A growing need exists for reliable in-vivo measurement of neuroinflammation to better characterise the inflammatory processes underlying various diseases and to inform the development of novel ...therapeutics that target deleterious glial activity. PET is well suited to quantify neuroinflammation and has the potential to discriminate components of the neuroimmune response. However, there are several obstacles to the reliable quantification of neuroinflammation by PET imaging. Despite these challenges, PET studies have consistently identified associations between neuroimmune responses and pathophysiology in brain disorders such as Alzheimer's disease. Tissue studies have also begun to clarify the meaning of changes in PET signal in some diseases. Furthermore, although PET imaging of neuroinflammation does not have an established clinical application, novel targets are under investigation and a small but growing number of studies have suggested that this imaging modality could have a role in drug development. Future studies are needed to further improve our knowledge of the cellular mechanisms that underlie changes in PET signal, how immune response contributes to neurological disease, and how it might be therapeutically modified.
Abstract There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy ...studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of 11 CDPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased 11 CDPA-713 binding to TSPO, may be linked to history of NFL play. 11 CDPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to deficits in verbal learning and memory after NFL play.
IMPORTANCE: Microglia, the resident immune cells of the central nervous system, play an important role in the brain’s response to injury and neurodegenerative processes. It has been proposed that ...prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury. OBJECTIVE: To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level–, and body mass index–matched control participants. This study was conducted at an academic research institution in Baltimore, Maryland, from January 29, 2015, to February 18, 2016. MAIN OUTCOMES AND MEASURES: Positron emission tomography–based regional measures of TSPO using 11CDPA-713, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural magnetic resonance imaging, and neuropsychological performance. RESULTS: The mean (SD) ages of the 14 NFL participants and 16 control participants were 31.3 (6.1) years and 27.6 (4.9) years, respectively. Players reported a mean (SD) of 7.0 (6.4) years (range, 1-21 years) since the last self-reported concussion. Using 11CDPA-713 positron emission tomographic data from 12 active or former NFL players and 11 matched control participants, the NFL players showed higher total distribution volume in 8 of the 12 brain regions examined (P < .004). We also observed limited change in white matter fractional anisotropy and mean diffusivity in 13 players compared with 15 control participants. In contrast, these young players did not differ from control participants in regional brain volumes or in neuropsychological performance. CONCLUSIONS AND RELEVANCE: The results suggest that localized brain injury and repair, indicated by higher TSPO signal and white matter changes, may be associated with NFL play. Further study is needed to confirm these findings and to determine whether TSPO signal and white matter changes in young NFL athletes are related to later onset of neuropsychiatric symptoms.
IMPORTANCE: The use of high-field magnetic resonance spectroscopy (MRS) in multiple brain regions of a large population of human participants facilitates in vivo study of localized or diffusely ...altered brain metabolites in patients with first-episode psychosis (FEP) compared to healthy participants. OBJECTIVE: To compare metabolite levels in 5 brain regions between patients with FEP (evaluated within 2 years of onset) and healthy controls, and to explore possible associations between targeted metabolite levels and neuropsychological test performance. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional design used 7-T MRS at a research MR imaging facility in participants recruited from clinics at the Johns Hopkins Schizophrenia Center and the local population. Eighty-one patients who had received a DSM-IV diagnosis of FEP within the last 2 years and 91 healthy age-matched (but not sex-matched) volunteers participated. MAIN OUTCOMES AND MEASURES: Brain metabolite levels including glutamate, glutamine, γ-aminobutyric acid (GABA), N-acetylaspartate, N-acetylaspartyl glutamate, and glutathione, as well as performance on neuropsychological tests. RESULTS: The mean (SD) age of 81 patients with FEP was 22.3 (4.4) years and 57 were male, while the mean (SD) age of 91 healthy participants was 23.3 (3.9) years and 42 were male. Compared with healthy participants, patients with FEP had lower levels of glutamate (F1,162 = 8.63, P = .02), N-acetylaspartate (F1,161 = 5.93, P = .03), GABA (F1,163 = 6.38, P = .03), and glutathione (F1,162 = 4.79, P = .04) in the anterior cingulate (all P values are corrected for multiple comparisons); lower levels of N-acetylaspartate in the orbitofrontal region (F1,136 = 7.23, P = .05) and thalamus (F1,133 = 6.78, P = .03); and lower levels of glutathione in the thalamus (F1,135 = 7.57, P = .03). Among patients with FEP, N-acetylaspartate levels in the centrum semiovale white matter were significantly correlated with performance on neuropsychological tests, including processing speed (r = 0.48; P < .001), visual (r = 0.33; P = .04) and working (r = 0.38; P = .01) memory, and overall cognitive performance (r = 0.38; P = .01). CONCLUSIONS AND RELEVANCE: Seven-tesla MRS offers insights into biochemical changes associated with FEP and may be a useful tool for probing brain metabolism that ranges from neurotransmission to stress-associated pathways in participants with psychosis.
Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography and radioligands binding to the ...translocator protein (TSPO), which is expressed in glial cells in the brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined whether patients with first-episode psychosis and schizophrenia had altered TSPO levels compared with healthy control subjects.
PubMed was searched for studies comparing patients with psychosis with healthy control subjects using second-generation TSPO radioligands. The outcome measure was total distribution volume (VT), an index of TSPO levels, in frontal cortex, temporal cortex, and hippocampus. Bayes factors (BFs) were applied to examine the relative support for higher, lower, or no difference in patients’ TSPO levels compared with healthy control subjects.
Five studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy control subjects, were included. BFs showed strong support for lower VT in patients relative to no difference (all BFs > 32), or relative to higher VT (all BFs > 422), in all brain regions. From the posterior distributions, mean patient–control differences in standardized VT values were −0.48 for frontal cortex (95% credible interval CredInt = −0.88 to 0.09), −0.47 for temporal cortex (CredInt = −0.87 to −0.07), and −0.63 for hippocampus (CredInt = −1.00 to −0.25).
The lower levels of TSPO observed in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.
With the movement toward precision medicine in healthcare, recent studies of individuals with psychosis have begun to explore positron emission tomography (PET) as a tool to test for biochemical ...signatures that may distinguish subtypes of psychosis that guide subtype-specific therapeutic interventions. This review presents selected PET findings that exemplify early promise in using molecular imaging to predict treatment response, provide rationale for new therapeutic targets, and monitor target engagement in biomarker-defined subtypes of psychosis. PET data, among other data types, may prove useful in the scientific pursuit of identifying precision strategies to improve clinical outcomes for individuals with psychosis.
Involvement of oxidative stress in the pathophysiology of schizophrenia (SZ) is suggested by studies of peripheral tissue. Nonetheless, it is unclear how such biological changes are linked to ...relevant, pathological neurochemistry, and brain function. We designed a multi-faceted study by combining biochemistry, neuroimaging, and neuropsychology to test how peripheral changes in a key marker for oxidative stress, glutathione (GSH), may associate with central neurochemicals or neuropsychological performance in health and in SZ. GSH in dorsal anterior cingulate cortex (dACC) was acquired as a secondary 3T
H-MRS outcome using a MEGA-PRESS sequence. Fifty healthy controls and 46 patients with SZ were studied cross-sectionally, and analyses were adjusted for effects of confounding variables. We observed lower peripheral total GSH in SZ compared to controls in extracellular (plasma) and intracellular (lymphoblast) pools. Total GSH levels in plasma positively correlated with composite neuropsychological performance across the total population and within patients. Total plasma GSH levels were also positively correlated with the levels of Glx in the dACC across the total population, as well as within each individual group (controls, patients). Furthermore, the levels of dACC Glx and dACC GSH positively correlated with composite neuropsychological performance in the patient group. Exploring the relationship between systemic oxidative stress (in particular GSH), central glutamate, and cognition in SZ will benefit further from assessment of patients with more varied neuropsychological performance.
OBJECTIVE:Despite viral suppression, HIV-associated cognitive impairment persists and may be partially due to persistent immune signalling by cells of the myeloid-lineage. Here, we aimed to ...understand the contribution of activated microglia located in vulnerable brain regions (e.g. frontal, subcortical) of HIV-infected, virally suppressed (HIV+VS) individuals in relation to cognitive and motor function.
DESIGN:Twenty-one HIV+VS individuals underwent PET with CDPA-713 to image the translocator protein 18 kDa (TSPO), a marker of microglial activation, and completed a comprehensive neuropsychological test battery.
METHODS:Multivariable linear regressions were used to examine the contribution of CDPA-713 binding to cognitive performance.
RESULTS:Higher CDPA-713 binding was associated with lower cognition among HIV+VS individuals. CDPA-713 binding in middle frontal gyrus/frontal cortex, hippocampus/temporal cortex and occipital cortex was inversely associated with performance on a number of cognitive domains, including verbal memory, processing speed/attention/concentration, executive function, working memory and motor function. CDPA-713 binding in parietal cortex, cerebellum and thalamus was associated with only specific cognitive domains including visual construction and verbal memory. Binding was not associated with global cognitive performance.
CONCLUSION:The findings add to the growing body of evidence that immune-mediated brain injury may contribute to domain specific, HIV-associated, cognitive vulnerabilities despite viral suppression.
Purpose
Dynamic glucose enhanced (DGE) MRI has shown potential for imaging glucose delivery and blood–brain barrier permeability at fields of 7T and higher. Here, we evaluated issues involved with ...translating d‐glucose weighted chemical exchange saturation transfer (glucoCEST) experiments to the clinical field strength of 3T.
Methods
Exchange rates of the different hydroxyl proton pools and the field‐dependent T2 relaxivity of water in d‐glucose solution were used to simulate the water saturation spectra (Z‐spectra) and DGE signal differences as a function of static field strength B0, radiofrequency field strength B1, and saturation time tsat. Multislice DGE experiments were performed at 3T on 5 healthy volunteers and 3 glioma patients.
Results
Simulations showed that DGE signal decreases with B0, because of decreased contributions of glucoCEST and transverse relaxivity, as well as coalescence of the hydroxyl and water proton signals in the Z‐spectrum. At 3T, because of this coalescence and increased interference of direct water saturation and magnetization transfer contrast, the DGE effect can be assessed over a broad range of saturation frequencies. Multislice DGE experiments were performed in vivo using a B1 of 1.6 µT and a tsat of 1 second, leading to a small glucoCEST DGE effect at an offset frequency of 2 ppm from the water resonance. Motion correction was essential to detect DGE effects reliably.
Conclusion
Multislice glucoCEST‐based DGE experiments can be performed at 3T with sufficient temporal resolution. However, the effects are small and prone to motion influence. Therefore, motion correction should be used when performing DGE experiments at clinical field strengths.
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