Sex differences and age-related changes in vertebral body volume and volumetric bone mineral density at the thoracolumbar spine using opportunistic QCT.

Objectives: To quantitatively investigate the age- and sex-related longitudinal changes in trabecular volumetric bone mineral density (vBMD) and vertebral body volume at the thoracolumbar spine in adults. Methods: We retrospectively included 168 adults (mean age 58.7 ± 9.8 years, 51 women) who received ≥7 MDCT scans over a period of ≥6.5 years (mean follow-up 9.0 ± 2.1 years) for clinical reasons. Level-wise vBMD and vertebral body volume were extracted from 22720 thoracolumbar vertebrae using a convolutional neural network (CNN)-based framework with asynchronous calibration and correction of the contrast media phase. Human readers conducted semiquantitative assessment of fracture status and bony degenerations. Results: In the 40-60 years age group, women had a significantly higher trabecular vBMD than men at all thoracolumbar levels (p<0.05 to p<0.001). Conversely, men, on average, had larger vertebrae with lower vBMD. This sex difference in vBMD did not persist in the 60-80 years age group. While the lumbar (T12-L5) vBMD slopes in women only showed a non-significant trend of accelerated decline with age, vertebrae T1-11 displayed a distinct pattern, with women demonstrating a significantly accelerated decline compared to men (p<0.01 to p<0.0001). Between baseline and last follow-up examinations, the vertebral body volume slightly increased in women (T1-12: 1.1 ± 1.0 cm3; L1-5: 1.0 ± 1.4 cm3) and men (T1-12: 1.2 ± 1.3 cm3; L1-5: 1.5 ± 1.6 cm3). After excluding vertebrae with bony degenerations, the residual increase was only small in women (T1-12: 0.6 ± 0.6 cm3; L1-5: 0.7 ± 0.7 cm3) and men (T1-12: 0.7 ± 0.6 cm3; L1-5: 1.2 ± 0.8 cm3). In non-degenerated vertebrae, the mean change in volume was <5% of the respective vertebral body volumes. Conclusion: Sex differences in thoracolumbar vBMD were apparent before menopause, and disappeared after menopause, likely attributable to an accelerated and more profound vBMD decline in women at the thoracic spine. In patients without advanced spine degeneration, the overall volumetric changes in the vertebral body appeared subtle.

Long-term reproducibility of opportunistically assessed vertebral bone mineral density and texture features in routine clinical multi-detector computed tomography using an automated segmentation framework.

Background: To investigate reproducibility of texture features and volumetric bone mineral density (vBMD) extracted from trabecular bone in the thoracolumbar spine in routine clinical multi-detector computed tomography (MDCT) data in a single scanner environment. Methods: Patients who underwent two routine clinical thoraco-abdominal MDCT exams at a single scanner with a time interval of 6 to 26 months (n=203, 131 males; time interval mean, 13 months; median, 12 months) were included in this observational study. Exclusion criteria were metabolic and hematological disorders, bone metastases, use of bone-active medications, and history of osteoporotic vertebral fractures (VFs) or prior diagnosis of osteoporosis. A convolutional neural network (CNN)-based framework was used for automated spine labeling and segmentation (T5-L5), asynchronous Hounsfield unit (HU)-to-BMD calibration, and correction for the intravenous contrast medium phase. Vertebral vBMD and six texture features [varianceglobal, entropy, short-run emphasis (SRE), long-run emphasis (LRE), run-length non-uniformity (RLN), and run percentage (RP)] were extracted for mid- (T5-T8) and lower thoracic (T9-T12), and lumbar vertebrae (L1-L5), respectively. Relative annual changes were calculated in texture features and vBMD for each vertebral level and sorted by sex, and changes were checked for statistical significance (P<0.05) using paired t-tests. Root mean square coefficient of variation (RMSCV) and root mean square error (RMSE) were calculated as measures of variability. Results: SRE, LRE, RLN, and RP exhibited substantial reproducibility with RMSCV-values below 2%, for both sexes and at all spine levels, while vBMD was less reproducible (RMSCV =11.9-16.2%). Entropy showed highest variability (RMSCV =4.34-7.69%) due to statistically significant increases [range, mean ± standard deviation: (4.40±5.78)% to (8.36±8.66)%, P<0.001]. RMSCV of varianceglobal ranged from 1.60% to 3.03%. Conclusions: Opportunistic assessment of texture features in a single scanner environment using the presented CNN-based framework yields substantial reproducibility, outperforming vBMD reproducibility. Lowest scan-rescan variability was found for higher-order texture features. Further studies are warranted to determine, whether microarchitectural changes to the trabecular bone may be assessed through texture features.

Cost-effectiveness of opportunistic QCT-based osteoporosis screening for the prediction of incident vertebral fractures.

Objectives: Opportunistic quantitative computed tomography (oQCT) derived from non-dedicated routine CT has demonstrated high accuracy in diagnosing osteoporosis and predicting incident vertebral fractures (VFs). We aimed to investigate the cost-effectiveness of oQCT screening compared to dual-energy X-ray absorptiometry (DXA) as the standard of care for osteoporosis screening. Methods: Three screening strategies ("no osteoporosis screening", "oQCT screening", and "DXA screening") after routine CT were simulated in a state-transition model for hypothetical cohorts of 1,000 patients (women and men aged 65 years) over a follow-up period of 5 years (base case). The primary outcomes were the cumulative costs and the quality-adjusted life years (QALYs) estimated from a U.S. health care perspective for the year 2022. Cost-effectiveness was assessed based on a willingness-to-pay (WTP) threshold of $70,249 per QALY. The secondary outcome was the number of prevented VFs. Deterministic and probabilistic sensitivity analyses were conducted to test the models' robustness. Results: Compared to DXA screening, oQCT screening increased QALYs in both sexes (additional 2.40 per 1,000 women and 1.44 per 1,000 men) and resulted in total costs of $3,199,016 and $950,359 vs. $3,262,934 and $933,077 for women and men, respectively. As a secondary outcome, oQCT screening prevented 2.6 and 2.0 additional VFs per 1,000 women and men, respectively. In the probabilistic sensitivity analysis, oQCT screening remained cost-effective in 88.3% (women) and 90.0% (men) of iterations. Conclusion: oQCT screening is a cost-effective ancillary approach for osteoporosis screening and has the potential to prevent a substantial number of VFs if considered in daily clinical practice.

Incidental vertebral fracture prediction using neuronal network-based automatic spine segmentation and volumetric bone mineral density extraction from routine clinical CT scans.

Objectives: To investigate vertebral osteoporotic fracture (VF) prediction by automatically extracted trabecular volumetric bone mineral density (vBMD) from routine CT, and to compare the model with fracture prevalence-based prediction models. Methods: This single-center retrospective study included patients who underwent two thoraco-abdominal CT scans during clinical routine with an average inter-scan interval of 21.7 ± 13.1 months (range 5-52 months). Automatic spine segmentation and vBMD extraction was performed by a convolutional neural network framework (anduin.bonescreen.de). Mean vBMD was calculated for levels T5-8, T9-12, and L1-5. VFs were identified by an expert in spine imaging. Odds ratios (ORs) for prevalent and incident VFs were calculated for vBMD (per standard deviation decrease) at each level, for baseline VF prevalence (yes/no), and for baseline VF count (n) using logistic regression models, adjusted for age and sex. Models were compared using Akaike's and Bayesian information criteria (AIC & BIC). Results: 420 patients (mean age, 63 years ± 9, 276 males) were included in this study. 40 (25 female) had prevalent and 24 (13 female) had incident VFs. Individuals with lower vBMD at any spine level had higher odds for VFs (L1-5, prevalent VF: OR,95%-CI,p: 2.2, 1.4-3.5,p=0.001; incident VF: 3.5, 1.8-6.9,p<0.001). In contrast, VF status (2.15, 0.72-6.43,p=0.170) and count (1.38, 0.89-2.12,p=0.147) performed worse in incident VF prediction. Information criteria revealed best fit for vBMD-based models (AIC vBMD=165.2; VF status=181.0; count=180.7). Conclusions: VF prediction based on automatically extracted vBMD from routine clinical MDCT outperforms prediction models based on VF status and count. These findings underline the importance of opportunistic quantitative osteoporosis screening in clinical routine MDCT data.

Endovascular thrombectomy is cost-effective in acute basilar artery occlusion stroke.

Objective: Endovascular thrombectomy is a long-established therapy for acute basilar artery occlusion (aBAO). Unlike for anterior circulation stroke, cost-effectiveness of endovascular treatment has not been evaluated and is urgently needed to calculate expected health benefits and financial rewards. The aim of this study was therefore to simulate patient-level costs, analyze the economic potential of endovascular thrombectomy in patients with acute basilar artery occlusion (aBAO), and identify major determinants of cost-effectiveness. Methods: A Markov model was developed to compare outcome and cost parameters between patients treated by endovascular thrombectomy and patients treated by best medical care, based on four recent prospective clinical trials (ATTENTION, BAOCHE, BASICS, and BEST). Treatment outcomes were derived from the most recent literature. Uncertainty was addressed by deterministic and probabilistic sensitivity analyses. Willingness to pay per QALY thresholds were set at 1x gross domestic product per capita, as recommended by the World Health Organization. Results: Endovascular treatment of acute aBAO stroke yielded an incremental gain of 1.71 quality-adjusted life-years per procedure with an incremental cost-effectiveness ratio of $7,596 per QALY. This was substantially lower than the Willingness to pay of $63,593 per QALY. Lifetime costs were most sensitive to costs of the endovascular procedure. Conclusion: Endovascular treatment is cost-effective in patients with aBAO stroke.

DUSP15 expression is reduced in the hippocampus of Myrf knock-out mice but attention and object recognition memory remain intact.

The atypical protein tyrosine phosphatase enzyme, dual-specificity phosphate 15 (DUSP15) is thought to be activated by myelin regulatory factor (MyRF) and to have a role in oligodendrocyte differentiation. Here, we assess whether Dusp15 is reduced in the hippocampus of mice with conditional knock-out of Myrf in oligodendrocyte precursor cells. Using quantitative polymerase chain reaction (qPCR) we found that Dusp15 expression was indeed lower in these mice. Alterations in myelin have been associated with Alzheimer's disease (AD), autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Symptoms of these disorders can include impairments of object recognition and attention. We, therefore tested the mice in the object recognition task (ORT) and 5-choice serial reaction time task (5CSRTT). However, we did not find behavioural impairments indicating that attentional abilities and object recognition are not impacted by reduced oligodendrogenesis and hippocampal Dusp15 expression. Gaining insight into the role of newly formed oligodendrocytes and Dusp15 expression is helpful for the development of well targeted treatments for myelin dysregulation.

Automated Opportunistic Osteoporosis Screening in Routine Computed Tomography of the Spine: Comparison With Dedicated Quantitative CT.

Opportunistic osteoporosis screening in nondedicated routine computed tomography (CT) is of increasing importance. The purpose of this study was to compare lumbar volumetric bone mineral density (vBMD) assessed by a convolutional neural network (CNN)-based framework in routine CT to vBMD from dedicated quantitative CT (QCT), and to evaluate the ability of vBMD and surrogate measurements of Hounsfield units (HU) to distinguish between patients with and without osteoporotic vertebral fractures (VFs). A total of 144 patients (median age: 70.7 years, 93 females) with clinical routine CT (eight different CT scanners, 120 kVp or 140 kVp, with and without intravenous contrast medium) and dedicated QCT acquired within ≤30 days were included. Vertebral measurements included (i) vBMD from the CNN-based approach including automated vertebral body labeling, segmentation, and correction of the contrast media phase for routine CT data (vBMD_OPP), (ii) vBMD from dedicated QCT (vBMD_QCT), and (iii) noncalibrated HU from vertebral bodies of routine CT data as previously proposed for immanent opportunistic osteoporosis screening based on CT attenuation. The intraclass correlation coefficient (ICC) for vBMD_QCT versus vBMD_OPP indicated better agreement (ICC = 0.913) than the ICC for vBMD_QCT versus noncalibrated HU (ICC = 0.704). Bland-Altman analysis showed data points from 137 patients (95.1%) within the limits of agreement (LOA) of -23.2 to 25.0 mg/cm3 for vBMD_QCT versus vBMD_OPP. Osteoporosis (vBMD <80 mg/cm3 ) was detected in 89 patients (vBMD_QCT) and 88 patients (vBMD_OPP), whereas no patient crossed the diagnostic thresholds from normal vBMD to osteoporosis or vice versa. In a subcohort of 88 patients (thoracolumbar spine covered by imaging for VF reading), 69 patients showed one or more prevalent VFs, and the performance for discrimination between patients with and without VFs was best for vBMD_OPP (area under the curve [AUC] = 0.862; 95% confidence interval [CI], 0.771-0.953). In conclusion, automated opportunistic osteoporosis screening in routine CT of various scanner setups is feasible and may demonstrate high diagnostic accuracy for prevalent VFs. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Proposed diagnostic volumetric bone mineral density thresholds for osteoporosis and osteopenia at the cervicothoracic spine in correlation to the lumbar spine.

OBJECTIVES: To determine the correlation between cervicothoracic and lumbar volumetric bone mineral density (vBMD) in an average cohort of adults and to identify specific diagnostic thresholds for the cervicothoracic spine on the individual subject level. METHODS: In this HIPPA-compliant study, we retrospectively included 260 patients (59.7 ± 18.3 years, 105 women), who received a contrast-enhanced or non-contrast-enhanced CT scan. vBMD was extracted using an automated pipeline ( https://anduin.bonescreen.de ). The association of vBMD between each vertebra spanning C2-T12 and the averaged values at the lumbar spine (L1-L3) was analyzed before and after semiquantitative assessment of fracture status and degeneration, and respective vertebra-specific cut-off values for osteoporosis were calculated using linear regression. RESULTS: In both women and men, trabecular vBMD decreased with age in the cervical, thoracic, and lumbar regions. vBMD values of cervicothoracic vertebrae showed strong correlations with lumbar vertebrae (L1-L3), with a median Pearson value of r = 0.87 (range: rC2 = 0.76 to rT12 = 0.96). The correlation coefficients were significantly lower (p < 0.0001) without excluding fractured and degenerated vertebrae, median r = 0.82 (range: rC2 = 0.69 to rT12 = 0.93). Respective cut-off values for osteoporosis peaked at C4 (209.2 mg/ml) and decreased to 83.8 mg/ml at T12. CONCLUSION: Our data show a high correlation between clinically used mean L1-L3 values and vBMD values elsewhere in the spine, independent of age. The proposed cut-off values for the cervicothoracic spine therefore may allow the determination of low bone mass even in clinical cases where only parts of the spine are imaged. KEY POINTS: vBMD of all cervicothoracic vertebrae showed strong correlation with lumbar vertebrae (L1-L3), with a median Pearson's correlation coefficient of r = 0.87 (range: rC2 = 0.76 to rT12 = 0.96). The correlation coefficients were significantly lower (p < 0.0001) without excluding fractured and moderate to severely degenerated vertebrae, median r = 0.82 (range: rC2 = 0.69 to rT12 = 0.93). We postulate that trabecular vBMD < 200 mg/ml for the cervical spine and < 100 mg/ml for the thoracic spine are strong indicators of osteoporosis, similar to < 80 mg/ml at the lumbar spine.

Automated detection of the contrast phase in MDCT by an artificial neural network improves the accuracy of opportunistic bone mineral density measurements.

OBJECTIVES: To determine the accuracy of an artificial neural network (ANN) for fully automated detection of the presence and phase of iodinated contrast agent in routine abdominal multidetector computed tomography (MDCT) scans and evaluate the effect of contrast correction for osteoporosis screening. METHODS: This HIPPA-compliant study retrospectively included 579 MDCT scans in 193 patients (62.4 ± 14.6 years, 48 women). Three different ANN models (2D DenseNet with random slice selection, 2D DenseNet with anatomy-guided slice selection, 3D DenseNet) were trained in 462 MDCT scans of 154 patients (threefold cross-validation), who underwent triphasic CT. All ANN models were tested in 117 unseen triphasic scans of 39 patients, as well as in a public MDCT dataset containing 311 patients. In the triphasic test scans, trabecular volumetric bone mineral density (BMD) was calculated using a fully automated pipeline. Root-mean-square errors (RMSE) of BMD measurements with and without correction for contrast application were calculated in comparison to nonenhanced (NE) scans. RESULTS: The 2D DenseNet with anatomy-guided slice selection outperformed the competing models and achieved an F1 score of 0.98 and an accuracy of 98.3% in the test set (public dataset: F1 score 0.93; accuracy 94.2%). Application of contrast agent resulted in significant BMD biases (all p < .001; portal-venous (PV): RMSE 18.7 mg/ml, mean difference 17.5 mg/ml; arterial (AR): RMSE 6.92 mg/ml, mean difference 5.68 mg/ml). After the fully automated correction, this bias was no longer significant (p > .05; PV: RMSE 9.45 mg/ml, mean difference 1.28 mg/ml; AR: RMSE 3.98 mg/ml, mean difference 0.94 mg/ml). CONCLUSION: Automatic detection of the contrast phase in multicenter CT data was achieved with high accuracy, minimizing the contrast-induced error in BMD measurements. KEY POINTS: • A 2D DenseNet with anatomy-guided slice selection achieved an F1 score of 0.98 and an accuracy of 98.3% in the test set. In a public dataset, an F1 score of 0.93 and an accuracy of 94.2% were obtained. • Automated adjustment for contrast injection improved the accuracy of lumbar bone mineral density measurements (RMSE 18.7 mg/ml vs. 9.45 mg/ml respectively, in the portal-venous phase). • An artificial neural network can reliably reveal the presence and phase of iodinated contrast agent in multidetector CT scans ( https://github.com/ferchonavarro/anatomy_guided_contrast_c ). This allows minimizing the contrast-induced error in opportunistic bone mineral density measurements.

Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with episodes of inflammatory demyelination and remyelination. While remyelination has been linked with functional recovery in MS patients, there is evidence of ongoing tissue damage despite complete myelin repair. In this study, we investigated the long-term consequences of an acute demyelinating white matter CNS lesion. For this purpose, acute demyelination was induced by 5-week-cuprizone intoxication in male C57BL/6 J mice, and the tissues were examined after a 7-month recovery period. While myelination and oligodendrocyte densities appeared normal, ongoing axonal degeneration and glia cell activation were found in the remyelinated corpus callosum. Neuropathologies were paralleled by subtle gait abnormalities evaluated using DigiGait™ high speed ventral plane videography. Gene array analyses revealed increased expression levels of various inflammation related genes, among protein kinase c delta (PRKCD). Immunofluorescence stains revealed predominant microglia/macrophages PRKCD expression in both, cuprizone tissues and post-mortem MS lesions. These results support the hypothesis that chronic microglia/macrophages driven tissue injury represents a key aspect of progressive neurodegeneration and functional decline in MS.

High Speed Ventral Plane Videography as a Convenient Tool to Quantify Motor Deficits during Pre-Clinical Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is the most commonly used multiple sclerosis animal model. EAE mice typically develop motor deficits in a caudal-to-rostral pattern when inflammatory lesions have already developed. However, to monitor more subtle behavioral deficits during lesion development (i.e., pre-clinical phase), more sophisticated methods are needed. Here, we investigated whether high speed ventral plane videography can be applied to monitor early motor deficits during 'pre-clinical' EAE. For this purpose, EAE was induced in C57BL/6 mice and gait abnormalities were quantified using the DigiGait™ apparatus. Gait deficits were related to histopathological changes. 10 out of 10 control (100%), and 14 out of 18 (77.8%) pre-clinical EAE mice could be evaluated using DigiGait™. EAE severity was not influenced by DigiGait™-related mice handlings. Most gait parameters recorded from day 6 post-immunization until the end of the experiment were found to be stable in control mice. During the pre-clinical phase, when conventional EAE scorings failed to detect any functional impairment, EAE mice showed an increased Swing Time, increased %Swing Stride, decreased %Stance Stride, decreased Stance/Swing, and an increased Absolute Paw Angle. In summary, DigiGait™ is more sensitive than conventional scoring approaches to study motor deficits during the EAE pre-clinical phase.

Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination.

Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to brain atrophy are poorly understood, partly due to the lack of appropriate animal models to study this aspect of the disease. The purpose of this study was to assess brain volumes and neuro-axonal degeneration after acute and chronic cuprizone-induced demyelination. C57BL/6 male mice were intoxicated with cuprizone for up to 12 weeks. Brain volume, as well as total numbers and densities of neurons, were determined using design-based stereology. After five weeks of cuprizone intoxication, despite severe demyelination, brain volumes were not altered at this time point. After 12 weeks of cuprizone intoxication, a significant volume reduction was found in the corpus callosum and diverse subcortical areas, particularly the internal capsule and the thalamus. Thalamic volume loss was accompanied by glucose hypermetabolism, analyzed by [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography. This study demonstrates region-specific brain atrophy of different subcortical brain regions after chronic cuprizone-induced demyelination. The chronic cuprizone demyelination model in male mice is, thus, a useful tool to study the underlying mechanisms of subcortical brain atrophy and to investigate the effectiveness of therapeutic interventions.

Visualization of the Breakdown of the Axonal Transport Machinery: a Comparative Ultrastructural and Immunohistochemical Approach.

Axonal damage is a major factor contributing to disease progression in multiple sclerosis (MS) patients. On the histological level, acute axonal injury is most frequently analyzed by anti-amyloid precursor protein immunohistochemistry. To what extent this method truly detects axonal injury, and whether other proteins and organelles are as well subjected to axonal transport deficits in demyelinated tissues is not known. The aim of this study was to correlate ultrastructural morphology with the immunohistochemical appearance of acute axonal injury in a model of toxin-induced oligodendrocyte degeneration. C57BL/6J mice were intoxicated with 0.25% cuprizone to induce demyelination. The corpus callosum was investigated by serial block-face scanning electron microscopy (i.e., 3D EM), immunohistochemistry, and immunofluorescence microscopy. Brain tissues of progressive MS patients were included to test the relevance of our findings in mice for MS. Volumes of axonal swellings, determined by 3D EM, were comparable to volumes of axonal spheroids, determined by anti-APP immunofluorescence stains. Axonal swellings were present at myelinated and non-myelinated axonal internodes. Densities of amyloid precursor protein (APP)+ spheroids were highest during active demyelination. Besides APP, vesicular glutamate transporter 1 and mitochondrial proteins accumulated at sites of axonal spheroids. Such accumulations were found as well in lesions of progressive MS patients. In this correlative ultrastructural-immunohistochemical study, we provide strong evidence that breakdown of the axonal transport machinery results in focal accumulations of mitochondria and different synaptic proteins. We provide new marker proteins to visualize acute axonal injury, which helps to further understand the complex nature of axonal damage in progressive MS.