ABSTRACT
We present a Bayesian full-spectral-fitting analysis of 75 massive ($M_* \gt 10^{10.3} \, \mathrm{M_\odot }$) UVJ-selected galaxies at redshifts of 1.0 < z < 1.3, combining extremely deep ...rest-frame ultraviolet spectroscopy from VANDELS with multiwavelength photometry. By the use of a sophisticated physical plus systematic uncertainties model, constructed within the bagpipes code, we place strong constraints on the star-formation histories (SFHs) of individual objects. We first constrain the stellar mass versus stellar age relationship, finding a steep trend towards earlier average formation time with increasing stellar mass (downsizing) of $1.48^{+0.34}_{-0.39}$ Gyr per decade in mass, although this shows signs of flattening at $M_* \gt 10^{11} \, \mathrm{M_\odot }$. We show that this is consistent with other spectroscopic studies from 0 < z < 2. This relationship places strong constraints on the AGN-feedback models used in cosmological simulations. We demonstrate that, although the relationships predicted by simba and illustristng agree well with observations at z = 0.1, they are too shallow at z = 1, predicting an evolution of ≲0.5 Gyr per decade in mass. Secondly, we consider the connections between green-valley, post-starburst, and quiescent galaxies, using our inferred SFH shapes and the distributions of galaxy physical properties on the UVJ diagram. The majority of our lowest-mass galaxies ($M_* \sim 10^{10.5} \, \mathrm{M_\odot }$) are consistent with formation in recent (z < 2), intense starburst events, with time-scales of ≲500 Myr. A second class of objects experience extended star-formation epochs before rapidly quenching, passing through both green-valley and post-starburst phases. The most massive galaxies in our sample are extreme systems: already old by z = 1, they formed at z ∼ 5 and quenched by z = 3. However, we find evidence for their continued evolution through both AGN and rejuvenated star-formation activity.
OBJECTIVETo present the National Prion Disease Pathology Surveillance Centerʼs (NPDPSC’s) experience using CSF real-time quaking-induced conversion (RT-QuIC) as a diagnostic test, to examine factors ...associated with false-negative RT-QuIC results, and to investigate the impact of RT-QuICs on prion disease surveillance.
METHODSBetween May 2015 and April 2018, the NPDPSC received 10,498 CSF specimens that were included in the study. Sensitivity and specificity analyses were performed on 567 autopsy-verified cases. Prion disease type, demographic characteristics, specimen color, and time variables were examined for association with RT-QuIC results. The effect of including positive RT-QuIC cases in prion disease surveillance was examined.
RESULTSThe diagnostic sensitivity and specificity of RT-QuIC across all prion diseases were 90.3% and 98.5%, respectively. Diagnostic sensitivity was lower for fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease, sporadic fatal insomnia, variably protease sensitive prionopathy, and the VV1 and MM2 subtypes of sporadic Creutzfeldt-Jakob disease. Individuals with prion disease and negative RT-QuIC results were younger and had lower tau levels and nonelevated 14-3-3 levels compared to RT-QuIC–positive cases. Sensitivity was high throughout the disease course. Some cases that initially tested RT-QuIC negative had a subsequent specimen test positive. Including positive RT-QuIC cases in surveillance statistics increased laboratory-based case ascertainment of prion disease by 90% over autopsy alone.
CONCLUSIONSRT-QuIC has high sensitivity and specificity for diagnosing prion diseases. Sensitivity limitations are associated with prion disease type, age, and related CSF diagnostic results. RT-QuIC greatly improves laboratory-based prion disease ascertainment for surveillance purposes.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that second-generation RT-QuIC identifies prion disease with a sensitivity of 90.3% and specificity of 98.5% among patients being screened for these diseases due to concerning symptoms.
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
Genetic aspects of human prion diseases Appleby, Brian S.; Shetty, Shashirekha; Elkasaby, Mohamed
Frontiers in neurology,
10/2022, Letnik:
13
Journal Article
Recenzirano
Odprti dostop
Human prion diseases are rapidly progressive and fatal neurodegenerative conditions caused by a disease-causing isoform of the native prion protein. The prion protein gene (
PRNP
) encodes for the ...cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic, and acquired.
PRNP
polymorphisms and pathogenic variants play a large role in the frequency, age at onset, and clinicopathologic phenotype of prion diseases. Genetic prion diseases will be covered in detail and information necessary for clinical care, predictive genetic testing, and genetic counseling will be reviewed. Because the prion protein is necessary for transmission and neurotoxicity, many experimental treatments targeting its production are being investigated and hold potential promise as a disease modifying treatment for all forms of prion disease, including asymptomatic mutation carriers. This article will review genetic aspects of human prion disease and their influence on epidemiology, clinicopathologic phenotype, diagnostics, clinical management, and potential treatment approaches.
Objectives Individuals with mild cognitive impairment (MCI) are at high risk of developing dementia and/or Alzheimer disease (AD). Among persons with MCI, depression and anxiety have been associated ...with an increased risk of incident dementia. We examined whether neuropsychiatric symptoms in MCI increased the risk of incident dementia (all-cause) and incident AD. Design Longitudinal cohort study followed annually (median: 1.58 years). Setting National Alzheimer's Coordinating Center database combining clinical data from 29 Alzheimer's Disease Centers. Participants A total of 1,821 participants with MCI. Measurements 1) Progression to dementia (all-cause) or AD, 2) Neuropsychiatric Inventory Questionnaire (NPI-Q), 3) Geriatric Depression Scale (GDS), 4) Clinical Dementia Rating Global Score and Sum of Boxes, and 5) Mini-Mental State Examination (MMSE). The association of covariates with risk of incident dementia or AD was evaluated with hazard ratios (HR) determined by Cox proportional-hazards models adjusted for age, ethnicity, Clinical Dementia Rating Global Score and Sum of Boxes, and MMSE. Results A total of 527 participants (28.9%) progressed to dementia and 454 (24.9%) to AD. Baseline GDS > 0 was associated with an increased risk of incident dementia (HR: 1.47, 95% CI: 1.17–1.84) and AD (HR: 1.45, 95% CI: 1.14–1.83). Baseline NPI > 0 was associated with an increased risk of incident dementia (HR: 1.37, 95% CI: 1.12–1.66) and AD (HR: 1.35, 95% CI: 1.09–1.66). Conclusions Neuropsychiatric symptoms in MCI are associated with significantly an increased risk of incident dementia and AD. Neuropsychiatric symptoms may be among the earliest symptoms of preclinical stages of AD and targeting them therapeutically might delay transition to dementia.
•Previous clinical trials in prion diseases have yielded important information.•Clinical trials in prion disease should consider prion disease-specific aspects.•Clinical trials in prion disease ...should consider clinically meaningful outcomes.•International collaboration will improve our ability to conduct clinical trials.
Human prion diseases are usually rapid neurodegenerative illnesses that are invariably fatal. Despite several clinical trials, no effective treatment has been discovered in humans. Although prior clinical trials have not been successful, they provided information that is vital for the formation of future clinical trials. Among these findings is the realization that there are several prion disease-specific aspects that must be considered when conducting clinical trials. The rarity, rapidity, and clinical heterogeneity of prion disease affect study enrollment and the ability to measure treatment effects. In addition to affecting results, study methodology may also influence study enrollment. In this review, we explore several challenges to conducting clinical trials in prion disease and suggest some practical considerations.
Alzheimer's disease (AD) is the most common cause of dementia and a major cause of morbidity and mortality. The greatest risk factor for AD is age and as many countries are experiencing an aging ...population, the expected rise in AD threatens to have serious medical and socioeconomic impact in the coming decades. The only approved medications for AD are symptomatic and there are no currently available disease modifying treatments. Hence, a disease modifying treatment is desperately needed for AD not only for proper care and management of affected patients, but also to reduce society's socioeconomic burden. Developing novel compounds for any indication is a time, effort, and money consuming endeavor and most treatments never make it to market. Other research and development strategies are needed, especially for the treatment of AD. We provide a review of the current literature in assessing possibilities of repurposing medications currently used for non-AD indications. Many different compounds from many different pharmacological classes have already been studied in an AD context. We provide a "pragmatic drug repurposing score" for each of these compounds based on type of studies conducted, number of possible mechanisms of action, efficacy in AD and other neurodegenerative disease studies, tolerability profile, and their ability to cross the blood brain barrier. The current data suggest several compounds worthy of further study as treatments for AD. Compounds with the highest scores include lithium, minocycline, exenatide, valproic acid, methylene blue, and nicotine.
Chronic wasting disease (CWD) is a prion-related transmissible spongiform encephalopathy of cervids, including deer, elk, reindeer, sika deer, and moose. CWD has been confirmed in at least 26 U.S. ...states, three Canadian provinces, South Korea, Finland, Norway, and Sweden, with a notable increase in the past 5 years. The continued geographic spread of this disease increases the frequency of exposure to CWD prions among cervids, humans, and other animal species. Since CWD is now an established wildlife disease in North America, proactive steps, where possible, should be taken to limit transmission of CWD among animals and reduce the potential for human exposure.
Prion diseases are difficult to recognize as many symptoms are shared among other neurologic pathologies and the full spectra of symptoms usually do not appear until late in the disease course. ...Additionally, many commonly used laboratory markers are non-specific to prion disease. The recent introduction of second-generation real time quaking induced conversion (RT-QuIC) has revolutionized pre-mortem diagnosis of prion disease due to its extremely high sensitivity and specificity. However, RT-QuIC does not provide prognostic data and has decreased diagnostic accuracy in some rarer, atypical prion diseases. The objective of this review is to provide an overview of the current clinical utility of fluid-based biomarkers, neurodiagnostic testing, and brain imaging in the diagnosis of prion disease and to suggest guidelines for their clinical use, with a focus on rarer prion diseases with atypical features. Recent advancements in laboratory-based testing and imaging criteria have shown improved diagnostic accuracy and prognostic potential in prion disease, but because these diagnostic tests are not sensitive in some prion disease subtypes and diagnostic test sensitivities are unknown in the event that CWD transmits to humans, it is important to continue investigations into the clinical utility of various testing modalities.
The current classification of sporadic Creutzfeldt–Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the ...pathologic prion protein (PrP
Sc
), defining two major PrP
Sc
types (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (
PRNP
). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrP
Sc
type and codon 129 genotype on
PRNP
mutated allele, each showing distinctive histopathological characteristics, irrespectively of the
PRNP
associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrP
Sc
type of intermediate size (“i”) between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a “thickened” synaptic pattern in E200K carriers, cerebellar “stripe-like linear granular deposits” in those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M”i”). A few isolated cases linked to rare
PRNP
haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrP
Sc
significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis.
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