Publications by authors named "Simon Mead"

178 Publications

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

BMC Neurol 2021 Jun 28;21(1):248. Epub 2021 Jun 28.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.

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.
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http://dx.doi.org/10.1186/s12883-021-02274-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237416PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Alzheimer's disease neuropathological change three decades after iatrogenic amyloid-β transmission.

Acta Neuropathol 2021 Jul 28;142(1):211-215. Epub 2021 May 28.

Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, WC1N 3BG, UK.

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http://dx.doi.org/10.1007/s00401-021-02326-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217014PMC
July 2021

Plasma amyloid-β ratios in autosomal dominant Alzheimer's disease: the influence of genotype.

Brain 2021 Apr 23. Epub 2021 Apr 23.

Dementia Research Centre, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.

In-vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-beta peptides in disease pathogenesis, however less is known about the behaviour of these mutations in-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at-risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-beta42:38, 42:40 and 38:40 ratios between presenilin1 and amyloid precursor protein carriers. We examined the relationship between plasma and in-vitro models of amyloid-beta processing and tested for associations with parental age at onset. 39 participants were mutation carriers (28 presenilin1 and 11 amyloid precursor protein). Age- and sex-adjusted models showed marked differences in plasma amyloid-beta between genotypes: higher amyloid-beta42:38 in presenilin1 versus amyloid precursor protein (p < 0.001) and non-carriers (p < 0.001); higher amyloid-beta38:40 in amyloid precursor protein versus presenilin1 (p < 0.001) and non-carriers (p < 0.001); while amyloid-beta42:40 was higher in both mutation groups compared to non-carriers (both p < 0.001). Amyloid-beta profiles were reasonably consistent in plasma and cell lines. Within presenilin1, models demonstrated associations between amyloid-beta42:38, 42:40 and 38:40 ratios and parental age at onset. In-vivo differences in amyloid-beta processing between presenilin1 and amyloid precursor protein carriers provide insights into disease pathophysiology, which can inform therapy development.
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http://dx.doi.org/10.1093/brain/awab166DOI Listing
April 2021

Cognitive decline heralds onset of symptomatic inherited prion disease.

Brain 2021 Apr;144(3):989-998

Department of Neuropsychology, NHNN, University College London Hospitals NHS Foundation Trust, London, UK.

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.
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http://dx.doi.org/10.1093/brain/awaa409DOI Listing
April 2021

Evaluation of plasma tau and neurofilament light chain biomarkers in a 12-year clinical cohort of human prion diseases.

Mol Psychiatry 2021 Mar 5. Epub 2021 Mar 5.

MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK.

Prion diseases are fatal neurodegenerative conditions with highly accurate CSF and imaging diagnostic tests, but major unmet needs for blood biomarkers. Using ultrasensitive immuno-assays, we measured tau and neurofilament light chain (NfL) protein concentrations in 709 plasma samples taken from 377 individuals with prion disease during a 12 year prospective clinical study, alongside healthy and neurological control groups. This provides an unprecedented opportunity to evaluate their potential as biomarkers. Plasma tau and NfL were increased across all prion disease types. For distinguishing sCJD from control groups including clinically-relevant "CJD mimics", both show considerable diagnostic value. In sCJD, NfL was substantially elevated in every sample tested, including during early disease with minimal functional impairment and in all follow-up samples. Plasma tau was independently associated with rate of clinical progression in sCJD, while plasma NfL showed independent association with severity of functional impairment. In asymptomatic PRNP mutation carriers, plasma NfL was higher on average in samples taken within 2 years of symptom onset than in samples taken earlier. We present biomarker trajectories for nine mutation carriers healthy at enrolment who developed symptoms during follow-up. NfL started to rise as early as 2 years before onset in those with mutations typically associated with more slowly progressive clinical disease. This shows potential for plasma NfL as a "proximity marker", but further work is needed to establish predictive value on an individual basis, and how this varies across different PRNP mutations. We conclude that plasma tau and NfL have potential to fill key unmet needs for biomarkers in prion disease: as a secondary outcome for clinical trials (NfL and tau); for predicting onset in at-risk individuals (NfL); and as an accessible test for earlier identification of patients that may have CJD and require more definitive tests (NfL). Further studies should evaluate their performance directly in these specific roles.
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http://dx.doi.org/10.1038/s41380-021-01045-wDOI Listing
March 2021

Bank vole prion protein extends the use of RT-QuIC assays to detect prions in a range of inherited prion diseases.

Sci Rep 2021 Mar 4;11(1):5231. Epub 2021 Mar 4.

MRC Prion Unit at UCL, Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London, W1W 7FF, UK.

The cerebrospinal fluid (CSF) real-time quaking-induced conversion assay (RT-QuIC) is an ultrasensitive prion amyloid seeding assay for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) but several prion strains remain unexplored or resistant to conversion with commonly used recombinant prion protein (rPrP) substrates. Here, bank vole (BV) rPrP was used to study seeding by a wide range of archived post-mortem human CSF samples from cases of sporadic, acquired and various inherited prion diseases in high throughput 384-well format. BV rPrP substrate yielded positive reactions in 70/79 cases of sporadic CJD [Sensitivity 88.6% (95% CI 79.5-94.7%)], 1/2 variant CJD samples, and 9/20 samples from various inherited prion diseases; 5/57 non-prion disease control CSFs had positive reactions, yielding an overall specificity of 91.2% (95% CI 80.1-97.1%). Despite limitations of using post-mortem samples and our results' discrepancy with other studies, we demonstrated for the first time that BV rPrP is susceptible to conversion by human CSF samples containing certain prion strains not previously responsive in conventional rPrPs, thus justifying further optimisation for wider diagnostic and prognostic use.
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http://dx.doi.org/10.1038/s41598-021-84527-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933407PMC
March 2021

A novel presenilin 1 duplication mutation (Ile168dup) causing Alzheimer's disease associated with myoclonus, seizures and pyramidal features.

Neurobiol Aging 2021 Jul 5;103:137.e1-137.e5. Epub 2021 Feb 5.

Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK. Electronic address:

Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease. We report the clinical, imaging and postmortem findings of kindred carrying a novel duplication mutation (Ile168dup) in the PSEN1 gene. We interpret the pathogenicity of this novel variant and discuss the additional neurological features (pyramidal dysfunction, myoclonus and seizures) that accompanied cognitive decline. This report broadens the clinical phenotype of PSEN1 insertion mutations while also highlighting the importance of considering duplication, insertion and deletion mutations in cases of young onset dementia.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.032DOI Listing
July 2021

Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease.

Lancet Neurol 2021 03;20(3):235-246

National Reference Center for Transmissible Spongiform Encephalopathies, Department of Neurology, University Medical Center Göttingen, Göttingen, Germany; German Center for Neurodegenerative Diseases, Göttingen, Germany.

Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrP). Effective therapeutics are currently not available and accurate diagnosis can be challenging. Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF proteins 14-3-3, MRI, and EEG. Supportive biomarkers, such as high CSF total tau, could aid the diagnostic process. However, discordant studies have led to controversies about the clinical value of some established surrogate biomarkers. Development and clinical application of disease-specific protein aggregation and amplification assays, such as real-time quaking induced conversion (RT-QuIC), have constituted major breakthroughs for the confident pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Updated criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease, including application of RT-QuIC, should improve early clinical confirmation, surveillance, assessment of PrP seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under investigation.
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http://dx.doi.org/10.1016/S1474-4422(20)30477-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285036PMC
March 2021

Genetic testing in dementia - utility and clinical strategies.

Nat Rev Neurol 2021 Jan 9;17(1):23-36. Epub 2020 Nov 9.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, UK.

Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information.
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http://dx.doi.org/10.1038/s41582-020-00416-1DOI Listing
January 2021

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.

Am J Hum Genet 2020 11 5;107(5):802-814. Epub 2020 Oct 5.

University of Cape Town/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, 7935, South Africa.

The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675008PMC
November 2020

Putaminal diffusion tensor imaging measures predict disease severity across human prion diseases.

Brain Commun 2020 8;2(1):fcaa032. Epub 2020 Apr 8.

UCL Institute of Neurology, London, UK.

Therapeutic trials of disease-modifying agents in neurodegenerative disease typically require several hundred participants and long durations for clinical endpoints. Trials of this size are not feasible for prion diseases, rare dementia disorders associated with misfolding of prion protein. In this situation, biomarkers are particularly helpful. On diagnostic imaging, prion diseases demonstrate characteristic brain signal abnormalities on diffusion-weighted MRI. The aim of this study was to determine whether cerebral water diffusivity could be a quantitative imaging biomarker of disease severity. We hypothesized that the basal ganglia were most likely to demonstrate functionally relevant changes in diffusivity. Seventy-one subjects (37 patients and 34 controls) of whom 47 underwent serial scanning (23 patients and 24 controls) were recruited as part of the UK National Prion Monitoring Cohort. All patients underwent neurological assessment with the Medical Research Council Scale, a functionally orientated measure of prion disease severity, and diffusion tensor imaging. Voxel-based morphometry, voxel-based analysis of diffusion tensor imaging and regions of interest analyses were performed. A significant voxel-wise correlation of decreased Medical Research Council Scale score and decreased mean, radial and axial diffusivities in the putamen bilaterally was observed ( < 0.01). Significant decrease in putamen mean, radial and axial diffusivities over time was observed for patients compared with controls ( = 0.01), and there was a significant correlation between monthly decrease in putamen mean, radial and axial diffusivities and monthly decrease in Medical Research Council Scale ( < 0.001). Step-wise linear regression analysis, with dependent variable decline in Medical Research Council Scale, and covariates age and disease duration, showed the rate of decrease in putamen radial diffusivity to be the strongest predictor of rate of decrease in Medical Research Council Scale ( < 0.001). Sample size calculations estimated that, for an intervention study, 83 randomized patients would be required to provide 80% power to detect a 75% amelioration of decline in putamen radial diffusivity. Putamen radial diffusivity has potential as a secondary outcome measure biomarker in future therapeutic trials in human prion diseases.
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http://dx.doi.org/10.1093/braincomms/fcaa032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425333PMC
April 2020

Enteral feeding is associated with longer survival in the advanced stages of prion disease.

Brain Commun 2019 10;1(1):fcz012. Epub 2019 Sep 10.

National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK.

To report the frequency, complications, survival and motivations for enteral feeding in UK patients with prion diseases. We analysed data from an ongoing prospective observational cohort study of UK patients with prion diseases ( = 635). Gastrostomy-treated cases were matched by age, gender, disease aetiology, severity, duration and a genetic predictor of survival (ratio 1:3.1). The main outcome was survival (unadjusted log-rank test); secondary outcomes were future functional impairments, complications and retrospective carer interviews to determine qualitative benefits and motivations. Enteral feeding is uncommon in UK patients with prion diseases (= 26/635; 4.1%), but more frequent in acquired (7/41, 17.1%) and inherited (7/128, 5.5%) compared with sporadic disease (12/466, 2.6%;  = 3 × 10 chi-squared), and used mostly at advanced stages. Enteral feeding was complicated by infection and the need for reinsertions, but associated with markedly longer survival at advanced neurodisability (median 287 days, range 41-3877 versus 17 days, range 0-2356; log-rank test in three aetiologies each  < 0.01). Interviews revealed different motivations for enteral feeding, including perceived quality of life benefits. We provide Class II evidence that enteral feeding prolongs the akinetic-mute phase of all aetiological types of prion disease. These data may help support decision making in palliative care. Enteral feeding is an important potential confounder in prion disease clinical trials that use survival as an endpoint.
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http://dx.doi.org/10.1093/braincomms/fcz012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425295PMC
September 2019

Potential human transmission of amyloid β pathology: surveillance and risks.

Lancet Neurol 2020 10 16;19(10):872-878. Epub 2020 Sep 16.

Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium.

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid β after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid β through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid β might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid β can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid β transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically.
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http://dx.doi.org/10.1016/S1474-4422(20)30238-6DOI Listing
October 2020

Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study.

Lancet Neurol 2020 10 16;19(10):840-848. Epub 2020 Sep 16.

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms.

Methods: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country.

Findings: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10; heterozygous model p=1·01 × 10), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions.

Interpretation: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders.

Funding: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.
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http://dx.doi.org/10.1016/S1474-4422(20)30273-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220892PMC
October 2020

Marked abnormalities of plasma protein biomarkers in Creutzfeldt-Jakob disease (CJD).

Authors:
Simon Mead

J Neurol Neurosurg Psychiatry 2020 11 14;91(11):1137. Epub 2020 Sep 14.

MRC Prion Unit at UCL, UCL Institute of Neurology, London, London, UK

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http://dx.doi.org/10.1136/jnnp-2020-324307DOI Listing
November 2020

Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt-Jakob disease.

Acta Neuropathol 2020 12 12;140(6):863-879. Epub 2020 Sep 12.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London, W1W 7FF, UK.

Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Our case-control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 × 10). Nine of these sites were taken forward in a replication study, performed in an independent case-control (n = 186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case-control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer's disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications.
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http://dx.doi.org/10.1007/s00401-020-02224-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666287PMC
December 2020

A blood miRNA signature associates with sporadic Creutzfeldt-Jakob disease diagnosis.

Nat Commun 2020 08 7;11(1):3960. Epub 2020 Aug 7.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London, W1W 7FF, UK.

Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are available for diagnosis or disease monitoring. Here, we profile blood microRNA (miRNA) expression in sCJD. Sequencing of 57 sCJD patients, and healthy controls reveals differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicates in an independent cohort using quantitative PCR, with concomitant upregulation of four mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes parallels the lack of association between rate of decline in miRNA expression, and rate of disease progression in a longitudinal cohort of samples from 21 patients. Finally, the miRNA signature shows a high level of accuracy in discriminating sCJD from Alzheimer's disease. These findings highlight molecular alterations in the periphery in sCJD which provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.
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http://dx.doi.org/10.1038/s41467-020-17655-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414116PMC
August 2020

Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer's disease: a longitudinal cohort study.

Mol Psychiatry 2020 Jul 14. Epub 2020 Jul 14.

Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.

Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer's disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO -9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85-0.98]) and presymptomatic (EYO ≥ -7 years) (AUC 0.86 [95% CI 0.72-0.94]) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.
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http://dx.doi.org/10.1038/s41380-020-0838-xDOI Listing
July 2020

Genetic risk factors for Creutzfeldt-Jakob disease.

Neurobiol Dis 2020 08 18;142:104973. Epub 2020 Jun 18.

MRC Prion Unit at University College London (UCL), UCL Institute of Prion Diseases, 33 Cleveland Street, W1W 7FF, United Kingdom. Electronic address:

Prion diseases are a group of fatal neurodegenerative disorders of mammals that share a central role for prion protein (PrP, gene PRNP) in their pathogenesis. Prions are infectious agents that account for the observed transmission of prion diseases between humans and animals in certain circumstances. The prion mechanism invokes a misfolded and multimeric assembly of PrP (a prion) that grows by templating of the normal protein and propagates by fission. Aside from the medical and public health notoriety of acquired prion diseases, the conditions have attracted interest as it has been realized that common neurodegenerative disorders share so-called prion-like mechanisms. In this article we will expand on recent evidence for new genetic loci that alter the risk of human prion disease. The most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), is characterized by the seemingly spontaneous appearance of prions in the brain. Genetic variation within PRNP is associated with all types of prion diseases, in particular, heterozygous genotypes at codons 129 and 219 have long been known to be strong protective factors against sCJD. A large number of rare mutations have been described in PRNP that cause autosomal dominant inherited prion diseases. Two loci recently identified by genome-wide association study increase sCJD risk, including variants in or near to STX6 and GAL3ST1. STX6 encodes syntaxin-6, a component of SNARE complexes with cellular roles that include the fusion of intracellular vesicles with target membranes. GAL3ST1 encodes cerebroside sulfotransferase, the only enzyme that sulfates sphingolipids to make sulfatides, a major lipid component of myelin. We discuss how these roles may modify the pathogenesis of prion diseases and their relevance for other neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.nbd.2020.104973DOI Listing
August 2020

Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS.

PLoS Biol 2020 06 9;18(6):e3000725. Epub 2020 Jun 9.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom.

Inherited prion diseases are caused by autosomal dominant coding mutations in the human prion protein (PrP) gene (PRNP) and account for about 15% of human prion disease cases worldwide. The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis, to-date spontaneous formation of disease-relevant, transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Here, we report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which model the PRNP A117V mutation causing inherited prion disease (IPD) including Gerstmann-Sträussler-Scheinker (GSS) disease phenotypes in humans. By studying brain samples from uninoculated groups of mice, we discovered that some mice (≥475 days old) spontaneously generated abnormal PrP assemblies, which after inoculation into further groups of 117VV Tg30 mice, produced a molecular and neuropathological phenotype congruent with that seen after transmission of brain isolates from IPD A117V patients to the same mice. To the best of our knowledge, the 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited prion disease in humans.
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http://dx.doi.org/10.1371/journal.pbio.3000725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282622PMC
June 2020

Prevalence in Britain of abnormal prion protein in human appendices before and after exposure to the cattle BSE epizootic.

Acta Neuropathol 2020 06 30;139(6):965-976. Epub 2020 Mar 30.

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology Queen Square, London, WC1N 3BG, United Kingdom.

Widespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE. Immunohistochemistry for abnormal PrP was performed on 29,516 samples from appendices removed between 1962 and 1979 from persons born between 1891 through 1965, and from those born after 1996 that had been operated on from 2000 through 2014. Seven appendices were positive for abnormal PrP, of which two were from the pre-BSE-exposure era and five from the post BSE-exposure period. None of the seven positive samples were from appendices removed before 1977, or in patients born after 2000 and none came from individuals diagnosed with vCJD. There was no statistical difference in the prevalence of abnormal PrP across birth and exposure cohorts. Two interpretations are possible. Either there is a low background prevalence of abnormal PrP in human lymphoid tissues that may not progress to vCJD. Alternatively, all positive specimens are attributable to BSE exposure, a finding that would necessitate human exposure having begun in the late 1970s and continuing through the late 1990s.
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http://dx.doi.org/10.1007/s00401-020-02153-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244468PMC
June 2020

Preclinical biomarkers of prion infection and neurodegeneration.

Curr Opin Neurobiol 2020 04 25;61:82-88. Epub 2020 Feb 25.

National Prion Clinic, Box 98, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit at UCL, Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London W1W 7FF, United Kingdom. Electronic address:

Therapeutic strategies and study designs for neurodegenerative diseases have started to explore the potential of preventive treatment in healthy people, emphasising characterisation of biomarkers capable of indicating proximity to clinical onset. This need is even more pressing for individuals at risk of prion disease given its rarity which virtually precludes the probability of recruiting enough numbers for well powered preventive trials based on clinical endpoints. Experimental mouse inoculation studies have revealed a rapid exponential rise in infectious titres followed by a relative plateau of considerable duration before clinical onset. This clinically silent incubation period represents a potential window of opportunity for the adaptation of ultrasensitive prion seeding assays to define the onset of prion infection, and for neurodegenerative biomarker discovery through similarly sensitive digital immunoassay platforms.
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http://dx.doi.org/10.1016/j.conb.2020.01.009DOI Listing
April 2020

Empowering Better End-of-Life Dementia Care (EMBED-Care): A mixed methods protocol to achieve integrated person-centred care across settings.

Int J Geriatr Psychiatry 2020 08 15;35(8):820-832. Epub 2020 Jan 15.

Cicely Saunders Institute of Palliative Care, Policy & Rehabilitation, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK.

Objectives: Globally, the number of people with dementia who have palliative care needs will increase fourfold over the next 40 years. The Empowering Better End-of-Life Dementia Care (EMBED-Care) Programme aims to deliver a step change in care through a large sequential study, spanning multiple work streams.

Methods: We will use mixed methods across settings where people with dementia live and die: their own homes, care homes, and hospitals. Beginning with policy syntheses and reviews of interventions, we will develop a conceptual framework and underpinning theory of change. We will use linked data sets to explore current service use, care transitions, and inequalities and predict future need for end-of-life dementia care. Longitudinal cohort studies of people with dementia (including young onset and prion dementias) and their carers will describe care transitions, quality of life, symptoms, formal and informal care provision, and costs. Data will be synthesised, underpinned by the Knowledge-to-Action Implementation Framework, to design a novel complex intervention to support assessment, decision making, and communication between patients, carers, and inter-professional teams. This will be feasibility and pilot tested in UK settings. Patient and public involvement and engagement, innovative work with artists, policymakers, and third sector organisations are embedded to drive impact. We will build research capacity and develop an international network for excellence in dementia palliative care.

Conclusions: EMBED-Care will help us understand current and future need, develop novel cost-effective care innovations, build research capacity, and promote international collaborations in research and practice to ensure people live and die well with dementia.
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http://dx.doi.org/10.1002/gps.5251DOI Listing
August 2020

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.

Lancet Neurol 2020 02 3;19(2):145-156. Epub 2019 Dec 3.

Institut du Cerveau et de la Moelle épinière & Centre de Référence des Démences Rares ou précoces, Institut de la Mémoire et de la Maladie d'Alzheimer, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France.

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.

Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.

Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.

Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.

Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.
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http://dx.doi.org/10.1016/S1474-4422(19)30394-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007771PMC
February 2020

Familial Creutzfeldt-Jakob Disease in an Indian Kindred.

Ann Indian Acad Neurol 2019 Oct-Dec;22(4):458-461. Epub 2019 Oct 25.

MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK.

It is now known that the inherited prion disease is caused by over 60 different mutations in the Prion protein (PRNP) gene. Four missense mutations at codons 102, 178, 200 and 210, account for over 95% of these cases. In this study we describe, a large Indian family with familial Creutzfeldt Jakob Disease (fCJD). One affected member presented with a presenile dementia, a protracted clinical course and characateristic MRI features. Genetic analysis revealed a D178N mutation in the 2 affected individuals and 7 unaffected members. The neuropathological examination of the brain of one of the affected member was conspicuous by spongiform degeneration, neuronal loss and gliosis. This is a detailed report of a genetically and neuropathologically proven fCJD from India.
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http://dx.doi.org/10.4103/aian.AIAN_214_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839320PMC
October 2019

Prion disease diagnosis using subject-specific imaging biomarkers within a multi-kernel Gaussian process.

Neuroimage Clin 2019 25;24:102051. Epub 2019 Oct 25.

Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; School of Biomedical Engineering & Imaging Sciences, King's College London, King's Health Partners, St Thomas' Hospital, London, SE1 7EH, United Kingdom.

Prion diseases are a group of rare neurodegenerative conditions characterised by a high rate of progression and highly heterogeneous phenotypes. Whilst the most common form of prion disease occurs sporadically (sporadic Creutzfeldt-Jakob disease, sCJD), other forms are caused by prion protein gene mutations, or exposure to prions in the diet or by medical procedures, such us surgeries. To date, there are no accurate quantitative imaging biomarkers that can be used to predict the future clinical diagnosis of a healthy subject, or to quantify the progression of symptoms over time. Besides, CJD is commonly mistaken for other forms of dementia. Due to the heterogeneity of phenotypes and the lack of a consistent geometrical pattern of disease progression, the approaches used to study other types of neurodegenerative diseases are not satisfactory to capture the progression of human form of prion disease. In this paper, using a tailored framework, we aim to classify and stratify patients with prion disease, according to the severity of their illness. The framework is initialised with the extraction of subject-specific imaging biomarkers. The extracted biomakers are then combined with genetic and demographic information within a Gaussian Process classifier, used to calculate the probability of a subject to be diagnosed with prion disease in the next year. We evaluate the effectiveness of the proposed method in a cohort of patients with inherited and sporadic forms of prion disease. The model has shown to be effective in the prediction of both inherited CJD (92% of accuracy) and sporadic CJD (95% of accuracy). However the model has shown to be less effective when used to stratify the different stages of the disease, in which the average accuracy is 85%, whilst the recall is 59%. Finally, our framework was extended as a differential diagnosis tool to identify both forms of CJD among another neurodegenerative disease. In summary we have developed a novel method for prion disease diagnosis and prediction of clinical onset using multiple sources of features, which may have use in other disorders with heterogeneous imaging features.
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http://dx.doi.org/10.1016/j.nicl.2019.102051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978211PMC
September 2020

Genetic Factors in Mammalian Prion Diseases.

Annu Rev Genet 2019 12 19;53:117-147. Epub 2019 Sep 19.

Medical Research Council Prion Unit at UCL, Institute of Prion Diseases, University College London, London W1W 7FF, United Kingdom; email:

Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene () and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of , whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non- factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.
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http://dx.doi.org/10.1146/annurev-genet-120213-092352DOI Listing
December 2019

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.

PLoS One 2019 8;14(7):e0218111. Epub 2019 Jul 8.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218111PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613773PMC
February 2020
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