Volume 137, Issue 11, November 2014

This scientific commentary refers to ‘ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism’ by Peters et al. (doi:10.1093/brain/awu216).

This scientific commentary refers to ‘Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid’ by Fritschi et al. (doi: 10.1093/brain/awu255).

This scientific commentary refers to ‘Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers’ by Freischmidt et al. (doi: 10.1093/brain/awu249).

This scientific commentary refers to ‘Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma’ by Hinzman et al. (doi:10.1093/brain/awu241).

Peeters et al. review current knowledge regarding the phenotypes, causative genes, and disease mechanisms associated with proximal SMN1-negative spinal muscular atrophies (SMA). They describe the molecular and cellular functions enriched among causative genes, and discuss the challenges facing the post-genomics era of SMA research.

Valosin-containing protein (VCP) facilitates protein degradation via the proteasomal and autophagic pathways. VCP mutations are associated with a spectrum of disorders including frontotemporal dementia, Paget's disease and hereditary spastic paraplegia. Gonzalez et al. further expand this spectrum by identifying a missense mutation in VCP that causes Charcot-Marie-Tooth disease type 2.

Leigh disease is a progressive neurodegenerative disorder of childhood. Peters et al. identify novel causative mutations in ECHS1, which encodes the mitochondrial enzyme short-chain enoyl-CoA hydratase, in two siblings with fatal Leigh disease. The mutations affect valine metabolism and result in the pathological accumulation of reactive intermediates.

Fritschi et al. assess the potency of soluble amyloid seeds in the brains and cerebrospinal fluid of patients with Alzheimer's disease, and their value as a disease biomarker. The seeding activity of soluble amyloid is orders of magnitude greater in brain extracts than in the cerebrospinal fluid.

Pareés et al. demonstrate that sensory attenuation—whereby self-generated stimuli produce weaker sensations than externally-generated stimuli—is impaired in patients with functional movement disorders. Loss of sensory attenuation has been associated with loss of a sense of agency, which may explain why these patients experience their abnormal movements as involuntary.

Much of the clinical disability in Charcot-Marie-Tooth disease 1A results from secondary axon loss. Hantke et al. show that the transcription factor c-Jun is upregulated in Schwann cells in a mouse model of the disorder, and that this protects against axon loss. Targeting this axon-supportive mechanism may have therapeutic potential.

Little is known about the preclinical phase of amyotrophic lateral sclerosis (ALS). Freischmidt et al. reveal strikingly similar microRNA profiles in patients with familial ALS and pre-manifest mutation carriers, with specific microRNAs downregulated largely independently of the causative mutations. The possibility of presymptomatic disease modifying treatment should be investigated in ALS.

Altered cAMP signalling may contribute to migraine. In a placebo-controlled crossover study, Guo et al. show that cilostazol—a selective inhibitor of the cAMP-degrading enzyme PDE3—induces delayed migraine-like attacks in 12 of 14 migraine patients without aura. The results support a key role for intracellular cAMP accumulation in migraine induction.

Hinzman et al. characterize the haemodynamic response to cortical spreading depolarization in patients with severe traumatic brain injury. Pathological inverse neurovascular coupling (hypoperfusion) is more common than physiological coupling (hyperaemia) and is associated with impaired cerebrovascular autoregulation. Thus, spreading depolarizations may exacerbate ischaemic conditions.

Edelmann et al. compare brain morphology in long-term adult survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy alone to that of individuals treated with cranial radiation, and to healthy controls. Substantial white matter abnormalities are seen in leukaemia survivors, regardless of treatment, and are associated with neurocognitive impairment.

Leucine-rich, glioma inactivated 1 (LGI1) is a secreted protein linked to seizures of both genetic and autoimmune aetiology. Using conditional mouse knockouts, Boillot et al. show that LGI1 depletion in cortical excitatory neurons, but not inhibitory interneurons, contributes to seizure pathogenesis. LGI1 is essential for proper circuit functioning throughout life.

Accumulating evidence suggests that sports-related concussion has long-term sequelae. Tremblay et al. show that ageing retired athletes with a history of concussions exhibit diffuse abnormalities in white matter tracts. The abnormalities are associated with cognitive decline relative to matched controls, suggesting that concussions exacerbate the ageing process.

Barow et al. show that deep brain stimulation rapidly suppresses enhanced low-frequency pallidal activity in patients with phasic dystonia, and suggest that improvements in phasic movements directly reflect modulation of pathological basal ganglia activity. By contrast, improvements in tonic features may result from long-term plastic changes within the motor network.

A variable number of tandem repeats in the SLC6A3 gene affects striatal dopamine reuptake. Habak et al. examine the performance of patients with Parkinson's disease on a functional MRI set-shifting task and neuropsychological test battery. Results reveal an effect of SLC6A3 genotype on fronto-striatal activation and cognition in Parkinson's disease.

Niethammer et al. aim to improve the differential diagnosis of corticobasal degeneration by identifying a metabolic covariance pattern associated with the disorder, and validating it in independent patient and control populations. They develop an automated logistic algorithm to discriminate between corticobasal degeneration and related syndromes on a prospective single-case basis.

Patients with behavioural variant frontotemporal dementia caused by the C9orf72 hexanucleotide repeat expansion show distinct but variable brain atrophy. Using task-free functional MRI, Lee et al. reveal that convergent intrinsic connectivity network alterations emerge in patients with C9orf72 and sporadic disease, even in C9orf72 carriers with undetectable brain atrophy.

Corticobasal syndrome typically presents as motor dysfunction, but cognitive and behavioural changes are also recognised. Kumfor et al. now further expand the phenotype by revealing widespread deficits in emotion processing. The impairments are more severe than in Alzheimer’s disease, and are associated with basal ganglia and paracentral/precuneus atrophy.

Aoki et al. demonstrate that individuals with autism spectrum disorders are impaired in recognising others' social emotions in the absence of direct cues, such as facial expressions, and that intranasal oxytocin reduces this deficit at both behavioural and neural levels. Oxytocin may have therapeutic potential for improving communication and social interaction in autism spectrum disorders.