Diagnostic and prognostic value of human prion detection in cerebrospinal fluid.

OBJECTIVE: Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. METHODS: We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases that were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and type 1 or type 2 human prions on diagnostic performance. RESULTS: The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1-2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, whereas genetic prion diseases revealed distinct profiles for each PRNP gene mutation. INTERPRETATION: The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and tau proteins, and together with PRNP gene sequencing the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease-two important considerations for envisioned therapeutic interventions. ANN NEUROL 2017;81:79-92.

A rare case of rapidly progressive dementia with elevated RT-QuIC and negative 14-3-3 and tau proteins.

Creutzfeldt-Jakob disease (CJD) is characterized by rapidly progressing dementia with death usually occurring within 6 months. There is no verified disease-specific pre-mortem diagnostic test besides brain biopsy. We describe a 66 y old previously high functioning male who presented with a 5 month history of rapidly progressive dementia. Neurological examination revealed a score of 19/30 on MOCA testing. An extensive workup into various causes of dementia including electroencephalography and imaging studies was unremarkable. The cerebrospinal fluid was sent to National Prion Disease Center and it revealed elevated RT-QuIC levels with negative 14-3-3 and T tau proteins. Based on literature review, our case is one of few living subjects with elevated RT-QuIC levels and negative 14-3-3 and tau proteins.

A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt-Jakob disease.

OBJECTIVE: To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein (qualitative) in the diagnosis of prion disease. METHODS: We made measurements on 420 live subjects, who subsequently underwent a postmortem neuropathology examination, including protein chemistry, immunohistochemistry, and histology. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were optimized for maximum efficiency (accuracy). RESULTS: We found tau and 14-3-3 proteins to be closely correlated, but tau had a significantly better ability to predict disease status than 14-3-3 protein. Also, tau distinguished disease status at least as well as when both assays' results are combined in a variety of ways. Importantly, the area under the receiver operating characteristic curve for tau (0.82) was significantly larger than that for 14-3-3 protein (0.68) (p < 0.001). Diagnostic test statistics are provided for the study subjects with 58.3% prevalence, and for a more typical, nonselected, 7.5% prevalence as received by our center. CONCLUSION: In this study, tau is superior to 14-3-3 protein as a marker in the diagnosis of Creutzfeldt-Jakob disease, and is as efficient singly compared to a variety of combinations with 14-3-3 protein. This is the first study of this magnitude to examine prion disease diagnostic tests in a carefully characterized patient population with detailed statistical evaluation.

Primary hyperparathyroidism with a low-normal, atypical serum parathyroid hormone as shown by discordant immunoassay curves.

CONTEXT: In patients with primary hyperparathyroidism (PHP), one expects to find a serum PTH in the high or high-normal range. The presence of a low-normal PTH in PHP can be difficult to explain. OBJECTIVE: Our objective was to investigate the cause of a low-normal serum PTH in a patient with PHP. PATIENT: A 57-yr-old asymptomatic white female from the private practice of F.W.L. presented with an 8-yr history of a rising serum calcium from 10.5-11.6 mg/dl (2.63-2.88 mmol/liter) and a low-normal serum intact PTH of 29.2 pg/ml. After localization of a parathyroid adenoma by [(18)F]fluorodesoxyglucose positron emission tomography scanning, a 120-mg parathyroid adenoma was removed with the achievement of normocalcemia for the subsequent 2 yr. METHODS: Routine pre- and postoperative serum intact PTH assays were preformed at both the Quest Diagnostics regional laboratory in Pittsburgh, Pennsylvania, and at the Quest Diagnostics Nichols Institute in California. In addition, intact, biointact, and C-terminal assays were measured in undiluted, 1:2 diluted, and 1:4 diluted sera at the Nichols Institute. PTH gene sequence analysis was performed from DNA extracted both from the parathyroid adenoma and the patient's peripheral blood leukocytes. RESULTS: Dilution, with correction for the dilution factor, of the preoperative serum produced a progressive rise in the intact, biointact, and the C-terminal assays, whereas no dilution effect was seen in postoperative serum. No intragenic mutations in the pre-pro-PTH coding region were found in either the parathyroid adenoma or matched blood DNA samples. CONCLUSIONS: The discordant preoperative immunoassay curves with dilution could not be explained by the adenoma producing a mutated PTH. Furthermore, an autoantibody against the PTH produced by the adenoma is ruled out by the prompt loss of the dilution effect in the three PTH assays within 1 wk of the adenoma's excision. A posttranslational effect on the PTH molecule within the adenoma remains a possible explanation for the discordant immunoassay curves. Our report emphasizes that one cannot always rule out PHP because of a low-normal serum intact or biointact PTH. Repeated PTH measurements after serum dilution in suspected cases of PHP with low-normal PTH levels may be a useful method for detecting atypical forms of PTH.

Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis.

Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.