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In Prion Diseases, misfolding of neuronal prion protein (PrPC) to a pathogenic isomer (PrPSC) is associated with neuronal death. Previous pathological studies have demonstrated increased immunoreactivity of PrPC at Aβ plaques in Alzheimer's Disease, and it has been suggested that this either reflects a role for PrPC in the neuronal response to stress or is a feature of the neuropathogenesis of atypical subtypes of Alzheimer's disease. In this paper we utilised western blotting to examine the molecular characteristics of PrP in frozen Hippocampal tissue from 7 cases of Alzheimer's Disease in which prion protein expression was demonstrated by immunohistochemistry, before using Restriction Fragment Length Polymorphism (RFLP) methodology to define the genotype of the codon 129 polymorphism of PRNP in each case. We observed PrP accumulating as globular structures at A plaques, and within ependymal cells lining the lateral ventricle. Immunohistochemistry also showed that PrPC and Superoxide dismutase-1 where deposited in a similar pattern at Aβ plaques. Western blotting revealed that PrP in Alzheimer's disease is composed of the same 208-residue peptide expressed in non-diseased brain. Quantitative western blot analysis demonstrated increased levels of PrPC in a short duration case of Alzheimer's Disease, while, in the remaining cases, levels of PrPC decreased in parallel with increasing disease duration and decreasing brain mass. RFLP genotyping revealed that all codon 129 genotypes (M/M, M/V, V/V) were represented in our study cohort. Our data suggest that increased levels of PrPC may account for PrP immunoreactivity at plaques in Alzheimer's disease, and that PrP deposition is not restricted to certain atypical subtypes of Alzheimer's disease.

IntroductionThere are no disease-modifying treatments for Parkinson’s disease (PD). We undertook the first drug screen in PD patient tissue and idntified ursodeoxycholic acid (UDCA) as a promising mitochondrial rescue agent. The aims of this trial are to determine safety and tolerability of UDCA in PD at 30 mg/kg, confirm the target engagement of UDCA, apply a novel motion sensor-based approach to quantify disease progression objectively, and estimate the mean effect size and its variance on the change in motor severity.Methods and analysisThis is a phase II, two-centre, double-blind, randomised, placebo-controlled trial of UDCA at a dose of 30 mg/kg in 30 participants with early PD. Treatment duration is 48 weeks, followed by an 8-week washout phase. Randomisation is 2:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48 and 56. The primary outcome is safety and tolerability. Secondary outcomes will compare the change between baseline and week 48 using the following three approaches: the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part 3 in the practically defined ‘OFF’ medication state; confirmation of target engagement, applying 31Phosphorus MR Spectroscopy to assess the levels of ATP and relevant metabolites in the brain; and objective quantification of motor impairment, using a validated, motion sensor-based approach. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups. For each secondary outcome, the change from baseline will be summarised within treatment groups using summary statistics and appropriate statistical tests assessing for significant differences. All outcomes will use an intention-to-treat analysis population.Ethics and disseminationThis trial has been approved by the East of England – Cambridgeshire and Hertfordshire Research Ethics committee. Results will be disseminated in peer-reviewed journals, presentations at scientific meetings and to patients in a lay-summary format.Trial registration numberNCT03840005.

Background Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease‐modifying therapies. Objective Cross‐sectional and longitudinal survey of prodromal PD signs among glucocerebrosidase carriers. Design Prospective assessment of 82 glucocerebrosidase mutation carriers and 35 controls over 4 to 5 years for prodromal clinical PD features. Results At all time points, olfactory (measured using University of Pennsylvania Smell Identification Test) and cognitive (Montreal Cognitive Assessment) function and the International Parkinson and Movement Disorder Society UPDRS parts II and III scores were significantly worse amongst glucocerebrosidase mutation carriers. Progression to microsmia (odds ratio: 8.5; 95% confidence interval: 2.6–28.2; P

The 22q11 deletion syndrome (22q11DS) is one of the most common genomic disorders in humans. There is an increased risk of Parkinson's disease (PD) in individuals with 22q11DS. The characteristic motor features of PD begin when more than 50% of dopaminergic neurons in the substantia nigra have degenerated. Before this, there is a prodromal period, of up to 20 years, in which nonmotor features such as hyposmia, autonomic dysfunction, rapid eye movement sleep behavior disorder, and subtle motor dysfunction can occur. We used validated clinical tools to investigate the presence of prodromal markers of PD in 50 adults with 22q11DS and 14 matched deletion-negative controls. The median score on the University of Pennsylvania Smell Identification Test was significantly lower in the 22q11 deletion group, and 44% scored in the hyposmic range (P=0.024). Individuals with 22q11DS were significantly more likely to report autonomic symptoms (urinary dysfunction or constipation, P=0.016). Twenty-eight percent of 22q11DS participants scored above the threshold for rapid eye movement sleep behavior disorder on a screening questionnaire (P=0.022). Four 22q11DS participants had parkinsonian motor signs on examination, which did not fulfill the diagnostic criteria for PD. We report prodromal markers of PD in 22q11DS. These may help identify individuals with 22q11 deletion at risk of neurological disease. However, the significance of these signs needs to be confirmed by longitudinal studies of development of PD.

A 39-year-old woman presented to the neurology clinic with an abnormal gait. Subsequent investigations confirmed a rare neurodegenerative disease. This case highlights the key clinical features and diagnostic approach to neuroferritinopathy, and describes the discovery of the disease in a family from Cumbria in the north west of England.

The objective of this study was to review available data on negligence claims for neurological disease treated by National Health Service (NHS) clinicians in England and Wales. The study design was a retrospective review of the NHS Litigation Authority (NHSLA) database, which holds data on negligence claims against NHS clinicians from 1995 to 2005. This database was searched to retrieve abstracts of claims concerning neurological disease treated by clinicians of all specialities. Abstracts were systematically reviewed to extract the following information: speciality of clinician, pathology involved, misadventure, patient injury and value of claim. A complete data set was available for 559 cases. The chi-squared test was used to investigate differences in negligence claims between neurologists/neurosurgeons and non-specialists. The speciality most frequently cited was neurosurgery (241) followed by neurology (172). Non-neurologists and non-neurosurgeons were the defendant in 146 cases, predominantly general physicians (42), orthopaedic surgeons (39) and emergency physicians (33). The most common pathologies were intervertebral disc disease (27%), CNS tumours (21%), CNS infection (11%) and subarachnoid haemorrhage (9%). The most frequent misadventure was diagnostic error (44%). In 47% of cases major permanent injury (e.g. blindness, hemiplegia) resulted from the misadventure. The patient died in 17% of cases. The total cost for all closed claims was £37 million (2% of expenditure on claims for medical and surgical specialities over 1995 to 2005). This is the first systematic study of negligence claims for the treatment of neurological disorders in the UK. The prominence of diagnostic error highlights the need for early assessment by neurologists and prompt use of neuroimaging during the acute phase.

INTRODUCTION In contemporary medical practice most diagnoses are based on key features of the patient’s history, backed up by laboratory and radiological investigations, while comparatively few diagnoses are made mainly on the basis of the physical examination. This decline in the importance of physical examination has been attributed to the development of modern diagnostic techniques, which now answer the diagnostic questions previously addressed by the physical examination. Arguably, neurology should be the specialty to have benefited most from such technological advances, particularly in imaging, with the development of CT, MR and PET scanning. Despite this, it is still an article of faith by some that the ability to perform a comprehensive neurological examination is vital in the assessment of diseases of the brain and peripheral nervous system – and so it must be done, and taught, properly. To investigate whether advances in modern diagnostic techniques have or have not rendered some

Both Gaucher disease patients and heterozygous glucocerebrosidase mutation carriers are at increased risk of Parkinson's disease. Retinal thinning has been reported in early Parkinson's disease. Here we used optical coherence tomography to demonstrate thinning of the retinal ganglion cell layer in Gaucher disease patients and carriers who manifest clinical markers of potential early neurodegeneration. Optical coherence tomography may help identify Gaucher disease patients and carriers at increased risk of developing Parkinson's disease., Highlights • Gaucher disease patients and carriers are at increased risk of Parkinson’s disease • Retinal thinning is reported in Parkinson's disease • Retinal thinning can be detected by optical coherence tomography (OCT) • We utilized OCT to detect retinal thinning in Gaucher disease patients and carriers

Neuroferritinopathy is an autosomal dominant extrapyramidal movement disorder, caused by FTL gene mutations. Iron decreases the MR T2* decay time, therefore increasing the R2* (R2* = 1 /T2*), which correlates with brain tissue iron content. 3T structural and quantitative MR imaging assessment of R2* in 10 patients with neuroferritinopathy demonstrated a unique pattern of basal ganglia cavitation involving the substantia nigra in older patients and increasing thalamic R2* signal intensity detectable during 6 months. Increasing R2* signal intensity in the thalamus correlated with progression on a clinical rating scale measuring dystonia severity. Thalamic R2* signal intensity is a clinically useful method of objectively tracking disease progression in this form of neurodegeneration with brain iron accumulation.

Distal myopathies are a clinically and genetically heterogenous group of disorders in which the distal limb musculature is selectively or disproportionately affected. Precisely defining specific categories is a challenge because of overlapping clinical phenotypes, making it difficult to decide which of the many known causative genes to screen in individual cases. In this study we define the distinguishing magnetic resonance imaging findings in myotilin myopathy by studying 8 genealogically unrelated cases due to the same point mutation in TTID. Proximally, the vastii, biceps femoris and semimembranosus were involved with sparing of gracilis and sartorius. Distally, soleus, gastrocnemius, tibialis anterior, extensor hallicus and extensor digitorum were involved. This pattern contrasts with other distal myopathies and provides further support for the role of imaging in the clinical investigation of muscle disease.

Iron accumulates within the basal ganglia and dentate nuclei during normal aging.1 More intense iron deposition has been demonstrated within the substantia nigra in Parkinson disease, and structures affected by β amyloid plaques in Alzheimer disease, implicating iron deposition in the pathogenesis of common neurodegenerative diseases, possibly through increased oxidative stress.2,3 Direct evidence supporting a causal role for iron deposition in neurodegenerative conditions comes from a group of genetic disorders termed neurodegeneration with brain iron accumulation (NBIA), in which a variety of genetic defects in iron metabolism lead to brain iron accumulation with neuronal death in the affected brain regions.4 Four subtypes of NBIA have been defined at the molecular genetic level. Pantothenate kinase associated neurodegeneration (PKAN, NBIA type one, MIM 234200), formerly known as Hallervorden-Spatz syndrome, is caused by mutation of the pantothenate kinase 2 gene (PANK2).5 Infantile neuroaxonal dystrophy (INAD, MIM 256600) is a recessive disorder with psychomotor regression due to mutations in PLA2G6.6 Mutations of the ferritin light chain gene (FTL1) cause the adult onset autosomal dominant movement disorder neuroferritinopathy (FTL, NBIA type two, hereditary ferritinopathy, MIM 606159).7 A further form of NBIA is aceruloplasminemia (aCp, MIM 604290), an autosomal recessive ceruloplasmin deficiency which results in iron deposition in the reticuloendothelial system and brain, presenting with diabetes and an extrapyramidal movement disorder in adult life.8 Extensive phenotypic overlap presents a major challenge in the clinical diagnosis of different subtypes of NBIA, particularly in the early stages. Although molecular genetic testing can provide the definitive diagnosis, comprehensive testing is only available on a research basis, and the genetic defect remains undefined in a large subgroup of patients with so-called NBIA of unknown cause. A reliable clinical investigation capable of predicting the genetic diagnosis would be useful to inform genetic counseling, predict the disease course, and ensure appropriate enrollment in clinical trials of new treatments. Dramatic evidence of focal brain iron accumulation on brain imaging is usually the first indication of NBIA, but the features distinguishing the different subtypes have yet to be defined.

(2004). Clinical diagnosis of cervical dystonia. European Journal of General Practice: Vol. 10, No. 2, pp. 73-74.

Both Gaucher disease patients and heterozygous glucocerebrosidase mutation carriers are at increased risk of Parkinson's disease. Retinal thinning has been reported in early Parkinson's disease. Here we used optical coherence tomography to demonstrate thinning of the retinal ganglion cell layer in Gaucher disease patients and carriers who manifest clinical markers of potential early neurodegeneration. Optical coherence tomography may help identify Gaucher disease patients and carriers at increased risk of developing Parkinson's disease.

The introduction of thrombolysis for the treatment of acute ischaemic stroke has increased the importance of prompt and accurate diagnosis. Research has shown a high rate of misdiagnosis of acute stroke in the community by paramedics and primary care doctors (PCDs). In this study, referral letters for presumed acute stroke or Transient Ischaemic Attack (TIA) were audited to assess the diagnostic accuracy of PCDs and the quality of the referral letters. In 30 % of cases, the diagnosis of stroke was correct. Important stroke mimics included sepsis, delirium and functional disorders. PCDs may benefit from a stroke recognition tool to increase diagnostic accuracy.

cause movement disorders. CT brain and chest radiograph were normal. It was decided not to perform MRI brain as it was felt that the probability of an ischaemic lesion not visualised by CT was very low. Routine bloods demonstrated no abnormalities in the full blood count, liver function or renal function. The patient had been noted to be hyponatraemic for at least 2 years (around 125–130 mmol/l), but her plasma osmolarity was normal and there had been no recent changes in her plasma sodium levels. ESR was 8 mm/h. Thyroid function, blood glucose, calcium, magnesium, phosphate, serum caeruloplasmin, vitamin D and parathyroid hormone levels were all normal. The anti-streptolysin O titre was normal ( ! 200 U/ml). Anti-nuclear antibody (titre 1: 160) and anti-cardiolipin antibodies were positive, but the patient did not meet the American College of Rheumatology criteria for SLE or anti-phospholipid antibody syndrome and was anti-dsDNA negative with normal serum complement. Anti-basal ganglia antibodies were negative. Given the late age of onset and lack of family history it was decided not to perform genetic testing for Huntington’s disease. CA-125 was elevated but pelvic ultrasound and CT abdomen demonstrated no ovarian or other malignancy. The patient was discharged 12 days after admission with no further occurrence of chorea.

Wellcome Trust/MRC Joint Call in Neurodegeneration award United Kingdom Medical Research Council Wellcome Trust Parkinson's Disease UK Kattan Trust Objectives: To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods: A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. the right: left asymmetry index and striatal asymmetry index was calculated.Results: Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). the asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.Conclusions: the asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss. UCL, Dept Clin Neurosci, Inst Neurol, London, England Birmingham Womens Hosp, Reg Genet Unit, Dept Clin Genet, Birmingham, W Midlands, England Natl Taiwan Univ Hosp, Coll Med, Dept Neurol, Taipei, Taiwan Natl Taiwan Univ Hosp, Coll Med, Dept Nucl Med, Taipei, Taiwan Hosp Israelita Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, São Paulo, Brazil Hosp Univ Insular Gran Canaria, Dept Neurol, Parkinsons & Movement Disorders Unit, Las Palmas Gran Canaria, Spain Univ Salerno, Ctr Neurodegenerat Dis, Salerno, Fisciano Provin, Italy UCL, Inst Neurol, Sobell Dept Motor Sci, London, England Universidade Federal de São Paulo, Dept Neurol, São Paulo, Brazil Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands Aristotle Univ Thessaloniki, G Papanikolaou Hosp, Dept Neurol 3, GR-54006 Thessaloniki, Greece Gen Hosp S Michele AOB G Brotzu, Neurol Serv, Cagliari, Italy Gen Hosp S Michele AOB G Brotzu, Stroke Unit, Cagliari, Italy Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy Universidade Federal de São Paulo UNIFESP, EPM, Div Movement Disorders, São Paulo, Brazil UCL Inst Neurol, Dept Mol Neurosci, London, England Univ Navarra, Div Neurosci, Ctr Appl Med Res, Neurogenet Lab, E-31080 Pamplona, Spain CNR, Inst Biostruct & Bioimaging, I-80125 Naples, Italy Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden Universidade Federal de São Paulo, Dept Neurol, São Paulo, Brazil Universidade Federal de São Paulo UNIFESP, EPM, Div Movement Disorders, São Paulo, Brazil Wellcome Trust/MRC Joint Call in Neurodegeneration award: WT089698 United Kingdom Medical Research Council: G1001983 Web of Science

American Pscyho is a dark comedy focusing on the life of mass murdering yuppie Patrick Bateman. The film's central theme is the conflict between individuality and the demands of society. Bateman's yuppie lifestyle requires absolute conformity. Appearance is all important; the right suit and shoes make or break an individual. To ensure acceptance Bateman's social group all dress alike. Thus clothes become uniform, preventing expressions of individuality and denying Bateman …