Evaluation of amyloid status in a cohort of elderly individuals with memory complaints: validation of the method of quantification and determination of positivity thresholds

Objective

Our aim is to validate the process steps implemented by the French CATI platform to assess amyloid status, obtained from 18F-Florbetapir PET scans, in a cohort of 318 cognitively normal subjects participating in the INSIGHT-preAD study. Our objective was to develop a method with partial volume effect correction (PVEC) on untransformed PET images, using an automated pipeline (“RACHEL”) adapted to large series of patients and including quality checks of results.

Methods

We compared RACHEL using different options (with and without PVEC, different sets of regions of interest), to two other methods validated in the literature, referred as the “AVID” and “CAEN” methods. A standard uptake value ratio (SUVR) was obtained with the different methods for participants to another French study, IMAP, including 26 normal elderly controls (NEC), 11 patients with mild cognitive impairment (MCI) and 16 patients with Alzheimer’s disease (AD). We determined two cutoffs for RACHEL method by linear correlation with the other methods and applied them to the INSIGHT-preAD subjects.

Results

RACHEL including PVEC and a combination of the whole cerebellum and the pons as a reference region allowed the best discrimination between NEC and AD participants. A strong linear correlation was found between RACHEL and the other two methods and yielded the two cutoffs of 0.79 and 0.88. According to the more conservative threshold, 19.8% of the INSIGHT-preAD subjects would be considered amyloid positive, and 27.7% according to the more liberal threshold.

Conclusions

With our method, we clearly discriminated between NEC with negative amyloid status and patients with clinical AD. Using a linear correlation with other validated cutoffs, we could infer our own positivity thresholds and apply them to an independent population. This method might be useful to the community, especially when the optimal cutoff could not be obtained from a population of healthy young adults or from correlation with post-mortem results.

     

Detection and quantification of chronic cerebrovascular disease: comparison of MR imaging, SPECT, and CT

Twenty patients with angiographically proved occlusion of the internal carotid artery (ICA) (19 unilateral, one bilateral) were studied with magnetic resonance (MR) imaging, iodine-123 iodoamphetamine (IMP) single photon emission computed tomography (SPECT), xenon-133 SPECT, and computed tomography (CT). All patients had a history of stroke or prolonged reversible ischemic neurologic deficit for more than 4 weeks. By regions of interest, T1, T2, regional cerebral blood flow (rCBF), and the number and size of the lesions were determined. The data were expressed as interhemispheric ratios (diseased/nondiseased). The highest ratios obtained were for MR imaging (T1, 2.60 +/- 0.42; T2, 1.61 +/- 0.22 [mean +/- standard deviation]) followed by Xe-133 SPECT (0.58 +/- 0.13) and IMP SPECT (0.56 +/- 0.13). Correlation coefficients for MR imaging (1/T1, 1/T2) and IMP SPECT were below .21. The lesion size was greatest on IMP SPECT images, intermediate on MR images, and least on CT scans. However, MR imaging was superior in detection of pathologic areas (detection rates: MR, 100%; IMP SPECT, 91%; CT, 79%). Relaxation times do not correlate with rCBF.     

Computer-assisted quantification of interstitial lung disease associated with rheumatoid arthritis: preliminary technical validation

Purpose

To validate a threshold-based prototype software application (MeVis PULMO 3D) for quantification of chronic interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) using variable threshold settings for segmentation of diseased lung areas.

Methods

Twenty-two patients with rheumatoid arthritis were included and underwent thin-section CT (4 × 1.25 mm collimation). CT scans were assessed by two observers for extent of ILD (EoILD), and twice by MeVis PULMO 3D for each protocol. MeVis PULMO 3D used four segmentation threshold (ST) settings (ST = −740, −780, −800 and −840 HU). Pulmonary function tests were obtained in all patients. Statistical evaluation used 95% limits of agreement (LoA) and linear regression analysis.

Results

There was total concordance between the software measurements. Interobserver agreement was good (LoA = −28.36 to 17.58%). EoILD by readers correlated strongly with DL_CO (r = −0.702, p < 0.0001) and moderately with FVC (r = −0.523, p = 0.018). There was close correlation between readers and MeVis PULMO 3D with best results for ST <780 HU (EoILD vs. MeVis PULMO 3D: r = 0.650 for ST = −800 and −840 HU, respectively; p = 0.002). MeVis PULMO 3D correlated best with DL_CO at ST of −800 HU (r = −0.44, −0.49, −0.58 and −0.57 for ST = −740, −780, −800 and −840, respectively; p = 0.007-0.05) and moderately with FVC (r = −0.44, −0.51, −0.59 and −0.45 for ST = −740, −780, −800 and −840), respectively; p = 0.007-0.05).

Conclusion

The MeVis PULMO 3D system used holds promise to become a valuable instrument for quantification of chronic ILD in patients with RA when using the threshold value of −800 HU, with evidence of the closest correlations, both with human observers and physiologic impairment.     

Comparison of quantitative atherosclerotic plaque burden from coronary CT angiography in patients with first acute coronary syndrome and stable coronary artery disease

BackgroundCoronary CTA allows characterization of non-calcified and calcified plaque and identification of high-risk plaque features.ObjectiveWe aimed to quantitatively characterize and compare coronary plaque burden from CTA in patients with a first acute coronary syndrome (ACS) and controls with stable coronary artery disease.Materials and methodsWe retrospectively analyzed consecutive patients with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina with a first ACS, who underwent CTA as part of their initial workup before invasive coronary angiography and age- and gender-matched controls with stable chest pain; controls also underwent CTA with subsequent invasive angiography (total n = 28). Culprit arteries were identified in ACS patients. Coronary arteries were analyzed by automated software to quantify calcified plaque (CP), noncalcified plaque (NCP), and low-density NCP (LD-NCP, attenuation <30 Hounsfield units) volumes, and corresponding burden (plaque volume × 100%/vessel volume), stenosis, remodeling index, contrast density difference (maximum percent difference in attenuation/cross-sectional area from proximal cross-section), and plaque length.ResultsACS patients had fewer lesions (median, 1), with higher total NCP and LD-NCP burdens (NCP: 57.4% vs 41.5%; LD-NCP: 12.5% vs 8%; P ≤ .04), higher maximal stenoses (85.6% vs 53.0%; P = .003) and contrast density differences (46.1 vs 16.3%; P < .006). Per-patient CP burden was not different between ACS and controls. NCP and LD-NCP plaque burden was higher in culprit vs nonculprit arteries (NCP: 57.8% vs 9.5%; LD-NCP: 8.4% vs 0.6%; P ≤ .0003); CP was not significantly different. Culprit arteries had increased plaque lengths, remodeling indices, stenoses, and contrast density differences (46.1% vs 10.9%; P ≤ .001).ConclusionNoninvasive quantitative coronary artery analysis identified several differences for ACS, both on per-patient and per-vessel basis, including increased NCP, LD-NCP burden, and contrast density difference.     

Association of neutrophil-to-lymphocyte ratio with non-calcified coronary artery burden in psoriasis: Findings from an observational cohort study

BackgroundInflammation in the form of elevated high-sensitivity c-reactive protein (hs-CRP) has been shown to be critical in the development of atherothrombosis. Psoriasis, a chronic inflammatory skin disease, is associated with high systemic-inflammation, elevated neutrophil-to-lymphocyte ratio (NLR) and accelerated non-calcified coronary artery burden (NCB) by coronary computed tomography angiography (CCTA). We hypothesized that NLR would associate with early, rupture-prone atherosclerosis assessed as NCB independent of hs-CRP.Methods316 consecutive psoriasis participants were recruited with 233 having one-year follow-up as part of a prospective, observational cohort study design. CCTA scans were performed to assess NCB in all three major epicardial coronary arteries.ResultsPatients with above average NLR (>mean: 2.29 ?± ?1.21) were older (mean ?± ?SD; 52.0 ?± ?12.8 vs. 47.9 ?± ?12.6, p ?= ?0.002), had higher hs-CRP (med. IQR: 2.3 (0.9–7.3) vs. 1.4 (0.7–3.2), p ?= ?0.001) and had higher NCB (mean ?± ?SD; 1.21 ?± ?0.58 vs. 1.13 ?± ?0.49, p ?= ?0.018) when compared to patients with below average NLR. NLR associated with psoriasis area severity index score (β ?= ?0.14, p ?= ?0.017), hs-CRP (β ?= ?0.16, p ?= ?0.005), as well as NCB independent of traditional risk factors, body mass index, statin use and hs-CRP (β ?= ?0.08, p ?= ?0.009). One year of biologic therapy for psoriasis was associated with a reduction in NLR (?14.5%, p ?< ?0.001), and this change in NLR associated with change in NCB in fully adjusted models and beyond hs-CRP (β ?= ?0.17, p ?= ?0.002).ConclusionNLR associated with psoriasis severity, hs-CRP and NCB at baseline. Biologic therapy reduced NLR over time and this change in NLR associated with the change in NCB at one-year. Taken together, these findings suggest that NLR may capture psoriasis patients at higher risk of NCB due to residual inflammation not fully captured by hs-CRP.     

静息态fMRI确定双手运动相关脑区——种子点选择对结果的影响

目的探讨种子点的选择对静息态fMRI确定双手运动相关脑区的影响。方法对31例(男15例,女16例)健康被试者行组块设计的双手运动和静息态fMRI扫描。采用DPARSFV2.0软件和SPM8软件进行数据处理,选取任务状态下各独立激活簇的最大激活点为种子点,分别计算静息状态下全脑功能连接图,计算静息状态下各功能连接图与任务状态激活图之间的空间相关系数。结果任务状态下得到15个独立的激活脑区,进而生成15个种子点,其中辅助运动区(SMA)为种子点的功能连接图与任务状态激活图空间分布一致性最强,空间相关系数最大;以初级运动皮质(M1区)及背侧前运动皮质(PMd)为种子点的功能连接图包括双侧M1区及SMA;以腹侧前运动皮质(PMv)为种子点所得功能连接图主要为PMv和PMd;以壳核(Pu)、丘脑(Th)、小脑前叶(CbAL)、小脑后叶(CbPL)为种子点所得功能连接图主要为种子点周围及其镜像脑区。结论静息状态下,以SMA为种子点能获得与手运动任务激活图有较好一致性的功能连接图,以M1及PMd为种子点能较好显示M1区。     

静息态fMRI确定双手运动相关脑区——种子点选择对结果的影响

目的 探讨种子点的选择对静息态fMRI确定双手运动相关脑区的影响.方法 对31例（男15例,女16例）健康被试者行组块设计的双手运动和静息态fMRI扫描.采用DPARSF V2.0软件和SPM8软件进行数据处理,选取任务状态下各独立激活簇的最大激活点为种子点,分别计算静息状态下全脑功能连接图,计算静息状态下各功能连接图与任务状态激活图之间的空间相关系数.结果 任务状态下得到15个独立的激活脑区,进而生成15个种子点,其中辅助运动区（SMA）为种子点的功能连接图与任务状态激活图空间分布一致性最强,空间相关系数最大;以初级运动皮质（M1区）及背侧前运动皮质（PMd）为种子点的功能连接图包括双侧M1区及SMA;以腹侧前运动皮质（PMv）为种子点所得功能连接图主要为PMv和PMd;以壳核（Pu）、丘脑（Th）、小脑前叶（CbAL）、小脑后叶（CbPL）为种子点所得功能连接图主要为种子点周围及其镜像脑区.结论 静息状态下,以SMA为种子点能获得与手运动任务激活图有较好一致性的功能连接图,以M1及PMd为种子点能较好显示M1区.     

Diagnosis and quantification of hepatic fibrosis with diffusion weighted MR imaging: preliminary results

PURPOSE: Diagnosis and quantification of hepatic fibrosis are especially important in patients with chronic liver disease. Liver biopsy remains the gold standard for diagnosis of cirrhosis but has several limitations. The purpose of this study was to determine the usefulness of diffusion-weighted MR imaging, for the diagnosis of cirrhosis and quantification of hepatic fibrosis, and to define the best sequence parameters for this evaluation. METHODS AND MATERIALS: Diffusion-weighted imaging using a 1.5 T MR unit was performed in 14 healthy volunteers and 13 cirrhotic patients. Sets of 8 images with different b values (200, 400, 600, and 800 sec/mm2) and different TR (3500 and 5000 ms) were acquired with breath-holding. Apparent diffusion coefficients (ADCs) were calculated. Correlation between Child-Pugh scores, serum hyaluronate concentrations and ADCs were performed. RESULTS: ADCs were significantly lower in cirrhotic patients (2,055 10-3) compared to controls (2,915 10-3) (p<0.05) when the b value was 200 s/mm2 and the TR was 5000 ms. Significant correlations were observed between Child-Pugh scores and ADCs (p<0.05), and between serum hyaluronate concentrations and ADCs (p<0.05), when the b value was 400 sec/mm2 and the TR was 5000 ms. CONCLUSION: Our preliminary study showed that the measurement of ADCs has good potential for diagnosis and quantification of hepatic fibrosis, especially when using b values of 200 sec/mm2 and 400 sec/mm2.     

The first results from the Danish ACL reconstruction registry: epidemiologic and 2 year follow-up results from 5,818 knee ligament reconstructions

Anterior cruciate ligament (ACL) reconstruction is presently evolving rapidly. In order to monitor the developments in surgical methods and clinical outcome, a national clinical database for knee ligament reconstructions was established in 2005 in Denmark. This study presents the first data with 2 year follow-up from the Danish ACL registry. All orthopaedic departments performing ACL reconstructions in Denmark, inlcuding private clinics, report to the registry. The database includes both surgery- and patient-related data. The surgeon reports anamnestic, objective knee laxity and operative data including graft and implant choices. At 1 year control, complications, reoperations, and objective knee laxity are recorded. The patient registers the Knee injury and Osteoarthritis Outcome Score (KOOS) and Tegner function score preoperatively and at 1, 5 and 10 years follow-up. During the first 30 months, 5,872 knee-ligament reconstructions were registered. A total of 4,972 were primary ACL reconstructions, 443 were ACL revisions and 457 multiligament reconstructions. A total of 85% of all knee ligament reconstruction were reported to the database. A total of 71% of primary ACL reconstruction used hamstring tendon grafts and 21% used patella tendon graft. Meniscus injuries were treated in 35% of all patients. A total of 17% had significant cartilage lesions. At 2 years follow-up 3% of primary recontructions were revised. Follow-up KOOS demonstrated specific differences between primary ACL, revision ACL, and multiligament reconstructions. Sports/recreation score were 40, 32, 28 and quality of life score were 40, 32, 33 for the respective groups. This study presents the first follow-up data from a national ACL registry. These data will become new international reference materials for outcome measures before and after ACL surgery. The database will enable future monitoring of ACL reconstruction techniques and outcome.     

Sinus cut-off sign: a helpful sign in the CT diagnosis of diaphragmatic rupture associated with pleural effusion

The objective of our study was to describe the "sinus cut-off" sign at CT in the diagnosis of diaphragmatic rupture in patients with blunt abdominal trauma complicated with pleural effusion, and evaluate its utility in an experimental model. Between January 2004 and March 2005, we observed an unusual interruption of costophrenic sinus at CT in three patients with blunt abdominal trauma accompanied with pleural effusion. This observation prompted us to evaluate the utility of this sign in an experimental model. Laparotomically, we created 2 cm diapragmatic lacerations at each hemidiaphragm in two rabbits and pushed up the abdominal viscera with omentum through the defect. To simulate hemothorax, we also injected 5-10 mL of diluted contrast material into the pleural space. Using a dual-slice helical CT scanner, limited thoracoabdominal CT examination was performed before and after injection of intrapleural contrast material. The images were analyzed for the presence of CT signs for diaphragmatic injury. The left posterior costophrenic sulcus was interrupted in all of the three patients with left pleural effusion. While it was associated with other findings of diaphragmatic injury, the "sinus cut-off sign" was the sole finding in one patient. The sinus cut-off sign was observed on the CT scans of 100% of the rabbits with a left and right sided diaphragmatic rupture. The "sinus cut-off sign" is useful and can increase the CT detection of acute diaphragmatic injury associated with pleural effusion.     

Improved mapping and quantification of serotonin transporter availability in the human brainstem with the HRRT

Purpose

The serotonin system is involved in many physiological functions and clinical conditions. Serotonergic neurons originate from the raphe nuclei in the brainstem, and reliable estimates of receptor/transporter availability in the raphe in vivo are thus of interest. Though positron emission tomography (PET) can be used to quantify receptor distribution in the brain, high noise levels prevent reliable estimation of radioligand binding in small regions such as the raphe. For this purpose, parametric imaging in combination with high-resolution PET systems may provide images with reduced noise levels and sufficient contrast for reliable quantification. This study examined the potential to evaluate radioligand binding in brainstem nuclei, and assessed the effect of improved resolution on the outcome measures.

Methods

For comparative purposes, radioligand binding was measured with an ECAT EXACT HR PET system (resolution about 4.5 mm FWHM) and a high-resolution research tomograph (HRRT) system (resolution about 1.5 mm FWHM). Six subjects were examined with both systems on the same day using the serotonin transporter radioligand [¹¹C]MADAM. Parametric images of binding potential (BP _ND) were obtained using a wavelet-aided approach. Regions of interest (ROIs) were delineated using a threshold-based semiautomatic delineation procedure for five brainstem structures. Regional BP _ND values were estimated by applying the ROIs to the parametric images, and the percentage difference in BP _ND between the systems was calculated.

Results

Signals for [¹¹C]MADAM binding were obtained for all five brainstem structures. Overall, the HRRT provided 30–40 % higher BP _ND values than the HR (p?=?0.0017), independent of thresholds used in the ROI delineation procedure.

Conclusion

The methodology used enabled the estimation of [¹¹C]MADAM binding in the small nuclei of the brainstem. Differences in the BP _ND values calculated using data from the two systems were mainly attributable to their differing resolutions. The estimated BP _ND values provided lower across-subject variability than those previously obtained using compartment analysis. This procedure may therefore facilitate quantitative studies of receptor/transporter availability in the brainstem.     

Thoracic aorta calcification but not inflammation is associated with increased cardiovascular disease risk: results of the CAMONA study

Purpose

Arterial inflammation and vascular calcification are regarded as early prognostic markers of cardiovascular disease (CVD). In this study we investigated the relationship between CVD risk and arterial inflammation (¹⁸F-FDG PET/CT imaging), vascular calcification metabolism (Na¹⁸F PET/CT imaging), and vascular calcium burden (CT imaging) of the thoracic aorta in a population at low CVD risk.

Methods

Study participants underwent blood pressure measurements, blood analyses, and ¹⁸F-FDG and Na¹⁸F PET/CT imaging. In addition, the 10-year risk for development of CVD, based on the Framingham risk score (FRS), was estimated. CVD risk was compared across quartiles of thoracic aorta ¹⁸F-FDG uptake, Na¹⁸F uptake, and calcium burden on CT.

Results

A total of 139 subjects (52 % men, mean age 49 years, age range 21?–?75 years, median FRS 6 %) were evaluated. CVD risk was, on average, 3.7 times higher among subjects with thoracic aorta Na¹⁸F uptake in the highest quartile compared with those in the lowest quartile of the distribution (15.5 % vs. 4.2 %; P?<?0.001). CVD risk was on average, 3.7 times higher among subjects with a thoracic aorta calcium burden on CT in the highest quartile compared with those in the lowest two quartiles of the distribution (18.0 % vs. 4.9 %; P?<?0.001). CVD risk was similar in subjects in all quartiles of thoracic aorta ¹⁸F-FDG uptake.

Conclusion

Our findings indicate that an unfavourable CVD risk profile is associated with marked increases in vascular calcification metabolism and vascular calcium burden of the thoracic aorta, but not with arterial inflammation.

     

Carotid artery atherosclerosis is not associated with hyoid proximity: Results from a cross-sectional and longitudinal cohort study

IntroductionCervical internal carotid artery (ICA) atherosclerotic plaque and stenosis is often asymmetric. We hypothesized that hyoid bone proximity to the ICA also may be asymmetric and may increase the risk of traumatic endothelial injury and accelerate atherosclerotic stenosis.MethodsA retrospective cross-sectional and longitudinal cohort design evaluated consecutive adult patients at 3 hospitals who underwent repeat computed tomography angiography (CTA) of the neck 2 calendar years apart (01/2000–07/2017). ICA plaque thickness, luminal stenosis, and their progression over time were compared between side with the nearer hyoid wing (proximal side) to the further side (distal side).ResultsSixty-six patients were included with a median age of 64y (IQR 53–73), 37 (56.1%) female, had a median hyoid-ICA distance of 3.06 mm (IQR 1.27–6.20 mm) and median difference between sides of 2.11 mm (IQR 0.70–3.97 mm). The median plaque thickness was 3.5 mm (IQR 2–4) and median stenosis was 10% (IQR 0–33%). Comparing the proximal to distal side, there was no difference in ICA plaque thickness (median 2.5 mm [IQR 1–4] vs. 3.0 mm [IQR 2–4], p = 0.366) or stenosis (7% [IQR 0–31%] vs. 12% [IQR 0–39%], p = 0.21). After a median follow-up of 1002 days (range 392–3397 days), there was no difference in the change in plaque thickness (0.5 cm [IQR 0–1] vs. 0.0 cm [IQR −0.5–0.5], p = 0.21) or stenosis (0% [IQR −2.5–13%] vs. 0% [IQR −6–5%], p = 0.34) between proximal and distal ICAs.ConclusionsThe presence and progression of atherosclerotic plaque and stenosis were unrelated to hyoid-ICA distance in this cross-sectional and longitudinal cohort study.     

Carotid artery atherosclerosis is not associated with hyoid proximity: Results from a cross-sectional and longitudinal cohort study

IntroductionCervical internal carotid artery (ICA) atherosclerotic plaque and stenosis is often asymmetric. We hypothesized that hyoid bone proximity to the ICA also may be asymmetric and may increase the risk of traumatic endothelial injury and accelerate atherosclerotic stenosis.MethodsA retrospective cross-sectional and longitudinal cohort design evaluated consecutive adult patients at 3 hospitals who underwent repeat computed tomography angiography (CTA) of the neck 2 calendar years apart (01/2000–07/2017). ICA plaque thickness, luminal stenosis, and their progression over time were compared between side with the nearer hyoid wing (proximal side) to the further side (distal side).ResultsSixty-six patients were included with a median age of 64y (IQR 53–73), 37 (56.1%) female, had a median hyoid-ICA distance of 3.06 mm (IQR 1.27–6.20 mm) and median difference between sides of 2.11 mm (IQR 0.70–3.97 mm). The median plaque thickness was 3.5 mm (IQR 2–4) and median stenosis was 10% (IQR 0–33%). Comparing the proximal to distal side, there was no difference in ICA plaque thickness (median 2.5 mm [IQR 1–4] vs. 3.0 mm [IQR 2–4], p = 0.366) or stenosis (7% [IQR 0–31%] vs. 12% [IQR 0–39%], p = 0.21). After a median follow-up of 1002 days (range 392–3397 days), there was no difference in the change in plaque thickness (0.5 cm [IQR 0–1] vs. 0.0 cm [IQR −0.5–0.5], p = 0.21) or stenosis (0% [IQR −2.5–13%] vs. 0% [IQR −6–5%], p = 0.34) between proximal and distal ICAs.ConclusionsThe presence and progression of atherosclerotic plaque and stenosis were unrelated to hyoid-ICA distance in this cross-sectional and longitudinal cohort study.     

Differentiation of multiple sclerosis from other inflammatory disorders and cerebrovascular disease: value of spinal MR imaging

PURPOSE: To determine the value of magnetic resonance (MR) imaging in the spinal cord to differentiate multiple sclerosis (MS) from other inflammatory disorders and cerebrovascular diseases (together, other neurologic disease [OND]). MATERIALS AND METHODS: The study population included 66 patients with OND and 25 patients with MS, who were matched for age, sex, and symptom duration or severity. Brain MR imaging included gadolinium-enhanced T1-weighted and dual-echo T2-weighted spin-echo sequences to assess the number, size, and appearance of lesions, contrast enhancement, and compatibility with diagnostic criteria for MS. Spinal cord MR imaging included cardiac-triggered gadolinium-enhanced sagittal T1-weighted spin-echo and dual-echo T2-weighted sequences to assess the general appearance (normal, focal lesion, diffuse abnormality) and number or size of focal lesions. Images obtained in MS and OND patients were compared. Specificity, sensitivity, accuracy, and positive and negative predictive values with MR images were calculated. RESULTS: Brain images were abnormal in all MS patients and in 65% of OND patients. Abnormal cord images were found in 92% of MS and 6% of OND patients. The combination of brain and spinal cord images increased accuracy of diagnosis compared with use of brain images alone. CONCLUSION: In contrast to MS, cord lesions are very uncommon in OND. This finding can help differentiate these disorders.