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IntroductionMRI sensitivity of up to 96% for pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) has previously been reported. However, in 2012, Carswell et al. found that the initial neuroradio- logical report often failed to identify CJD-associated MRI changes (47% sensitivity). These patients were at a more advanced stage of disease when referred to specialist services. Here we assessed whether there has been a change over time.MethodsWe reviewed MRI scans of 106 patients (sCJD=102, IPD=4) referred to the NPC between 2015- 2019, and compared our findings with the formal reports from referring centres. We recorded the MRC Scale scores at initial patient assessment.ResultsWe found characteristic MRI abnormalities in 101 out of 102 sCJD cases. A differential diagnosis of CJD was documented on the neuroradiological reports of 70 of these cases, giving a significantly improved sensitivity of 69% compared to 2012. There was no association between the location of signal change and reporting accuracy. Patients had less advanced disease compared to 2012.ConclusionsMRI reporting of sCJD by referring centres has improved, but further improvement seems possible. We re-emphasize the importance of analysing scans thoroughly for characteristic MRI patterns of sCJD to enable earlier identification of these patients.daniellesequeira@nhs.net|ABN Bursary26

ObjectiveTo 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.MethodsReview 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).ResultsPatients 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.ConclusionThe combination of diffusion-weighted MRI analysis and CSF RT-QuIC allowed a perfect classification of sCJD versus its mimics in this study.

Background Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. Methods In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. Results We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. Conclusions Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials.

Prion diseases are a group of fatal neurodegenerative diseases that can be sporadic, inherited or acquired. Inherited prion diseases are caused by mutations in the prion protein gene, PRNP , usually single nucleotide substitutions or structural variants of an octapeptide repeat encoding region. Although the classical presentation of sporadic Creutzfeldt Jakob disease (CJD) is rapidly progressive ataxia, myoclonus and cognitive decline, the presentation of genetic cases is variable and decline can be much slower. Prion diseases can mimic many neurodegenerative diseases. Genetic dementias are pleiotropic, with similar clinical syndromes being caused by mutations in different genes; additionally, mutations in a single gene may cause diverse clinical phenotypes. Due to the diagnostic difficulties arising from this clinical and genetic heterogeneity, next-generation sequencing technologies including gene panels and exome sequencing are helpful in elucidating genetic causes of dementia.1 Here we report a novel variant in PRNP in a patient diagnosed with semantic dementia, a variant of frontotemporal dementia (FTD). Patients with semantic dementia develop progressive loss of semantic knowledge resulting in significant early language impairment, with subsequent wider cognitive impairment and behavioural problems. MRI appearances are characteristic with focal asymmetric anteroinferior temporal lobe atrophy. The predominant histopathological finding is accumulation of Tar DNA-binding protein 43 (TDP-43) deposits in the temporal and frontal lobes, although other pathologies, including Alzheimer’s disease, are occasionally observed.2 A Mendelian genetic aetiology is rarely documented. A woman in her seventh decade presented with a 1-year history of rapidly progressive language problems and behavioural change. She had particular difficulty naming objects and suffered from impaired comprehension, but had preserved recognition of faces and …

Frontotemporal dementia (FTD) is a neurodegenerative disease associated with impaired behaviour, language and motor function. Around a third of FTD is familial, with mutations in microtubule-associated protein tau ( MAPT ), progranulin ( GRN ) and chromosome 9 open reading frame 72 ( C9orf72 ) being the most common genetic causes. No other risk factors for FTD had been identified until a genome-wide association study of patients with the most common pathological form of FTD, frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), showed an association with single nucleotide polymorphisms (SNPs) in a region encoding transmembrane protein 106b (TMEM106b).1 For the rs1990622 SNP the minor G allele was found to be less common in patients with FTLD-TDP than in a healthy control population, that is, those expressing this allele were less likely to develop disease, and this effect was greatest in those with GRN mutations (who have FTLD-TDP pathology).1 Further studies of FTD cohorts have replicated the finding in other GRN cohorts, in those with C9orf72 expansions (who also have FTLD-TDP pathology) and in one undifferentiated clinical FTD cohort.2 3 Furthermore, neuroimaging studies have shown reduced left hemispheric grey matter volume in those carrying the major (risk) A allele within a healthy population cohort,4 and reduced functional connectivity in those homozygous for the risk allele in a GRN cohort.5 In this study we investigate the association of the rs1990622 SNP with cortical volumes in a clinically diagnosed FTD cohort and a subset of cases with likely FTLD-TDP. The UCL FTD DNA cohort database was searched for those with volumetric MRI. Data were available from 198 patients with an FTD spectrum disorder: 87 with behavioural variant FTD (bvFTD), 46 with non-fluent variant primary progressive aphasia …

Objectives There have been reports of patients with antibodies to neuronal antigens misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Conversely, low levels of antibodies to neuronal proteins have been reported in patients with sCJD. However, the frequency of misdiagnoses, or of antibodies in patients with subsequently confirmed sCJD, is not clear. Methods We reviewed 256 consecutive cases of sCJD seen in the National Prion Clinic, of whom 150 had sera previously referred for selected antibody tests. Eighty-two available samples were retested for antibodies to N -methyl-d-aspartate receptor (NMDAR), the glycine receptor (GlyR), voltage-gated potassium channel (VGKC)-complex and the associated proteins, leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2). Results Four of the initial 150 sera referred were positive; two had antibodies to NMDAR, and two to the VGKC-complex, one of which was also positive for GlyR antibodies. Of the 82 sCJD sera retested, one had VGKC-complex antibodies confirming the previous result, two had CASPR2 and GlyR antibodies and one had CASPR2 and NMDAR antibodies; all antibodies were at low levels. Over the same period three patients with autoimmune encephalitis and high VGKC-complex antibodies were initially referred as sCJD. Conclusions This study indicates that

Hereditary spastic paraparesis (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder characterised by progressive lower limb spasticity and weakness. Some forms have been associated with white matter lesions and complex phenotypes. This study was prompted by the diagnosis of multiple sclerosis (MS) in two sisters from a large pedigree with hereditary spastic paraparesis. Twelve affected members of the extended family were examined (MRI and EEG were carried out and evoked potentials measured in five), and historical information was obtained from six affected deceased persons. The inherited disease phenotype was confirmed as autosomal dominant hereditary spastic paraparesis associated with epilepsy in four affected persons. None of the extended family had evidence of MS. Genetic analysis of the family has shown linkage to chromosome 2p and sequencing of the spastin gene has identified a 1406delT frameshift mutation in exon 10. This kindred demonstrates the clinical heterogeneity of HSP associated with spastin mutations. The possible relevance of the concurrence of HSP and MS in the sib pair is discussed.

Ataxia is common in various forms of human prion diseases but there is a dearth of validated assessment tools and data on the subject. Originally used for inherited cerebellar ataxias, the Scale for Assessment and Rating of cerebellar Ataxia (SARA) and Composite Cerebellar Functional Severity Score (CCFS) have been incorporated into the National Prion Monitoring Cohort (NPMC) as semi-quantitative measures of posture, gait, kinetic dysfunction and speech in patients with sporadic and inherited Creutzfeldt-Jakob disease (CJD). SARA and CCFS assessments were completed for patients with sporadic CJD (sCJD, n=119), and inherited prion disease (IPD, n=46). Patients were concurrently scored on the Medical Research Council Prion Disease Rating Scale (MRC PDRS), a functionally-oriented measure of disease progression validated in CJD patients. SARA scores in sCJD and IPD patients showed a strong, statistically significant correlation with the MRC PDRS. The SARA score may be useful in providing semi-quantitative evidence of deteriorating co-ordination in sCJD and IPD patients; serial attainment of scores could represent an objective measure of response to clinical therapeutic trials in CJD.

The estimation of pathogenicity and penetrance of novel gene variants presents significant challenges, particularly with Mendelian segregation analysis in the absence of a family history. Here, we illustrate the value of an integrated approach with the utilisation of available large-scale population data. A 76-year old woman with no family history of Creutzfeldt-Jakob Disease (CJD) presented with abrupt onset upper limb tremor, evolving rapidly into gait apraxia, non-fluent dysphasia, abulia, visual hallucinations, myoclonus, akinetic mutism and death over 8 weeks. Her Magnetic Resonance Imaging (MRI) demonstrated cortical and basal ganglia diffusion restriction while the EEG showed generalised periodic complexes. Prion protein gene PRNP sequencing unexpectedly revealed a T201S mutation; codon 129 was methionine homozygous (MM). In silico missense substitution analysis methods predicted non-radical changes given the structural similarities of both serine and threonine with polar uncharged side chains. Despite that, T201S is only detected in 1 in 60,706 individuals within the Broad Institute9s ExAC large-scale population genomic database. Literature search identified 1 other pathologically confirmed case of CJD with T201S mutation and 129MM, also without family history in Danish surveillance data. Overall, this would suggest that the variant is likely to be deleterious, but probably of incomplete penetrance.

Prion diseases are a diverse group of neurodegenerative diseases, caused by prion protein misfolding. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other risk variants have been suggested. Copy number variants (CNVs) are known to confer risk in several related neuropsychiatric and neurodegenerative conditions. Here, we report the first genome-wide analysis for CNV-associated risk in sCJD (n=1147) and publicly available controls (n=5427). We also investigated UK patients with vCJD (n=114) and elderly women from Papua New Guinea resistant to kuru, who were compared with healthy young Fore population controls (n=395). There were no statistically significant alterations in the burden of CNV duplications or deletions in any disease group or geographic region after correction for multiple testing. Heterozygous deletions of 39 region of the PARK2 gene were found in 3 sCJD patients and no controls (p=0.001, uncorrected). A cell-based prion infection assay did not confirm the role of PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.

In a previous study of the UCL frontotemporal dementia (FTD) cohort, 40% of patients reported some family history of dementia but only 20% carried a mutation in GRN or MAPT. Since then, other genes have been shown to cause FTD and more widespread next-generation sequencing (NGS) offers the potential to simultaneously screen for all known causal genes. We applied a validated 17-gene NGS dementia panel combined with PCR-based assessments of the C9orf72 and PRNP expansions to the UCL FTD DNA cohort (n=381). We classified mutations by likelihood of pathogenicity and compared with demographic and clinical data. 39% of patients report some family history but only 13% had an autosomal-dominant history. 27.6% of patients carried a deleterious variant; a further 6.0% had potentially deleterious variants. Most deleterious mutations were found in C9orf72, GRN or MAPT, while other genes amounted to 6.8%. Only 26.9% of patients with a strong family history did not have a deleterious mutation. Custom panel provide affordable high-quality sequencing. With additional C9orf72 testing, they can assess the most FTD genes and mutations in more unusual genes occur at a significant rate. NGS identifies an abundance of novel or uncertain variants; these will require considerable work to classify correctly.

Background and aims Huntington’s disease (HD) is an autosomal-dominant condition and defined by a triad of movement, cognitive, and psychiatric symptoms. However, some patients in whom HD is suspected do not carry the CAG expansion in the Huntingtin gene (HTT). These cases, with symptoms on the HD spectrum, but without the HTT expansion, are called HD phenocopy syndromes. Their most frequent known cause has recently been identified as C9orf72, but recessive conditions can also mimic HD. Next generation sequencing technologies (NGS) facilitate the simultaneously screening of genes linked to other neurodegenerative conditions. Methods We applied a validated 17-gene NGS dementia panel (PRNP, PSEN1, PSEN2, APP, GRN, MAPT, TREM2, CHMP2B, CSF1R, FUS, ITM2B, NOTCH3, SERPINI1, SQSTM1, TARDBP, TYROBP and VCP) combined with PCR-based assessments of the C9orf72 and PRNP expansions to the UCL HD phenocopy cohort (n = 444). We classified mutations by likelihood of pathogenicity and compared with clinical data, including HD-likeness and family history. Results In the cohort, 7.2% of all patients displayed the complete triad of symptoms, and for 46.9% of these a relevant family history was reported. A further 32.7% presented with 2/3 of the triad, 20.3% of these had a relevant family history. Overall, a relevant family history was reported for 24% of patients. In the 409 cases processed so far, yet to be tested for the C9orf72 and PRNP expansions, 4.5% of patients were found to carry a (likely) deleterious variant, a further 4.1% carried a potentially deleterious variant and 7.9% carried a higher-risk allele. Conclusions A custom panel provides affordable high quality sequencing. These panels can now help identify mutations in genes not previously linked to HD phenocopies, and reduce the number of cases where even with a strong family history no genetic mutation is found. This ongoing work will help to provide answers to patients and families, who present with an HD syndrome without the diagnostic certainty of the HTT expansion.

Although PrP-amyloid and amyloid β plaques found in Alzheimer's disease (AD) are composed of different peptides, they share common physicochemical properties,1 including a high β-sheet secondary structure and the binding of agents that label amyloid. As amyloid β load can be measured in patients with AD by use of positron emission tomography (PET) and the radiotracer carbon-11-labelled Pittsburgh compound B (11C-PiB), it is possible that 11C-PiB PET could be an in vivo marker of PrP-amyloid. We evaluated whether 11C-PiB PET can reliably demonstrate the presence of abnormal PrP-amyloid deposition in patients who are affected by, or at risk of, human prion disease. This would be of potential clinical importance in early diagnosis, in identifying asymptomatic patients who might benefit from proposed therapeutic interventions, and in monitoring treatment efficacy. Ethical approval for the study was granted by the Research Ethics Committee of the National Hospital for Neurology and Neurosurgery (NHNN) and written informed consent was obtained from subjects. Exclusions included pregnancy, contraindication to MRI, history of cancer in the last 5 years (except skin and prostate) and patients who were unable to give valid informed consent. One patient with variant Creutzfeldt–Jakob disease (vCJD), two symptomatic patients with P102L mutation and two asymptomatic PRNP mutation carriers referred to the National Prion Clinic, NHNN, London, UK, were recruited (four males, age range 25–62 years). Ten control subjects (six males, age range 55–75 years) were also investigated. All subjects underwent an MRI examination using a GE Signa LX 1.5T MRI system at NHNN …

Quantitative MRI measures can detect the presence of microstructural pathology in human prion disease not visible on conventional MR imaging. Few studies have examined longitudinal change and correlation with clinical measures. To test if longitudinal change could be identified on quantitative MRI, we performed a multiple-parameter analysis in the largest data set of patients with prion disease to date. Multiple-parameter analysis of quantitative MRI sequences including diffusion tensor imaging, magnetisation transfer ratio and T2-weighted imaging was performed in 106 subjects (37 asymptomatic gene mutation carriers, 39 symptomatic patients and 30 healthy controls). The analysis included voxel-based morphometry, voxel-based analysis of diffusion tensor imaging and magnetisation transfer imaging measures, grey and white matter histograms and region of interest analysis. Symptomatic patients showed significant longitudinal grey matter atrophy. Additionally a significant decrease in magnetisation transfer ratio and mean diffusivity was observed in grey matter structures; the decline in all MRI parameters strongly correlated with a decline in a functionally orientated outcome measure, the MRC Prion Disease Rating Scale. These data show that multi-parameter MRI analysis can identify longitudinal microstructural grey matter changes and may be able to provide objective and anatomically-specific biomarkers of disease progression in future clinical trials.

Background In many cases where Huntington’s disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. Most of these individuals remain without a genetic diagnosis. A repeat expansion in the C9orf72 gene has been identified as the major cause of familial and sporadic frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Aim To determine whether the C9orf72 expansion mutation causes HD phenocopies. Methods A cohort of 514 HD phenocopy patients were analysed for the C9orf72 expansion using repeat-primed PCR. In cases where the expansion was found, Southern hybridisation was performed to determine expansion size. Clinical case notes were reviewed to determine the phenotype of expansion-positive cases. Results 10 subjects (1.95%) had the expansion, making it the commonest identified genetic cause of HD-phenocopy presentations. The size of expansion was not significantly different from that associated with other clinical presentations of C9orf72 expanded cases. The C9orf72 expansion-positive subjects were characterised by the presence of movement disorders including dystonia, chorea, myoclonus, tremor and rigidity. Furthermore the age of onset in this cohort was lower than previously reported for subjects with the C9orf72 expansion, and included one case with paediatric onset. Conclusions This study extends the known phenotype of the C9orf72 expansion, both in age of onset and movement disorder symptoms. We propose a revised clinico-genetic algorithm for the investigation of HD-phenocopy patients based on these data.

Mutations in the progranulin gene ( GRN ) cause familial frontotemporal lobar degeneration (FTLD) associated with type 3 TDP-43 positive inclusions.1 The clinical phenotype associated with progranulin mutations continues to be defined, although patients present usually with either behavioural symptoms (behavioural variant FTLD) or a progressive aphasia. However, patients have also been described with a corticobasal syndrome (CBS), extending the pathological associations of this disorder into the TDP-43 proteinopathies.1 Neuroanatomically, CBS is usually associated with asymmetrical frontal and parietal lobe deficits, and there is evidence that progranulin mutations are also associated with early parietal lobe involvement and asymmetrical hemispheric atrophy.2 We describe a novel mutation in the GRN gene causing a CBS in family DRC219. This family was originally described as having “familial dementia lacking specific pathological features presenting with clinical features of corticobasal degeneration” in Brown et al .3 DRC219 is a family from the south of England with a history of an autosomal dominant dementia. The proband was seen and investigated at the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. Her grandmother died aged 61 and had been said to have abnormal behaviour for a few years prior to death. Her mother died aged 54, with the onset of memory and behavioural problems in her 40s, as well as a left hemiparesis. The proband’s brother also had a progressive behavioural syndrome with symptoms of inappropriate social behaviour …

Background Pathological studies show more prominent cerebral amyloid angiopathy (CAA) in Presenilin (PS1) mutations after codon 200 and APP mutations within the amyloid-β coding domain. We investigated whether mutation site influences the degree and location of white matter hyperintensities (WMH) on MRI. Methods 52 FAD patients with mutations in APP (13) or PS1 (18 pre-, 21 post-codon 200) and 25 controls underwent MRI. WMH were visually rated using the age- related white matter change (ARWMC) scale. Rank-sum tests were used to assess group differences. Results The PS1 post-200 group had a higher median total ARWMC score (3) than the pre-200 group (0, p=0.013) and controls (0, p=0.005). This was driven by an increased parieto-occipital ARWMC score. Mean disease onset-age was higher in the post- compared to pre-200 PS1 group (46.7 vs 39.2 yrs, p=0.0006). There was no difference in ARWMC score between controls and the pre-200 or APP cohort. The only APP intradomain mutation subject (A692G, Flemish) had a disproportionately high total ARWMC score (14) compared to the APP group median (0). Conclusion The PS1 post-200 group had more severe WMH and a later age at onset than PS1 pre-200. The increased, predominantly parieto-occipital, WMH most likely represent CAA given the subjects9 young age and lack of comorbidities. Study of the differential influence of FAD mutations can inform our understanding of AD pathophysiology, with potentially important implications for clinical trials.

The need to find a prion disease neuroimaging biomarker is important with the development of therapeutic agents. Diffusion tensor imaging (DTI) is an MRI sequence that can visualise white matter changes in the brain. Voxel-based analysis of DTI and voxel based morphometry (VBM) was performed on 17 asymptomatic prion protein gene mutation carriers, 14 symptomatic inherited prion disease patients, seven sporadic CJD patients (sCJD) and 24 healthy controls. There were significant differences found in grey matter voxels between the symptomatic and the control patients in the cortex bilaterally. In addition there was reduced fractional anisotropy in the corpus callosum, frontal white matter, internal capsule, optic radiation and cerebellum; these regions did not overlap with areas of brain atrophy. In the asymptomatic patients there were directional changes seen in keeping with the symptomatic patients, but due to the small patient number no statistically significant differences were found with VBM and voxel based analysis of DTI. In sCJD grey matter changes were found in the thalamus on VBM but voxel based analysis of DTI demonstrated change in the corpus callosum, thalamus and cerebellar white matter. These data show that voxel based analysis of DTI can detect significant microstructural white matter changes in the absence of its loss. DTI may prove to be a useful biomarker in prion disease.

PRION-1, the largest clinical trial in prion disease to date, showed no effect of the experimental therapeutic quinacrine on survival. Here we report analyses showing that quinacrine had no demonstrable benefit (p>0.4) when assessed by a range of rating scales. These included neurocognitive (Mini-Mental State Examination, ADAScog), psychiatric (Brief Psychiatric Rating Scale), global (Rankin and Global Impression of Change), clinician-rated (Clinician9s Dementia Rating (CDR)) and functional (Barthel) scales. These rating scales have several potential benefits over survival as an outcome measure: here we assess their validity and performance over 77 person-years follow-up in 101 symptomatic patients in PRION-1. Overall, across a range of models applied, we found that the Barthel and CDR scales were most robust to the difficulties posed by a prion disease clinical trial. A combination of selected subcomponents from these two scales gave increased power to detect clinically relevant effects in a future clinical trial of feasible size, compared to use of survival alone. We also discuss our work refining the use of these scales in the National Prion Monitoring Cohort, an ongoing prospective observational study of all types of human prion disease in the UK, and how this will inform the planning of future therapeutic trials.

MRC Prion-1 Trial enabled investigation of longitudinal MRI and cognitive assessments as potential biomarkers for future therapeutic trials in human prion diseases. The cross-sectional data provides opportunity to examine neuroanatomical differences in patients with inherited prion diseases (IPD) and controls. Voxel-based morphometry (VBM) and voxel-based analysis of magnetisation transfer ratio (VBA-MTR) was performed on 17 symptomatic (IS) IPD patients, 6 asymptomatic (AS) mutation carriers and 13 controls (Co). An ANCOVA consisting of diagnostic grouping (Co, IS, AS) with age and total intracranial volume as covariates and a threshold of p

As the vCJD outbreak evolves we are alert to possible changes in the clinicopathological phenotype, investigations and genetic analysis. MRI typically shows high signal in the pulvinar nucleus on T2W images and has recently been added to the CJD diagnostic criteria. Here we report MRI findings prompting a diagnosis of sporadic CJD by the current WHO criteria in two recent British patients seen by the NHS National Prion Clinic. Quantitative analysis confirmed greater T2W signal hyperintensity in caudate and putamen than the pulvinar. The neuropathological analysis showed characteristic PrP deposition diagnostic of vCJD, in addition to intense and widespread accumulation of abnormally phosphorylated tau protein. PRNP sequencing revealed methionine homozygosity at codon 129 in both patients. Correct diagnosis during life might have been obtained by tonsillar biopsy. Our retrospective blinded review of 60 suspected vCJD patients showed that while MRI had considerable diagnostic value, there were false positive and negative studies, particularly in early vCJD. Tonsillar biopsy had 100% sensitivity and specificity at all disease stages. Biopsy may allow early diagnosis in atypical clinico-pathological phenotypes of vCJD, avoiding unnecessary investigations, and allow rapid inclusion in therapeutic trials. A conclusive diagnosis during life can be of importance to patients and carers.

There has been intense interest in treating neurodegenerative conditions by passive immunotherapy. Here we describe the treatment of mice infected intraperitoneally (ip) with 104.6 infectious units of Rocky Mountain Laboratory (RML) prions, with bi-weekly injections of ip anti-prion monoclonal antibodies (mAbs). Mab ICSM18 (prion protein (PrP) epitope 143–153) raised to recombinant PrP, and ICSM35 (prion protein epitope 93–105) raised to an alternatively folded form of PrP, were both used at doses of 1 mg/week, or 0.25 mg/week. Treatment was given when prion infection was well established, 30 days after inoculation. Treatment resulted in a reduction in disease-related PrP (PrPSc) in the spleen and a significant extension in survival with both mAbs. ICSM18 showed a dose response and was more potent than ICSM35 with a 40% survival at 300 days postinfection using a dose of 1 mg/week. mAb treatment did not disrupt the normal function of the immune system. We have successfully demonstrated that the course of RML prion infection in mice can be safely attenuated by the early treatment with anti-PrP mAbs, at lower doses than previously reported. Humanised versions of these two mAbs will undergo safety-testing prior to manufacture for first-in-man study.

The inherited prion diseases (IPD) are a group of dominantly inherited neurodegenerative disorders caused by mutation of the prion protein gene ( PRNP ). Although clinically heterogeneous, IPDs are generally associated with progressive dementia, ataxia and with characteristic pathology. Here we describe a quite distinct and consistent phenotype in nine patients from a family with a novel Y163X PRNP truncation mutation. The major clinical features consist of chronic diarrhoea, profound autonomic failure and a predominantly axonal sensory peripheral neuropathy in early adulthood. Prior to genetic analyses, the clinical diagnosis was hereditary sensory and autonomic neuropathy (HSAN), which was followed by cognitive decline and seizures only much later, in the fifth to sixth decade. Neuropathological assessments reveal extensive central nervous system prion protein deposition including cerebral amyloid angiopathy and secondary tauopathy. Remarkably, abnormal prion protein deposition was also seen in the duodenum which may have contributed to presentation with diarrhoea. Molecular analysis of proteinase-resistant material from brain shows evidence of aggregation and covalent cross-linking of a misfolded and truncated prion protein entity. The association of autonomic failure, diarrhoea, and neuropathy should prompt PRNP testing and precautions for iatrogenic transmission. Abnormal anchorless PrP may deposit in peripheral tissues and be associated with nonneurological presentations.