Using Narrow Band Photometry to Detect Young Brown Dwarfs in IC348

We report the discovery of a population of young brown dwarf candidates in the open star cluster IC348 and the development of a new spectroscopic classification technique using narrow band photometry. Observations were made using FLITECAM, the First Light Camera for SOFIA, at the 3-m Shane Telescope at Lick Observatory. FLITECAM is a new 1-5 micron camera with an 8 arcmin field of view. Custom narrow band filters were developed to detect absorption features of water vapor (at 1.495 microns) and methane (at 1.66 microns) characteristic of brown dwarfs. These filters enable spectral classification of stars and brown dwarfs without spectroscopy. FLITECAM's narrow and broadband photometry was verified by examining the color-color and color-magnitude characteristics of stars whose spectral type and reddening was known from previous surveys. Using our narrow band filter photometry method, it was possible to identify an object measured with a signal-to-noise ratio of 20 or better to within +/-3 spectral class subtypes for late-type stars. With this technique, very deep images of the central region of IC348 (H ~ 20.0) have identified 18 sources as possible L or T dwarf candidates. Out of these 18, we expect that between 3 - 6 of these objects are statistically likely to be background stars, with the remainder being true low-mass members of the cluster. If confirmed as cluster members then these are very low-mass objects (~5 Mjupiter). We also describe how two additional narrow band filters can improve the contrast between M, L, and T dwarfs as well as provide a means to determine the reddening of an individual object.Comment: 43 pages, 17 figures. Accepted for publication in the Astrophysical Journal 27 June 200

Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers

A Cross-Match of 2MASS and SDSS: Newly-Found L and T Dwarfs and an Estimate of the Space Densitfy of T Dwarfs

We report new L and T dwarfs found in a cross-match of the SDSS Data Release 1 and 2MASS. Our simultaneous search of the two databases effectively allows us to relax the criteria for object detection in either survey and to explore the combined databases to a greater completeness level. We find two new T dwarfs in addition to the 13 already known in the SDSS DR1 footprint. We also identify 22 new candidate and bona-fide L dwarfs, including a new young L2 dwarf and a peculiar L2 dwarf with unusually blue near-IR colors: potentially the result of mildly sub-solar metallicity. These discoveries underscore the utility of simultaneous database cross-correlation in searching for rare objects. Our cross-match completes the census of T dwarfs within the joint SDSS and 2MASS flux limits to the 97% level. Hence, we are able to accurately infer the space density of T dwarfs. We employ Monte Carlo tools to simulate the observed population of SDSS DR1 T dwarfs with 2MASS counterparts and find that the space density of T0-T8 dwarf systems is 0.0070 (-0.0030; +0.0032) per cubic parsec (95% confidence interval), i.e., about one per 140 cubic parsecs. Compared to predictions for the T dwarf space density that depend on various assumptions for the sub-stellar mass function, this result is most consistent with models that assume a flat sub-stellar mass function dN/dM ~ M^0. No >T8 dwarfs were discovered in the present cross-match, though less than one was expected in the limited area (2099 sq. degrees) of SDSS DR1.Comment: To appear in ApJ, Feb 10, 2008 issue. 37 pages, including 12 figures and 14 table

Imaging and CSF analyses effectively distinguish CJD from its mimics

OBJECTIVE: To review clinical and investigation findings in patients referred to a specialist prion clinic who were suspected to have sporadic Creutzfeldt-Jakob disease (sCJD) and yet were found to have an alternative final diagnosis. METHODS: Review the clinical findings and investigations in 214 patients enrolled into the UK National Prion Monitoring Cohort Study between October 2008 and November 2015 who had postmortem confirmed sCJD and compare these features with 50 patients referred over the same period who had an alternative final diagnosis (CJD mimics). RESULTS: Patients with an alternative diagnosis and those with sCJD were of similar age, sex and frequency of dementia but CJD mimics had a longer clinical history. Myoclonus, rigidity and hallucinations were more frequent in patients with sCJD but these features were not helpful in classifying individual patients. Alzheimer's disease, dementia with Lewy bodies and genetic neurodegenerative disorders were alternative diagnoses in more than half of the CJD mimic cases, and 10% had an immune-mediated encephalopathy; lymphoma, hepatic encephalopathy and progressive multifocal leukoencephalopathy were seen more than once. Diffusion-weighted MRI was the most useful readily available test to classify cases correctly (92% CJD, 2% CJD mimics). The CSF cell count, 14-3-3 protein detection and S100B were of limited value. A positive CSF RT-QuIC test, introduced during the course of the study, was found in 89% of tested CJD cases and 0% CJD mimics. CONCLUSION: The combination of diffusion-weighted MRI analysis and CSF RT-QuIC allowed a perfect classification of sCJD versus its mimics in this study

Chronic wasting disease prions are not transmissible to transgenic mice overexpressing human prion protein

Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids, including mule deer, white-tailed deer, Rocky Mountain elk and moose. CWD-infected cervids have been reported in 14 USA states, two Canadian provinces and in South Korea. The possibility of a zoonotic transmission of CWD prions via diet is of particular concern in North America where hunting of cervids is a popular sport. To investigate the potential public health risks posed by CWD prions, we have investigated whether intracerebral inoculation of brain and spinal cord from CWD-infected mule deer transmits prion infection to transgenic mice overexpressing human prion protein with methionine or valine at polymorphic residue 129. These transgenic mice have been utilized in extensive transmission studies of human and animal prion disease and are susceptible to BSE and vCJD prions, allowing comparison with CWD. Here, we show that these mice proved entirely resistant to infection with mule deer CWD prions arguing that the transmission barrier associated with this prion strain/host combination is greater than that observed with classical BSE prions. However, it is possible that CWD may be caused by multiple prion strains. Further studies will be required to evaluate the transmission properties of distinct cervid prion strains as they are characterized

Cognitive decline heralds onset of symptomatic inherited prion disease

The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers that predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in individuals with the inherited prion disease mutation P102L. We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease. Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive clinical findings (n = 24). In the longitudinal analysis, we analysed data from 24 patients who were presymptomatic at the time of recruitment and were followed up over a period of up to 17 years, of whom 16 remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but similar set of tests (Trail Making Test part A, Stroop test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease. In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms [area under the curve = 0.83 (95% confidence interval, 0.62–1.00), P = 0.009]. Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of inherited prion disease. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine

Case report of homozygous E200D mutation of PRNP in apparently sporadic Creutzfeldt-Jakob disease

Background: Inherited prion diseases are rare autosomal dominant disorders associated with diverse clinical presentations. All are associated with mutation of the gene that encodes prion protein (PRNP). Homozygous mutations with atypical clinical phenotypes have been described but are extremely rare. Case presentation: A Chinese patient presented with a rapidly progressive cognitive and motor disorder in the clinical spectrum of sCJD. Investigations strongly suggested a diagnosis of CJD. He was found to carry a homozygous mutation at PRNP codon 200 (E200D), but there was no known family history of the disorder. The estimated allele frequency of E200D in East Asian populations is incompatible with it being a highly penetrant mutation in the heterozygous state. Conclusion: In our view the homozygous PRNP E200D genotype is likely to be causal of CJD in this patient. Homotypic PrP interactions are well known to favour the development of prion disease. The case is compatible with recessively inherited prion disease

Cognitive decline heralds onset of symptomatic inherited prion disease

The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers which predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in healthy people with the inherited prion disease mutation P102L (Rudge et al, Brain 2019). We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease (Caine et al., 2015; 2018). Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive clinical findings (n = 24). In the longitudinal analysis, we analysed data from twenty four patients who were presymptomatic at the time of recruitment and were followed up over a period of up to seventeen years, of whom sixteen remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but very similar set of tests (Trail Making Test part A, Stroop Test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease (Caine et al., 2015; 2018). In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms (AUC = .83 (95% CI, 0.62-1.00), p =.009). Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of IPD. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine

Stochastic Modelling Approach to the Incubation Time of Prionic Diseases

Transmissible spongiform encephalopathies like the bovine spongiform encephalopathy (BSE) and the Creutzfeldt-Jakob disease (CJD) in humans are neurodegenerative diseases for which prions are the attributed pathogenic agents. A widely accepted theory assumes that prion replication is due to a direct interaction between the pathologic (PrPsc) form and the host encoded (PrPc) conformation, in a kind of an autocatalytic process. Here we show that the overall features of the incubation time of prion diseases are readily obtained if the prion reaction is described by a simple mean-field model. An analytical expression for the incubation time distribution then follows by associating the rate constant to a stochastic variable log normally distributed. The incubation time distribution is then also shown to be log normal and fits the observed BSE data very well. The basic ideas of the theoretical model are then incorporated in a cellular automata model. The computer simulation results yield the correct BSE incubation time distribution at low densities of the host encoded protein