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PurposeThe purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28.Methods[11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19–80 years; BMI range 17.6–36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts.ResultsThere were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects.ConclusionThese findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

Most prior work with positron emission tomography (PET) dopamine subtype 2/3 receptor (D2/3 R) non-selective antagonist tracers suggests that obese (OB) individuals exhibit lower D2/3 Rs when compared with normal weight (NW) individuals. A D3 -preferring D2/3 R agonist tracer, [11 C](+)PHNO, has demonstrated that body mass index (BMI) was positively associated with D2/3 R availability within striatal reward regions. To date, OB individuals have not been studied with [11 C](+)PHNO. We assessed D2/3 R availability in striatal and extrastriatal reward regions in 14 OB and 14 age- and gender-matched NW individuals with [11 C](+)PHNO PET utilizing a high-resolution research tomograph. Additionally, in regions where group D2/3 R differences were observed, secondary analyses of 42 individuals that constituted an overweight cohort was done to study the linear association between BMI and D2/3 R availability in those respective regions. A group-by-brain region interaction effect (F7, 182 =2.08, p=0.047) was observed. Post hoc analyses revealed that OB individuals exhibited higher tracer binding in D3 -rich regions: the substantia nigra/ventral tegmental area (SN/VTA) (+20%; p=0.02), ventral striatum (VST) (+14%; p<0.01), and pallidum (+11%; p=0.02). BMI was also positively associated with D2/3 R availability in the SN/VTA (r=0.34, p=0.03), VST (r=0.36, p=0.02), and pallidum (r=0.30, p=0.05) across all subjects. These data suggest that individuals who are obese have higher D2/3 R availability in brain reward regions densely populated with D3 Rs, potentially identifying a novel pharmacologic target for the treatment of obesity.

Most prior work with positron emission tomography (PET) dopamine subtype 2/3 receptor (D R) non-selective antagonist tracers suggests that obese (OB) individuals exhibit lower D Rs when compared with normal weight (NW) individuals. A D -preferring D R agonist tracer, [ C](+)PHNO, has demonstrated that body mass index (BMI) was positively associated with D R availability within striatal reward regions. To date, OB individuals have not been studied with [ C](+)PHNO. We assessed D R availability in striatal and extrastriatal reward regions in 14 OB and 14 age- and gender-matched NW individuals with [ C](+)PHNO PET utilizing a high-resolution research tomograph. Additionally, in regions where group D R differences were observed, secondary analyses of 42 individuals that constituted an overweight cohort was done to study the linear association between BMI and D R availability in those respective regions. A group-by-brain region interaction effect (F =2.08, p=0.047) was observed. Post hoc analyses revealed that OB individuals exhibited higher tracer binding in D -rich regions: the substantia nigra/ventral tegmental area (SN/VTA) (+20%; p=0.02), ventral striatum (VST) (+14%; p<0.01), and pallidum (+11%; p=0.02). BMI was also positively associated with D R availability in the SN/VTA (r=0.34, p=0.03), VST (r=0.36, p=0.02), and pallidum (r=0.30, p=0.05) across all subjects. These data suggest that individuals who are obese have higher D R availability in brain reward regions densely populated with D Rs, potentially identifying a novel pharmacologic target for the treatment of obesity.

Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BPND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lower BPND in CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BPND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions of BPND (calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BPND in the D2R-rich dorsal striatum and greater BPND in the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BPND that were correlated with regional estimates of D2R-related and D3R-related proportions of BPND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration. •[11C]-(+)-PHNO binding potential reflects the relative local availability of both D2 and D3 receptors.•Regional analysis indicated alterations in D2R-rich and D3R-rich regions in cocaine-use disorder.•ICA identified source-based patterns of receptor availability consistent with DA circuitry.•Source intensities suggest CUD-related differences may also be present in D2R/D3R-mixed regions.

Dopamine type 2 and type 3 receptors (D R/D R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D R availability and greater D R availability in regions primarily expressing D R or D R concentrations, respectively. However, these CUD-related alterations in D R and D R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D R/D R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D R and D R availability using regional and source-based analyses of [ C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BP ) in CUD in the midbrain, consistent with prior [ C]-(+)-PHNO research, and lower BP in CUD in the dorsal striatum, consistent with research using non-selective D R/D R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BP (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D R-related proportions of BP (calculated using independent reports of [ C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D R/D R research in CUD, demonstrating both lower BP in the D R-rich dorsal striatum and greater BP in the D R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [ C]-(+)-PHNO BP that were correlated with regional estimates of D R-related and D R-related proportions of BP , were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D R/D R concentration.

Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [11C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age. Forty-two healthy control subjects (9 females, 33 males; age range 19–55years) were scanned with [11C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. Regional [11C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=−0.56, corrected p=0.0008) and putamen (r=−0.45, corrected p=0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [11C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.

OBJECTIVES/SPECIFIC AIMS: The serotonin receptor 6 (5-HT6) is a potential therapeutic target given its distribution in brain regions that are important in depression, anxiety, and cognition. This study sought to investigate the effects of age on 5-HT6 receptor availability using 11C GSK215083, a PET ligand with affinity for 5-HT6 in the striatum and 5-HT2A in the cortex. METHODS/STUDY POPULATION: In total, 28 healthy male subjects (age range: 23–52 years) were scanned with 11C-GSK215083 on the HR+PET scanner. Time-activity curves in regions-of-interest were fitted with multilinear analysis-1 method. Binding potentials (BPND) were calculated using cerebellum as the reference region and corrected for partial volume effects. RESULTS/ANTICIPATED RESULTS: In 5-HT6 rich areas, regional 11C-GSK215083 displayed a negative correlation between BPND and age in the caudate ( r =−0.41, p =0.03) (14% change per decade), and putamen ( r =−0.30, p =0.04) (11% change per decade), but not in the ventral striatum and pallidum. Negative correlation with age was also seen in cortical regions ( r =−0.41, p =0.03) (7% change per decade), consistent with the literature on 5-HT2A availability. DISCUSSION/SIGNIFICANCE OF IMPACT: This is the first in vivo study in humans to examine the effect of age on 5-HT6 receptor availability. The study demonstrated a significant age-related decline in 5-HT6 availability (BPND) in the caudate and putamen.

ObjectivePrevious imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [11C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age.MethodsForty-two healthy control subjects (9 females, 33 males; age range 19–55years) were scanned with [11C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images.ResultsRegional [11C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=−0.56, corrected p=0.0008) and putamen (r=−0.45, corrected p=0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions.ConclusionIn accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [11C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.

Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BPND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lowerBPNDin CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources ofBPND(striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions ofBPND(calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lowerBPNDin the D2R-rich dorsal striatum and greaterBPNDin the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNOBPNDthat were correlated with regional estimates of D2R-related and D3R-related proportions ofBPND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration.

Clinical text reports from head computed tomography (CT) represent rich, incompletely utilized information regarding acute brain injuries and neurologic outcomes. CT reports are unstructured; thus, extracting information at scale requires automated natural language processing (NLP). However, designing new NLP algorithms for each individual injury category is an unwieldy proposition. An NLP tool that summarizes all injuries in head CT reports would facilitate exploration of large data sets for clinical significance of neuroradiological findings. To automatically extract acute brain pathological data and their features from head CT reports. This diagnostic study developed a 2-part named entity recognition (NER) NLP model to extract and summarize data on acute brain injuries from head CT reports. The model, termed BrainNERD, extracts and summarizes detailed brain injury information for research applications. Model development included building and comparing 2 NER models using a custom dictionary of terms, including lesion type, location, size, and age, then designing a rule-based decoder using NER outputs to evaluate for the presence or absence of injury subtypes. BrainNERD was evaluated against independent test data sets of manually classified reports, including 2 external validation sets. The model was trained on head CT reports from 1152 patients generated by neuroradiologists at the Yale Acute Brain Injury Biorepository. External validation was conducted using reports from 2 outside institutions. Analyses were conducted from May 2020 to December 2021. Performance of the BrainNERD model was evaluated using precision, recall, and F1 scores based on manually labeled independent test data sets. A total of 1152 patients (mean [SD] age, 67.6 [16.1] years; 586 [52%] men), were included in the training set. NER training using transformer architecture and bidirectional encoder representations from transformers was significantly faster than spaCy. For all metrics, the 10-fold cross-validation performance was 93% to 99%. The final test performance metrics for the NER test data set were 98.82% (95% CI, 98.37%-98.93%) for precision, 98.81% (95% CI, 98.46%-99.06%) for recall, and 98.81% (95% CI, 98.40%-98.94%) for the F score. The expert review comparison metrics were 99.06% (95% CI, 97.89%-99.13%) for precision, 98.10% (95% CI, 97.93%-98.77%) for recall, and 98.57% (95% CI, 97.78%-99.10%) for the F score. The decoder test set metrics were 96.06% (95% CI, 95.01%-97.16%) for precision, 96.42% (95% CI, 94.50%-97.87%) for recall, and 96.18% (95% CI, 95.151%-97.16%) for the F score. Performance in external institution report validation including 1053 head CR reports was greater than 96%. These findings suggest that the BrainNERD model accurately extracted acute brain injury terms and their properties from head CT text reports. This freely available new tool could advance clinical research by integrating information in easily gathered head CT reports to expand knowledge of acute brain injury radiographic phenotypes.