Nature Reviews Neurology最新文献

Neuromyelitis optica (NMO) spectrum disorder (NMOSD) is a relapsing inflammatory disease of the CNS, characterized by the presence of serum aquaporin 4 (AQP4) autoantibodies (AQP4-IgGs) and core clinical manifestations such as optic neuritis, myelitis, and brain or brainstem syndromes. Some people exhibit clinical characteristics of NMOSD but test negative for AQP4-IgG, and a subset of these individuals are now recognized to have serum autoantibodies against myelin oligodendrocyte glycoprotein (MOG) — a condition termed MOG antibody-associated disease (MOGAD). Therefore, the concept of NMOSD is changing, with a disease spectrum emerging that includes AQP4-IgG-seropositive NMOSD, MOGAD and double-seronegative NMOSD. MOGAD shares features with NMOSD, including optic neuritis and myelitis, but has distinct pathophysiology, clinical profiles, neuroimaging findings (including acute disseminated encephalomyelitis and/or cortical encephalitis) and biomarkers. AQP4-IgG-seronegative NMOSD seems to be a heterogeneous condition and requires further study. MOGAD can manifest as either a monophasic or a relapsing disease, whereas NMOSD is usually relapsing. This Review summarizes the history and current concepts of NMOSD and MOGAD, comparing epidemiology, clinical features, neuroimaging, pathology and immunology. In addition, we discuss new monoclonal antibody therapies for AQP4-IgG-seropositive NMOSD that target complement, B cells or IL-6 receptors, which might be applied to MOGAD in the near future.

Adaptive deep brain stimulation (DBS) improves motor symptoms and quality of life in people with Parkinson disease compared with continuous DBS, the results of a pilot trial suggest. The study included four people with Parkinson disease, each of whom received continuous and adaptive DBS at different times to enable comparison of the effects. Adaptive stimulation was personalized according to motor cortical signals that were identified as biomarkers of fluctuations in motor function. When compared with the effects of continuous stimulation in each individual, adaptive stimulation reduced the time with motor symptoms and improved the participants’ quality of life with respect to normal daily activities.

Metabolic rewiring of a population of tumour-associated macrophages facilitates progression of glioblastoma, new research has revealed. A multi-omics approach demonstrated that the macrophages develop a lipid-laden phenotype, in which they accumulate cholesterol after uptake of myelin debris. Transfer of this accumulated cholesterol to glioblastoma cells helps to meet the high metabolic requirements of the tumour and sustain its growth. These mechanistic insights provide an opportunity for therapeutic targeting of lipid-laden macrophages.

After a stroke, circulating, cell-free DNA causes inflammasome activation in atherosclerotic plaques that can lead to recurrent stroke, work in a mouse model has shown. In a model of stroke-induced recurrent ischaemia, increased inflammation in plaques in the common carotid artery resulted from activation of the AIM2 inflammasome by cell-free DNA that primarily originated from neutrophil extracellular traps (NETs). The increased inflammation led to plaque rupture and a secondary stroke. Administration of DNase after stroke reduced the risk of recurrent events in the mice, suggesting that this mechanism could be targeted therapeutically.

A pro-inflammatory serum profile has been associated with frontotemporal lobar degeneration (FLTD) in new research, increasing the likelihood that blood-based biomarkers can be used for assessment of neuroinflammation in people with dementia. The researchers analysed cytokines in the serum of 214 people with syndromes associated with FTLD and 29 healthy individuals. Their analysis identified a profile of pro-inflammatory cytokines that was associated with FLTD. Stronger expression of this serum profile was associated with greater central neuroinflammation, as indicated by evidence of microglial activation on PET imaging, and with shorter survival.

Migraine is a disabling neurological disorder that affects more than one billion people worldwide. The clinical presentation is characterized by recurrent headache attacks, which are often accompanied by photophobia, phonophobia, nausea and vomiting. Although the pathogenesis of migraine remains incompletely understood, mounting evidence suggests that specific signalling molecules are involved in the initiation and modulation of migraine attacks. These signalling molecules include pituitary adenylate cyclase-activating polypeptide (PACAP), a vasoactive peptide that is known to induce migraine attacks when administered by intravenous infusion to people with migraine. Discoveries linking PACAP to migraine pathogenesis have led to the development of drugs that target PACAP signalling, and a phase II trial has provided evidence that a monoclonal antibody against PACAP is effective for migraine prevention. In this Review, we explore the molecular and cellular mechanisms of PACAP signalling, shedding light on its role in the trigeminovascular system and migraine pathogenesis. We then discuss emerging therapeutic strategies that target PACAP signalling for the treatment of migraine and consider the research needed to translate the current knowledge into a treatment for migraine in the clinic.

Progressive multiple sclerosis poses a considerable challenge in the evaluation of disease progression and treatment response owing to its multifaceted pathophysiology. Traditional clinical measures such as the Expanded Disability Status Scale are limited in capturing the full scope of disease and treatment effects. Advanced imaging techniques, including MRI and PET scans, have emerged as valuable tools for the assessment of neurodegenerative processes, including the respective role of adaptive and innate immunity, detailed insights into brain and spinal cord atrophy, lesion dynamics and grey matter damage. The potential of cerebrospinal fluid and blood biomarkers is increasingly recognized, with neurofilament light chain levels being a notable indicator of neuro-axonal damage. Moreover, patient-reported outcomes are crucial for reflecting the subjective experience of disease progression and treatment efficacy, covering aspects such as fatigue, cognitive function and overall quality of life. The future incorporation of digital technologies and wearable devices in research and clinical practice promises to enhance our understanding of functional impairments and disease progression. This Review offers a comprehensive examination of these diverse evaluation tools, highlighting their combined use in accurately assessing disease progression and treatment efficacy in progressive multiple sclerosis, thereby guiding more effective therapeutic strategies.

Stiff-person syndrome (SPS) is the prototypical and most common autoimmune neuronal hyperexcitability disorder. It presents with stiffness in the limbs and axial muscles, stiff gait with uncontrolled falls, and episodic painful muscle spasms triggered by anxiety, task-specific phobias and startle responses, collectively leading to disability. Increased awareness of SPS among patients and physicians has created concerns about diagnosis, misdiagnosis and treatment. This Review addresses the evolving diagnostic challenges in SPS and overlapping glutamic acid decarboxylase (GAD) antibody spectrum disorders, highlighting the growing number of overdiagnoses and focusing on the progress made in our understanding of SPS pathophysiology, antibodies against GAD and other inhibitory synaptic antigens, and the fundamentals of neuronal hyperexcitability. It considers the role of impaired GABAergic or glycinergic inhibition in the cortex and at multiple levels in the neuraxis; the underlying autoimmunity and involvement of GAD antibodies; immunopathogenic mechanisms beyond antibodies, including environmental triggers; familial and immunogenetic susceptibility; and potential T cell cytotoxicity. Finally, the mechanistic rationale for target-specific therapeutic interventions is presented along with the available therapeutic approaches, including enhancers of GABA signalling drugs and immunotherapies.