Brain

Compston, Alastair

doi: 10.1093/brain/awn356pmid: 19168453

Compston, Alastair

doi: 10.1093/brain/awn360pmid: N/A

Goadsby, Peter J.

doi: 10.1093/brain/awn321pmid: 19098031

Ito, Daisuke; Suzuki, Norihiro

doi: 10.1093/brain/awn216pmid: 18790819

The Seipin/BSCL2 gene was originally identified as a loss-of-function gene for congenital generalized lipodystrophy type 2 (CGL2), a condition characterized by severe lipoatrophy, insulin resistance, hypertriglyceridaemia and mental retardation. Recently, gain-of-toxic-function mutations (namely, mutations N88S and S90L) in the seipin gene have been identified in autosomal dominant motor neuron diseases such as Silver syndrome/spastic paraplegia 17 (SPG17) (OMIM #270685) and distal hereditary motor neuropathy type V (dHMN-V) (OMIM #182960). Detailed phenotypic analyses have revealed that upper motor neurons, lower motor neurons and peripheral motor axons are variously affected in patients with these mutations. The clinical spectrum for these mutations is broad, encompassing Silver syndrome, some variants of Charcot-Marie-Tooth disease type 2, dHMNV and spastic paraplegia, even within a common pedigree. Therefore, we propose that seipin-related motor neuron diseases can be collectively referred to as ‘seipinopathies’. Expression of the seipin protein can be detected in motor neurons in the spinal cord and white matter in the frontal lobe. This is consistent with the distribution of seipinopathies in the upper and lower motor neurons. Recent studies have shown that seipin, an endoplasmic reticulum (ER)-resident membrane protein, is an N-glycosylated protein that is proteolytically cleaved into N- and C-terminal fragments and is polyubiquitinated. Interestingly, the N88S and S90L mutations are in the N-glycosylation motif, and these mutations enhance ubiquitination and degradation of seipin by the ubiquitin–proteasome system (UPS). Furthermore, both mutations appear to result in proteins that are improperly folded, which leads to accumulation of the mutant protein in the ER. We have shown that expression of mutant forms of seipin in cultured cells activates the unfolded protein response (UPR) pathway and induces ER stress-mediated cell death. These findings suggest that seipinopathies are novel conformational diseases and that neurodegeneration in these diseases is tightly associated with ER stress, which has recently been reported to be associated with other neurodegenerative diseases. Further study of the pathological mechanisms of the mutant forms of seipin may lead to important new insights into motor neuron diseases, including other spastic paraplegia diseases and amyotrophic lateral sclerosis.

Schytz, Henrik Winther; Birk, Steffen; Wienecke, Troels; Kruuse, Christina; Olesen, Jes; Ashina, Messoud

doi: 10.1093/brain/awn307pmid: 19052139

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0–2 h) and post-hospital (2–12 h) phases. Mean blood flow velocity in the middle cerebral artery (VMCA) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2–11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in VMCA and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.

Xue, Mengzhou; Fan, Yan; Liu, Shuhong; Zygun, David A.; Demchuk, Andrew; Yong, V. Wee

doi: 10.1093/brain/awn215pmid: 18772219

Proteases such as matrix metalloproteinases (MMPs) and thrombin are implicated in intracerebral haemorrhage (ICH) but their interactions amongst one another and interdependency remain to be defined. The latter is important since proteases acting through different mechanisms to inflict neurotoxicity would require separate targeting compared with proteases acting through the same cascade. We reported recently that MMP-9 and thrombin combined to promote neurotoxicity in ICH; however, as there was still substantial injury when both MMP-9 and thrombin were inhibited, we sought other factors that also contribute to ICH pathology. MMP-3, another member of the MMP family, has been correlated with poor prognosis in ICH in humans and it has been shown to increase rapidly after ICH in animals. Moreover, MMP-3 can convert the MMP-9 zymogen to its active form. Thus, we have examined whether MMP-3 is neurotoxic and addressed whether its potential effect in ICH is dependent on, or additional to, damage inflicted by MMP-9 and thrombin. We report that cultured neurons are killed by MMP-3 and that neuronal death is most marked when all three proteases, MMP-3, MMP-9 and thrombin, are combined. In vivo, the injection of autologous blood into the right striatum to produce ICH injury resulted in MMP-3 expression within 3 h. The blood-induced lesion and neuronal death was significantly reduced in MMP-3 or MMP-9 null mice compared with wild-type counterparts, and MMP-3 and -9 double null mice had even less brain damage. Significantly, pathological destruction after ICH was least in MMP-3 and -9 double null mice treated with a thrombin antagonist, hirudin. These results provide insights into molecules that inflict neurotoxicity in ICH and demonstrate that multiple proteases would need to be targeted simultaneously to successfully reduce ICH neurotoxicity.

Hodapp, Maike; Vry, Julia; Mall, Volker; Faist, Michael

doi: 10.1093/brain/awn287pmid: 18984603

In healthy children, short latency leg muscle reflexes are profoundly modulated throughout the step cycle in a functionally meaningful way and contribute to the electromyographic (EMG) pattern observed during gait. With maturation of the corticospinal tract, the reflex amplitudes are depressed via supraspinal inhibitory mechanisms. In the soleus muscle the rhythmic part of the modulation pattern is present in children with cerebral palsy (CP), but the development of tonic depression with increasing age, as seen in healthy children, is disturbed. Treadmill training clinically improves the walking pattern in children with CP. Presuming that short latency reflexes contribute significantly to the walking pattern, a change in the modulation may occur after training. The aim of this study was to assess whether treadmill training also improves the soleus reflex modulation during gait in children with CP. Seven children with CP underwent brief treadmill training for 10 min a day over 10 consecutive days; all of them were functional walkers. Soleus Hoffmann (H-) reflexes were investigated during walking on a treadmill before the first, and one day after the last, training session. Treadmill training led to a considerable clinical improvement in gait velocity. After 10 days of training, soleus H-reflexes during gait were almost completely depressed during the swing phase. The complete suppression of the soleus H-reflex during the swing phase, which is also exhibited by healthy subjects, could reflect an improvement towards a functionally more useful pattern. In conclusion, treadmill training can induce changes in the modulation of short latency reflexes during gait.

Anderson, Vicki; Spencer-Smith, Megan; Leventer, Rick; Coleman, Lee; Anderson, Peter; Williams, Jackie; Greenham, Mardee; Jacobs, Rani

doi: 10.1093/brain/awn293pmid: 19168454

Until recently, the impact of early brain insult (EBI) has been considered to be less significant than for later brain injuries, consistent with the notion that the young brain is more flexible and able to reorganize in the context of brain insult. This study aimed to evaluate this notion by comparing cognitive and behavioural outcomes for children sustaining EBI at different times from gestation to late childhood. Children with focal brain insults were categorized according to timing of brain insult, represented by six developmental periods: (i) Congenital (n = 38): EBI: first–second trimester; (ii) Perinatal (n = 33); EBI: third trimester to 1 month post-natal; (iii) Infancy (n = 23): EBI: 2 months–2 years post-birth; (iv) Preschool (n = 19): EBI: 3–6 years; (v) Middle Childhood (n = 31): EBI: 7–9 years; and (vi) Late Childhood (n = 19): EBI: after age 10. Groups were similar with respect to injury and demographic factors. Children were assessed for intelligence, academic ability, everyday executive function and behaviour. Results showed that children with EBI were at increased risk for impairment in all domains assessed. Furthermore, children sustaining EBI before age 2 years recorded global and significant cognitive deficits, while children with later EBI performed closer to normal expectations, suggesting a linear association between age at insult and outcome. In contrast, for behaviour, children with EBI from 7 to 9 years performed worse than those with EBI from 3 to 6 years, and more like those with younger insults, suggesting that not all functions share the same pattern of vulnerability with respect to age at insult.

Simner, Julia; Harrold, Jenny; Creed, Harriet; Monro, Louise; Foulkes, Louise

doi: 10.1093/brain/awn292pmid: 19015159

We show that the neurological condition of synaesthesia—which causes fundamental differences in perception and cognition throughout a lifetime—is significantly represented within the childhood population, and that it manifests behavioural markers as young as age 6 years. Synaesthesia gives rise to a merging of cognitive and/or sensory functions (e.g. in grapheme-colour synaesthesia, reading letters triggers coloured visual photisms) and adult synaesthesia is characterized by a fixed pattern of paired associations for each synaesthete (e.g. if a is carmine red, it is always carmine red). We demonstrate that the onset of this systematicity can be detected in young grapheme-colour synaesthetes, but is an acquired trait with a protracted development. We show that grapheme-colour synaesthesia develops in a way that supersedes the cognitive growth of non-synaesthetic children (with both average and superior abilities) in a comparable paired association task. With methodology based on random sampling and behavioural tests of genuineness, we reveal the prevalence of grapheme-colour synaesthesia in children (over 170 000 grapheme-colour synaesthetes ages 0–17 in the UK, and over 930 000 in the US), the progression of the condition in longitudinal testing, and the developmental differences between synaesthetes and non-synaesthetes in matched tasks. We tested 615 children age 6–7 years from 21 primary schools in the UK. Each child was individually assessed with a behavioural test for grapheme-colour synaesthesia, which first detects differences between synaesthetes and non-synaesthetes, and then tracks the development of each group across 12 months (from ages 6/7 to 7/8 years). We show that the average UK primary school has 2–3 grapheme-colour synaesthetes at any time (and the average US primary school has five) and that synaesthetic associations (e.g. a = carmine red) develop from chaotic pairings into a system of fixed, consistent cogno-sensory responses over time. Our study represents the first assessment of synaesthesia in a randomly sampled childhood population demonstrating the real-time development of the condition. We discuss the complex profile of benefits and costs associated with synaesthesia, and our research calls for a dialogue between researchers, clinicians and educators to highlight the prevalence and characteristics of this unusual condition.

Weiss, Peter H.; Fink, Gereon R.

doi: 10.1093/brain/awn304pmid: 19028762

In synaesthesia, stimulation of a sensory modality triggers abnormal additional perceptions. Voxel-based morphometry (VBM) was used in 18 grapheme-colour synaesthetes to investigate the neuro-anatomical basis of their abnormal perceptions. More specifically, we tested the hypothesis that in synaesthesia altered connectivity in temporo-occipital and parietal areas may be associated with grey matter (GM) changes. The data reveal increased GM volumes in fusiform and intraparietal cortices. These findings are consistent with the two-stage model of grapheme-colour synaesthesia implying cross-activation at the level of the fusiform gyrus (FG) and ‘hyperbinding’ at the level of the parietal cortex. The observed structural differences in grapheme-colour synaesthetes with abnormal additional perceptions may also shed some light on the neural bases of abnormal perceptions in neurological and psychiatric disorders.