Review Articles in 2014

Despite a growing emphasis on biomarkers in research into Alzheimer disease (AD) and Parkinson disease (PD), there is little consensus as to which biomarkers are most effective. In this Review, Lleó and colleagues discuss cerebrospinal fluid (CSF) biomarkers for AD and PD, with a particular emphasis on applicability to clinical trials. Compared with AD, less is known about CSF biomarkers in PD, and the authors highlight several areas for further research.

The network between mitochondia is in a constant state of flux, with organelles fusing and separating in response to cellular metabolic demands. Disturbances to mitochondrial fusion and fission have been observed in several human diseases, and in this Review, Florence Burté and colleagues discuss how the mitochondrial network might play a crucial part in neurodegeneration. The authors focus on major protein mediators of mitochondrial dynamics, including optic atrophy protein and the mitofusins, and trace the involvement of mitochondrial dynamics in autosomal dominant optic atrophy, Charcot–Marie–Tooth disease and other disorders.

Despite the promise that many potential neuroprotective treatments for Parkinson disease (PD) have shown in preclinical studies, the benefits have not been replicated in recent clinical trials. In this Review, Athauda and Foltynie discuss the reasons for this 'failure to translate', and propose strategies to avoid such eventualities in the future, including improved trial design and repositioning of existing drugs. They also review the most promising drugs that are currently in preclinical development or clinical testing for their neuroprotective properties in PD.

Disruption of circadian rhythms in neurodegenerative disorders not only contributes to morbidity and poor quality of life, but could also be involved in driving the disease process itself. Restoration of circadian rhythmicity via behavioural or pharmacological interventions might, therefore, slow down disease progression. In this Review, Videnovic and colleagues provide an overview of the circadian system, and summarize current understanding of the dysfunction of circadian rhythms in Alzheimer disease, Parkinson disease and Huntington disease.

Despite a wealth of data generated by neuroimaging research in Parkinson disease (PD), no imaging techniques are currently recommended for routine clinical use. In this Review, Marios Politis assesses the various PET, single-photon emission CT, MRI and other imaging modalities that could aid the differential diagnosis and assessment of patients with PD. He then looks to the future of neuroimaging, including newly developed radioligands and combined-modality approaches, and discusses how research and clinical practice might better address the needs of patients.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a common and severe adverse effect of cytostatic drugs that can limit dose and choice of chemotherapy, and can lead to delay or discontinuation of cytostatic treatment. Most drugs that are in use for neuropathic pain have failed to alleviate CIPNP in clinical trials. Here, Sisignano et al. review the mechanisms through which the most commonly used cytostatic drugs cause CIPNP, and suggest mechanism-based treatment options.

Genome-wide association studies (GWASs) are uncovering genetic variants that are associated with the risk of stroke, and with specific stroke subtypes. In this Review, Markus and Bevan explore the implications of these associations for predictive testing, clinical management and new therapeutic approaches, as well as insights into stroke pathophysiology. They also outline considerations for future studies, so as to maximize the potential of GWASs.

Activation of the immune system during pregnancy can have varied effects on fetal development, and converging evidence highlights maternal immune activation as a risk factor for multiple neurological conditions. In this Review, Knuesel and colleagues discuss the involvement of maternal immune activation in schizophrenia, austim spectrum disorders, epilepsy and other disorders. The authors then discuss how preclinical data indicate a possible link between prenatal exposure to infection and susceptibility to neurodegenerative disease, and they go on to identify fertile ground for further translational research.

Amyotrophic lateral sclerosis (ALS) is a genotypically and phenotypically heterogeneous disease, as reflected in the variability in age and site of onset, extent of extramotor involvement, and survival. Cognitive involvement is also common, and corroborates the connection between ALS and frontotemporal lobar degeneration. In this article, Robberecht and Swinnen review phenotypic heterogeneity in ALS and discuss some of its implications for understanding ALS pathogenesis and development of therapeutic interventions.

Functional and structural connectivity measures, assessed by means of functional and diffusion MRI, are emerging as potential intermediate biomarkers for Alzheimer disease and other neurodegenerative disorders. In this article, Pievani et al. evaluate the evidence that connectivity biomarkers are associated downstream with clinical phenotypes and topographic brain imaging markers of neurodegeneration, and upstream with molecular determinants of neurodegeneration and susceptibility genes.

The fifth edition of the American Psyciatric Association's Diagnostic and Statistical Manual for Mental Disorders (DSM-5) was published in 2013, and with it came new diagnostic criteria for mild cognitive impairment and dementia. In this Review, members of the working group tasked with writing the DSM-5 criteria for neurocognitive disorders present the new approach to categorization and diagnosis. Three key syndromes are recognized—delirium, mild neurocognitive disorder and major neurocognitive disorder—and each can have distinct aetiological subtypes.

Chronic subdural haematoma (CSDH)—an 'old' collection of blood and blood breakdown products in the subdural space—is one of the most common neurological disorders, especially among elderly individuals. The current consensus is that symptomatic CSDH is best treated by surgical evacuation, usually via burr hole craniostomy. This Review provides an overview of the contemporary management of CSDH, and considers future approaches that could optimize patient care and outcomes.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease with wide-ranging clinical manifestations that can involve the CNS and PNS. In this article, Jeltsch-David and Muller review the clinical features and pathogenesis of neuropsychiatric SLE (NPSLE), focusing on the aspects that might aid identification of biomarkers. They also discuss the classification and treatment of NPSLE, and identify avenues for future research.

Noninvasive brain stimulation (NIBS) is a promising approach for facilitating recovery of motor function after stroke, but trials assessing its efficacy have provided contradictory results. Di Pino and colleagues propose a unified 'bimodal balance–recovery model' for stroke recovery that takes into account the individual residual structural reserve and could aid tailoring of treatment for individual patients, thereby increasing the efficacy of NIBS in stroke rehabilitation.

Primary progressive aphasia (PPA) is caused by asymmetric, selective neurodegeneration of cerebral areas involved in language. Agrammatic and semantic PPAs are typically manifestations of frontotemporal lobar degeneration, whereas the logopenic PPA is more often associated with Alzheimer disease pathology. Here, Mesulam et al. review the subclassification, clinical features and neuropathology of PPA, and discuss how increased knowledge of PPA has advanced our understanding of the neural substrates of the language network.

In complex regional pain syndromes (CRPS), pain—typically of neuropathic type—in the affected limb is accompanied by a variety of sensory, motor and autonomic signs and symptoms. Treatment for CRPS has been largely adapted from therapies for neuropathic pain states, but a better understanding of CRPS pathologenesis might provide opportunities for mechanism-based treatment. Here, the authors discuss available and emerging mechanism-based treatments in CRPS, including pharmacotherapy targeting central and peripheral sensitization and aberrant inflammatory response; sympathetic ganglion block interventions; and alleviation of symptoms by reversing body perception disturbances.

Neuromyelitis optica (NMO) is characterized by inflammatory demyelinating lesions of the spinal cord and optic nerve, and can lead to paralysis and blindness. Currently, several treatment options for NMO exist, but many have been adapted from multiple sclerosis, and no controlled clinical trials specific to NMO have been conducted to date. Here, Marios Papadopoulos and colleagues review the various treatment strategies in NMO, and discuss the drugs that are in development or could be repurposed to treat this condition.

Patients with multiple sclerosis (MS) frequently experience depression, which profoundly reduces quality of life, and increases disease mortality. In this Review, Feinstein and colleagues present multiple approaches to the diagnosis and quanitfication of mood disorders, and critically evaluate the various treatment options for MS-related depression.The authors also discuss the extent to which depression can be teased apart from the neurological, immunological and psychosocial sequelae of MS.

Guillain–Barré syndrome (GBS) is a postinfectious disease characterized by rapidly progressive, symmetrical weakness of the extremities, and can lead to life-threatening complications such as respiratory insufficiency and autonomic dysfunction. Here, van den Berg et al. describe the immune pathogenesis and clinical characteristics of GBS and its subtypes, and highlight the importance of careful diagnostic assessment of patients and the possible additional diagnostic value of cerebrospinal fluid examinations and nerve conduction tests. The authors review treatment options and prognosis, including novel predictive models, for patients with GBS.

Optic neuritis is an inflammatory optic neuropathy that is frequently—but not always—associated with multiple sclerosis (MS). Despite recent developments in laboratory, imaging and electrophysiological techniques, no consensus guidelines have yet been formulated for the diagnostic work-up in patients presenting with optic neuritis. In this Review, Petzold and colleagues contribute to the development of such a consensus by proposing an investigation protocol for optic neuritis.