Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course-a joint PhD student course at University College London and University of Gothenburg.

Until relatively recently, a diagnosis of probable Alzheimer's disease (AD) and other neurodegenerative disorders was principally based on clinical presentation, with post-mortem examination remaining a gold standard for disease confirmation. This is in sharp contrast to other areas of medicine, where fluid biomarkers, such as troponin levels in myocardial infarction, form an integral part of the diagnostic and treatment criteria. There is a pressing need for such quantifiable and easily accessible tools in neurodegenerative diseases.In this paper, based on lectures given at the 2019 Biomarkers in Neurodegenerative Diseases Course, we provide an overview of a range of cerebrospinal fluid (CSF) and blood biomarkers in neurodegenerative disorders, including the 'core' AD biomarkers amyloid ß (Aß) and tau, as well as other disease-specific and general markers of neuroaxonal injury. We then highlight the main challenges in the field, and how those could be overcome with the aid of new methodological advances, such as assay automation, mass spectrometry and ultrasensitive immunoassays.As we hopefully move towards an era of disease-modifying treatments, reliable biomarkers will be essential to increase diagnostic accuracy, allow for earlier diagnosis, better participant selection and disease activity and treatment effect monitoring.

Heparin-induced thrombocytopaenia presenting as acute aortic mural thrombosis.

Heparin-induced thrombocytopaenia (HIT) is a life and limb-threatening acquired autoimmune complication of heparin-based treatment, characterised by thrombocytopaenia and thrombosis. We present a case of a 77-year-old female with concomitant metastatic ovarian and breast cancer who presented to our institution with worsening shortness of breath. She had been diagnosed with acute pulmonary embolism 1 month earlier that was treated with therapeutic low molecular weight heparin (LMWH). In view of her worsening symptoms, CT imaging was performed. This demonstrated significant progression of the bilateral pulmonary emboli and new mural thrombosis of the thoracic aorta, despite being compliant with therapeutic anticoagulation. She had also developed thrombocytopaenia since commencing LMWH, which raised the clinical suspicion of HIT syndrome. The HIT pre-test probability score was intermediate and LMWH was immediately discontinued pending further investigation. She was commenced on rivaroxaban, a direct oral anticoagulant, and her platelet count soon recovered. Laboratory testing was strongly positive on both immunological and functional assays, thus confirming a diagnosis of HIT syndrome. A repeat CT scan 3 weeks later showed a reduction in the overall thrombus load. Whilst venous thrombosis is observed in as many as half of patients with HIT, arterial thrombosis is a far less common event. Furthermore, arterial involvement usually affects the distal vessels with significant atherosclerotic burden and typically presents as acute limb ischaemia or ischaemic stroke. Aortic thrombosis, as in this case, is a rare complication of HIT syndrome.

Autophagy in childhood neurological disorders.

Autophagy is a tightly modulated lysosomal degradation pathway. Genetic disorders of autophagy during nervous system development may lead to developmental delay, neurodegeneration, and other neurological signs in children. Here we aimed to summarize single gene disorders that perturb various steps of autophagy pathway and their roles in the causation of childhood neurological diseases. Numerous childhood-onset disorders are caused by mutations that impact the autophagy pathway. These can manifest with a range of features including ataxia, spastic paraplegia, and intellectual disability. Defective proteins causing such diseases can interfere with autophagy flux at different stages of the itinerary. Defective autophagy may be an important contributor to the pathological features of various childhood neurodegenerative diseases and lead to the accumulation of aberrant protein and dysfunctional organelles. Insights into the relevant cell biological processes may help understand pathophysiological mechanisms and inspire autophagy-restoring therapeutic approaches. WHAT THIS PAPER ADDS: Numerous childhood-onset disorders are caused by mutations that impact the autophagy pathway. Defective autophagy is a feature of some mutations that cause ataxia, spastic paraplegia, and intellectual disability.

AUTOFAGIA EN TRASTORNOS NEUROLÓGICOS INFANTILES: La autofagia es una vía de degradación lisosomal estrechamente modulada. Los trastornos genéticos de la autofagia durante el desarrollo del sistema nervioso pueden llevar a retrasos en el desarrollo, neurodegeneración y otros signos neurológicos en los niños. Aquí nos propusimos resumir los trastornos de un solo gen que perturban varios pasos de la vía de autofagia y sus funciones en la causa de las enfermedades neurológicas infantiles. Numerosos trastornos de inicio en la infancia son causados ​​por mutaciones que afectan la vía de la autofagia. Estos pueden manifestarse con una variedad de características que incluyen ataxia, paraplejia espástica y discapacidad intelectual. Las proteínas defectuosas que causan tales enfermedades pueden interferir con el flujo de autofagia en diferentes etapas del itinerario. La autofagia defectuosa puede contribuir de manera importante a las características patológicas de diversas enfermedades neurodegenerativas infantiles y conducir a la acumulación de proteínas aberrantes y orgánulos disfuncionales. La información sobre los procesos biológicos celulares relevantes puede ayudar a comprender los mecanismos fisiopatológicos e inspirar enfoques terapéuticos de restauración de la autofagia.

AUTOFAGIA EM DESORDENS NEUROLÓGICAS DA INFÂNCIA: Autofagia é uma via de degradação lisossômica fortemente modulada. Desordens genéticas de autofagia durante o desenvolvimento do sistema nervoso central podem causar atraso do desenvolvimento, neurodegeneração, e outros sinais neurológicos em crianças. Aqui, visamos sintetizar desordens de genes únicos que perturbam várias etapas da via de autofagia, e seu papel na ocorrência de doenças neurológicas da infância. Várias desordens de início na infância são causadas por mutações que afetam a via da autofagia. Estas podem se manifestar com uma variedade de aspectos incluindo ataxia, paraplegia espástica, e deficiência intelectual. Proteínas defeituosas que causam tais doenças podem inteferir com o fluxo de autofagia em diferentes estágios do itinerário. A autofagia defeituosa pode ser um fator importante contrbuindo para aspectos patológicos de diversas doenças neurodegenerativas da infância e causar acúmulo de proteínas aberrantes e organelas disfuncionais. A compreensão dos processos biológicos celulares relevantes pode ajudar a compreender mecanismos patofisiológicos e inspirar abordagens terapêuticas que restaurem a autofagia.