Harpreet Hyare

The cognitive profile of prion disease: a prospective clinical and imaging study

Prion diseases are dementing illnesses with poorly defined neuropsychological features. This is probably because the most common form, sporadic Creutzfeldt‐Jakob disease, is often rapidly progressive with pervasive cognitive decline making detailed neuropsychological investigation difficult. This study, which includes patients with inherited, acquired (iatrogenic and variant) and sporadic forms of the disease, is the only large‐scale neuropsychological investigation of this patient group ever undertaken and aimed to define a neuropsychological profile of human prion diseases.

Distinct neuropsychological profiles correspond to distribution of cortical thinning in inherited prion disease caused by insertional mutation

Background The human prion diseases are a group of universally fatal neurodegenerative disorders associated with the auto-catalytic misfolding of the normal cell surface prion protein (PrP). Mutations causative of inherited human prion disease (IPD) include an insertion of six additional octapeptide repeats (6-OPRI) and a missense mutation (P102L) with large families segregating for each mutation residing in southern England. Here we report for the first time the neuropsychological and clinical assessments in these two groups. Method The cognitive profiles addressing all major domains were obtained for 26 patients (18 6-OPRI, 8 P102L) and the cortical thickness determined using 1.5T MRI in a subset of 10 (six 6-OPRI, four P102L). Results The cognitive profiles were different in patients with the two mutations in the symptomatic phase of the disease. The 6-OPRI group had lower premorbid optimal levels of functioning (assessed on the NART) than the P102L group. In the symptomatic phase of the disease the 6-OPRI patients had significantly more executive dysfunction than the P102L group and were more impaired on tests of perception and nominal functions. There was anecdotal evidence of low premorbid social performance in the 6-OPRI but not P102L patients. Cortical thinning distribution correlated with the neuropsychological profile in the 6-OPRI group principally involving the parietal, occipital and posterior frontal regions. The small number of patients in the P102L group precluded statistical comparison between the groups. Conclusions The 6-OPRI patients had more widespread and severe cognitive dysfunction than the P102L group and this correlated with cortical thinning distribution.

PATU2 Novel truncation mutation of PRNP causes chronic diarrhoea, sensory neuropathy and autonomic failure associated with prion protein deposition in the cerebral blood vessels and small bowel

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.

Neuroanatomical correlates of prion disease progression - a 3T longitudinal voxel-based morphometry study

Purpose MRI has become an essential tool for prion disease diagnosis. However there exist only a few serial MRI studies of prion patients, and these mostly used whole brain summary measures or region of interest based approaches. We present here the first longitudinal voxel-based morphometry (VBM) study in prion disease. The aim of this study was to systematically characterise progressive atrophy in patients with prion disease and identify whether atrophy in specific brain structures correlates with clinical assessment. Methods Twenty-four prion disease patients with early stage disease (3 sporadic, 2 iatrogenic, 1 variant and 18 inherited CJD) and 25 controls were examined at 3T with a T1-weighted 3D MPRAGE sequence at multiple time-points (2–6 examinations per subject, interval range 0.1–3.2 years). Longitudinal VBM provided intra-subject and inter-subject image alignment, allowing voxel-wise comparison of progressive structural change. Clinical disease progression was assessed using the MRC Prion Disease Rating Scale. Firstly, in patients, we determined the brain regions where grey and white matter volume change between baseline and final examination correlated with the corresponding change in MRC Scale score. Secondly, in the 21/24 patients with interscan interval longer than 3 months, we identified regions where annualised rates of regional volume change in patients were different from rates in age-matched controls. Given the heterogeneity of the cohort, the regions identified reflect the common features of the different prion sub-types studied. Results In the patients there were multiple regions where volume loss significantly correlated with decreased MRC scale, partially overlapping with anatomical regions where yearly rates of volume loss were significantly greater than controls. The key anatomical areas involved included: the basal ganglia and thalamus, pons and medulla, the hippocampal formation and the superior parietal lobules. There were no areas demonstrating volume loss significantly higher in controls than patients or negative correlation between volume and MRC Scale score. Conclusions Using 3T MRI and longitudinal VBM we have identified key anatomical regions of progressive volume loss which correlate with an established clinical disease severity index and are relevant to clinical deterioration. Localisation of the regions of progressive brain atrophy correlating most strongly with clinical decline may help to provide more targeted imaging endpoints for future clinical trials.

MRI findings of the brain in human African trypanosomiasis: a case series and review of the literature

Human African Trypanosomiasis (HAT) is a neglected tropical disease that affected 3797 people worldwide in 2014. Without treatment mortality approaches 100%. Due to its low incidence and non-specific clinical features, diagnosis can be challenging and the role of MRI in diagnosis of HAT has not been evaluated outside of case reports. We carried out a retrospective, institutional review of three patients presenting with neurological stage (Stage 2) HAT presenting to the Hospital of Tropical Diseases, London between 2004 and 2016. MRI brain was performed in both the acute and follow-up stages of their infection. In addition to confirming that the most common MRI abnormality is T 2 weighted fluid-attenuated inversion recovery (T2W FLAIR) high signal intensity in the supratentorial white matter, this series has identified radiological findings not previously reported in the literature. In the acute stages, restricted diffusion can be seen in the internal capsules and splenium of the corpus callosum and microhaemorrhages not related to melarsoprol have been identified. Furthermore, the signal abnormality appears to be largely reversible upon treatment with regression associated with mild atrophy demonstrated on follow-up MRI post-treatment. We conclude that although direct microscopy remains the mainstay of diagnosis with serological and polymerase chain reaction (PCR) testing providing useful adjuncts, MRI brain can be helpful in assessing neurological involvement and may provide important prognostic information post-treatment.

022 Voxelwise analysis of cerebral diffusion tensor imaging in prion diseases

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.

POD01 Misleading MRI in two recent patients with variant Creutzfeldt–Jakob disease emphasises the importance of tissue diagnosis

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.