Association between mammillary body atrophy and memory impairment in retired athletes with a history of repetitive mild traumatic brain injury.

Cognitive dysfunction, especially memory impairment, is a typical clinical feature of long-term symptoms caused by repetitive mild traumatic brain injury (rmTBI). The current study aims to investigate the relationship between regional brain atrophy and cognitive impairments in retired athletes with a long history of rmTBI. Overall, 27 retired athletes with a history of rmTBI (18 boxers, 3 kickboxers, 2 wrestlers, and 4 others; rmTBI group) and 23 age/sex-matched healthy participants (control group) were enrolled. MPRAGE on 3 T MRI was acquired and segmented. The TBV and TBV-adjusted regional brain volumes were compared between groups, and the relationship between the neuropsychological test scores and the regional brain volumes were evaluated. Total brain volume (TBV) and regional brain volumes of the mammillary bodies (MBs), hippocampi, amygdalae, thalami, caudate nuclei, and corpus callosum (CC) were estimated using the SPM12 and ITK-SNAP tools. In the rmTBI group, the regional brain volume/TBV ratio (rmTBI vs. control group, Mann-Whitney U test, p < 0.05) underwent partial correlation analysis, adjusting for age and sex, to assess its connection with neuropsychological test results. Compared with the control group, the rmTBI group showed significantly lower the MBs volume/TBV ratio (0.13 ± 0.05 vs. 0.19 ± 0.03 × 10-3, p < 0.001). The MBs volume/TBV ratio correlated with visual memory, as assessed, respectively, by the Rey-Osterrieth Complex Figure test delayed recall (ρ = 0.62, p < 0.001). In conclusion, retired athletes with rmTBI have MB atrophy, potentially contributing to memory impairment linked to the Papez circuit disconnection.

In vivo PET classification of tau pathologies in patients with frontotemporal dementia.

Frontotemporal dementia refers to a group of neurodegenerative disorders with diverse clinical and neuropathological features. In vivo neuropathological assessments of frontotemporal dementia at an individual level have hitherto not been successful. In this study, we aim to classify patients with frontotemporal dementia based on topologies of tau protein aggregates captured by PET with 18F-florzolotau (aka 18F-APN-1607 and 18F-PM-PBB3), which allows high-contrast imaging of diverse tau fibrils in Alzheimer's disease as well as in non-Alzheimer's disease tauopathies. Twenty-six patients with frontotemporal dementia, 15 with behavioural variant frontotemporal dementia and 11 with other frontotemporal dementia phenotypes, and 20 age- and sex-matched healthy controls were included in this study. They underwent PET imaging of amyloid and tau depositions with 11C-PiB and 18F-florzolotau, respectively. By combining visual and quantitative analyses of PET images, the patients with behavioural variant frontotemporal dementia were classified into the following subgroups: (i) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three-repeat tauopathies (n = 3), (ii) predominant tau accumulations in posterior cortical and subcortical structures indicative of four-repeat tauopathies (n = 4); (iii) amyloid and tau accumulations consistent with Alzheimer's disease (n = 4); and (iv) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localizations of brain atrophy did not significantly differ among the identified behavioural variant frontotemporal dementia subgroups. The patients with other frontotemporal dementia phenotypes were also classified into similar subgroups. The results suggest that PET with 18F-florzolotau potentially allows the classification of each individual with frontotemporal dementia on a neuropathological basis, which might not be possible by symptomatic and volumetric assessments.

Positron Emission Tomography Assessments of Phosphodiesterase 10A in Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Phosphodiesterase 10A (PDE10A) is a highly expressed enzyme in the basal ganglia, where cortical glutamatergic and midbrain dopaminergic inputs are integrated. Therapeutic PDE10A inhibition effects on schizophrenia have been reported previously, but the status of this molecule in the living patients with schizophrenia remains elusive. Therefore, this study aimed to investigate the central PDE10A status in patients with schizophrenia and examine its relationship with psychopathology, cognition, and corticostriatal glutamate levels. STUDY DESIGN: This study included 27 patients with schizophrenia, with 5 antipsychotic-free cases, and 27 healthy controls. Positron emission tomography with [18F]MNI-659, a specific PDE10A radioligand, was employed to quantify PDE10A availability by measuring non-displaceable binding potential (BPND) of the ligand in the limbic, executive, and sensorimotor striatal functional subregions, and in the pallidum. BPND estimates were compared between patients and controls while controlling for age and gender. BPND correlations were examined with behavioral and clinical measures, along with regional glutamate levels quantified by the magnetic resonance spectroscopy. STUDY RESULTS: Multivariate analysis of covariance demonstrated a significant main effect of diagnosis on BPND (p = .03). A posthoc test showed a trend-level higher sensorimotor striatal BPND in patients, although it did not survive multiple comparison corrections. BPND in controls in this subregion was significantly and negatively correlated with the Tower of London scores, a cognitive subtest. Striatal or dorsolateral prefrontal glutamate levels did not correlate significantly with BPND in either group. CONCLUSIONS: The results suggest altered striatal PDE10A availability and associated local neural dysfunctions in patients with schizophrenia.

Two pathways differentially linking tau depositions, oxidative stress, and neuronal loss to apathetic phenotypes in progressive supranuclear palsy.

Patients with progressive supranuclear palsy (PSP) frequently exhibit apathy but the neuropathological processes leading to this phenotype remain elusive. We aimed to examine the involvement of tau protein depositions, oxidative stress (OS), and neuronal loss in the apathetic manifestation of PSP. Twenty patients with PSP and twenty-three healthy controls were enrolled. Tau depositions and brain volumes were evaluated via positron-emission tomography (PET) using a specific probe, 18F-PM-PBB3, and magnetic resonance imaging, respectively. Glutathione (GSH) levels in the anterior and posterior cingulate cortices were quantified by magnetic resonance spectroscopy. Tau pathologies were observed in the subcortical and cortical structures of the patient brains. The angular gyrus exhibited a positive correlation between tau accumulations and apathy scale (AS). Although PSP cases did not show GSH level alterations compared with healthy controls, GSH levels in posterior cingulate cortex were correlated with AS and tau depositions in the angular gyrus. Marked atrophy was observed in subcortical areas, and gray matter volumes in the inferior frontal gyrus and anterior cingulate cortex were positively correlated with AS but showed no correlation with tau depositions and GSH levels. Path analysis highlighted synergistic contributions of tau pathologies and GSH reductions in the posterior cortex to AS, in parallel with associations of gray matter atrophy in the anterior cortex with AS. Apathetic phenotypes may arise from PET-visible tau aggregation and OS compromising the neural circuit resilience in the posterior cortex, along with neuronal loss, with neither PET-detectable tau pathologies nor OS in the anterior cortex.

Impact of Amyloid and Tau PET on Changes in Diagnosis and Patient Management.

BACKGROUND AND OBJECTIVES: Previous studies have evaluated the diagnostic effect of amyloid PET in selected research cohorts. However, these studies did not assess the clinical impact of the combination of amyloid and tau PETs. Our objective was to evaluate the association of the combination of 2 PETs with changes in diagnosis, treatment, and management in a memory clinic cohort. METHODS: All participants underwent amyloid [18F]florbetaben PET and tau PET using [18F]PI-2620 or [18F]Florzolotau, which are potentially useful for the diagnosis of non-Alzheimer disease (AD) tauopathies. Dementia specialists determined a pre- and post-PET diagnosis that existed in both a clinical syndrome (cognitive normal [CN], mild cognitive impairment [MCI], and dementia) and suspected etiology, with a confidence level. In addition, the dementia specialists determined patient treatment in terms of ancillary investigations and management. RESULTS: Among 126 registered participants, 84.9% completed the study procedures and were included in the analysis (CN [n = 40], MCI [n = 25], AD [n = 20], and non-AD dementia [n = 22]). The etiologic diagnosis changed in 25.0% in the CN, 68.0% in the MCI, and 23.8% with dementia. Overall changes in management between pre- and post-PET occurred in 5.0% of CN, 52.0% of MCI, and 38.1% of dementia. Logistic regression analysis revealed that tau PET has stronger associations with change management than amyloid PET in all participants and dementia groups. DISCUSSION: The combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia, and the second-generation tau PET has a strong impact on the changes in diagnosis and management in memory clinics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia.

An optimized reference tissue method for quantification of tau protein depositions in diverse neurodegenerative disorders by PET with 18F-PM-PBB3 (18F-APN-1607).

Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90-110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.

A Machine Learning-Based Approach to Discrimination of Tauopathies Using [18 F]PM-PBB3 PET Images.

BACKGROUND: We recently developed a positron emission tomography (PET) probe, [18 F]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed. OBJECTIVE: We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities. METHODS: Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others. RESULTS: The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively. CONCLUSIONS: These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Findings of 18 F-PI-2620 tau PET imaging in patients with Alzheimer's disease and healthy controls in relation to the plasma P-tau181 levels in a Japanese sample.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD, abnormal tau accumulates within neurons of the brain, facilitated by extracellular ß-amyloid deposition, leading to neurodegeneration, and eventually, cognitive impairment. As this process is thought to be irreversible, early identification of abnormal tau in the brain is crucial for the development of new therapeutic interventions. AIMS: 18 F-PI-2620 is one of the second-generation tau PET tracers with presumably less off-target binding than its predecessors. Although a few clinical studies have recently reported the use of 18 F-PI-2620 tau PET in patients with AD, its applicability to AD is yet to be thoroughly examined. METHODS: In the present pilot study, we performed 18 F-PI-2620 tau PET in seven cases of probable AD (AD group) and seven healthy controls (HC group). Standardized uptake value ratios (SUVR) in regions of interest (ROIs) in the medial temporal region and neocortex were compared between the AD and HC groups. Furthermore, correlations between regional SUVR and plasma p-tau181 as well as cognitive test scores were also analyzed. RESULTS: The uptake of 18 F-PI-2620 was distinctly increased in the AD group across all the ROIs. SUVR in all the target ROIs were significantly correlated with plasma p-tau181 levels, as well as with MMSE and ADAS-cog scores. DISCUSSION & CONCLUSION: Our results add to accumulating evidence suggesting that 18 F-PI-2620 is a promising tau PET tracer that allows patients with AD to be distinguished from healthy controls, although a study with a larger sample size is warranted.

PET-based classification of corticobasal syndrome.

INTRODUCTION: Corticobasal degeneration (CBD) is the most common neuropathological substrate for clinically diagnosed corticobasal syndrome (CBS), while identifying CBD pathology in living individuals has been challenging. This study aimed to examine the capability of positron emission tomography (PET) to detect CBD-type tau depositions and neuropathological classification of CBS. METHODS: Sixteen CBS cases diagnosed by Cambridge's criteria and 12 cognitively healthy controls (HCs) underwent PET scans with 11C-PiB, 11C-PBB3, and 18F-FDG, along with T1-weighted magnetic resonance imaging. Amyloid positivity was assessed by visual inspection of 11C-PiB retentions. Tau positivity was judged by quantitative comparisons of 11C-PBB3 binding to HCs. RESULTS: Sixteen CBS cases consisted of two cases (13%) with amyloid and tau positivities indicative of Alzheimer's disease (AD) pathologies, 11 cases (69%) with amyloid negativity and tau positivity, and three cases (19%) with amyloid and tau negativities. Amyloid(-), tau(+) CBS cases showed increased retentions of 11C-PBB3 in the frontoparietal areas, basal ganglia, and midbrain, and reduced metabolism in the precentral gyrus and thalamus relative to HCs. The enhanced tau probe retentions in the frontal gray and white matters partially overlapped with metabolic deficits and atrophy and correlated with Clinical Dementia Rating scores. CONCLUSIONS: PET-based classification of CBS was in accordance with previous neuropathological reports on the prevalences of AD, non-AD tauopathies, and others in CBS. The current work suggests that 11C-PBB3-PET may assist the biological classification of CBS and understanding of links between CBD-type tau depositions and neuronal deteriorations leading to cognitive declines.

First-in-human in vivo imaging and quantification of monoacylglycerol lipase in the brain: a PET study with 18F-T-401.

PURPOSE: Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand 18F-T-401. METHODS: Seven healthy males underwent 120-min dynamic 18F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with 18F-T-401 within 2 weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis, were performed. Time-stability and test-retest reproducibility of 18F-T-401-PET were also evaluated. RESULTS: 18F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (VT) values by best identifiability. VT values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated VT values with a minimal bias even using truncated 60-min scan data. Test-retest reliability was also excellent with the use of MA1. CONCLUSIONS: Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. 18F-T-401 showed excellent test-retest reliability, reversible kinetics, and stable estimation of VT values consistent with known regional MAGL expressions. PET with 18F-T-401-PET is promising tool for measurement of central MAGL.

Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies.

Tau aggregates represent a key pathologic feature of Alzheimer's disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer's disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer's disease and non-Alzheimer's disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer's disease tauopathies compared with Alzheimer's disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer's disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid ß assessment and [18F]PI-2620 PET (Image acquisition at 60-90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer's disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer's disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer's disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer's disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60-90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer's disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer's disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer's disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer's disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

A first-in-human study of 11C-MTP38, a novel PET ligand for phosphodiesterase 7.

PURPOSE: Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains. METHODS: Seven healthy males underwent a 90-min PET scan after injection of 11C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (VTs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference. RESULTS: PET images with 11C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET. CONCLUSION: We have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.

High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies.

A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.

Differential associations of dopamine synthesis capacity with the dopamine transporter and D2 receptor availability as assessed by PET in the living human brain.

BACKGROUND: The dopamine (DA) neurotransmission has been implicated in fundamental brain functions, exemplified by movement controls, reward-seeking, motivation, and cognition. Although dysregulation of DA neurotransmission in the striatum is known to be involved in diverse neuropsychiatric disorders, it is yet to be clarified whether components of the DA transmission, such as synthesis, receptors, and reuptake are coupled with each other to homeostatically maintain the DA neurotransmission. The purpose of this study was to investigate associations of the DA synthesis capacity with the availabilities of DA transporters and D2 receptors in the striatum of healthy subjects. METHODS: First, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[ß-11C]DOPA and [18F]FE-PE2I, respectively, acquired from our past dual-tracer studies. Next, we investigated relationships between the DA synthesis capacity and D2 receptor availability employing PET data with L-[ß-11C]DOPA and [11C]raclopride, respectively, obtained from other previous dual-tracer assays. RESULTS: We found a significant positive correlation between the DA synthesis capacity and DA transporter availability in the putamen, while no significant correlations between the DA synthesis capacity and D2 receptor availability in the striatum. CONCLUSION: The intimate association of the DA synthesis rate with the presynaptic reuptake of DA indicates homeostatic maintenance of the baseline synaptic DA concentration. In contrast, the total abundance of D2 receptors, which consist of presynaptic autoreceptors and postsynaptic modulatory receptors, may not have an immediate relationship to this regulatory mechanism.

Binding of Dopamine D1 Receptor and Noradrenaline Transporter in Individuals with Autism Spectrum Disorder: A PET Study.

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, and temporal cortex) or NAT (thalamus and pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex and temporal cortex) and the "attention to detail" subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. Although a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.

Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies.

Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (1H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR "magnetic resonance spectroscopy"). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = -0.38; 95% CI, -0.69 to -0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = -0.50; 95% CI, -0.80 to -0.20), but not in unmedicated patients (SMD = -0.27; 95% CI, -0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.