas showed hypometabolism and/or GM loss in the absence of reduced [11C]ABP688 binding. Taken together, these findings suggest a differential neuronal vulnerability to FTLD pathology in bvFTD—similar to that seen in other neurodegenerative diseases (Double et al. 2010)—with reduced availability of mGluR5 possibly preceding neurodegeneration within select frontotemporal brain regions.
While at physiological concentrations glutamate is known to play a pivotal role in synaptic plasticity (Balschun et al. 2006; Huber et al. 2001)—with any given function of a given cortical region likely to depend on glutamatergic neurotransmission at some level (Francis 2009)—at high concentrations it has been shown to act as a neurotoxin, promoting neuronal injury and death in animal models (Rao et al. 2001; Rothstein 1996) and in neurodegenerative diseases, including AD (Francis 2003). In the case of AD, accumulation of β-amyloid is thought to inhibit astroglial glutamate uptake, resulting in increased extracellular levels of glutamate, which, under chronic conditions, lead to cell death via sustained elevations in intracellular calcium (Harkany et al. 2000). This excitotoxic scenario may explain decreased binding of [11C]ABP688 in that continued high levels of glutamate may alter the availability of its transmembrane allosteric binding site (Ametamey et al. 2007) by altering mGluR5 conformational states (Cabello et al. 2009; Canela et al. 2009; Changeux and Edelstein 2005; Romano et al. 1996). Indeed, affinity shifts in receptor–radioligand interactions have previously been described in the context of dopaminergic neurotransmission, where the affinity of a D2 PET radiopharmaceutical was altered following an amphetamine challenge (Narendran et al. 2004; Seneca et al. 2006; Wilson et al. 2005).
Recently, an expanded hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) was identified as the most common cause of familial FTD and amyotrophic lateral sclerosis (ALS), with mutations associated with deposition of TDP-43 pathology (DeJesus-Hernandez et al. 2011; Renton et al. 2011). While the pathogenic mechanism(s) by which this repeat expansion could cause disease remain unknown, induced pluripotent stem cell differentiated neurons from C9ORF72 ALS patients were shown to be highly susceptible to glutamate excitotoxicity (Donnelly et al. 2013). Related work on primary cells from TDP-43 transgenic mice showed an increased vulnerability to the toxic effects of excess glutamate (Swarup et al. 2011). Moreover, a recent study involving transgenic mice expressing the FTDP-17 mutation P301L in the human tau gene—resulting in the accumulation of hyperphosphorylated tau—showed a tau-dependent impairment of glutamate metabolism (Nilsen et al. 2013). These studies suggest that the pathogenicity of hyperphosphorylated tau and TDP-43—the molecular pathologies accounting for most cases of bvFTD (Mackenzie et al. 2011)—may involve glutamatergic excitotoxicity.
Certain methodological aspects, however, limit interpretation of the present findings. In addition to this study’s cross-sectional design and small sample size, the absence of histopathological data precludes conclusions about the homogeneity of the sample from the perspective of underlying molecular pathology. As such we were not able to address the possible interplay between different FTLD subtypes and possibly differing effects on mGluR5 availability. Moreover, potential limitations may accompany the use of VBM when applied to atrophic brains (Good et al. 2002).
Despite these caveats, our findings shed light on the possible role of glutamate excitotoxicity in the pathogenesis of bvFTD and suggest that [11C]ABP688 may prove a suitable non-invasive marker of glutamatergic neurotransmission in vivo. Larger prospective studies are required to validate these findings, to establish the trajectory of reduced mGluR5 availability relative to other biomarkers of neurodegeneration, and to address the potential link between the dysregulation of glutamatergic neurotransmission and bvFTD symptomatology.
The authors wish to thank the patients and their families for participating in this study. This work was supported by the Canadian Institutes of Health Research (CIHR) [MOP-11-51-31], the Alan Tiffin Foundation, the Alzheimer’s Association [NIRG-08-92090], and the Fonds de la recherche en santé du Québec (Chercheur boursier). The authors wish to acknowledge the help of the imaging staff at the Montreal Neurological Institute McConnell Brain Imaging Centre, including Reda Bouhachi, Simion Matei, Rick Fukasawa (PET Technologists), Ron Lopez, David Costa, Louise Marcotte (MRI Technologists), and André Cormier (Chief MRI Technologist).
Conflict of interest
The authors declare no conflict of interest.
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