APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

From technical to understandable: Artificial Intelligence Large Language Models improve the readability of knee radiology reports.

PURPOSE: The purpose of this study was to evaluate the effectiveness of an Artificial Intelligence-Large Language Model (AI-LLM) at improving the readability of knee radiology reports. METHODS: Reports of 100 knee X-rays, 100 knee computed tomography (CT) scans and 100 knee magnetic resonance imaging (MRI) scans were retrieved. The following prompt command was inserted into the AI-LLM: 'Explain this radiology report to a patient in layman's terms in the second person:[Report Text]'. The Flesch-Kincaid reading level (FKRL) score, Flesch reading ease (FRE) score and report length were calculated for the original radiology report and the AI-LLM generated report. Any 'hallucination' or inaccurate text produced by the AI-LLM-generated report was documented. RESULTS: Statistically significant improvements in mean FKRL scores in the AI-LLM generated X-ray report (12.7 ± 1.0-7.2 ± 0.6), CT report (13.4 ± 1.0-7.5 ± 0.5) and MRI report (13.5 ± 0.9-7.5 ± 0.6) were observed. Statistically significant improvements in mean FRE scores in the AI-LLM generated X-ray report (39.5 ± 7.5-76.8 ± 5.1), CT report (27.3 ± 5.9-73.1 ± 5.6) and MRI report (26.8 ± 6.4-73.4 ± 5.0) were observed. Superior FKRL scores and FRE scores were observed in the AI-LLM-generated X-ray report compared to the AI-LLM-generated CT report and MRI report, p < 0.001. The hallucination rates in the AI-LLM generated X-ray report, CT report and MRI report were 2%, 5% and 5%, respectively. CONCLUSIONS: This study highlights the promising use of AI-LLMs as an innovative, patient-centred strategy to improve the readability of knee radiology reports. The clinical relevance of this study is that an AI-LLM-generated knee radiology report may enhance patients' understanding of their imaging reports, potentially reducing the responder burden placed on the ordering physicians. However, due to the 'hallucinations' produced by the AI-LLM-generated report, the ordering physician must always engage in a collaborative discussion with the patient regarding both reports and the corresponding images. LEVEL OF EVIDENCE: Level IV.

From jargon to clarity: Improving the readability of foot and ankle radiology reports with an artificial intelligence large language model.

BACKGROUND: The purpose of this study was to evaluate the efficacy of an Artificial Intelligence Large Language Model (AI-LLM) at improving the readability foot and ankle orthopedic radiology reports. METHODS: The radiology reports from 100 foot or ankle X-Rays, 100 computed tomography (CT) scans and 100 magnetic resonance imaging (MRI) scans were randomly sampled from the institution's database. The following prompt command was inserted into the AI-LLM: "Explain this radiology report to a patient in layman's terms in the second person: [Report Text]". The mean report length, Flesch reading ease score (FRES) and Flesch-Kincaid reading level (FKRL) were evaluated for both the original radiology report and the AI-LLM generated report. The accuracy of the information contained within the AI-LLM report was assessed via a 5-point Likert scale. Additionally, any "hallucinations" generated by the AI-LLM report were recorded. RESULTS: There was a statistically significant improvement in mean FRES scores in the AI-LLM generated X-Ray report (33.8 ± 6.8 to 72.7 ± 5.4), CT report (27.8 ± 4.6 to 67.5 ± 4.9) and MRI report (20.3 ± 7.2 to 66.9 ± 3.9), all p < 0.001. There was also a statistically significant improvement in mean FKRL scores in the AI-LLM generated X-Ray report (12.2 ± 1.1 to 8.5 ± 0.4), CT report (15.4 ± 2.0 to 8.4 ± 0.6) and MRI report (14.1 ± 1.6 to 8.5 ± 0.5), all p < 0.001. Superior FRES scores were observed in the AI-LLM generated X-Ray report compared to the AI-LLM generated CT report and MRI report, p < 0.001. The mean Likert score for the AI-LLM generated X-Ray report, CT report and MRI report was 4.0 ± 0.3, 3.9 ± 0.4, and 3.9 ± 0.4, respectively. The rate of hallucinations in the AI-LLM generated X-Ray report, CT report and MRI report was 4%, 7% and 6%, respectively. CONCLUSION: AI-LLM was an efficacious tool for improving the readability of foot and ankle radiological reports across multiple imaging modalities. Superior FRES scores together with superior Likert scores were observed in the X-Ray AI-LLM reports compared to the CT and MRI AI-LLM reports. This study demonstrates the potential use of AI-LLMs as a new patient-centric approach for enhancing patient understanding of their foot and ankle radiology reports. Jel Classifications: IV.

Atypical Fibroxanthoma: Outcomes from a Large Single Institution Series.

BACKGROUND: Atypical fibroxanthomas (AFX) are rare malignant cutaneous neoplasms. Unfortunately, limited clinicopathologic and outcomes data on this cancer exists. OBJECTIVE: We report the clinical, pathologic, and treatment characteristics, as well as oncologic outcomes in this single-institution retrospective analysis. METHODS: This retrospective cohort study compiled clinical, pathologic, treatment, and outcome data for all patients with AFX on definitive excision diagnosed, evaluated, and treated primarily by surgical resection at a single institution between 2000-2020. Descriptive statistics evaluated clinical and pathologic characteristics. Kaplan-Meier method and Cox proportional-hazards models were used to evaluate overall survival and recurrence-free survival. RESULTS: 78 patients with AFX were identified. The majority were elderly, immunocompetent, Caucasian men. 85% of tumors were located on the head and neck. 63% of patients were correctly diagnosed only after complete resection of the index lesion. The median surgical margin was 1.0 cm. Overall, only 1.3% (1/78) of patients developed a local recurrence (RFS). No patients died of disease. CONCLUSION: This study suggests that resection margins of 1 cm achieve excellent local control with close to 99% RFS and 100% disease-specific survival.

Symptom persistence and recovery among COVID-19 survivors during a limited outbreak in Canterbury, New Zealand: a prospective cohort study.

BACKGROUND: In Canterbury, near complete identification of coronavirus disease 2019 (COVID-19) cases during a limited outbreak provides unique insights into sequelae. AIMS: The current study aimed to measure symptom persistence, time to return to normal activity, generalised anxiety and health-related quality of life (HrQoL) among COVID-19 survivors compared with uninfected participants. METHODS: The authors conducted a prospective cohort study of people tested for COVID-19 by reverse transcriptase polymerase chain reaction of nasopharyngeal swabs from 1 March to 30 June 2020. They enrolled participants who tested positive and negative at a 1:2 ratio, and administered community-acquired pneumonia, 7-item generalised anxiety disorder (GAD-7) and HrQoL (RAND-36) questionnaires. RESULTS: The authors recruited 145 participants, 48 with COVID-19 and 97 without COVID-19. The mean time from COVID-19 testing to completing the health questionnaire was 306 days. The mean age of patients was 46.7 years, and 70% were women. Four (8%) COVID-19-positive and eight (8%) COVID-19-negative participants required hospitalisation. Fatigue (30/48 [63%] vs 13/97 [13%]; P < 0.001), dyspnoea (13/48 [27%] vs 6/97 [6%]; P < 0.001) and chest pain (10/48 [21%] vs 1/97 [1%]; P < 0.001) were persistent in those with COVID-19. Fewer COVID-19-positive participants returned to normal activity levels (35/48 [73%] vs 94/97 97%; P < 0.001), with longer times taken (median 21 vs 14 days; P = 0.007). The GAD-7 and RAND-36 scores of both groups were similar across all anxiety and HrQoL subscales. CONCLUSIONS: Persistent symptoms and longer recovery times were found in COVID-19 survivors, but not impaired generalised anxiety levels or HrQoL compared with COVID-19-uninfected participants.

The small HDL particle hypothesis of Alzheimer's disease.

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

The effects of acute pain on cognitive skills in emergency department patients.

INTRODUCTION: Effective pain management results in improved patient satisfaction, reduced anxiety, and improved comfort. However, concern exists regarding the effects of pain medications on cognition and patient ability to consent for procedures, hospital admission, or to refuse recommended medical interventions. METHODS: This prospective, case-control study was conducted at a Level 1 Trauma Center. Eligible subjects included ED patients ages 18 and older with a triage pain score of 1 or higher, who received non-narcotic analgesic agents. Cognition was measured before and after non-narcotic pain medication using the Digit Symbol Substitution Test (DSST). A control group consisted of 35 healthy volunteers who completed the DSST at baseline and one hour. RESULTS: Among 46 subjects, the mean age was 33. The mean triage pain score was 7. Before medication, the average DSST score was 39.5. After medication, the average DSST score was 42.9. There was a significant within-subject average change in DSST score (pre-post) of 3.4 (95% confidence interval: 1.6, 5.2), p < 0.001. Among the control group, the mean baseline DSST score was 64.2 (SD 10.7). One hour later the mean DSST score had increased to 71.1 (SD 10.4). Overall, the mean within-subject change over time in DSST was 6.9 (SD 8.0) with 95% CI 4.2 to 9.7. There was not enough evidence to detect relationships between change in DSST scores and age, triage pain, triage HR, triage RR, change in pain scores, gender, ethnicity, mode of arrival nor insurance (all with p > 0.05). CONCLUSIONS: We found significant variation in DSST scores among ED patients with pain. Treatment of pain with nonsedating analgesic agents was not associated with improved scores on the Digit Symbol Substitution Test among ED patients with acute painful conditions, compared to control subjects.

Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.

Hydrogen Sulfide and Substance P Levels in Patients with Escherichia coli and Klebsiella pneumoniae Bacteraemia.

Hydrogen sulfide (H2S) and substance P (SP) are known from animal models and in vitro studies as proinflammatory mediators. In this study, peripheral blood concentrations of H2S and SP were measured in patients with Escherichia coli or Klebsiella pneumoniae bacteraemia. Fifty patients were recruited from general wards at Christchurch Hospital, during 2020-2021. Samples from age- and sex-matched healthy subjects previously recruited as controls for studies of cardiovascular disease were used as controls. The concentrations of H2S were higher than controls on day 0, day 1, and day 2, and SP was higher than controls on all 4 days. The concentrations of H2S were highest on day 0, whereas SP concentrations were higher on day 2 than other days. Interleukin-6 and C-reactive protein were significantly higher on day 0 and day 1, respectively. The concentrations of H2S and SP did not differ between 15 non-septic (SIRS 0-1) and the 35 septic subjects (SIRS ≥ 2). Substance P concentrations were higher in subjects with abdominal infection than urinary tract infections on day 0 (p = 0.0002) and day 1 (p = 0.0091). In conclusion, the peak H2S concentrations precede the SP peak in patients with Gram-negative bacteraemia, but this response varies with the site of infection.

Evidence that blood-CSF barrier transport, but not inflammatory biomarkers, change in migraine, while CSF sVCAM1 associates with migraine frequency and CSF fibrinogen.

OBJECTIVE: Our objective is to explore whether blood-cerebrospinal fluid (CSF) barrier biomarkers differ in episodic migraine (EM) or chronic migraine (CM) from controls. BACKGROUND: Reports of blood-brain barrier and blood-cerebrospinal fluid barrier (BCSFB) disruption in migraine vary. Our hypothesis is that investigation of biomarkers associated with blood, CSF, brain, cell adhesion, and inflammation will help elucidate migraine pathophysiology. METHODS: We recruited 14 control volunteers without headache disorders and 42 individuals with EM or CM as classified using the International Classification of Headache Disorders, 3rd edition, criteria in a cross-sectional study located at our Pasadena and Stanford headache research centers in California. Blood and lumbar CSF samples were collected once from those diagnosed with CM or those with EM during two states: during a typical migraine, before rescue therapy, with at least 6/10 level of pain (ictal); and when migraine free for at least 48 h (interictal). The average number of headaches per month over the previous year was estimated by those with EM; this enabled comparison of biomarker changes between controls and three headache frequency groups: <2 per month, 2-14 per month, and CM. Blood and CSF biomarkers were determined using antibody-based methods. RESULTS: Antimigraine medication was only taken by the EM and CM groups. Compared to controls, the migraine group had significantly higher mean CSF-blood quotients of albumin (Qalb : mean ± standard deviation (SD): 5.6 ± 2.3 vs. 4.1 ± 1.9) and fibrinogen (Qfib mean ± SD: 1615 ± 99.0 vs. 86.1 ± 55.0). Mean CSF but not plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were significantly higher in those with more frequent migraine: (4.5 ng/mL ± 1.1 in those with <2 headache days a month; 5.5 ± 1.9 with 2-14 days a month; and 7.1 ± 2.9 in CM), while the Qfib ratio was inversely related to headache frequency. We did not find any difference in individuals with EM or CM from controls for CSF cell count, total protein, matrix metalloproteinase-9, soluble platelet-derived growth factor receptor ß, tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, IL-8, IL-10, or C-reactive protein. CONCLUSIONS: The higher Qalb and Qfib ratios may indicate that the transport of these blood-derived proteins is disturbed at the BCSFB in persons with migraine. These changes most likely occur at the choroid plexus epithelium, as there are no signs of typical endothelial barrier disruption. The most striking finding in this hypothesis-generating study of migraine pathophysiology is that sVCAM-1 levels in CSF may be a biomarker of higher frequency of migraine and CM. An effect from migraine medications cannot be excluded, but there is no known mechanism to suggest they have a role in altering the CSF biomarkers.

Trends in low-frequency underwater noise off the Oregon coast and impacts of COVID-19 pandemic.

Approximately six years of underwater noise data recorded from the Regional Cabled Array network are examined to study long-term trends. The data originate from station HYS14 located 87 km offshore of Newport, OR. The results indicate that the third-octave band level centered at 63 Hz and attributable to shipping activity is reduced in the spring of 2020 by about 1.6 dB relative to the mean of the prior five years, owing to the reduced economic activity initiated by the COVID-19 pandemic. The results are subtle, as the noise reduction is less than the typical seasonal fluctuation associated with warming ocean surface temperatures in the summer that reduces mode excitation support at typical ship source depths, causing a repeated annual level change on the order of 4 dB at shipping frequencies. Seasonality of the noise contribution near 20 Hz from fin whales is also discussed. Corroboration of a COVID-19 effect on shipping noise is offered by an analysis of automatic identification system shipping data and shipping container activity for Puget Sound, over the same six-year period, which shows a reduction in the second quarter of 2020 by ∼19% and ∼17%, respectively, relative to the mean of the prior five years.

Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: Recommendations of an expert panel.

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes.

ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes.

The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of ß-amyloid (Aß). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation in vivo are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower Aß degradation capacity. Human CSF from APOE ε4/ε4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from APOE ε3/ε3 carriers. Enhancing ABCA1 activity rescued impaired Aß degradation in ApoE4-treated cells and reduced both ApoE and ABCA1 aggregation in the hippocampus of male ApoE4-targeted replacement mice. Together, our data demonstrate that aggregated and lipid-poor ApoE4 increases ABCA1 aggregation and decreases ABCA1 cell membrane recycling. Enhancing ABCA1 activity to reduce ApoE and ABCA1 aggregation is a potential therapeutic strategy for the prevention of ApoE4 aggregation-driven pathology.SIGNIFICANCE STATEMENT ApoE protein plays a key role in the formation of amyloid plaques, a hallmark of Alzheimer's disease (AD). ApoE4 is more aggregated and hypolipidated compared with ApoE3, but whether enhancing ApoE lipidation in vivo can reverse ApoE aggregation is not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). In this study, we demonstrated that the greater propensity of lipid-poor ApoE4 to aggregate decreased ABCA1 membrane recycling and its ability to lipidate ApoE. Importantly, enhancing ABCA1 activity to lipidate ApoE reduced ApoE and ABCA1 aggregation. This work provides critical insights into the interactions among ABCA1, ApoE lipidation and aggregation, and underscores the promise of stabilizing ABCA1 activity to prevent ApoE-driven aggregation pathology.

Impact of COVID-19 on Away Rotations in Surgical Fields.

The COVID-19 pandemic has presented a variety of challenges in the medical education curriculum, one of which is the possible loss of summer and fall away rotations for fourth year students applying into surgical subspecialties. Subsequently, a lack of in-person evaluations may have a major impact on an applicant's perception of the residency and the program's ability to assess the individual applicant. This is especially crucial for applicants without a home program in their specialty of interest, as away rotations are an important opportunity to confirm interest in pursuit of a subspecialty, obtain letters of recommendation, and make positive impressions at programs of interest. The objective of this article is to assess the current COVID-19 pandemic situation in light of away rotations and to provide recommendations for surgical subspecialty programs and applicants to have the best outcome during this upcoming application cycle. In particular, we emphasize the importance of implementing universal processes within each individual subspecialty. This will provide equitable opportunities for all applicants, minimizing potential biases or disadvantages based on geographic location or availability of a program at an applicant's home institution.

Nonconformist tendencies related to risky choices in female methamphetamine abstainers.

Background: Many experimental studies and theoretical models have tried to explain the multifaceted formation of drug addiction. In most addiction models, social factors are an important component; however, few empirical studies have investigated the social influences on the safe or risky choices of drug-addicted individuals during the abstinence stage. Objectives: To investigate the behavioral patterns of female methamphetamine abstainers under social influence. Methods: Thirty-seven female methamphetamine abstainers (average abstinence time: 8.61 ± 4.75 months) and 40 matched controls performed a gambling task in the presence of peers' choices. We applied both model-free and computational model-based analysis to examine how the decision patterns differed with social influence between the two groups. Results: 1) the choice data from the two groups showed a social influence effect such that participants made more risky choices when others made risky choices; 2) overall, the female methamphetamine abstainers made more risky choices in the social influence task; and 3) in the computational model parameters, the female methamphetamine abstainers exhibited more nonconforming attitudes (with negative other-conferred utility) with respect to peer influence, whereas controls showed higher conformity to peers. Conclusion: Our findings provide the first objective evidence that female methamphetamine abstainers show peer nonconformity. This nonconformist tendency may be a potential behavioral marker to track drug addiction and help to elucidate the mechanisms of decisions made by female methamphetamine abstainers.

A novel sensitive assay for detection of a biomarker of pericyte injury in cerebrospinal fluid.

INTRODUCTION: Blood-brain barrier (BBB) breakdown and loss of brain capillary pericytes contributes to cognitive impairment. Pericytes express platelet-derived growth factor receptor-ß (PDGFRß) that regulates brain angiogenesis and blood vessel stability. Elevated soluble PDGFRß (sPDGFRß) levels in cerebrospinal fluid (CSF) indicate pericyte injury and BBB breakdown, which is an early biomarker of human cognitive dysfunction. METHODS: A combination of reagents and conditions were tested, optimized, and validated on the Meso Scale Discovery electrochemiluminescence platform to develop a new sPDGFRß immunoassay that was used to measure sPDGFRß in human CSF from 147 individuals. RESULTS: We developed standard operating procedures for a highly sensitive and reproducible sPDGFRß immunoassay with a dynamic range from 100 to 26,000 pg/mL, and confirmed elevated CSF sPDGFRß levels in individuals with cognitive dysfunction. DISCUSSION: This assay could be applied at different laboratories to study brain pericytes and microvascular damage in relation to cognition in disorders associated with neurovascular and cognitive dysfunction.

SECONDARY WALL ASSOCIATED MYB1 is a positive regulator of secondary cell wall thickening in Brachypodium distachyon and is not found in the Brassicaceae.

Grass biomass is comprised chiefly of secondary walls that surround fiber and xylem cells. A regulatory network of interacting transcription factors in part regulates cell wall thickening. We identified Brachypodium distachyon SECONDARY WALL ASSOCIATED MYB1 (SWAM1) as a potential regulator of secondary cell wall biosynthesis based on gene expression, phylogeny, and transgenic plant phenotypes. SWAM1 interacts with cellulose and lignin gene promoters with preferential binding to AC-rich sequence motifs commonly found in the promoters of cell wall-related genes. SWAM1 overexpression (SWAM-OE) lines had greater above-ground biomass with only a slight change in flowering time while SWAM1 dominant repressor (SWAM1-DR) plants were severely dwarfed with a striking reduction in lignin of sclerenchyma fibers and stem epidermal cell length. Cellulose, hemicellulose, and lignin genes were significantly down-regulated in SWAM1-DR plants and up-regulated in SWAM1-OE plants. There was no reduction in bioconversion yield in SWAM1-OE lines; however, it was significantly increased for SWAM1-DR samples. Phylogenetic and syntenic analyses strongly suggest that the SWAM1 clade was present in the last common ancestor between eudicots and grasses, but is not in the Brassicaceae. Collectively, these data suggest that SWAM1 is a transcriptional activator of secondary cell wall thickening and biomass accumulation in B. distachyon.

Cerebral sodium (23Na) magnetic resonance imaging in patients with migraine - a case-control study.

OBJECTIVE: Evaluation of MRI-derived cerebral 23Na concentrations in patients with migraine in comparison with healthy controls. MATERIALS AND METHODS: In this case-control study, 24 female migraine patients (mean age, 34 ± 11 years) were enrolled after evaluation of standardized questionnaires. Half (n = 12) of the cohort suffered from migraine, the other half was impaired by both migraine and tension-type headaches (TTH). The combined patient cohort was matched to 12 healthy female controls (mean age, 34 ± 11 years). All participants underwent a cerebral 23Na-magnetic resonance imaging examination at 3.0 T, which included a T1w MP-RAGE sequence and a 3D density-adapted, radial gradient echo sequence for 23Na imaging. Circular regions of interests were placed in predetermined anatomic regions: cerebrospinal fluid (CSF), gray and white matter, brain stem, and cerebellum. External 23Na reference phantoms were used to calculate the total 23Na tissue concentrations. Pearson's correlation, Kendall Tau, and Wilcoxon rank sum test were used for statistical analysis. RESULTS: 23Na concentrations of all patients in the CSF were significantly higher than in healthy controls (p < 0.001). The CSF of both the migraine and mixed migraine/TTH group showed significantly increased sodium concentrations compared to the control group (p = 0.007 and p < 0.001). Within the patient cohort, a positive correlation between pain level and TSC in the CSF (r = 0.62) could be observed. CONCLUSION: MRI-derived cerebral 23Na concentrations in the CSF of migraine patients were found to be statistically significantly higher than in healthy controls. KEY POINTS: • Cerebral sodium MRI supports the theory of ionic imbalances and may aid in the challenging pathophysiologic understanding of migraine. • Case-control study shows significantly higher sodium concentrations in cerebrospinal fluid of migraineurs. • Cerebral sodium MRI may become a non-invasive imaging tool for drugs to modulate sodium, and hence migraine, on a molecular level, and influence patient management.

Undetectable gadolinium brain retention in individuals with an age-dependent blood-brain barrier breakdown in the hippocampus and mild cognitive impairment.

INTRODUCTION: Blood-brain barrier (BBB) breakdown is an early independent biomarker of human cognitive dysfunction, as found using gadolinium (Gd) as a contrast agent. Whether Gd accumulates in brains of individuals with an age-dependent BBB breakdown and/or mild cognitive impairment remains unclear. METHODS: We analyzed T1-weighted magnetic resonance imaging (MRI) scans from 52 older participants with BBB breakdown in the hippocampus 19-28 months after either cyclic or linear Gd agent. RESULTS: There was no change in T1-weighted signal intensity between the baseline contrast MRI and unenhanced MRI on re-examination in any of the studied 10 brain regions with either Gd agent suggesting undetectable Gd brain retention. DISCUSSION: Gd does not accumulate in brains of older individuals with a BBB breakdown in the hippocampus. Thus, Gd agents can be used without risk of brain retention within a ∼2-year follow-up to study BBB in the aging human brain in relation to cognition and/or other pathologies.

Vascular dysfunction-The disregarded partner of Alzheimer's disease.

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.