Whole-brain metabolic topography measured with hyperpolarized 13C-pyruvate MRI in 40 healthy individuals was correlated with microarray transcriptomic data from the Allen Human Brain Atlas. Spatial autocorrelation was addressed using both model-based and non-model-based methods, and two parcellation atlases with different numbers of regions were employed to reduce the likelihood of false positives. Brain regions with higher expression of transcripts characteristic of excitatory neurons showed an elevated bicarbonate-to-pyruvate ratio, indicating a higher flux through pyruvate dehydrogenase. Specifically, the Ex2 and Ex4 excitatory neuron subtypes showed the strongest enrichment among all cell-type gene sets. Collectively, these findings connect regional variations in metabolic neuroimaging profiles to underlying patterns of cellular gene expression, offering a framework for understanding the molecular basis of tissue-level metabolic organization.

Patients with brain metastases (BMs) experience altered neurological function due to cancer itself and treatment effects. Brain alterations may be underpinned by dysregulated cellular metabolism that can be measured with hyperpolarized [1-13C]pyruvate magnetic resonance imaging (HP [1-13C]pyruvate MRI). HP [1-13C]pyruvate MRI was used to detect altered brain metabolism in the normal appearing brain parenchyma of patients with BMs compared with healthy controls. Twelve patients with untreated BMs and 46 healthy controls were imaged with HP [1-13C]pyruvate MRI. The brain was parcellated into 132 regions and segmented into grey and white matter. Tumor-involved brain regions and hyperintense T2w FLAIR regions were excluded. Mean regional [1-13C]pyruvate, [1-13C]lactate, [13C]bicarbonate, 13C-lactate-to-pyruvate ratio, 13C-bicarbonate-to-pyruvate ratio, 13C-lactate-to-bicarbonate ratio, region volume, and grey and white matter density and volume were modeled using mixed effects linear regression. Patients exhibited a 65% (95% CI: 36% to 99%; p = 4 $$\times $$ 10-6) increase in the 13C-lactate-to-pyruvate ratio and 54% (95% CI: 19% to 99%; p = 0.002) increase in the 13C-bicarbonate-to-pyruvate ratio relative to controls. The superior parietal lobule showed the greatest increase in both metabolite ratios. Overall, frontal and parietal brain regions exhibited the greatest increases in 13C-lactate-to-pyruvate and 13C-bicarbonate-to-pyruvate ratios. Increased 13C-metabolite ratios warrant further investigation to determine causes of this metabolic shift and its relation to clinical outcomes. Clinical Trial Registry: Registered on ClinicalTrials.gov on October 4, 2017 with trial registration number NCT03324360.

Background:Brain metastases (BM) are increasingly treated with stereotactic radiosurgery (SRS); however, up to 30% of BM recur locally. This work investigated whether hyperpolarized (HP) [1-13C]-pyruvate MRI can be used to predict SRS treatment response in patients with BM. Methods:Eighteen patients with 44 BM were imaged with HP [1-13C]-pyruvate MRI prior to SRS. Treatment response was determined using the Response Assessment in Neuro-Oncology BM (RANO-BM) working group guidelines at 6-month follow-up. Fourteen parameters, including lesion [1-13C]-lactate to [13C]-bicarbonate, [1-13C]-lactate to [1-13C]-pyruvate and [13C]-bicarbonate to [1-13C]-pyruvate signal ratios, in addition to prognostic and dosimetric parameters, were analyzed using univariable and multivariable analysis. Results:Univariable analysis identified lesion [1-13C]-lactate to [13C]-bicarbonate ratio (P = .0003), lesion [13C]-bicarbonate to [1-13C]-pyruvate ratio (P = .0118), lesion volume (P = .0264), and the number of involved organs with metastases including the brain (P = .0448) as significant predictors of treatment response. The lesion [1-13C]-lactate to [13C]-bicarbonate ratio was predictive of response with the best overall performance, achieving an AUCROC = 0.88, AUCPRC = 0.83, sensitivity = 67% (CI: 40%-87%), specificity = 97% (CI: 90%-100%), and positive predictive value (PPV) = 91% (CI: 73%-100%). Conclusions:HP lesion [1-13C]-lactate to [13C]-bicarbonate ratio can predict SRS response with a high PPV.

Hyperpolarized- 13 C magnetic resonance imaging (HP- 13 C MRI) was used to image changes in 13 C-lactate signal during a visual stimulus condition in comparison to an eyes-closed control condition. Whole-brain 13 C-pyruvate, 13 C-lactate and 13 C-bicarbonate production was imaged in healthy volunteers (N=6, ages 24-33) for the two conditions using two separate hyperpolarized 13 C-pyruvate injections. BOLD-fMRI scans were used to delineate regions of functional activation. 13 C-metabolite signal was normalized by 13 C-metabolite signal from the brainstem and the percentage change in 13 C-metabolite signal conditions was calculated. A one-way Wilcoxon signed-rank test showed a significant increase in 13 C-lactate in regions of activation when compared to the remainder of the brain ( p = 0.02, V = 21). No significant increase was observed in 13 C-pyruvate ( p = 0.11, V = 17) or 13 C-bicarbonate ( p = 0.95, V = 3) signal. The results show an increase in 13 C-lactate production in the activated region that is measurable with HP- 13 C MRI.

PURPOSE:To test the hypothesis that lactate oxidation contributes to the   13 $$ {}^{13} $$ C-bicarbonate signal observed in the awake human brain using hyperpolarized   13 $$ {}^{13} $$ C MRI. METHODS:Healthy human volunteers (N = 6) were scanned twice using hyperpolarized   13 $$ {}^{13} $$ C-MRI, with increased radiofrequency saturation of   13 $$ {}^{13} $$ C-lactate on one set of scans.   13 $$ {}^{13} $$ C-lactate,   13 $$ {}^{13} $$ C-bicarbonate, and   13 $$ {}^{13} $$ C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon signed-rank test. RESULTS:Increased   13 $$ {}^{13} $$ C-lactate radiofrequency saturation resulted in a significantly lower   13 $$ {}^{13} $$ C-bicarbonate signal (p = 0.04). These changes were observed across the majority of brain regions. CONCLUSION:Radiofrequency saturation of   13 $$ {}^{13} $$ C-lactate leads to a decrease in   13 $$ {}^{13} $$ C-bicarbonate signal, demonstrating that the   13 $$ {}^{13} $$ C-lactate generated from the injected   13 $$ {}^{13} $$ C-pyruvate is being converted back to   13 $$ {}^{13} $$ C-pyruvate and oxidized throughout the human brain.

Purpose: To test the hypothesis that lactate oxidation contributes to the (13)13 C-bicarbonate signal observed in the awake human brain using hyperpolarized (13)13 C MRI.Methods: Healthy human volunteers (N = 6) were scanned twice using hyperpolarized (13)13 C-MRI, with increased radiofrequency saturation of (13)13 C-lactate on one set of scans. (13)13 C-lactate, (13)13 C-bicarbonate, and (13)13 C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon signed-rank test.Results: Increased (13)13 C-lactate radiofrequency saturation resulted in a significantly lower (13)13 C-bicarbonate signal (p = 0.04). These changes were observed across the majority of brain regions.Conclusion: Radiofrequency saturation of (13)13 C-lactate leads to a decrease in (13)13 C-bicarbonate signal, demonstrating that the (13)13 C-lactate generated from the injected (13)13 C-pyruvate is being converted back to (13)13 C-pyruvate and oxidized throughout the human brain.

Purpose To test the hypothesis that lactate shuttling contributes to the 13 C-lactate and 13 C-bicarbonate signal observed in the awake human brain using hyperpolarized 13 C MRI. Methods Healthy human volunteers (n = 6) were scanned twice using hyperpolarized 13 C-MRI, with reduced radiofrequency saturation of 13 C-lactate on one set of scans. 13 C-lactate, 13 C-bicarbonate, and 13 C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon sum rank test. Results Reduced 13 C-lactate radiofrequency saturation resulted in a significantly greater 13 C-bicarbonate signal ( p = 0.04). These changes were observed across the majority of brain regions. Conclusion Radiofrequency saturation of 13 C-lactate leads to a decrease in 13 C-bicarbonate signal, demonstrating that the 13 C-lactate generated from the injected 13 C-pyruvate is being converted back to 13 C-pyruvate and oxidized throughout the human brain.

It is well known that glucose is the primary source of energy in the brain, but mounting evidence suggests that at least some of this glucose is first converted to lactate and shuttled between cellular compartments before being oxidized in the TCA cycle. In this study, the hypothesis that this ”lactate shuttle” contributes to the 13 C-lactate and 13 C-bicarbonate signal observed in the awake human brain is tested using hyperpolarized 13 C MRI (HP 13 C-MRI).

In this study, hyperpolarized C-13 MRI (HP-C-13 MRI) was used to investigate changes in the uptake and metabolism of pyruvate with age. Hyperpolarized C-13-pyruvate was administered to healthy aging individuals (N = 35, ages 21-77) and whole-brain spatial distributions of C-13-lactate and C-13-bicarbonate production were measured. Linear mixed-effects regressions were performed to compute the regional percentage change per decade, showing a significant reduction in both normalized C-13-lactate and normalized C-13-bicarbonate production with age: -7%+/- 2%$$ -7\%\pm 2\% $$ per decade for C-13-lactate and -9%+/- 4%$$ -9\%\pm 4\% $$ per decade for C-13-bicarbonate. Certain regions, such as the right medial precentral gyrus, showed greater rates of change while the left caudate nucleus had a flat C-13-lactate versus age and a slightly increasing C-13-bicarbonate versus age. The results show that both the production of lactate (visible as C-13-lactate signal) as well as the consumption of monocarboxylates to make acetyl-CoA (visible as C-13-bicarbonate signal) decrease with age and that the rate of change varies by brain region.

Brain metastases are increasingly being treated with stereotactic radiosurgery; however, 20-30% of treated tumors recur locally post-treatment. Hyperpolarized [1- 13 C]pyruvate magnetic resonance imaging (HP 13 C MRI) is an emerging metabolic imaging modality that measures key metabolic phenotypes indicative of tumor biology. Here we investigate pre-treatment [1- 13 C]pyruvate uptake – a potential marker of monocarboxylate transporter 1 expression and tumor vascularity – via HP 13 C MR images as a predictor of local recurrence. [1- 13 C]pyruvate uptake establishes a robust predictive model (AUC = 0.73) and, as a result, can inform treatment decisions should the model predict a non-response to SRS.

Finasteride is not commercially available in a liquid format, which stimulated the development of a stable and simple finasteride suspension formulation. The objectives of this work were to develop and test a finasteride suspension for 1) simplicity to compound, 2) pharmaceutical acceptability, 3) stability, and 4) potential for occupational exposure. The stability of commercial 5-mg finasteride tablets (50 mg/150 mL) was evaluated in water, Oral Mix, and OralMix SF in amber polyethylene terephthalate bottles at 25°C or 4°C. Additional stability studies were carried out using sugar-free Finasteride Powder USP in amber polyethylene terephthalate bottles and tablets in water in polypropylene oral syringes. On study days 0, 1, 3, 7, 14, 28, 38, 49, 63, and 90, the finasteride concentration was determined using a validated stability-indicating liquid chromatographic method. The potential occupational airborne exposure was evaluated by attempting to measure finasteride in 1000 liters of room air following shaking and nebulization. Finasteride suspension/dispersion formulations were prepared in water, Oral Mix, and Oral Mix SF from tablets and pure powder. All formulations retained more than 94.3% of the initial finasteride concentration, with 95% confidence, when stored for up to 90 days at room temperature or 4°C. Simulations of occupational exposure failed to demonstrate the presence of finasteride in room air following attempts to nebulize finasteride mixtures. We conclude that 333-µg/mL suspension/dispersions of finasteride in water or Oral Mix products will have more than 94.3% of the initial finasteride concentration remaining after 90 days, regardless of the formulation, container, or storage temperature. Although we could not detect finasteride in room air, given the analytical limits of the study, we estimate that exposure would unlikely exceed 3.6-µg/1000 liters of room air. Nevertheless, since current regulations are based on "no safe limit," use of primary engineering controls and personal protective equipment as appropriate is recommended.

BACKGROUND:Delayed diagnosis of bloodstream infection (BSI) occurs in > 20% of older patients, with misdiagnosis in 35%. Our objective was to develop and validate a clinically useful screening tool to identify older patients with a high probability of having a BSI. METHODS:Hospitalized patients > 80 years old with BSI (n = 105/group) were evaluated for the tool development in this retrospective matched case-controlled study (learn cohort). The tool was validated in different retrospectively matched case and control patients > 80 years old (n = 120/group) and 65 to 79 years old (n = 250/group) (test cohort). Binary logistic regression was used to develop a screening tool using laboratory and clinical parameters that were significantly associated with BSI (P < 0.05; adjusted odds ratio (OR) > 1); and Classification and Regression Tree (CART) analysis was used to identify parameter breakpoints. Performance metrics were used to evaluate and validate the tool. RESULTS:The significant parameters associated with BSI were maximum temperature (Tmax)(> 37.55C)(OR = 42.575), neutrophils (> 7.95)(OR = 1.923), a change in level of consciousness (LOC) (Yes = 1, No = 0)(OR = 1.571), blood urea nitrogen (BUN)(> 10.05)(OR = 1.359), glucose (> 7.35)(OR = 1.167), albumin (< 33.5)(OR = 1.038) and alanine aminotransferase (ALT) (> 19.5)(OR = 1.005). The optimal screening tool [Ln (odds of BSI) = - 150.299 + 3.751(Tmax) + 0.654(neutrophils) + 0.452(change in LOC) + 0.307(BUN) + 0.154(glucose) + 0.038(albumin) + 0.005(ALT)] had favorable performance metrics in the learn and test cohorts (sensitivity, specificity and accuracy of 95% in the learn cohort and 77, 89, and 81% in the total test cohort); and performed better than using only temperature and neutrophil count. CONCLUSIONS:The validated tool had high predictive value which may improve early identification and management of BSI in older patients.

Brain metastases are increasingly being treated with stereotactic radiosurgery; however, 20-30% of treated tumors locally recure post treatment. Hyperpolarized [1-13C]pyruvate magnetic resonance imaging (HP 13C MRI) is an emerging metabolic imaging modality that measures key metabolic phenotypes indicative of aggressive tumor phenotypes. Here we show that the pre-treatment tumor 13C-lactate to 13C-bicarbonate ratio – a marker of glycolysis and (indirectly) oxidative phosphorylation – measured via HP [1-13C]pyruvate MRI is a robust predictor of local recurrence (AUCROC=0.95, p=0.0008; AUCPRC=0.92) and can inform treatment decisions should the model predict a non-response to SRS.

Motivation: The metabolic profile of normal appearing brain tissue in patients with brain metastases may be related to the course of disease. Goal(s): To test whether patients with brain metastases exhibit differential metabolism in normal appearing brain parenchyma compared to healthy control participants. Approach: Hyperpolarized [1-13C]-pyruvate and T1w MRI were used to compare the metabolism and volumes of normal appearing brain regions in patients and healthy control participants. Results: The lactate-to-bicarbonate (p=0.0004) and lactate-to-pyruvate (p=0.04) ratios were significantly increased in the normal appearing brain parenchyma of patients compared to controls. Impact: The metabolic profile of normal appearing brain parenchyma in patients with brain metastases exhibits significantly increased glycolytic metabolism compared to healthy control brains when imaged using hyperpolarized [1-13C]-pyruvate MRI and may be related to the course of disease.

Motivation: Increases in lactate production are believed to occur in occipital lobe regions in response to visual stimuli. Goal(s): In this study, whole-brain hyperpolarized-13C MRI was used to investigate how a visual stimulus affects occipital lobe 13C-lactate signal in healthy human volunteers. Approach: A set of two hyperpolarized-13C MRI scans were done. Participants (n = 6) viewed a flashing checkerboard stimulus during one of the 13C scans, and had their eyes closed for the second 13C scan. Results: Increased 13C-lactate signal was observed in the visual stimulus scans when compared to the eyes-closed scans in occipital lobe regions relative to non-occipital lobe regions. Impact: We have shown that hyperpolarized-13C MRI is capable of measuring differences in 13C-lactate signal in response to a visual stimuli. These findings support the idea of increases in lactate production in response to stimulus. Future studies will explore other stimuli.