Effect of the SARS-CoV-2 pandemic on colorectal cancer diagnosis and prognosis.

BACKGROUND AND STUDY AIMS: Our aim was to determine the impact of the SARS-CoV-2 pandemic on the diagnosis and prognosis of colorectal cancer (CRC). PATIENTS AND METHODS: This prospective cohort study included individuals diagnosed with CRC between March 13, 2019 and June 20, 2021 across 21 Spanish hospitals. Two time periods were compared: prepandemic (from March 13, 2019 to March 13, 2020) and pandemic (from March 14, 2020 to June 20, 2021, lockdown period and 1 year after lockdown). RESULTS: We observed a 46.9% decrease in the number of CRC diagnoses (95% confidence interval (CI): 45.1%-48.7%) during the lockdown and 29.7% decrease (95% CI: 28.1%-31.4%) in the year after the lockdown. The proportion of patients diagnosed at stage I significantly decreased during the pandemic (21.7% vs. 19.0%; p = 0.025). Centers that applied universal preprocedure SARS-CoV-2 PCR testing experienced a higher reduction in the number of colonoscopies performed during the pandemic post-lockdown (34.0% reduction; 95% CI: 33.6%-34.4% vs. 13.7; 95% CI: 13.4%-13.9%) and in the number of CRCs diagnosed (34.1% reduction; 95% CI: 31.4%-36.8% vs. 26.7%; 95% CI: 24.6%-28.8%). Curative treatment was received by 87.5% of patients diagnosed with rectal cancer prepandemic and 80.7% of patients during the pandemic post-lockdown period (p = 0.002). CONCLUSIONS: The COVID-19 pandemic has led to a decrease in the number of diagnosed CRC cases and in the proportion of stage I CRC. The reduction in the number of colonoscopies and CRC diagnoses was higher in centers that applied universal SARS-CoV-2 PCR screening before colonoscopy. In addition, the COVID-19 pandemic has affected curative treatment of rectal cancers.

Linked-color imaging versus high definition white-light endoscopy for evaluation of post-polypectomy scars of nonpedunculated lesions: LCI-Scar study.

BACKGROUND: Detection and treatment of recurrence after piecemeal endoscopic mucosal resection of nonpedunculated colorectal polyps are crucial for avoidance of post-colonoscopy cancer. Linked-color imaging (LCI) has demonstrated improved polyp detection but has never been assessed for evaluation of post-polypectomy scars. Our aim was to compare sensitivity and negative predictive value (NPV) between LCI and white-light endoscopy (WLE) for detection of post-polypectomy recurrence. METHODS: Patients undergoing surveillance colonoscopy after resection of lesions ≥15 mm were included in this prospective, single-center, randomized, crossover study. Each post-polypectomy scar underwent two examinations, one with LCI and the other with WLE, performed by two blinded endoscopists. Blue-light imaging (BLI) was then applied. A diagnosis of recurrence with a level of confidence was made for each modality and histopathology was the gold standard. RESULTS: 129 patients with 173 scars were included. Baseline patient, lesion, and procedural characteristics were similar in both arms. Recurrence was detected in 56/173 (32.4%), with 27/56 (48.2%) adenomas and 29/56 (51.8%) serrated lesions. LCI had greater sensitivity (96.4% [95%CI 87.8%-99.5%]) versus WLE (89.3% [95%CI 78.1%-95.9%]) and greater NPV (98.1% [95%CI 93.4%-99.8%] versus 94.6% [95%CI 88.7%-98.0%]). Paired concordance between modalities was 96.0%. In discordant cases, LCI identified four true-positive cases not detected by WLE and reclassified one false-positive of WLE. WLE reclassified two false positives of LCI without any increase in recurrence detection. CONCLUSIONS: LCI was highly accurate and had greater ability than WLE to rule out recurrence on post-polypectomy scars after resection of large polyps.

Role of Artificial Intelligence in Colonoscopy Detection of Advanced Neoplasias : A Randomized Trial.

BACKGROUND: The role of computer-aided detection in identifying advanced colorectal neoplasia is unknown. OBJECTIVE: To evaluate the contribution of computer-aided detection to colonoscopic detection of advanced colorectal neoplasias as well as adenomas, serrated polyps, and nonpolypoid and right-sided lesions. DESIGN: Multicenter, parallel, randomized controlled trial. (ClinicalTrials.gov: NCT04673136). SETTING: Spanish colorectal cancer screening program. PARTICIPANTS: 3213 persons with a positive fecal immunochemical test. INTERVENTION: Enrollees were randomly assigned to colonoscopy with or without computer-aided detection. MEASUREMENTS: Advanced colorectal neoplasia was defined as advanced adenoma and/or advanced serrated polyp. RESULTS: The 2 comparison groups showed no significant difference in advanced colorectal neoplasia detection rate (34.8% with intervention vs. 34.6% for controls; adjusted risk ratio [aRR], 1.01 [95% CI, 0.92 to 1.10]) or the mean number of advanced colorectal neoplasias detected per colonoscopy (0.54 [SD, 0.95] with intervention vs. 0.52 [SD, 0.95] for controls; adjusted rate ratio, 1.04 [99.9% CI, 0.88 to 1.22]). Adenoma detection rate also did not differ (64.2% with intervention vs. 62.0% for controls; aRR, 1.06 [99.9% CI, 0.91 to 1.23]). Computer-aided detection increased the mean number of nonpolypoid lesions (0.56 [SD, 1.25] vs. 0.47 [SD, 1.18] for controls; adjusted rate ratio, 1.19 [99.9% CI, 1.01 to 1.41]), proximal adenomas (0.94 [SD, 1.62] vs. 0.81 [SD, 1.52] for controls; adjusted rate ratio, 1.17 [99.9% CI, 1.03 to 1.33]), and lesions of 5 mm or smaller (polyps in general and adenomas and serrated lesions in particular) detected per colonoscopy. LIMITATIONS: The high adenoma detection rate in the control group may limit the generalizability of the findings to endoscopists with low detection rates. CONCLUSION: Computer-aided detection did not improve colonoscopic identification of advanced colorectal neoplasias. PRIMARY FUNDING SOURCE: Medtronic.

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome.

Serrated polyposis syndrome (SPS) is one of the most frequent polyposis syndromes characterized by an increased risk for developing colorectal cancer (CRC). Although SPS etiology has been mainly associated with environmental factors, germline predisposition to SPS could also be relevant for cases with familial aggregation or a family history of SPS/CRC. After whole-exome sequencing of 39 SPS patients from 16 families, we identified a heterozygous germline frameshift variant in the POLD1 gene (c.1941delG, p.(Lys648fs*46)) in a patient with SPS and CRC. Tumor presented an ultra-hypermutated phenotype and microsatellite instability. The POLD1 germline variant segregated in three additional SPS-affected family members. We attempted to create yeast and cellular models for this variant but were no viable. Alternatively, we generated patient-derived organoids (PDOs) from healthy rectal tissue of the index case, as well as from a control donor. Then, we challenged PDOs with a DNA-damaging agent to induce replication stress. No significant differences were observed in the DNA damage response between control and POLD1-Lys648fs PDOs, nor specific mutational signatures were observed. Our results do not support the pathogenicity of the analyzed POLD1 frameshift variant. One possible explanation is that haplosufficiency of the wild-type allele may be compensating for the absence of expression of the frameshift allele. Overall, future work is required to elucidate if functional consequences could be derived from POLD1 alterations different from missense variants in their proofreading domain. To our knowledge, our study presents the first organoid model for germline POLD1 variants and establishes the basis for its use as a model for disease in SPS, CRC and other malignancies.

Artificial intelligence in gastrointestinal endoscopy — Evolution to a new era

Artificial intelligence (AI) systems based on machine learning have evolved in the last few years with increasing applicability in gastrointestinal endoscopy. Thanks to AI, animage (input) can be transformed into a clinical decision(output). Although AI systems have been studied mainly toimprove detection (CADe) and characterization of colorectalpolyps (CADx), other indications are being currently investigated, including detection of blind spots, scope guidance,and delineation/measurement of lesions.The objective of this review is to summarize the current evidence on the applicability of AI systems in gastrointestinalendoscopy, to highlight the strengths and limitations of thetechnology involved, and to review the relevant regulatoryand ethical aspects for general implementation in gastrointestinal endoscopy. (AU)

In vivo computer-aided diagnosis of colorectal polyps using white light endoscopy.

Background and study aims Artificial intelligence is currently able to accurately predict the histology of colorectal polyps. However, systems developed to date use complex optical technologies and have not been tested in vivo. The objective of this study was to evaluate the efficacy of a new deep learning-based optical diagnosis system, ATENEA, in a real clinical setting using only high-definition white light endoscopy (WLE) and to compare its performance with endoscopists. Methods ATENEA was prospectively tested in real life on consecutive polyps detected in colorectal cancer screening colonoscopies at Hospital Clínic. No images were discarded, and only WLE was used. The in vivo ATENEA's prediction (adenoma vs non-adenoma) was compared with the prediction of four staff endoscopists without specific training in optical diagnosis for the study purposes. Endoscopists were blind to the ATENEA output. Histology was the gold standard. Results Ninety polyps (median size: 5 mm, range: 2-25) from 31 patients were included of which 69 (76.7 %) were adenomas. ATENEA correctly predicted the histology in 63 of 69 (91.3 %, 95 % CI: 82 %-97 %) adenomas and 12 of 21 (57.1 %, 95 % CI: 34 %-78 %) non-adenomas while endoscopists made correct predictions in 52 of 69 (75.4 %, 95 % CI: 60 %-85 %) and 20 of 21 (95.2 %, 95 % CI: 76 %-100 %), respectively. The global accuracy was 83.3 % (95 % CI: 74%-90 %) and 80 % (95 % CI: 70 %-88 %) for ATENEA and endoscopists, respectively. Conclusion ATENEA can accurately be used for in vivo characterization of colorectal polyps, enabling the endoscopist to make direct decisions. ATENEA showed a global accuracy similar to that of endoscopists despite an unsatisfactory performance for non-adenomatous lesions.

Epigenome-Wide DNA Methylation Profiling of Normal Mucosa Reveals HLA-F Hypermethylation as a Biomarker Candidate for Serrated Polyposis Syndrome.

Serrated polyposis syndrome (SPS) is associated with a high risk for colorectal cancer. Intense promoter hypermethylation is a frequent molecular finding in the serrated pathway and may be present in normal mucosa, predisposing to the formation of serrated lesions. To identify novel biomarkers for SPS, fresh-frozen samples of normal mucosa from 50 patients with SPS and 19 healthy individuals were analyzed by using the 850K BeadChip Technology (Infinium). Aberrant methylation levels were correlated with gene expression using a next-generation transcriptome profiling tool. Two validation steps were performed on independent cohorts: first, on formalin-fixed, paraffin-embedded tissue of the normal mucosa; and second, on 24 serrated lesions. The most frequently hypermethylated genes were HLA-F, SLFN12, HLA-DMA, and RARRES3; and the most frequently hypomethylated genes were PIWIL1 and ANK3 (Δß = 10%; P < 0.05). Expression levels of HLA-F, SLFN12, and HLA-DMA were significantly different between SPS patients and healthy individuals and correlated well with the methylation status of the corresponding differentially methylated region (fold change, >20%; r > 0.55; P < 0.001). Significant hypermethylation of CpGs in the gene body of HLA-F was also found in serrated lesions (Δß = 23%; false discovery rate = 0.01). Epigenome-wide methylation profiling has revealed numerous differentially methylated CpGs in normal mucosa from SPS patients. Significant hypermethylation of HLA-F is a novel biomarker candidate for SPS.

The "diagnose and leave in" strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial.

BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %-98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %-93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

Prevalence of adenomatous polyposis in a fecal immunochemical test-based colorectal cancer screening program and risk of advanced neoplasia during follow-up.

BACKGROUND : Current guidelines recommend genetic counseling and intensive colonoscopy surveillance for patients with ≥ 10 colorectal adenomas based on scarce data. We investigated the prevalence of this condition in a fecal immunochemical test (FIT)-based colorectal (CRC) screening program, and the incidence of metachronous lesions during follow-up. METHODS: We retrospectively included all FIT-positive participants with ≥ 10 adenomas at index colonoscopy between 2010 and 2018. Surveillance colonoscopies were collected until 2019. Patients with inherited syndromes, serrated polyposis syndrome, total colectomy, or lacking surveillance data were excluded. The cumulative incidence of CRC and advanced neoplasia were analyzed by Kaplan-Meier analysis. Risk factors for metachronous advanced neoplasia were investigated by multivariable logistic regression analysis. RESULTS: 215 of 9582 participants (2.2 %) had ≥ 10 adenomas. Germline genetic testing was performed in 92 % of patients with ≥ 20 adenomas, identifying two inherited syndromes (3.3 %). The 3-year cumulative incidence of CRC and advanced neoplasia were 1 % and 16 %, respectively. In 39 patients (24.2 %), no polyps were found on first surveillance colonoscopy. The presence of an advanced adenoma was independently associated with a higher risk of advanced neoplasia at first surveillance colonoscopy (odds ratio 3.91, 95 %CI 1.12-13.62; P = 0.03). Beyond the first surveillance colonoscopy, the risk of metachronous advanced neoplasia was lower. CONCLUSIONS: The prevalence of ≥ 10 adenomas in a FIT-based CRC screening program was 2.2 %; a small proportion of inherited syndromes were detected, even amongst those with ≥ 20 adenomas. A low rate of post-colonoscopy CRC was observed and the risk of advanced neoplasia beyond the first surveillance colonoscopy tended to progressively decrease throughout successive follow-ups.

Management and Outcomes of Bleeding Within 30 Days of Colonic Polypectomy in a Large, Real-Life, Multicenter Cohort Study.

BACKGROUND & AIMS: Management of delayed (within 30 days) postpolypectomy bleeding (DPPB) has not been standardized. Patients often undergo colonoscopies that do not provide any benefit. We aimed to identify factors associated with therapeutic intervention and active bleeding after DPPB. METHODS: We performed a retrospective study of 548 patients with bleeding within 30 days after an index polypectomy (DPPB; 71.9% underwent colonoscopy, 2.6% underwent primary angiographic embolization, and 25.5% were managed without intervention) at 6 tertiary centers in Spain, from January 2010 through September 2018. We collected demographic and medical data from patients. The primary outcomes were the need for therapeutic intervention and the presence of active bleeding during colonoscopy. RESULTS: A need for therapeutic intervention was associated independently with the use of antithrombotic agents, hemoglobin decrease greater than 2 g/dL, hemodynamic instability, and comorbidities (P < .05). The bleeding point during colonoscopy was identified in 344 patients; 74 of these patients (21.5%) had active bleeding. Active use of anticoagulants (odds ratio [OR], 2.6; 95% CI, 1.5-4.5), left-sided polyps (OR, 1.95; 95% CI, 1-3.8), prior use of electrocautery (OR, 2.6; 95% CI, 1.1-6.1), and pedunculated polyp morphology (OR, 1.8, 95% CI, 1-3.2) significantly increased the risk of encountering active bleeding. We developed a visual nomogram to estimate the risk of active bleeding. Overall, 43% of the cohort did not require any hemostatic therapy. Rebleeding (<6%) and transfusion requirements were low in those managed without intervention. CONCLUSIONS: In a study of patients with DPPB, we found that almost half do not warrant any therapeutic intervention. Colonoscopy often is overused for patients with DPPB. We identified independent risk factors for active bleeding that might be used to identify patients most likely to benefit from colonoscopy.

Factors associated with complete clip closure after endoscopic mucosal resection of large colorectal polyps.

BACKGROUND AND STUDY AIM : Delayed bleeding is a common adverse event following endoscopic mucosal resection (EMR) of large colorectal polyps. Prophylactic clip closure of the mucosal defect after EMR of nonpedunculated polyps larger than 20 mm reduces the incidence of severe delayed bleeding, especially in proximal polyps. This study aimed to evaluate factors associated with complete prophylactic clip closure of the mucosal defect after EMR of large polyps. METHODS : This is a post hoc analysis of the CLIP study (NCT01936948). All patients randomized to the clip group were included. Main outcome was complete clip closure of the mucosal resection defect. The defect was considered completely closed when no remaining mucosal defect was visible and clips were less than 1 cm apart. Factors associated with complete closure were evaluated in multivariable analysis. RESULTS : In total, 458 patients (age 65, 58 % men) with 494 large polyps were included. Complete clip closure of the resection defect was achieved for 338 polyps (68.4 %); closure was not complete for 156 (31.6 %). Factors associated with complete closure in adjusted analysis were smaller polyp size (odds ratio 1.06 for every millimeter decrease [95 % confidence interval 1.02-1.08]), good access (OR 3.58 [1.94-9.59]), complete submucosal lifting (OR 2.28 [1.36-3.90]), en bloc resection (OR 5.75 [1.48-22.39]), and serrated histology (OR 2.74 [1.35-5.56]). CONCLUSIONS : Complete clip closure was not achieved for almost one in three resected large nonpedunculated polyps. While stable access and en bloc resection facilitate clip closure, most factors associated with clip closure are not modifiable. This highlights the need for alternative closure options and measures to prevent bleeding.

Higher seroprevalence of hepatitis E virus in autoimmune hepatitis: Role of false-positive antibodies.

BACKGROUND AND AIMS: Recent studies have found an increase in the seroprevalence of hepatitis E virus (HEV) infection in patients with autoimmune hepatitis (AIH). We aimed to assess the prevalence of positive anti-HEV IgM and IgG, and HEV-RNA in a cohort of patients with AIH, to determine the impact of positive HEV serology on patient outcome, and to evaluate the role of hypergammaglobulinemia and positive autoantibodies in the presence of positive anti-HEV serology. METHODS: One hundred and five patients tested for HEV infection between 2014 and 2018 were included in the study: 50 with chronic AIH (more than 1 year on treatment), and 55 with an acute hepatitis (30 patients with acute AIH and 25 with non-AIH). RESULTS: Seroprevalence of HEV was higher in patients with acute AIH (17% vs 10% in patients with chronic AIH and 8% in patients with non-AIH). Patients with acute AIH and positive anti-HEV IgG were older (58 vs 40; P = .006), had higher IgG levels (27 g/dL vs 13 g/dL; P = .03) and antismooth muscle antibodies (ASMA) titres (1:160 vs 1:80; P = .045), and were more likely to have another autoimmune disease (60% vs 16%; P = .03). At the time of HEV testing, anti-HEV IgG positive patients had significantly higher serum IgG levels (17 g/L vs 11 g/L; P = .009), ANA (1:160 vs 1:60; P = .026) and ASMA titres (1:80 vs 1:40; P = .021). CONCLUSION: Seroprevalence of HEV in patients with AIH in Catalonia does not differ from that of the general population. The higher HEV seroprevalence in patients with acute AIH with higher levels of gammaglobulins and high antibody titres suggest the presence of cross-reactivity between HEV and liver antigens.

Endocuff-assisted colonoscopy for surveillance of serrated polyposis syndrome: a multicenter randomized controlled trial.

BACKGROUND AND STUDY AIMS: Serrated polyposis syndrome (SPS) is a condition with high risk for colorectal cancer. The Endocuff device has been shown to increase adenoma detection in the general and screening population. We aimed to ascertain whether Endocuff-assisted colonoscopy increases detection of serrated lesions in comparison with standard colonoscopy during the surveillance of patients with SPS.  METHODS: In a multicenter randomized controlled study, patients who met SPS criteria I and/or III under surveillance (previous resection of all serrated lesions ≥ 4 mm) were consecutively randomly allocated 1:1 to Endocuff-assisted colonoscopy or standard colonoscopy, performed by expert endoscopists. The main outcome was the mean number of serrated lesions detected per patient. RESULTS: 122 patients (standard colonoscopy n = 60; Endocuff-assisted colonoscopy n = 62; 59 % men; mean age 60.6 (standard deviation [SD] 7.5) were included at 4 centers. Baseline variables (demographic data, SPS phenotype, colorectal cancer [CRC] history, cumulative polyps, and follow-up), cecal intubation rate, and withdrawal time were similar between groups. There was no statistically significant difference between Endocuff-assisted colonoscopy and standard colonoscopy for the mean number of serrated lesions detected per patient: 5.8 (95 % confidence interval [95 %CI] 4.4 - 7.2) and 5.0 (3.9 - 6.1), respectively (P = 0.36). There were also no differences between Endocuff-assisted and standard colonoscopy for detection of sessile serrated lesions (mean number per patient 2.5 [1.3 - 3.6] vs. 2.0 [1.1 - 3.0], P = 0.54) and adenomas (0.9 [0.5 - 1.3] vs. 0.5 [0.3 - 0.7], P = 0.12). CONCLUSION: Use of Endocuff-assisted colonoscopy did not significantly increase the number of serrated lesion detected per patient during surveillance of SPS.

Ventilatory Cycle Measurements and Loop Gain in Central Apnea in Mining Drivers Exposed to Intermittent Altitude.

STUDY OBJECTIVES: By measuring the apnea length, ventilatory phase, respiratory cycle length, and loop gain, we can further characterize the central apneas of high altitude (CAHA). METHODS: Sixty-three drivers of all-terrain vehicles, working in a Peruvian mine located at 2,020 meters above sea level (MASL), were evaluated. A respiratory polygraph was performed in the first night they slept at high altitude. None of the subjects were exposed to oxygen during the test or acetazolamide in the preceding days of the test. RESULTS: Sixty-three respiratory polygraphs were performed, and 59 were considered for analysis. Forty-six (78%) were normal, 6 (10%) had OSA, and 7 (12%) had CAHA. Key data from subjects include: residing altitude: 341 ± 828 MASL, Lake Louise scoring: 0.4 ± 0.8, Epworth score: 3.4 ± 2.7, apneahypopnea index: 35.7 ± 19.3, CA index: 13.4 ± 14.2, CA length: 14.4 ± 3.6 sec, ventilatory length: 13.5 ± 2.9 sec, cycle length: 26.5 ± 4.0 sec, ventilatory length/CA length ratio 0.9 ± 0.3 and circulatory delay 13.3 ± 2.9 sec. Duty ratio media [ventilatory duration/cycle duration] was 0.522 ± 0 0.128 [0.308-0.700] and loop gain was calculated from the duty ratio utilizing this formula: LG = 2π / [(2πDR-sin(2πDR)]. All subjects have a high loop gain media 2.415 ± 1.761 [1.175-6.260]. Multiple correlations were established with loop gain values, but the only significant correlation detected was between central apnea index and loop gain. CONCLUSIONS: Twelve percent of the studied population had CAHA. Measurements of respiratory cycle in workers with CAHA are more similar to idiopathic central apneas rather than Hunter-Cheyne-Stokes respiration. Also, there was a high degree of correlation between severity of central apnea and the degree of loop gain. The abnormal breathing patterns in those subjects could affect the sleep quality and potentially increase the risk for work accidents.

Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication-free individuals with bipolar disorder: an in vivo 1H MRS study.

OBJECTIVES: While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy ((1)H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N-acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr). METHODS: Thirty-two medication-free BD subjects (33.8 +/- 10.2 years) and 32 matched controls (33.8 +/- 9.0 years) underwent a short echo-time (TE = 30 ms) (1)H MRS. An 8-cm(3) single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo-inositol, and glutamate were obtained, using the water signal as an internal reference. RESULTS: BD subjects had lower Cr + PCr [F((1,62)) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [F((1,62)) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites. CONCLUSIONS: These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.