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BackgroundIn the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation.MethodsWGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer’s disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD.ResultsClinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk.DiscussionWGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

MERTKencodes a receptor tyrosine kinase that regulates immune homeostasis via phagocytosis of apoptotic cells and cytokine-mediated immunosuppression. MERTKis highly expressed in the central nervous system (CNS), specifically in myeloid derived innate immune cells and its dysregulation is implicated in CNS pathologies including the autoimmune disease multiple sclerosis (MS). While the cell types and tissues that express MERTKhave been well described, the genetic elements that define the gene’s promoter and regulate specific transcription domains remain unknown. The primary objective of this study was to define and characterise the human MERTKpromoter region. We cloned and characterized the 5’ upstream region of MERTKto identify cis-acting DNA elements that promote gene transcription in luciferase reporter assays. In addition, promoter regions were tested for sensitivity to the anti-inflammatory glucocorticoid dexamethasone. This study identified identified both proximal and distal-acting DNA elements that promote transcription. The strongest promoter activity was identified in an ∼850 bp region situated 3 kb upstream of the MERTKtranscription start site. Serial deletions of this putative enhancer revealed that the entire region is essential for expression activity. Using in silicoanalysis, we identified several candidate transcription factor binding sites. Despite a well-established upregulation of MERTKin response to anti-inflammatory glucocorticoids, no DNA region within the 5 kb putative promoter was found to directly respond to dexamethasone treatment. Elucidating the genetic mechanisms that regulate MERTKexpression gives insights into gene regulation during homeostasis and disease, providing potential targets for therapeutic modulation of MERTKtranscription.

Remyelination in the CNS is the natural process of damage repair in demyelinating diseases such as multiple sclerosis (MS). However, remyelination becomes inadequate in many people with MS, which results in axonal degeneration and clinical disability. Enhancement of remyelination is a logical therapeutic goal; nevertheless, all currently licensed therapies for MS are immunomodulatory and do not support remyelination directly. Several molecular pathways have been identified as potential therapeutic targets to induce remyelination, and some of these have now been assessed in proof-of-concept clinical trials. However, trial design faces several obstacles: optimal clinical or paraclinical outcome measures to assess remyelination remain ill-defined, and identification of the ideal timing of therapy is also a crucial issue. In addition, realistic expectations are needed concerning the probable benefits of such therapies. Nevertheless, approaches that enhance remyelination are likely to be protective for axons and so could prevent long-term neurodegeneration. Future MS treatment paradigms, therefore, are likely to comprise a combinatorial approach that involves both immunomodulatory and regenerative treatments.

We assessed novel disability-based parameters and neuropathological features of the P0180-190 peptide-induced model of experimental autoimmune neuritis (EAN) in C57BL/6 mice. We show that functional assessments such as running capacity provide a more sensitive method for detecting alterations in disease severity than a classical clinical scoring paradigm. We performed detailed ultrastructural analysis and show for the first time that tomaculous neuropathy is a neuropathological feature of this disease model. In addition, we demonstrate that ultrastructural assessments of myelin pathology are sufficiently sensitive to detect significant differences in both mean G-ratio and mean axon diameter between mice with EAN induced with different doses of pertussis toxin. In summary, we have established a comprehensive assessment paradigm for discriminating variations in disease severity and the extent of myelin pathology in this model. Our findings indicate that this model is a powerful tool to study the pathogenesis of human peripheral demyelinating neuropathies and that this assessment paradigm could be used to determine the efficacy of potential therapies that aim to promote myelin repair and protect against nerve damage in autoimmune neuritides.

Approaches to investigate adult oligodendrocyte progenitor cells (OPCs) by targeted cell ablation in the rodent CNS have limitations in the extent and duration of OPC depletion. We have developed a pharmacogenetic approach for conditional OPC ablation, eliminating >98% of OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and ventricular-subventricular zone (V-SVZ)-derived neural precursor cells (NPCs), we found that new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+NG2+cells with the capacity to proliferate and migrate extensively throughout the dorsal anterior forebrain. Further application of this approach to ablate OPCs will advance knowledge of the function of both OPCs and oligodendrogenic NPCs in health and disease.

Nanodiamonds (NDs) containing silicon vacancy (SiV) defects were evaluated as a potential biomarker for the labeling and fluorescent imaging of neural precursor cells (NPCs). SiV-containing NDs were synthesized using chemical vapor deposition and silicon ion implantation. Spectrally, SiV-containing NDs exhibited extremely stable fluorescence and narrow bandwidth emission with an excellent signal to noise ratio exceeding that of NDs containing nitrogen-vacancy centers. NPCs labeled with NDs exhibited normal cell viability and proliferative properties consistent with biocompatibility. We conclude that SiV-containing NDs are a promising biomedical research tool for cellular labeling and optical imaging in stem cell research.

Perceived cognitive impairment in MS is associated with adverse changes in employment capacity, sexual function, and aspects of daily living. Studies have shown relationships between perceived cognitive impairment and objective neuropsychological functioning and mood. Subjective cognitive performance in people with MS has not previously been compared to their objective performance on a computerised cognitive battery.

•Patient satisfaction with telehealth was high with video consultations preferred.•Clinicians strongly preferred in-person visits which allow physical examination.•Telehealth-based EDSS was feasible but may under-estimate lower EDSS.•Treatment inertia may affect management decisions during telehealth consultations.

Commonly used measures of disability in patients with Multiple sclerosis (MS) inadequately reflect disease severity and progression. Further, cognitive deficits experienced by up to 70% of patients, are poorly represented by these measures. Saccadic eye movements may provide a powerful tool for the analysis of cognitive changes in MS, providing a surrogate measure of performance that extends more conventional measures. The cognitive control of eye movements has not previously been investigated in patients with MS. We studied antisaccade (AS) performance in 25 patients with MS and compared the results with 25 age matched healthy controls, to evaluate the resolution of response conflict between volitional and automatic processes. Experimental measures were also correlated with a battery of neuropsychological tests evaluating attention, working memory and executive processes, the most commonly reported cognitive deficits in MS. Compared to controls, patients with MS generated significantly more prosaccade errors, and AS latencies were prolonged and more variable. Error rates correlated significantly with scores on the commonly used PASAT. MS patients also exhibited poor spatial accuracy, with mean absolute error significantly larger and more variable than control subjects. The sensitivity of this task in dissociating function in MS, as well as clear correlation with a key measure of cognition, suggests that eye movements, may provide a surrogate measure of cognitive function in MS, with the potential to sensitively assess disease severity and progression.

The objective of this study was to determine the experience of disability and reported symptoms in multiple sclerosis in an Australian community sample, comparing the perceptions of patients, carers and treating doctors, and to examine effects on quality of life, carer stress and utilization of health services. The study design used a prospective cross sectional community survey. The participants were persons with a confirmed diagnosis of multiple sclerosis, with quantified neurological, mobility and cognitive deficits, from a tertiary hospital database (n101), who lived at home, and their carers and doctors. The study method used demographic, diagnostic and disease severity data extracted from the database. Structured interviews conducted at home included (1) open questionnaires for participant, carer and general practitioner, prioritizing symptomsproblems affecting daily living; and (2) standardized assessments for patient quality of life, caregiver strain and perceived burden of care. The mean age was 49 years (range 28–64). Those more severely affected had a significantly reduced quality of life and increased carer burden than those with milder disability, but discordance between patients, carers and doctors was noted in their perception of problems and symptom experience. Rates of depression (67) and work-related problems were high, but vocational support was rarely provided. Forty persons used interferon, of whom 20 had secondary progressive multiple sclerosis; 39 reported difficulty in accessing rehabilitation services and only 10 were referred to medical rehabilitation units. In conclusion, the rates of disability and symptom experience were similar to other series; however, access and utilization of appropriate rehabilitation and support services appears to be lacking. There were higher reported rates of depression and poor quality of life. Opportunities may possibly exist to re-deploy resources to develop vocational support, counselling and rehabilitation.

Immune-mediated therapies can reduce the relapse rate in multiple sclerosis. However, there is no clear-cut evidence that any of these therapies substantially alter the long-term outcome for patients with progressive multiple sclerosis. The neurological disability that all too frequently accompanies multiple sclerosis is ultimately due to injury to target cells, principally oligodendroglia, within the nervous system. Recent data suggest that activation of leukemia inhibitory factor-receptor signaling is an important component of a neurobiological response that serves to limit the extent of immune-mediated injury. Therefore, inactivation of this pathway could provide a novel approach to the treatment of demyelinating disease.

The cytoplasmic juxtamembrane region of the p75 neurotrophin receptor (p75NTR) has been found to be necessary and sufficient to initiate neural cell death. The region was named “Chopper” to distinguish it from CD95-like death domains. A 29-amino acid peptide corresponding to the Chopper region induced caspase- and calpain-mediated death in a variety of neural and non-neural cell types and was not inhibited by signaling through Trk (unlike killing by full-length p75NTR). Chopper triggered cell death only when bound to the plasma membrane by a lipid anchor, whereas non-anchored Chopper acted in a dominant-negative manner, blocking p75NTR-mediated death both in vitroand in vivo. Removal of the ectodomain of p75NTRincreased the potency of Chopper activity, suggesting that it regulates the association of Chopper with downstream signaling proteins.

The Poser criteria for diagnosing multiple sclerosis (MS) includes clinical, paraclinical and laboratory information.1We studied the influence of cerebrospinal fluid (CSF) biochemistry results on the categorisation of patients with suspected MS.A retrospective study was made of 138 patients who had CSF samples sent over a 1 year period to the laboratory for examination for oligoclonal bands. Using the Poser criteria, 23 patients were diagnosed as having definite MS and one patient as probable MS. Cerebrospinal fluid biochemistry upgraded the categorisation from probable to definite MS in 16 of these 24 patients (66%).In this study, we found oligoclonal bands to be more sensitive in the diagnosis of MS (96%) than either the concentration of IgG in the CSF (43·5%) or the IgG expressed as a percentage of the total protein in the CSF (71%). We conclude that CSF biochemistry is a valuable investigation in the evaluation of patients with suspected MS.

The immunopathogenesis of multiple sclerosis appears to be dependent on the interaction between major histocompatibility cpmplex molecules, T-cell receptors, and peptide antigens. The mechanisms regulating this ‘tripartite’ system and their relevance to immune-mediated experimental and human demyelination and potential treatment strategies are reviewed.

•Covid-19 pandemic can have implications for MS and neuroimmunology patients and potentially their adherence to disease modifying therapies (DMTs).•A large proportion of patients receiving DMT's for their MS expressed some degree of concern regarding the COVID-19 pandemic and their therapy in one MS centre in Australia.•The level of concern in most patients was at most mild however.•Patients ascribed similar concern to the risk of a relapse of their disease compared to the risk of contracting COVID-19, perhaps underscoring a willingness to continue their DMT despite the pandemic.

•The MSReactor battery could monitor for cognitive change in the clinic setting.•MSReactor battery correlates moderately with the Processing Speed Test.•The test-retest reliability was good for both tests over 6 months.•Depression and anxiety have minimal effect on MSReactor scores.•Manual dexterity has no effect on MSReactor and Processing Speed test scores.

The effects that immunomodulatory agents such as β-Interferon (IFN-β) exert upon cytokine production in autoimmune disease such as multiple sclerosis remain incompletely understood. The recent development of techniques to directly assess cytokine production within peripheral blood leucocytes promises to advance this field. β-Interferon treatment occasionally causes short-lived exacerbations of neurological dysfunction, often associated with systemic flu-like symptoms. Whereas these side effects usually occur and remit within the first few months of therapy, we have identifi ed several patients who have developed symptoms many months after the onset of treatment. To begin to investigate the cause of these late onset exacerbations, we assessed the intracellular cytokine profiles of two patients, one stable on IFN-β treatment and another experiencing side effects. The latter patient exhibited an increase in the percentage of monocytes that expressed g-Interferon after IFN-β administration, whereas no such modulation was seen in the patient without side effects.

IntroductionCladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently been listed on the pharmaceuticals benefit scheme (PBS) in Australia for treatment of relapsing MS. The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS up to 4 years in 75% of patients (based on annualised relapse rate). However, re-initiation of therapy after year 4 has not been studied.MethodsThis will be a multicentre, 6-year, phase IV, low interventional trial. Subjects considered for treatment with cladribine will receive an initial treatment course in year 1 and a continuing treatment course in year 2. After year 3, patients will have the option for re-dosing, if clinically indicated or to switch to another disease modifying therapy. Throughout the duration of the study we will assess blood based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation and RNA analysis as well as MRI findings (brain volume/lesion load) and cognitive performance.ResultsThis study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. The study is due to commence on March 14th.ConclusionsThis will be the first long-term efficacy trial of cladribine which offers re-initiation of therapy after the initial two courses. We expect this study will be an indication if any of the assessed biomarkers can be used to predict treatment efficacy or the need for re-initiation of Cladribine in MS patients.

Objective: To present four patients seen over a five‐year period who developed severe protracted encephalitic illnesses but whose outcomes were favourable. Clinical features: Of the four patients, aged 18, 22, 34 and 19, three presented with acute psychosis, and all had a prolonged clinical course requiring intensive care management. One patient had residual generalised seizures and the other three recovered fully. No infective or toxic agent could be identified but viral encephalitis was considered most likely. Outcome: Despite the protracted courses, the outcomes were favourable. This is in contrast to the generally poor outcomes in encephalitis caused by established infective agents such as herpes simplex type 1. Conclusions: When the aetiology and hence the natural history of the encephalitis is unknown, long‐term intensive support is appropriate.

A 61‐year‐old male receiving treatment for acute myelomonocytic leukaemia (AMML) developed weakness and sensory loss in the thumb, index and middle finger and half of the ring finger of the left hand as a result of a spontaneous haemorrhage into the carpal tunnel and forearm, an unusual cause of median nerve compression. These findings were confirmed by CT scanning and post‐mortem examination. This is the first report of spontaneous haemorrhage occurring in a patient with AMML.

Schwann cell death is a developmentally regulated phenomenon and is also induced after peripheral nerve axotomy in neonatal rodents. In this study, we explored whether ligand-induced activation of the low-affinity neurotrophin receptor (p75NTR) is responsible for inducing Schwann cell death in vivo. Administration of exogenous nerve growth factor (NGF) to the axotomized nerve site in wild-type animals resulted in a 2.6-fold increase in Schwann cell apoptosis in the distal nerve stumps compared to axotomy alone. No increase in apoptosis, above baseline levels, was seen in p75NTR-mutant mice either with or without NGF. When anti-NGF antibodies were administered to the site of the peripheral nerve lesion in wild-type mice there was a reduction in the percentage of Schwann cell apoptosis to levels seen in both the quiescent state and in the axotomized nerves of the p75NTR-mutant mice. These results demonstrate that apoptosis of Schwann cells in axotomized peripheral nerve is mediated predominantly through p75NTR signaling and initiated via endogenously produced NGF.