Objective
To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer F‐18‐AV‐1451 (previously known as T807), tailored to allow in ...vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.
Methods
We applied F‐18‐AV‐1451 phosphor screen autoradiography, F‐18‐AV‐1451 nuclear emulsion autoradiography, and H‐3‐AV‐1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration–tau, frontotemporal lobar degeneration–transactive response DNA binding protein 43 (TDP‐43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology.
Results
Our data suggest that F‐18‐AV‐1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non‐Alzheimer tauopathy brains or to lesions containing β‐amyloid, α‐synuclein, or TDP‐43. F‐18‐AV‐1451 off‐target binding to neuromelanin‐ and melanin‐containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified.
Interpretation
Our data suggest that F‐18‐AV‐1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament‐tau–containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non‐Alzheimer tauopathy cases and to the existence of some F‐18‐AV‐1451 off‐target binding. These findings provide important insights for interpreting in vivo patterns of F‐18‐AV‐1451 retention. Ann Neurol 2015 Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
Bipolar disorder is associated with high risk for suicidal behavior that often develops in adolescence and young adulthood. Elucidation of involved neural systems is critical for prevention. This ...study of adolescents and young adults with bipolar disorder with and without a history of suicide attempts combines structural, diffusion tensor, and functional MR imaging methods to investigate implicated abnormalities in the morphology and structural and functional connectivity within frontolimbic systems.
The study had 26 participants with bipolar disorder who had a prior suicide attempt (the attempter group) and 42 participants with bipolar disorder without a suicide attempt (the nonattempter group). Regional gray matter volume, white matter integrity, and functional connectivity during processing of emotional stimuli were compared between groups, and differences were explored for relationships between imaging modalities and associations with suicide-related symptoms and behaviors.
Compared with the nonattempter group, the attempter group showed significant reductions in gray matter volume in the orbitofrontal cortex, hippocampus, and cerebellum; white matter integrity in the uncinate fasciculus, ventral frontal, and right cerebellum regions; and amygdala functional connectivity to the left ventral and right rostral prefrontal cortex. In exploratory analyses, among attempters, there was a significant negative correlation between right rostral prefrontal connectivity and suicidal ideation and between left ventral prefrontal connectivity and attempt lethality.
Adolescent and young adult suicide attempters with bipolar disorder demonstrate less gray matter volume and decreased structural and functional connectivity in a ventral frontolimbic neural system subserving emotion regulation. Among attempters, reductions in amygdala-prefrontal functional connectivity may be associated with severity of suicidal ideation and attempt lethality.
Objective
To determine the association between changes in semiquantitative magnetic resonance imaging (MRI) biomarkers over 24 months and radiographic and pain progression over 48 months in knees ...with mild‐to‐moderate osteoarthritis (OA).
Methods
We undertook a nested case–control study as part of the Foundation for the National Institutes of Health Biomarkers Consortium Project. We used multivariable logistic regression models to examine the association between change over 24 months in semiquantitative MRI markers and radiographic and pain progression in knee OA. MRIs were read according to the MRI OA Knee Score system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa‐synovitis, and effusion‐synovitis.
Results
The most parsimonious model included changes in cartilage thickness and surface area, effusion‐synovitis, Hoffa‐synovitis, and meniscal morphology (C statistic 0.740). Compared with no worsening, worsening in cartilage thickness in ≥3 subregions was associated with 2.8‐fold (95% confidence interval 95% CI 1.3–5.9) greater odds of being a case, and worsening in cartilage surface area in ≥3 subregions was associated with 2.4‐fold (95% CI 1.3–4.4) greater odds of being a case. Worsening of meniscal morphology in any region was associated with 2.2‐fold (95% CI 1.3–3.8) greater odds of being a case. Worsening effusion‐synovitis and Hoffa‐synovitis were also associated with a greater odds of being a case (odds ratios 2.7 and 2.0, respectively).
Conclusion
Twenty‐four–month changes in cartilage thickness, cartilage surface area, effusion‐synovitis, Hoffa‐synovitis, and meniscal morphology were independently associated with OA progression, suggesting that these factors may serve as efficacy biomarkers in clinical trials of disease‐modifying interventions for knee OA.
We describe a treatment plan optimization method for intensity modulated proton therapy (IMPT) that avoids high values of linear energy transfer (LET) in critical structures located within or near ...the target volume while limiting degradation of the best possible physical dose distribution.
To allow fast optimization based on dose and LET, a GPU-based Monte Carlo code was extended to provide dose-averaged LET in addition to dose for all pencil beams. After optimizing an initial IMPT plan based on physical dose, a prioritized optimization scheme is used to modify the LET distribution while constraining the physical dose objectives to values close to the initial plan. The LET optimization step is performed based on objective functions evaluated for the product of LET and physical dose (LET×D). To first approximation, LET×D represents a measure of the additional biological dose that is caused by high LET.
The method is effective for treatments where serial critical structures with maximum dose constraints are located within or near the target. We report on 5 patients with intracranial tumors (high-grade meningiomas, base-of-skull chordomas, ependymomas) in whom the target volume overlaps with the brainstem and optic structures. In all cases, high LET×D in critical structures could be avoided while minimally compromising physical dose planning objectives.
LET-based reoptimization of IMPT plans represents a pragmatic approach to bridge the gap between purely physical dose-based and relative biological effectiveness (RBE)-based planning. The method makes IMPT treatments safer by mitigating a potentially increased risk of side effects resulting from elevated RBE of proton beams near the end of range.
Highlights • Contrast enhanced ultrasonography (CEUS) is increasingly used for non-hepatic applications. • There is a growing clinical use for a variety of pathologies of the kidney, testis, and ...small bowel. • Updated knowledge for proper use of CEUS in uncommon fields is provided.
Data are limited on the presence, distribution, and extent of subclinical atherosclerosis in middle-aged populations.
The PESA (Progression of Early Subclinical Atherosclerosis) study prospectively ...enrolled 4184 asymptomatic participants 40 to 54 years of age (mean age, 45.8 years; 63% male) to evaluate the systemic extent of atherosclerosis in the carotid, abdominal aortic, and iliofemoral territories by 2-/3-dimensional ultrasound and coronary artery calcification by computed tomography. The extent of subclinical atherosclerosis, defined as presence of plaque or coronary artery calcification ≥1, was classified as focal (1 site affected), intermediate (2-3 sites), or generalized (4-6 sites) after exploration of each vascular site (right/left carotids, aorta, right/left iliofemorals, and coronary arteries). Subclinical atherosclerosis was present in 63% of participants (71% of men, 48% of women). Intermediate and generalized atherosclerosis was identified in 41%. Plaques were most common in the iliofemorals (44%), followed by the carotids (31%) and aorta (25%), whereas coronary artery calcification was present in 18%. Among participants with low Framingham Heart Study (FHS) 10-year risk, subclinical disease was detected in 58%, with intermediate or generalized disease in 36%. When longer-term risk was assessed (30-year FHS), 83% of participants at high risk had atherosclerosis, with 66% classified as intermediate or generalized.
Subclinical atherosclerosis was highly prevalent in this middle-aged cohort, with nearly half of the participants classified as having intermediate or generalized disease. Most participants at high FHS risk had subclinical disease; however, extensive atherosclerosis was also present in a substantial number of low-risk individuals, suggesting added value of imaging for diagnosis and prevention.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01410318.
Objective
The use of magnetic resonance imaging (MRI)–detected inflammation and joint damage in the diagnosis of rheumatoid arthritis is recommended by a European League Against Rheumatism imaging ...task force. This recommendation is based on the sensitivity of MRI and not on specificity. Knowledge of the prevalence of MRI‐detected features in symptom‐free persons, however, is pivotal when considering MRI for diagnostic purposes.
Methods
From November 2013 to December 2014, 196 symptom‐free persons of different ages were recruited from the general population. Inclusion criteria were no history of inflammatory arthritis, no joint symptoms during the previous month, and no clinically detectable arthritis on physical examination. Contrast‐enhanced MRIs of the dominant metacarpophalangeal (MCP), wrist, and metatarsophalangeal (MTP) joints were obtained using a 1.5T scanner and scored by 2 readers for synovitis, bone marrow edema, tenosynovitis, and erosions. For analyses at the joint level, MRI‐detected inflammation was considered present if both readers scored the image as positive.
Results
Of 193 persons scanned (ages 19–89 years), only 28% had no single inflammatory feature and 22% had no erosions. Primarily low‐grade features were observed. All MRI features were positively correlated with age (P < 0.001). Preferential locations for synovitis were MCP2, MCP3, the wrists, and MTP1. Bone marrow edema was frequently present in MCP3, the scaphoid, and MTP1. Tenosynovitis was infrequent, except for in the extensor carpi ulnaris. Preferential locations for erosions were MCP2, MCP3, MCP5, the distal ulna, MTP1, and MTP5. Tables with age‐, location‐, and inflammation type–dependent frequencies were constructed. Simultaneous colocalized presence of synovitis, bone marrow edema, tenosynovitis, or erosions occurred.
Conclusion
MRI‐detected inflammation and erosions are prevalent in symptom‐free persons from the general population, especially at older ages and at preferential locations.
Structured
Objectives
To assess whether morphology and dimension of the upper airway differ between patients characterized by various craniofacial morphology.
Setting and Sample Population
Ninety ...young adult patients from the Postgraduate Clinic, Section of Orthodontics, Department of Dentistry, Health, Aarhus University, Denmark, with no obvious signs of respiratory diseases and no previous adeno‐tonsillectomy procedures. Thirty patients were characterized as Class I (−0.5 < ANB < 4.5), 30 as Class II (ANB > 4.5), and 30 as Class III (ANB < −0.5).
Material and Methods
Cone‐beam computed tomography (CBCT) scans obtained in a supine position for all patients. Cephalometric landmarks were identified in 3D. Sagittal and transversal dimensions, cross sections, and partial and total volumes of the upper airway were correlated with the cephalometric measurements in all three planes of space. The cross‐sectional minimal area of the upper airway was assessed as well.
Results
No statistical significant relationships between dimension and morphology of upper airways and skeletal malocclusion were found.
Conclusion
Differences in craniofacial morphology as identified by the sagittal jaw relationship were not correlated with variation in upper airway volumes. A clinical significant relation was detected between minimal area and total upper airway volume.
Background There is considerable evidence that the thalamus is abnormal in psychotic disorders. Resting-state functional magnetic resonance imaging has revealed an intriguing pattern of thalamic ...dysconnectivity in psychosis characterized by reduced prefrontal cortex (PFC) connectivity and increased somatomotor-thalamic connectivity. However, critical knowledge gaps remain with respect to the onset, anatomical specificity, and clinical correlates of thalamic dysconnectivity in psychosis. Methods Resting-state functional magnetic resonance imaging was collected on 105 healthy subjects and 148 individuals with psychosis, including 53 early-stage psychosis patients. Using all 253 subjects, the thalamus was parceled into functional regions of interest (ROIs) on the basis of connectivity with six a priori defined cortical ROIs covering most of the cortical mantle. Functional connectivity between each cortical ROI and its corresponding thalamic ROI was quantified and compared across groups. Significant differences in the ROI-to-ROI analysis were followed up with voxel-wise seed-based analyses to further localize thalamic dysconnectivity. Results ROI analysis revealed reduced PFC-thalamic connectivity and increased somatomotor-thalamic connectivity in both chronic and early-stage psychosis patients. PFC hypoconnectivity and motor cortex hyperconnectivity correlated in patients suggesting they result from a common pathophysiological mechanism. Seed-based analyses revealed thalamic hypoconnectivity in psychosis localized to dorsolateral PFC, medial PFC, and cerebellar areas of the well-described executive control network. Across all subjects, thalamic connectivity with areas of the fronto-parietal network correlated with cognitive functioning, including verbal learning and memory. Conclusions Thalamocortical dysconnectivity is present in both chronic and early stages of psychosis, includes reduced thalamic connectivity with the executive control network, and is related to cognitive impairment.
White matter (WM) signal abnormalities are demonstrated in various neurodevelopmental disorders on brain magnetic resonance imaging (MRI). The pattern of WM abnormalities can aid in the diagnostic ...process. This study aims to characterize the WM changes found in microdeletion/microduplication syndromes. Thirteen patients with neurodevelopmental disorders due to copy number variations were collected from a cohort of children with evidence of WM abnormalities on brain MRI, in two medical centers. A pediatric neuroradiologist blindly interpreted the MRI scans. Clinical and genetic findings were retrospectively extracted from the medical records. WM changes included: multifocal (10/13) periventricular (12/13) and subcortical (5/13) signal abnormalities and WM volume loss (6/13). Dysgenesis of the corpus callosum was depicted in 12/13. The main clinical features were: global developmental delay (13/13), hypotonia (11/13), epilepsy (10/13), dysmorphic features (9/13), microcephaly (6/13), short stature (6/13), and systemic involvement (6/13). We showed that different chromosomal micro‐rearrangement syndromes share similar MRI patterns of nonspecific multifocal predominantly periventricular WM changes associated with corpus callosum dysgenesis with or without WM and gray matter loss. Hence, the association of these features in a patient evaluated for global developmental delay/intellectual disability suggests a chromosomal micro‐rearrangement syndrome, and a chromosomal microarray analysis should be performed.
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