Neuropathology 2019 doi:10.1111/neup.12538 Case Report Variably protease-sensitive prionopathy mimicking frontotemporal dementia Miren Aizpurua,1 Sashika Selvackadunco,2 Helen Yull,3 Christopher M. Kipps,4,5 James W. Ironside3 and Istvan Bodi1,2 1Clinical Neuropathology, King’s College Hospital, NHS Foundation Trust, 2London Neurodegenerative Diseases Brain Bank, IOPPN, London, 3National Creutzfeldt-Jakob Disease Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, 4Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust and 5Clinical Neurosciences, University of Southampton, Southampton, UK Sporadic prion diseases are fatal neurodegenerative disor- like pattern in the absence of types 1 and 2 isoforms. These ders characterized clinically by rapidly progressive dementia features are diagnostic of VPSPr. VPSPr can mimic various and myoclonus. Variably protease-sensitive prionopathy neurodegenerative conditions; diagnosis requires both PrP (VPSPr) is a recently identified sporadic human prion disor- immunohistochemistry and Western blotting. The presence der that may present with a lengthy atypical clinical history. of patchy spongiform change in the absence of other neuro- Here, we describe a case of VPSPr in a patient with a degenerative pathology should raise suspicion of VPSPr, long history of suspected frontotemporal dementia (FTD). even in elderly patients with a lengthy clinical history. A 61-year-old man presented with speech difficulties, including naming objects and constructing multipart sen- Key words: Creutzfeldt–Jakob disease, prions, prion dis- tences, while there was no difficulty in comprehension. eases, prion protein, variably protease-sensitiveprionopathy. Movement abnormalities included slightly jerky pursuit, minor dysmetria of saccades and brisk reflexes. There was INTRODUCTION no family history of dementia. Later he developed Human prion diseases are fatal neurodegenerative disor- fi swallowing dif culties and the possibility of FTD with motor ders that are characterized neuropathologically by the neuron disease was suspected. He died at the age of 71 and abnormal accumulation of a misfolded prion protein (PrP) his brain was donated to the London Neurodegenerative in the central nervous system. The mechanism by which Diseases Brain Bank. The brain (1004 g) showed mild to the cellular PrP (PrPC) is converted into the pathogenic moderate atrophy, predominantly in the frontal lobe. His- scrapie-type PrP (PrPSc) appears to involve a post- tology revealed moderate spongiform microvacuolation translational change in PrPC conformation, from a predom- mostly affecting the frontal and parietal cortices, but also inantly α-helical into a predominantly β-sheet structure.1 present focally in the basal ganglia and the cerebellum. Only PrPSc is the major, if not the sole, component of the trans- mild Alzheimer pathology was found by extensive immuno- missible agent in prion diseases. PrPSc is relatively insolu- histochemistry, in keeping with BrainNet Europe stage II. Trans-activation response DNA-binding protein 43 kDa ble and aggregates extracellularly, possibly inducing and α-synuclein immunostains were negative. Immuno- adjacent tissue malfunction, although the exact pathologi- staining for prion protein (PrP) showed granular/synaptic cal mechanism is still unclear. Human prion diseases differ positivity in a patchy distribution, mainly within the deeper not only in their clinical and neuropathological features, cortex, and also revealed microplaques in the cerebellum but also in the biochemical features (differential glycosyla- and basal ganglia. Western blotting confirmed a low molec- tion and relatively resistance to proteinase digestion) of Sc ular weight protease-resistant PrP band with a faint ladder- PrP in the brain, making prionopathies a much more het- erogeneous group of disorders than initially considered. Human prion diseases are classified into three main cate- ’ gories: sporadic, acquired or genetic (familial). Sporadic Correspondence: Istvan Bodi, Clinical Neuropathology, ANC, King s – College Hospital NHS Foundation Trust, Denmark Hill, London SE5 Creutzfeldt Jakob disease (sCJD) is the most common 9RS, UK. Email: [email protected] human prion disease, occurring world-wide and characterized Received 12 December 2018; Revised 18 January 2019; Accepted clinically by rapidly progressive dementia and myoclonus. 21 January 2019. However, sCJD is known to be clinically and pathologically © 2019 The Authors. Neuropathology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Neuropathology This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2 M Aizpurua et al. heterogeneous, and is currently sub-classified into six sub- multipart sentences, but there was no difficulty with compre- types.2 The molecular basis for this heterogeneity is thought hension. There were no visuospatial errors, but he had diffi- to correspond to an interaction between the naturally occur- culty with writing and some spelling limitations. There were ring methionine/valine polymorphism at codon 129 of the no parkinsonian signs, but there was slightly jerky pursuit prion protein gene (PRNP) (MM, MV, or VV) and the both horizontally and vertically as well as possibly minor abnormal prion protein isoform in the brain, as determined dysmetria of saccades. There were occasional limb muscle by Western blot analysis of the protease-resistant band (ter- fasciculations without associated weakness. His Mini-Mental med PrPres) obtained by treating PrPSc with protease K. The State Examination was 26/30 and cognitive examination resulting bands are then classified by their molecular weight (ACE-R) score of 84/100. magnetic resonance imaging as type 1 or type 2.3,4 Recent investigations have identified showed generalized involutional change and several non- specific high signal lesions. The clinical features favored pri- another sporadic human prion disease, termed variably mary progressive non-fluent aphasia (PPA) and protease-sensitive prionopathy (VPSPr) which lacks PRNP hexylmethylpropylene amineoxine – single-photon emission mutations but is clinically and biochemically different from computed tomography scan showed an inferior frontal sporadic CJD.5 Here, we report a case of VPSPr in a UK hypoperfusion, in keeping with PPA in September 2014 patient with a lengthy clinical history mimicking (Fig. 1). Nerve conduction studies identified benign fascicu- frontotemporal dementia. lations, but nothing consistent with motor neuron disease (MND). Genetic testing for C9orf72 was negative. His neu- CLINICAL SUMMARY rodegenerative condition progressed following presentation, fi Brain donation to the London Neurodegenerative Diseases and he developed swallowing dif culties, subsequent aspira- Brain Bank for research was received from a 71-year-old tion pneumonias as well as seizures. He died at age man. He presented at the age of 69 with 8 years history of 71, 10 years after the initial presentation. speech difficulties. He apparently had a stressful time some years ago when selling his company and noticed that his PATHOLOGICAL FINDINGS speech was less fluent and he became prone to making dys- phasic errors. He also noticed a slight change in handwrit- According to our brain bank protocol the right half of the ing. Although the onset of the disease was very slow, his brain was sampled fresh and stored in a freezer at −80C, partner did highlight a substantial change in his attention, while the left half of the brain was fixed in formalin and some degree of repetitive questioning and memory distur- processed for neuropathological examination. The fresh bances such as loosing or misplacing objects and forgetting brain weight was 1004 g; the formalin fixed left brain the names of people and objects. He lost track of his weighed 509 g and the left brainstem and cerebellum hemi- thoughts if he was interrupted; however, there was no topo- sphere weighed 90 g. There was mild to moderate general- graphical disorientation. He had no difficulty with self-care ized cortical atrophy, slightly more prominent in the frontal and there were no mood or behavioral disturbance, lobe and around the Sylvian fissure. Mild ventricular dilata- although a slight reduction in motivation was observed. No tion and a slightly smaller hippocampus were also seen. visual hallucinations were reported. There was no family Histology of the brain revealed mild to moderate neuronal history of neurological disease. On examination, a mild loss in the neocortex, particularly in the frontal and parieto- expressive dysphasia with a degree of orobuccal apraxia was occipital lobes. This was associated with microvacuolation, observed; his speech was prone to error with longer words often involving the deeper cortical layers, and no areas of con- and he had difficulty in repeating polysyllabic words and fluent spongiform change were identified (Fig. 2A–C). The Fig. 1 99mTc – hexylmethylpropyl- ene amineoxine – single-photon emis- sion computed tomography scan of subject’s cerebral perfusion compared against age-matched controls, rendered on template brain at P <0.01threshold. Scan shows predominant left dorsolat- eral prefrontal cortex and insula hypo- perfusion consistent with a non-fluent aphasic syndrome. © 2019 The Authors. Neuropathology published by John Wiley & Sons