Recommendations for Additional Imaging on Head and Neck Imaging Examinations: Interradiologist Variation and Associated Factors.

BACKGROUND. A paucity of relevant guidelines may lead to pronounced variation among radiologists in issuing recommendations for additional imaging (RAI) for head and neck imaging. OBJECTIVE. The purpose of this article was to explore associations of RAI for head and neck imaging examinations with examination, patient, and radiologist factors and to assess the role of individual radiologist-specific behavior in issuing such RAI. METHODS. This retrospective study included 39,200 patients (median age, 58 years; 21,855 women, 17,315 men, 30 with missing sex information) who underwent 39,200 head and neck CT or MRI examinations, interpreted by 61 radiologists, from June 1, 2021, through May 31, 2022. A natural language processing (NLP) tool with manual review of NLP results was used to identify RAI in report impressions. Interradiologist variation in RAI rates was assessed. A generalized mixed-effects model was used to assess associations between RAI and examination, patient, and radiologist factors. RESULTS. A total of 2943 (7.5%) reports contained RAI. Individual radiologist RAI rates ranged from 0.8% to 22.0% (median, 7.1%; IQR, 5.2-10.2%), representing a 27.5-fold difference between minimum and a maximum values and 1.8-fold difference between 25th and 75th percentiles. In multivariable analysis, RAI likelihood was higher for CTA than for CT examinations (OR, 1.32), for examinations that included a trainee in report generation (OR, 1.23), and for patients with self-identified race of Black or African American versus White (OR, 1.25); was lower for male than female patients (OR, 0.90); and was associated with increasing patient age (OR, 1.09 per decade) and inversely associated with radiologist years since training (OR, 0.90 per 5 years). The model accounted for 10.9% of the likelihood of RAI. Of explainable likelihood of RAI, 25.7% was attributable to examination, patient, and radiologist factors; 74.3% was attributable to radiologist-specific behavior. CONCLUSION. Interradiologist variation in RAI rates for head and neck imaging was substantial. RAI appear to be more substantially associated with individual radiologist-specific behavior than with measurable systemic factors. CLINICAL IMPACT. Quality improvement initiatives, incorporating best practices for incidental findings management, may help reduce radiologist preference-sensitive decision-making in issuing RAI for head and neck imaging and associated care variation.

Development and External Validation of an Artificial Intelligence Model for Identifying Radiology Reports Containing Recommendations for Additional Imaging.

BACKGROUND. Reported rates of recommendations for additional imaging (RAIs) in radiology reports are low. Bidirectional encoder representations from transformers (BERT), a deep learning model pretrained to understand language context and ambiguity, has potential for identifying RAIs and thereby assisting large-scale quality improvement efforts. OBJECTIVE. The purpose of this study was to develop and externally validate an artificial intelligence (AI)-based model for identifying radiology reports containing RAIs. METHODS. This retrospective study was performed at a multisite health center. A total of 6300 radiology reports generated at one site from January 1, 2015, to June 30, 2021, were randomly selected and split by 4:1 ratio to create training (n = 5040) and test (n = 1260) sets. A total of 1260 reports generated at the center's other sites (including academic and community hospitals) from April 1 to April 30, 2022, were randomly selected as an external validation group. Referring practitioners and radiologists of varying sub-specialties manually reviewed report impressions for presence of RAIs. A BERT-based technique for identifying RAIs was developed by use of the training set. Performance of the BERT-based model and a previously developed traditional machine learning (TML) model was assessed in the test set. Finally, performance was assessed in the external validation set. The code for the BERT-based RAI model is publicly available. RESULTS. Among a total of 7419 unique patients (4133 women, 3286 men; mean age, 58.8 years), 10.0% of 7560 reports contained RAI. In the test set, the BERT-based model had 94.4% precision, 98.5% recall, and an F1 score of 96.4%. In the test set, the TML model had 69.0% precision, 65.4% recall, and an F1 score of 67.2%. In the test set, accuracy was greater for the BERT-based than for the TML model (99.2% vs 93.1%, p < .001). In the external validation set, the BERT-based model had 99.2% precision, 91.6% recall, an F1 score of 95.2%, and 99.0% accuracy. CONCLUSION. The BERT-based AI model accurately identified reports with RAIs, outperforming the TML model. High performance in the external validation set suggests the potential for other health systems to adapt the model without requiring institution-specific training. CLINICAL IMPACT. The model could potentially be used for real-time EHR monitoring for RAIs and other improvement initiatives to help ensure timely performance of clinically necessary recommended follow-up.

Electronic Health Record Order Entry-Based Interventions in Response to a Global Iodinated Contrast Media Shortage: Impact on Contrast-Enhanced CT Utilization.

BACKGROUND. Radiology informatics systems and clinical decision support tools in the electronic health record (EHR) can be leveraged to help impact ordering patterns in response to the ongoing global iodinated contrast media shortage. OBJECTIVE. The purpose of our study was to assess the impact of EHR order entry-based interventions, implemented as part of a health system's response to the global contrast media shortage, on contrast-enhanced CT utilization. METHODS. This retrospective study included 79,259 patients who underwent CT at a large multisite health system between April 1, 2022, and July 3, 2022. Two EHR-based interventions were implemented as part of the health system's response to the global contrast media shortage. A first EHR-based intervention on May 10, 2022, entailed creating an alert that appeared in a sidebar after any contrast-enhanced body CT orders, indicating the present shortage and recommending alternate imaging modalities. A second EHR-based intervention on May 16, 2022, required referrers to enter detailed clinical information for all contrast-enhanced body CT orders, which radiologists used when protocoling examinations. Data regarding CT orders and examinations performed were extracted from the electronic data warehouse. RESULTS. During the preintervention, first postintervention, and second postintervention periods, the mean number of patients who underwent contrast-enhanced CT per weekday was 726, 689, and 639, respectively (p for preintervention vs second postintervention periods, < .001). During the three periods, the mean number of patients who underwent CT per weekday was 1350, 1323, and 1314 (p < .001). During the three periods, the mean number of patients who underwent contrast-enhanced body CT per weekday was 561, 532, and 492 (p < .001). During the three periods, the mean number of orders for CT with IV contrast media per weekday was 154, 143, and 131 (p < .001). During the three periods, the mean number of orders for CT without IV contrast media per weekday was 196, 202, and 221 (p < .001). CONCLUSION. EHR order entry-based interventions implemented in response to the global contrast media shortage significantly reduced contrast-enhanced CT utilization in a large health system. CLINICAL IMPACT. The findings indicate the ability to rapidly achieve changes in ordering clinician behavior and subsequent clinical practice using systemwide EHR changes.

Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns.

Parkinson's disease is a progressive neurodegenerative disorder characterized by the intracellular accumulation of insoluble alpha-synuclein aggregates into Lewy bodies and neurites. Increasing evidence indicates that Parkinson's disease progression results from the spread of pathologic alpha-synuclein through neuronal networks. However, the exact mechanisms underlying the propagation of abnormal proteins in the brain are only partially understood. The objective of this study was first to describe the long-term spatiotemporal distributions of Lewy-related pathology in mice injected with alpha-synuclein preformed fibrils and then to recreate these patterns using a computational model that simulates in silico the spread of pathologic alpha-synuclein. In this study, 87 2-3-month-old non-transgenic mice were injected with alpha-synuclein preformed fibrils to generate a comprehensive post-mortem dataset representing the long-term spatiotemporal distributions of hyperphosphorylated alpha-synuclein, an established marker of Lewy pathology, across the 426 regions of the Allen Mouse Brain Atlas. The mice were injected into either the caudoputamen, nucleus accumbens or hippocampus, and followed over 24 months with pathologic alpha-synuclein quantified at seven intermediate time points. The pathologic patterns observed at each time point in this high-resolution dataset were then compared to those generated using a Susceptible-Infected-Removed (SIR) computational model, an agent-based model that simulates the spread of pathologic alpha-synuclein for every brain region taking simultaneously into account the effect of regional brain connectivity and Snca gene expression. Our histopathological findings showed that differentially targeted seeding of pathological alpha-synuclein resulted in unique propagation patterns over 24 months and that most brain regions were permissive to pathology. We found that the SIR model recreated the observed distributions of pathology over 24 months for each injection site. Null models showed that both Snca gene expression and connectivity had a significant influence on model fit. In sum, our study demonstrates that the combination of normal alpha-synuclein concentration and brain connectomics contributes to making brain regions more vulnerable to the pathological process, providing support for a prion-like spread of pathologic alpha-synuclein. We propose that this rich dataset and the related computational model will help test new hypotheses regarding mechanisms that may alter the spread of pathologic alpha-synuclein in the brain.

Utility of Patient-Reported Risk Factors for Identifying Advanced Chronic Kidney Disease Before Outpatient CT: Comparison With Recent ACR/NKF Consensus Criteria.

BACKGROUND. Practices vary for screening patients for risk of renal dysfunction before administration of iodinated contrast medium. A 2020 American College of Radiology/National Kidney Foundation (ACR/NKF) consensus statement provided streamlined screening criteria. OBJECTIVE. The purpose of this study was to assess the yield of patient-reported risk factors for identifying estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 before outpatient CT. METHODS. This retrospective study was performed at a health system that implemented an electronic screening form for patients to complete before outpatient CT encounters to report undergoing dialysis, taking cancer-treating medications, having kidney disease, undergoing prior kidney surgery, having diabetes mellitus treated with medication, having hypertension treated with medication, or having multiple myeloma. Patients with any risk factor were required to undergo eGFR testing before CT. Of 44,708 patients completing the form from June 1, 2020, through February 28, 2021, 10,256 patients (5315 men, 4941 women; mean age, 66.8 ± 11.9 [SD] years; range, 21-98 years) underwent eGFR testing on the day of CT. Multivariable regression analysis for predicting reduced eGFR was performed. Findings were compared with those from theoretic use of the ACR/NKF criteria. RESULTS. Same-day testing yielded eGFR less than 30 mL/min/1.73 m2 in 1.4% (144/10,256) of patients. The only significant independent predictors of low eGFR were dialysis (odds ratio [OR], 203.30], kidney disease (OR, 12.55), and diabetes mellitus treated with medication (OR, 2.44). If the ACR/NKF criteria (only kidney disease, defined as dialysis, kidney disease, or prior kidney surgery) had been followed as a trigger for eGFR testing, the number of patients needing testing would have decreased 89.7%, from 10,256 to 1059; yield would have increased to 7.2% (76/1059); and 47.2% (68/144) of patients with low eGFR would have been missed. If the ACR/NKF criteria had been followed but diabetes mellitus been considered a required rather than an optional criterion, the number of patients needing testing would have decreased 77.1%, to 2353; yield would have increased to 4.0% (95/2353); and 34.0% (49/144) of patients with low eGFR would have been missed. CONCLUSION. Using patient-reported risk factors resulted in frequent eGFR testing but low yield of low eGFR. Commonly applied risk factors were not independently associated with low eGFR. CLINICAL IMPACT. Application of ACR/NKF criteria would substantially reduce eGFR testing, but patients with renal dysfunction would be missed. The statement should consider omitting kidney surgery as a trigger for eGFR testing and including diabetes mellitus as a required trigger.

Sex effects on brain structure in de novo Parkinson's disease: a multimodal neuroimaging study.

Parkinson's disease varies in severity and age of onset. One source of this variability is sex. Males are twice as likely as females to develop Parkinson's disease, and tend to have more severe symptoms and greater speed of progression. However, to date, there is little information in large cohorts on sex differences in the patterns of neurodegeneration. Here we used MRI and clinical information from the Parkinson Progression Markers Initiative to measure structural brain differences between sexes in Parkinson's disease after regressing out the expected effect of age and sex. We derived atrophy maps from deformation-based morphometry of T1-weighted MRI and connectivity from diffusion-weighted MRI in de novo Parkinson's disease patients (149 males: 83 females) with comparable clinical severity, and healthy control participants (78 males: 39 females). Overall, even though the two patient groups were matched for disease duration and severity, males demonstrated generally greater brain atrophy and disrupted connectivity. Males with Parkinson's disease had significantly greater tissue loss than females in 11 cortical regions including bilateral frontal and left insular lobe, right postcentral gyrus, left inferior temporal and cingulate gyrus and left thalamus, while females had greater atrophy in six cortical regions, including regions in the left frontal lobe, right parietal lobe, left insular gyrus and right occipital cortex. Local efficiency of white matter connectivity showed greater disruption in males in multiple regions such as basal ganglia, hippocampus, amygdala and thalamus. These findings support the idea that development of Parkinson's disease may involve different pathological mechanisms and yield distinct prognosis in males and females, which may have implications for research into neuroprotection, and stratification for clinical trials.

Gray matter volume and estimated brain age gap are not linked with sleep-disordered breathing.

Alzheimer's disease (AD) and sleep-disordered breathing (SDB) are prevalent conditions with a rising burden. It is suggested that SDB may contribute to cognitive decline and advanced aging. Here, we assessed the link between self-reported SDB and gray matter volume in patients with AD, mild cognitive impairment (MCI) and healthy controls (HCs). We further investigated whether SDB was associated with advanced brain aging. We included a total of 330 participants, divided based on self-reported history of SDB, and matched across diagnoses for age, sex and presence of the Apolipoprotein E4 allele, from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Gray-matter volume was measured using voxel-wise morphometry and group differences in terms of SDB, cognitive status, and their interaction were assessed. Further, using an age-prediction model fitted on gray-matter data of external datasets, we predicted study participants' age from their structural images. Cognitive decline and advanced age were associated with lower gray matter volume in various regions, particularly in the bilateral temporal lobes. Brains age was well predicted from the morphological data in HCs and, as expected, elevated in MCI and particularly in AD subjects. However, there was neither a significant difference between regional gray matter volume in any diagnostic group related to the SDB status, nor in SDB-by-cognitive status interaction. Moreover, we found no difference in estimated chronological age gap related to SDB, or by-cognitive status interaction. Contrary to our hypothesis, we were not able to find a general or a diagnostic-dependent association of SDB with either gray-matter volumetric or brain aging.

Activation of ATP-sensitive K-channel promotes the anticonvulsant properties of cannabinoid receptor agonist through mitochondrial ATP level reduction.

Cannabinoid receptor (CBR) agonist could act as a protective agent against seizure susceptibility in animal models of epilepsy. Studies have shown that potassium channels could play a key role in ameliorating neuronal excitability. In this study, we attempted to evaluate how CBRs and Adenosine Tri-Phosphate (ATP)-sensitive potassium channels collaborate to affect seizure susceptibility by changing the clonic seizure threshold (CST). We used male Naval Medical Research Institute (NMRI) mice and treated them with the following drugs: cromakalim (a potassium channel opener, 10 µg/kg), glibenclamide (a potassium channel blocker, 0.03 and 1 mg/kg), 0.5 mg/kg of AM-251 (a selective CB1 antagonist), AM-630 (a selective CB2 antagonist), and 0.5, 3, and 10 mg/kg of WIN 55,212-2 (a nonselective agonist of CBRs); and CST was appraised after each type of administration. Also, we evaluated the ATP level of the hippocampus in each treatment to clarify the interaction between the cannabinoid system and potassium channel. Our results showed that administration of WIN 55,212-2 at 10 mg/kg significantly increased CST (P < 0.001). This change could be reversed by using AM-251(P < 0.001) but not AM-630. Also, either cromakalim (10 µg/kg) or glibenclamide (0.03 and 1 mg/kg) could not significantly affect the CST. In addition, glibenclamide (1 mg/kg) could reverse the anticonvulsant effect of WIN 55,212-2 (10 mg/kg) on CST (P < 0.001). However, the anticonvulsant effect was observed when cromakalim (10 µg/kg) was added to WIN 55,212-2 at its subeffective dose (3 mg/kg) in comparison to single-treated animals. Interestingly, we observed that CB1 agonist could significantly decrease ATP level. In conclusion, CB1 agonist accomplishes at least a part of its anticonvulsant actions through ATP-sensitive potassium channels, probably by decreasing the mitochondrial ATP level to open the potassium channel to induce its anticonvulsant effect.

Relationship between cerebrospinal fluid biomarkers and structural brain network properties in Parkinson's disease.

BACKGROUND: Pathological accumulation of α-synuclein, amyloid-ß42 , and tau proteins in the brain is considered critical for development of various neurodegenerative diseases. OBJECTIVES: We investigated the association between CSF levels of these biomarkers, brain structural connectivity, and the UPDRS in PD. METHODS: Diffusion tensor images and CSF biomarkers (α-synuclein, amyloid-ß42 , total tau, and phosphorylated tau181) from 132 drug-naïve, nondemented PD patients and 61 healthy controls were obtained from the Parkinson's Progression Markers Initiative database. After network reconstruction of structural connectivity patterns, global interconnectivity measures (including global efficiency, clustering coefficient, and characteristic path length) and local efficiency were calculated. Network properties and CSF biomarkers were compared between PD patients and healthy controls. The association of CSF biomarkers with network properties and UPDRS-III score was investigated. RESULTS: Global measures (but not local efficiency) and CSF α-synuclein were significantly lower in PD patients. Global efficiency and clustering coefficient correlated positively with α-synuclein, Aß42 , and total tau CSF levels. Furthermore, these CSF biomarkers showed no significant association with the UPDRS-III score. CONCLUSIONS: This study examined the association of CSF biomarkers that reflect the brain pathology, with structural brain connectivity and UPDRS-III in PD. Our results revealed an association between the abnormal aggregation of α-synuclein, Aß42 , and tau proteins and structural connectivity disruption in PD patients. In summary, a combination of structural imaging and measurement of CSF biomarkers provide a better understanding of the pathogenesis of PD. © 2018 International Parkinson and Movement Disorder Society.

The Impact of Mammographic, Radiologist, and Patient Factors on the Likelihood of Probably Benign (BI-RADS 3) Assessment at Diagnostic Mammography.

OBJECTIVE: To evaluate the association of mammographic, radiologist, and patient factors on BI-RADS 3 assessment at diagnostic mammography in patients recalled from screening mammography. METHODS: This Institutional Review Board-approved retrospective study of consecutive unique diagnostic mammography examinations in asymptomatic patients recalled from screening mammography March 5, 2014, to December 31, 2019, was conducted in a single large United States health care institution. Mammographic features (mass, calcification, distortion, asymmetry), breast density, prior examination, and BI-RADS assessment were extracted from reports by natural language processing. Patient age, race, and ethnicity were extracted from the electronic health record. Radiologist years in practice, recall rate, and number of interpreted diagnostic mammograms were calculated. A mixed effect logistic regression model evaluated factors associated with likelihood of BI-RADS 3 compared with other BI-RADS assessments. RESULTS: A total of 12 080 diagnostic mammography examinations were performed during the study period, yielding 2010 (16.6%) BI-RADS 3 and 10 070 (83.4%) other BI-RADS assessments. Asymmetry (odds ratio [OR] = 6.49, P <.001) and calcification (OR = 5.59, P <.001) were associated with increased likelihood of BI-RADS 3 assessment; distortion (OR = 0.20, P <.001), dense breast parenchyma (OR = 0.82, P <.001), prior examination (OR = 0.63, P = .01), and increasing patient age (OR = 0.99, P <.001) were associated with decreased likelihood. Mass, patient race or ethnicity, and radiologist factors were not significantly associated with BI-RADS 3 assessment. Malignancy rate for BI-RADS 3 lesions was 1.6%. CONCLUSION: Asymmetry and calcifications had an increased likelihood of BI-RADS 3 assessment at diagnostic evaluation with low likelihood of malignancy, while radiologist features had no association.

Actionability of Recommendations for Additional Imaging in Head and Neck Radiology.

PURPOSE: The aims of this study were to measure the actionability of recommendations for additional imaging (RAIs) in head and neck CT and MRI, for which there is a near complete absence of best practices or guidelines; to identify the most common recommendations; and to assess radiologist factors associated with actionability. METHODS: All head and neck CT and MRI radiology reports across a multi-institution, multipractice health care system from June 1, 2021, to May 31, 2022, were retrospectively reviewed. The actionability of RAIs was scored using a validated taxonomy. The most common RAIs were identified. Actionability association with radiologist factors (gender, years out of training, fellowship training, practice type) and with trainees was measured using a mixed-effects model. RESULTS: Two hundred nine radiologists generated 60,543 reports, of which 7.2% (n = 4,382) contained RAIs. Only 3.9% of RAIs (170 of 4,382) were actionable. More than 60% of RAIs were for eight examinations: thyroid ultrasound (14.1%), neck CT (12.6%), brain MRI (6.9%), chest CT (6.5%), neck CT angiography (5.5%), temporal bone CT (5.3%), temporal bone MRI (5.2%), and pituitary MRI (4.6%). Radiologists >23 years out of training (odds ratio, 0.39; 95% confidence interval, 0.15-1.02; P = .05) and community radiologists (odds ratio, 0.53; 95% confidence interval, 0.22-1.31; P = .17) had substantially lower estimated odds of making actionable RAIs than radiologists <7 years out of training and academic radiologists, respectively. CONCLUSIONS: The studied radiologists rarely made actionable RAIs, which makes it difficult to identify and track clinically necessary RAIs to timely performance. Multifaceted quality improvement initiatives including peer comparisons, clinical decision support at the time of reporting, and the development of evidence-based best practices, may help improve tracking and timely performance of clinically necessary RAIs.

Development and Assessment of an Information Technology Intervention to Improve the Clarity of Radiologist Follow-up Recommendations.

Importance: It is challenging to ensure timely performance of radiologist-recommended additional imaging when radiologist recommendation language is incomplete or ambiguous. Objective: To evaluate whether voluntary use of an information technology tool with forced structured entry of recommendation attributes was associated with improved completeness of recommendations for additional imaging over time. Design, Setting, and Participants: This cohort study of imaging report data was performed at an academic quaternary care center in Boston, Massachusetts, and included consecutive adults with radiology examinations performed from September 12 to 13, 2019 (taxonomy validation), October 14 to 17, 2019 (before intervention), April 5 to 7, 2021 (1 week after intervention), and April 4 to 7, 2022 (1 year after intervention), with reports containing recommendations for additional imaging. A radiologist scored the 3 groups (preintervention group, 1-week postintervention group, and 1-year postintervention group) of 336 consecutive radiology reports (n = 1008) with recommendations for additional imaging. Intervention: Final implementation on March 27, 2021, of a voluntary closed-loop communication tool embedded in radiologist clinical workflow that required structured entry of recommendation attributes. Main Outcomes and Measures: The a priori primary outcome was completeness of recommendations for additional imaging, defined in a taxonomy created by a multidisciplinary expert panel. To validate the taxonomy, 2 radiologists independently reviewed and scored language attributes as present or absent in 247 consecutive radiology reports containing recommendations for additional imaging. Agreement was assessed with Cohen κ. Recommendation completeness over time was compared with with 1-sided Fisher exact tests and significance set at P < .05. Results: Radiology-related information for consecutive radiology reports from the 4 time periods was collected from the radiology department data warehouse, which does not include data on patient demographic characteristics or other nonimaging patient medical information. The panel defined 5 recommendation language attributes: complete (contains imaging modality, time frame, and rationale), ambiguous (equivocal, vague language), conditional (qualifying language), multiplicity (multiple options), and alternate (language favoring a different examination to that ordered). Two radiologists had more than 90% agreement (κ > 0.8) for these attributes. Completeness with use of the tool increased more than 3-fold, from 14% (46 of 336) before the intervention to 46% (153 of 336) (P < .001) 1 year after intervention; completeness in the corresponding free-text report language increased from 14% (46 of 336) before the intervention to 25% (85 of 336) (P < .001) 1 year after the intervention. Conclusions and Relevance: This study suggests that supplementing free-text dictation with voluntary use of a structured entry tool was associated with improved completeness of radiologist recommendations for additional imaging as assessed by an internally validated taxonomy. Future research is needed to assess the association with timely performance of clinically necessary recommendations and diagnostic errors. The taxonomy can be used to evaluate and build interventions to modify radiologist reporting behaviors.

Complementary hemispheric lateralization of language and social processing in the human brain.

Humans have a unique ability to use language for social communication. The neural architecture for language comprehension and production may have prominently emerged in the brain areas that were originally involved in social cognition. Here, we directly tested the fundamental link between language and social processing using functional magnetic resonance data (MRI) data from over 1,000 human subjects. Cortical activations in language and social tasks showed a striking similarity with a complementary hemispheric lateralization. Within core language areas, left-lateralized activations in the language task were mirrored by right-lateralized activations in the social task. Outside these areas, the activations were left lateralized in both tasks, perhaps indicating multimodal integration of social and semantic information. Our findings could have important implications in understanding neurocognitive mechanisms of social disorders such as autism.

The clinical significance of histone deacetylase-8 in human breast cancer.

Recent studies have shown that the histone deacetylase-8 (HDAC8), as one of the HDACs, regulates the expression and activity of various genes involved in cancer initiation and progression. The HDAC8 plays an epigenetic role to dysregulate expressions or to interact with transcription factors. Most researchers had focused on the HDAC 1-3 and 6, but today the HDAC8 isotype is a promising target in cancer therapy. Different studies, on breast cancer (BC) cells, have recently shown the HDAC8 overexpression and suggested its oncogenic potential. It seems that the HDAC8 could be a novel and promising target in breast cancer treatment. Some studies on BC demonstrated therapeutic properties of the inhibitors of HDAC8 such as suberoylanilide hydroxamic acid (SAHA), Trichostatin A, valproic acid, sodium butyrate, 1,3,4 oxadiazole with alanine hybrid [(R)-2-amino-N-((5-phenyl-1,3,4-oxadiazol-2-yl) methyl) propanamide (10b)], N-(2-Hydroxyphenyl)-2propylpentanamide (compound 2) and PCI-34051. In this review, we highlight the role and existing inhibitors of HDAC8 in BC pathogenesis and therapy.

Brain atrophy progression in Parkinson's disease is shaped by connectivity and local vulnerability.

Brain atrophy has been reported in the early stages of Parkinson's disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell-type distribution and gene expression combine to determine the pattern of disease progression also remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here, we used MRI data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over 1, 2 and 4 years compared with baseline. We derived atrophy maps for four time points using deformation-based morphometry applied to T1-weighted MRI from 120 de novo Parkinson's disease patients, 74 of whom had imaging at all four time points (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). In order to determine factors that may influence neurodegeneration, we related atrophy progression to brain structural and functional connectivity, cell-type expression and gene ontology enrichment analyses. After regressing out the expected age and sex effects associated with normal ageing, we found that atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was inversely related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson's disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson's disease. All brain maps generated here are available on request.

Orbitofrontal-Striatal Structural Alterations Linked to Negative Symptoms at Different Stages of the Schizophrenia Spectrum.

Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset.

Genetic influence is linked to cortical morphology in category-selective areas of visual cortex.

Human visual cortex contains discrete areas that respond selectively to specific object categories such as faces, bodies, and places. A long-standing question is whether these areas are shaped by genetic or environmental factors. To address this question, here we analyzed functional MRI data from an unprecedented number (n = 424) of monozygotic (MZ) and dizygotic (DZ) twins. Category-selective maps were more identical in MZ than DZ twins. Within each category-selective area, distinct subregions showed significant genetic influence. Structural MRI analysis revealed that the 'genetic voxels' were predominantly located in regions with higher cortical curvature (gyral crowns in face areas and sulcal fundi in place areas). Moreover, we found that cortex was thicker and more myelinated in genetic voxels of face areas, while it was thinner and less myelinated in genetic voxels of place areas. This double dissociation suggests a differential development of face and place areas in cerebral cortex.

White Matter Microstructural Properties Associated with Impaired Attention in Chronic Schizophrenia: A Multi-Center Study.

Attention as a key cognitive function is impaired in schizophrenia, interfering with the normal daily life of the patients. Previous studies on the microstructural correlates of attention in schizophrenia were limited to single fibers, did not include a control group, or did not adjust for drug dosage. In the current study, we investigated the association between microstructural properties of the white matter fibers and attention tests in 81 patients and 79 healthy controls from the Mind Clinical Imaging Consortium database. Integrity measures of superior longitudinal fasciculus, cingulum, genu, and splenium were extracted after tractography. Using an interaction model between diagnosis and microstructural properties, and adjusting for age, gender, acquisition site, education, and cumulative drug usage dose, and after correcting for family-wise error, we showed decreased integrity in the patients and a significant negative association between fractional anisotropy of the tracts and trail making test part A with a greater expected decrease in the attention per unit of decrease of integrity in the patients compared to the healthy controls. Our findings suggest that decreased integrity of the bilateral cingulum, and splenium, are independent of the cumulative drug dosage, age, gender, and site, and may underlie the impaired attention in the schizophrenia.

Predicting severity and prognosis in Parkinson's disease from brain microstructure and connectivity.

OBJECTIVES: Investigating biomarkers to demonstrate progression of Parkinson's disease (PD) is of high priority. We investigated the association of brain structural properties with progression of clinical outcomes and their ability to differentiate clinical subtypes of PD. METHODS: A comprehensive set of clinical features was evaluated at baseline and 4.5-year follow-up for 144 de-novo PD patients from the Parkinson's Progression Markers Initiative. We created a global composite outcome (GCO) by combining z-scores of non-motor and motor symptoms, motor signs, overall activities of daily living and global cognition, as a single numeric indicator of prognosis. We classified patients into three subtypes based on multi-domain clinical criteria: 'mild motor-predominant', 'intermediate' and 'diffuse-malignant'. We analyzed diffusion-weighted scans at the early drug-naïve stage and extracted fractional anisotropy and mean diffusivity (MD) of basal ganglia and cortical sub-regions. Then, we employed graph theory to calculate network properties and used network-based statistic to investigate our primary hypothesis. RESULTS: Baseline MD of globus pallidus was associated with worsening of motor severity, cognition, and GCO after 4.5 years of follow-up. Connectivity disruption at baseline was correlated with decline in cognition, and increase in GCO. Baseline MD of nucleus accumbens, globus pallidus and basal-ganglia were linked to clinical subtypes at 4.5-year of follow-up. Disruption in sub-cortical networks associated with being subtyped as 'diffuse-malignant' versus 'mild motor-predominant' after 4.5 years. CONCLUSIONS: Diffusion imaging analysis at the early de-novo stage of PD was able to differentiate clinical sub-types of PD after 4.5 years and was highly associated with future clinical outcomes of PD.