Reviews & Analysis

Since the development of life support technology, the precise definition of death has been challenging. James Bernat outlines the brain criteria and the circulatory–respiratory criteria of death, and discusses controversial issues surrounding these definitions, such as a lack of standardization in the field. Ethical challenges in the context of organ donation are also considered.

The amyloid cascade hypothesis, which posits that amyloid-β accumulation is the key event in Alzheimer disease neurodegeneration, has dominated the field for 20 years. Recent findings, however, show that neuronal-injury biomarkers are independent of amyloid-β, calling for reconsideration of the pathological cascade and assessment of alternative therapeutic strategies.

Mild traumatic brain injury (TBI) is defined as a head trauma resulting in a brief loss of consciousness and/or alteration of mental state. Diagnostic methods to determine the extent of injury to the brain and potential long-term damage in patients are lacking. In this Review, the authors discuss the need for fluid biomarkers of mild TBI, and the potential validation of biomarkers before clinical implementation.

The treatment of Bell palsy remains a matter of debate. A recent update of the American Academy of Neurology practice parameter concluded that corticosteroids should be offered to increase the probability of facial nerve recovery. The benefits of antiviral treatment, however, have not been established.

Results from two phase III trials show the potency of alemtuzumab—a T-cell and B-cell depleting antibody—in reducing clinical and paraclinical measures of disease activity in relapsing–remitting multiple sclerosis. The effects of this immunotherapeutic agent highlight the relevance of T lymphocytes in the early pathogenesis of disease.

For patients with malignant glioma—a tumour that carries a very poor prognosis—resective surgery is the primary treatment approach. Whether the extent of resection affects prognosis, however, has been the subject of debate. Eyupoglu et al. describe advances in surgical imaging techniques that have enabled improvement in both assessment of resection extent and maximal feasible tumour removal. Preoperative and postsurgical factors that influence patient outcome are described, along with discussion of clinical data suggesting that maximal surgical resection is in the best interest of patients with malignant glioma.

In 2012, studies of autosomal dominant Alzheimer disease (AD), late-onset AD, and a rare genetic mutation of amyloid precursor protein provided support for the critical role of amyloid in AD pathogenesis. Increasing evidence implicated cell-to-cell transmission in the spread of tau and amyloid, highlighting novel targets for therapeutic intervention.

2012 witnessed important developments for multiple sclerosis, including successful phase III trials of novel oral therapeutics and identification of the potassium channel KIR4.1 as an autoimmune target. Additionally, the lung was highlighted as an important site for immune-cell programming, and the relevance of a TNF receptor variant was clarified.

Eye movement responses are altered in patients with age-related neurodegenerative diseases such as Huntington disease or Parkinson disease. In this Review, the authors describe the oculomotor features of various neurodegenerative diseases and discuss the potential utility of laboratory and clinical assessment of eye movements in monitoring of onset and progression in patients with these disorders.

In 2012, researchers published extensively on the genetic and clinicopathological characterization of patients with the newly discovered C9ORF72 repeat expansions, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Novel ALS-linked genes and genetic modifiers were identified through screening in animal models and patients.

Research on epilepsies in 2012 has substantially advanced our knowledge of these often devastating conditions. From important discoveries that revealed causative factors and the molecular basis of disease, to major implications for surgical decision-making, these studies set the scene for future advances in the field.

Several clinical trials and experimental studies that could have a major impact on the treatment of patients with ischaemic stroke were published in 2012. The studies cover all therapeutic options, including stroke prevention, recanalization and thrombolysis, neuroprotection, and promising new therapeutic approaches focused on neurorepair.

Research in movement disorders in 2012 has improved our understanding of the pathogenic mechanisms of disease and led to development of potential novel therapeutic approaches. Key advances were linked to mechanisms underlying spread of neurodegenerative pathology, immunotherapy, stem cells, genetics and deep brain stimulation in parkinsonism and related disorders.

Transient amnesic syndromes, such as transient global amnesia and transient epileptic amnesia, are often difficult to diagnose. Recent studies, however, have examined the structural and functional underpinnings of these disorders. In this Review, Bartsch and Butler discuss how these studies have improved our understanding of transient amnesic syndromes, summarizing the key clinical aspects of different amnesic disorders and providing recommendations for diagnosis and patient management.

The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer disease (AD). Guojun Bu and colleagues describe the pathogenic links between Apo-E4 and neurodegeneration, including amyloid-β-dependent mechanisms and impairment of neurovascular function. The authors suggest potential strategies to target Apo-E, which could provide important additions to therapeutic options for AD.