NAAG synthetase deficiency has only low influence on pathogenesis in a Canavan disease mouse model.

Canavan disease (CD) is a leukodystrophy caused by mutations in the N-acetylaspartate (NAA) hydrolase aspartoacylase (ASPA). Inability to degrade NAA and its accumulation in the brain results in spongiform myelin degeneration. NAA is mainly synthesized by neurons, where it is also a precursor of the neuropeptide N-acetylaspartylglutamate (NAAG). Hydrolysis of this peptide by glutamate carboxypeptidases is an additional source of extracellular NAA besides the instant neuronal release of NAA. This study examines to what extent NAA released from NAAG contributes to NAA accumulation and pathogenesis in the brain of Aspanur7/nur7 mutant mice, an established model of CD. Towards this aim, Aspanur7/nur7 mice with additional deficiencies in NAAG synthetase genes Rimklb and/or Rimkla were generated. Loss of myelin in Aspanur7/nur7 mice was not significantly affected by Rimkla and Rimklb deficiency and there was also no obvious change in the extent of brain vacuolation. Astrogliosis was slightly reduced in the forebrain of Rimkla and Rimklb double deficient Aspanur7/nur7 mice. However, only minor improvements at the behavioral level were found. The brain NAA accumulation in CD mice was, however, not significantly reduced in the absence of NAAG synthesis. In summary, there was only a weak tendency towards reduced pathogenic symptoms in Aspanur7/nur7 mice deficient in NAAG synthesis. Therefore, we conclude that NAAG metabolism has little influence on NAA accumulation in Aspanur7/nur7 mice and development of pathological symptoms in CD.

Prion propagation estimated from brain diffusion MRI is subtype dependent in sporadic Creutzfeldt-Jakob disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a transmissible brain proteinopathy. Five main clinicopathological subtypes (sCJD-MM(V)1, -MM(V)2C, -MV2K, -VV1, and -VV2) are currently distinguished. Histopathological evidence suggests that the localisation of prion aggregates and spongiform lesions varies among subtypes. Establishing whether there is an initial site with detectable imaging abnormalities (epicentre) and an order of lesion propagation would be informative for disease early diagnosis, patient staging, management and recruitment in clinical trials. Diffusion magnetic resonance imaging (MRI) is the most-used and most-sensitive test to detect spongiform degeneration. This study was designed to identify, in vivo and for the first time, subtype-dependent epicentre and lesion propagation in the brain using diffusion-weighted images (DWI), in the largest known cross-sectional dataset of autopsy-proven subjects with sCJD. We estimate lesion propagation by cross-sectional DWI using event-based modelling, a well-established data-driven technique. DWI abnormalities of 594 autopsy-diagnosed subjects (448 patients with sCJD) were scored in 12 brain regions by 1 neuroradiologist blind to the diagnosis. We used the event-based model to reconstruct sequential orderings of lesion propagation in each of five pure subtypes. Follow-up data from 151 patients validated the estimated sequences. Results showed that epicentre and ordering of lesion propagation are subtype specific. The two most common subtypes (-MM1 and -VV2) showed opposite ordering of DWI abnormality appearance: from the neocortex to subcortical regions, and vice versa, respectively. The precuneus was the most likely epicentre also in -MM2 and -VV1 although at variance with -MM1, abnormal signal was also detected early in cingulate and insular cortices. The caudal-rostral sequence of lesion propagation that characterises -VV2 was replicated in -MV2K. Combined, these data-driven models provide unprecedented dynamic insights into subtype-specific epicentre at onset and propagation of the pathologic process, which may also enhance early diagnosis and enable disease staging in sCJD.

Neuropathology of Animal Prion Diseases.

Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrPC) into a misfolded pathological isoform (PrPSc or prion- proteinaceous infectious particle) that self-propagates by conformational conversion of PrPC. Yet by an unknown mechanism, PrPC can fold into different PrPSc conformers that may result in different prion strains that display specific disease phenotype (incubation time, clinical signs and lesion profile). Although the pathways for neurodegeneration as well as the involvement of brain inflammation in these diseases are not well understood, the spongiform changes, neuronal loss, gliosis and accumulation of PrPSc are the characteristic neuropathological lesions. Scrapie affecting small ruminants was the first identified TSE and has been considered the archetype of prion diseases, though atypical and new animal prion diseases continue to emerge highlighting the importance to investigate the lesion profile in naturally affected animals. In this report, we review the neuropathology and the neuroinflammation of animal prion diseases in natural hosts from scrapie, going through the zoonotic bovine spongiform encephalopathy (BSE), the chronic wasting disease (CWD) to the newly identified camel prion disease (CPD).

An Atypical Presentation of Heroin Inhalation Induced Leukoencephalopathy (Chasing the Dragon).

Heroin leukoencephalopathy is associated with 'Chasing the dragon,' which is a heroin vapour inhalation method that is different from smoking or sniffing heroin. The clinical presentation ranges from mild to severe disease. Mild disease is characterized by inattentiveness and ataxia. In moderate diseases, extrapyramidal symptoms predominate, and finally, severe disease is characterized by generalized motor impairment, with death occurring in two-third of cases. We now report a rare presentation of the disease in a 60-year-old female with a past medical history of heroin abuse who presented to ED with signs and symptoms of confusion and restlessness. MRI brain without contrast showed diffuse symmetric increased intensity signals throughout the white matter. Electroencephalogram (EEG) revealed mild diffuse slowing with no lateralization. The patient was started on Vitamin E and was transferred to a rehab facility with following up neurology as an outpatient.

Familial Creutzfeldt-Jakob Disease in an Indian Kindred.

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.

Mathematical models for the diffusion magnetic resonance signal abnormality in patients with prion diseases.

In clinical practice signal hyperintensity in the cortex and/or in the striatum on magnetic resonance (MR) diffusion-weighted images (DWIs) is a marker of sporadic Creutzfeldt-Jakob Disease (sCJD). MR diagnostic accuracy is greater than 90%, but the biophysical mechanisms underpinning the signal abnormality are unknown. The aim of this prospective study is to combine an advanced DWI protocol with new mathematical models of the microstructural changes occurring in prion disease patients to investigate the cause of MR signal alterations. This underpins the later development of more sensitive and specific image-based biomarkers. DWI data with a wide a range of echo times and diffusion weightings were acquired in 15 patients with suspected diagnosis of prion disease and in 4 healthy age-matched subjects. Clinical diagnosis of sCJD was made in nine patients, genetic CJD in one, rapidly progressive encephalopathy in three, and Gerstmann-Sträussler-Scheinker syndrome in two. Data were analysed with two bi-compartment models that represent different hypotheses about the histopathological alterations responsible for the DWI signal hyperintensity. A ROI-based analysis was performed in 13 grey matter areas located in affected and apparently unaffected regions from patients and healthy subjects. We provide for the first time non-invasive estimate of the restricted compartment radius, designed to reflect vacuole size, which is a key discriminator of sCJD subtypes. The estimated vacuole size in DWI hyperintense cortex was in the range between 3 and 10 µm that is compatible with neuropathology measurements. In DWI hyperintense grey matter of sCJD patients the two bi-compartment models outperform the classic mono-exponential ADC model. Both new models show that T2 relaxation times significantly increase, fast and slow diffusivities reduce, and the fraction of the compartment with slow/restricted diffusion increases compared to unaffected grey matter of patients and healthy subjects. Analysis of the raw DWI signal allows us to suggest the following acquisition parameters for optimized detection of CJD lesions: b = 3000 s/mm(2) and TE = 103 ms. In conclusion, these results provide the first in vivo estimate of mean vacuole size, new insight on the mechanisms of DWI signal changes in prionopathies and open the way to designing an optimized acquisition protocol to improve early clinical diagnosis and subtyping of sCJD.