IMPORTANCE: Early diagnosis is a requirement for future treatment of prion diseases. Magnetic resonance imaging (MRI) with diffusion-weighted images and improved real-time quaking-induced conversion ...(RT-QuIC) in cerebrospinal fluid (CSF) have emerged as reliable tests. OBJECTIVES: To assess the sensitivity and specificity of diffusion MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) with a new criterion (index test) of at least 1 positive brain region among the cortex of the frontal, parietal, temporal, and occipital lobes; the caudate; the putamen; and the thalamus. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study with a prospective and a retrospective arm was performed from January 1, 2003, to October 31, 2018. MRIs were collected from 1387 patients with suspected sCJD consecutively referred to the National Prion Disease Pathology Surveillance Center as part of a consultation service. INTERVENTION: Magnetic resonance imaging. Four neuroradiologists blinded to the diagnosis scored the MRIs of 200 randomly selected patients. One neuroradiologist scored the MRIs of all patients. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of the index test compared with currently used criteria and CSF diagnostic (improved RT-QuIC, 14-3-3, and tau CSF tests). RESULTS: A total of 872 patients matched the inclusion criteria (diffusion MRI and autopsy-confirmed diagnosis), with 619 having sCJD, 102 having other prion diseases, and 151 having nonprion disease. The primary analysis included 200 patients (mean SD age, 63.6 12.9 years; 100 50.0% male). Sensitivity of the index test of 4 neuroradiologists was 90% to 95% and superior to sensitivity of current MRI criteria (69%-76%), whereas specificity was 90% to 100% and unchanged. Interrater reliability of the 4 neuroradiologists was high (κ = 0.81), and individual intrarater reliability was excellent (κ ≥0.87). The sensitivity of the index test of 1 neuroradiologist for 770 patients was 92.1% (95% CI, 89.7%-94.1%) and the specificity was 97.4% (95% CI, 93.4%-99.3%) compared with a sensitivity of 69.8% (95% CI, 66.0%-73.4%; P < .001) and a specificity of 98.0% (95% CI, 94.3%-99.6%; P > .99) according to the current criteria. For 88 patients, index test sensitivity (94.9%; 95% CI, 87.5%-98.6%) and specificity (100%; 95% CI, 66.4%-100%) were similar to those of improved RT-QuIC (86.1% 95% CI, 76.5%-92.8% and 100% 95% CI, 66.4%-100%, respectively). Lower specificities were found for 14-3-3 and tau CSF tests in 452 patients. CONCLUSIONS AND RELEVANCE: In this study, the diagnostic performance of diffusion MRI with the new criterion was superior to that of current standard criteria and similar to that of improved RT-QuIC. These results may have important clinical implications because MRI is noninvasive and typically prescribed at disease presentation.
This trial showed that in patients with lymphangioleiomyomatosis (LAM), a progressive, cystic lung disease in women, sirolimus therapy was associated with stabilization of lung function, reduction in ...symptoms, and improvement in qualityof-life measures.
Lymphangioleiomyomatosis (LAM) is an uncommon systemic disease that is associated with cystic destruction of the lung, chylous pleural effusions, and abdominal tumors such as renal angiomyolipomas.
1
,
2
LAM affects women almost exclusively and occurs sporadically, developing in about 5 persons per 1 million; it also affects 30 to 40% of women with tuberous sclerosis complex (TSC). Lung function, measured as the forced expiratory volume in 1 second (FEV
1
), declines at the rate of 75 to 118 ml per year
3
–
5
; clinically important respiratory impairment, recurrent pneumothoraxes, and hypoxemia develop in most patients within a decade after the . . .
Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma ...(GBM) expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas).
Gene expression array, single nucleotide polymorphism (SNP) array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III) from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson). Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP) was assigned using prediction models by Fine et al.
Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs.
GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Temporal arteritis peaks during the 8th decade, affecting patients with frequent comorbidities who are especially prone to adverse effects of corticosteroid therapy. Perivascular inflammation ...involving small periadventitial vessels is not uncommon in otherwise normal temporal artery biopsies (TAB). As ischemic events occur in patients with non-temporal artery based inflammation, it has been recommended any vascular inflammation within temporal artery biopsies be treated with corticosteroids. We sought to determine whether such patients are at increased risk for temporal arteritis-like adverse events compared with age-matched controls devoid of inflammatory infiltrates. TABs without transmural temporal arteritic damage accessioned between 2002 and 2012 were reviewed for inflammation (>15 perivascular lymphocytes) involving small blood vessels and/or temporal artery adventitia. 278/343 (81%) of TABs were negative for transmural arteritis. Inflammation involving small vessels and/or temporal artery adventitia was present in 56 cases (20%). Age-matched controls were available for 39 cases. With a mean follow up of 5 years (range 1-11 years), 6/39 (15%) of patients developed stroke, cardiovascular events or died, compared with 7/39 (18%) of age matched controls. None of the patients with study-positive TAB had documented steroid therapy prior to, or after, temporal artery biopsy. Our results demonstrate that patients with inflammation involving only small vessels or temporal artery adventitia are not at increased risk for temporal arteritis- like adverse events, and suggest that the risks of protracted corticosteroid therapy in this elderly population likely exceed any potential benefits. We advise against diagnosing vasculitis in the absence of temporal arteritic damage.
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible through iatrogenic routes due to abundant infectious prions misfolded forms of the prion protein (PrP
...) in the central nervous system (CNS). Some epidemiological studies have associated sCJD risk with non-CNS surgeries. We explored the potential prion seeding activity and infectivity of skin from sCJD patients. Autopsy or biopsy skin samples from 38 patients 21 sCJD, 2 variant CJD (vCJD), and 15 non-CJD were analyzed by Western blotting and real-time quaking-induced conversion (RT-QuIC) for PrP
Skin samples from two patients were further examined for prion infectivity by bioassay using two lines of humanized transgenic mice. Western blotting revealed dermal PrP
in one of five deceased sCJD patients and one of two vCJD patients. However, the more sensitive RT-QuIC assay detected prion seeding activity in skin from all 23 CJD decedents but not in skin from any non-CJD control individuals (with other neurological conditions or other diseases) during blinded testing. Although sCJD patient skin contained ~10
- to 10
-fold lower prion seeding activity than did sCJD patient brain tissue, all 12 mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation. Our study demonstrates that the skin of sCJD patients contains both prion seeding activity and infectivity, which raises concerns about the potential for iatrogenic sCJD transmission via skin.
Gerstmann-Sträussler-Scheinker disease (GSS) is an inherited neurodegenerative disorder associated with mutations in the prion protein gene and accumulation of misfolded PrP with protease-resistant ...fragments (PrP(res)) of 6-8 kDa. With the exception of a few GSS cases characterized by co-accumulation of PrP(res) of 21 kDa, efforts to transmit GSS to rodents have been unsuccessful. As a result, GSS subtypes exclusively associated with 6-8 kDa PrP(res) have often been considered as non-transmissible proteinopathies rather than true prion diseases. We show that GSS with P102L, A117V and F198S mutations transmit efficiently and produce distinct pathological phenotypes in bank voles (M. glareolus), irrespective of the presence of 21 kDa PrP(res) in the inoculum, demonstrating that GSS is a genuine prion disease characterized by both transmissibility and strain variation.
Both pro- and antioncogenic properties have been attributed to EphA2 kinase. We report that a possible cause for this apparent paradox is diametrically opposite roles of EphA2 in regulating cell ...migration and invasion. While activation of EphA2 with its ligand ephrin-A1 inhibited chemotactic migration of glioma and prostate cancer cells, EphA2 overexpression promoted migration in a ligand-independent manner. Surprisingly, the latter effects required phosphorylation of EphA2 on serine 897 by Akt, and S897A mutation abolished ligand-independent promotion of cell motility. Ephrin-A1 stimulation of EphA2 negated Akt activation by growth factors and caused EphA2 dephosphorylation on S897. In human astrocytoma, S897 phosphorylation was correlated with tumor grades and Akt activation, suggesting that the Akt-EphA2 crosstalk may contribute to brain tumor progression.
Amyloid beta (Aβ) deposition in the neocortex is a major hallmark of Alzheimer's disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease ...progression. The prion strain–like model of disease heterogeneity suggests the existence of different conformers of Aβ. We explored this paradigm using conformation-dependent immunoassay (CDI) for Aβ and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the Aβ conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of Aβ with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from Aβ plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs—quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of Aβ deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of Aβ accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct Aβ conformers (strains) in the rapid progression of AD.
Objective
Sporadic Creutzfeldt–Jakob disease (sCJD) comprises several subtypes as defined by genetic and prion protein characteristics, which are associated with distinct clinical and pathological ...phenotypes. To date, no clinical test can reliably diagnose the subtype. We established two procedures for the antemortem diagnosis of sCJD subtype using diffusion magnetic resonance imaging (MRI).
Methods
MRI of 1,458 patients referred to the National Prion Disease Pathology Surveillance Center were collected through its consultation service. One neuroradiologist blind to the diagnosis scored 12 brain regions and generated a lesion profile for each MRI scan. We selected 487 patients with autopsy‐confirmed diagnosis of “pure” sCJD subtype and at least one positive diffusion MRI examination. We designed and tested two data‐driven procedures for subtype diagnosis: the first procedure—prion subtype classification algorithm with MRI (PriSCA_MRI)—uses only MRI examinations; the second—PriSCA_MRI + Gen—includes knowledge of the prion protein codon 129 genotype, a major determinant of sCJD subtypes. Both procedures were tested on the first MRI and the last MRI follow‐up.
Results
PriSCA_MRI classified the 3 most prevalent subtypes with 82% accuracy.
PriSCA_MRI + Gen raised the accuracy to 89% and identified all subtypes.
Individually, the 2 most prevalent sCJD subtypes, MM1 and VV2, were diagnosed with sensitivities up to 95 and 97%, respectively. The performances of both procedures did not change in 168 patients with longitudinal MRI studies when the last examination was used.
Interpretation
This study provides the first practical algorithms for antemortem diagnosis of sCJD subtypes. MRI diagnosis of subtype is likely to be attainable at early disease stages to prognosticate clinical course and design future therapeutic trials. ANN NEUROL 2021;89:560–572
Atypical teratoid/rhabdoid tumor is a rare malignant CNS tumor that most often affects children ≤ 3 years old. The Central Brain Tumor Registry of the United States contains the largest aggregation ...of population-based incidence data for primary CNS tumors in the US. Its data were used to describe the incidence, associated trends, and relative survival after diagnosis of atypical teratoid/rhabdoid tumor.
Using data from 50 cancer registries between 2001 and 2010, age-adjusted incidence rates per 100 000 and 95% CIs were calculated by sex, race, Hispanic ethnicity, age at diagnosis, and location of tumor in the CNS for children aged 0 to 19 years. Relative survival rates and 95% CIs were also calculated.
The average annual age-adjusted incidence rate was 0.07 (95% CI: 0.07, 0.08). Incidence rates did not significantly vary by sex, race, or ethnicity. Age had a strong effect on incidence rate, with highest incidence among children <1 year, and decreasing incidence with increasing age. The 6-month, 1-year, and 5-year relative survival rates for all ages were 65.0%, 46.8%, and 28.3%, respectively. Atypical teratoid/rhabdoid tumor can occur anywhere in the CNS, but supratentorial tumors were more common with increasing age.
We confirm differences in survival by age at diagnosis, treatment pattern, and location of tumor in the brain. This contributes to our understanding of these tumors and may stimulate research leading to improved treatment of this devastating childhood disease.
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