Brain - recent issues

Clinical trials for the treatment of spinal cord injury: cervical and lumbar enlargements versus thoracic area

Rahimi-Movaghar, V. — 2009-06-24

Response: Clinical trials for the treatment of spinal cord injury: Cervical and lumbar enlargements versus thoracic area

Mackay-Sim, A. — 2009-06-24

Step training with severely damaged spinal cord

Wernig, A., Wernig, S. — 2009-06-24

Reply: Step training with severely damaged spinal cord

Phelps, P. E., Ramon-Cueto, A., Roy, R. R., Edgerton, V. R. — 2009-06-24

Change in grey matter volume cannot be assumed to be due to cognitive behavioural therapy

Kindlon, T. — 2009-06-24

Reply: Change in grey matter volume cannot be assumed to be due to cognitive behavioural therapy

de Lange, F. P., Bleijenberg, G., van der Meer, J. W. M., Hagoort, P., Toni, I. — 2009-06-24

Editorial

Compston, A. — 2009-06-24

Action recognition in the premotor cortex. By Vittorio Gallese, Luciano Fadiga, Leonardo Fogassi and Giacomo Rizzolatti. Brain 1996: 119; 593-609.

Compston, A. — 2009-06-24

Sodium channelopathy of peripheral nerve: tightening the genotype-phenotype relationship

Schorge, S., Kullmann, D. M. — 2009-06-24

The use of visual feedback, in particular mirror visual feedback, in restoring brain function

Ramachandran, V. S., Altschuler, E. L. — 2009-06-24

This article reviews the potential use of visual feedback, focusing on mirror visual feedback, introduced over 15 years ago, for the treatment of many chronic neurological disorders that have long been regarded as intractable such as phantom pain, hemiparesis from stroke and complex regional pain syndrome. Apart from its clinical importance, mirror visual feedback paves the way for a paradigm shift in the way we approach neurological disorders. Instead of resulting entirely from irreversible damage to specialized brain modules, some of them may arise from short-term functional shifts that are potentially reversible. If so, relatively simple therapies can be devised—of which mirror visual feedback is an example—to restore function.

Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation

2009-06-24

Inherited erythromelalgia (IEM), an autosomal dominant disorder characterized by severe burning pain in response to mild warmth, has been shown to be caused by gain-of-function mutations of sodium channel Na_v1.7 which is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Almost all physiologically characterized cases of IEM have been associated with onset in early childhood. Here, we report the voltage-clamp and current-clamp analysis of a new Na_v1.7 mutation, Q10R, in a patient with clinical onset of erythromelalgia in the second decade. We show that the mutation in this patient hyperpolarizes activation by only –5.3 mV, a smaller shift than seen with early-onset erythromelalgia mutations, but similar to that of I136V, another mutation that is linked to delayed-onset IEM. Using current-clamp, we show that the expression of Q10R induces hyperexcitability in DRG neurons, but produces an increase in excitability that is smaller than the change produced by I848T, an early-onset erythromelalgia mutation. Our analysis suggests a genotype–phenotype relationship at three levels (clinical, cellular and molecular/ion channel), with mutations that produce smaller effects on sodium channel activation being associated with a smaller degree of DRG neuron excitability and later onset of clinical signs.

The pattern and diagnostic criteria of sensory neuronopathy: a case-control study

2009-06-24

Acquired sensory neuronopathies encompass a group of paraneoplastic, dysimmune, toxic or idiopathic disorders characterized by degeneration of peripheral sensory neurons in dorsal root ganglia. As dorsal root ganglia cannot easily be explored, the clinical diagnosis of these disorders may be difficult. The question as to whether there exists a common clinical pattern of sensory neuronopathies, allowing the establishment of validated and easy-to-use diagnostic criteria, has not yet been addressed. In this study, logistic regression was used to construct diagnostic criteria on a retrospective study population of 78 patients with sensory neuronopathies and 56 with other sensory neuropathies. For this, sensory neuronopathy was provisionally considered as unambiguous in 44 patients with paraneoplastic disorder or cisplatin treatment and likely in 34 with a dysimmune or idiopathic setting who may theoretically have another form of neuropathy. To test the homogeneity of the sensory neuronopathy population, likely candidates were compared with unambiguous cases and then the whole population was compared with the other sensory neuropathies population. Criteria accuracy was checked on 37 prospective patients referred for diagnosis of sensory neuropathy. In the study population, sensory neuronopathy showed a common clinical and electrophysiological pattern that was independent of the underlying cause, including unusual forms with only patchy sensory loss, mild electrical motor nerve abnormalities and predominant small fibre or isolated lower limb involvement. Logistic regression allowed the construction of a set of criteria that gave fair results with the following combination: ataxia in the lower or upper limbs + asymmetrical distribution + sensory loss not restricted to the lower limbs + at least one sensory action potential absent or three sensory action potentials <30% of the lower limit of normal in the upper limbs + less than two nerves with abnormal motor nerve conduction study in the lower limbs.

PMP22 expression in dermal nerve myelin from patients with CMT1A

2009-06-24

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a 1.4 Mb duplication on chromosome 17p11.2, which contains the peripheral myelin protein-22 (PMP22) gene. Increased levels of PMP22 in compact myelin of peripheral nerves have been demonstrated and presumed to cause the phenotype of CMT1A. The objective of the present study was to determine whether an extra copy of the PMP22 gene in CMT1A disrupts the normally coordinated expression of PMP22 protein in peripheral nerve myelin and to evaluate PMP22 over-expression in patients with CMT1A and determine whether levels of PMP22 are molecular markers of disease severity. PMP22 expression was measured by taking skin biopsies from patients with CMT1A (n = 20) and both healthy controls (n = 7) and patients with Hereditary Neuropathy with liability to Pressure Palsies (HNPP) (n = 6), in which patients have only a single copy of PMP22. Immunological electron microscopy was performed on the skin biopsies to quantify PMP22 expression in compact myelin. Similar biopsies were analysed by real time PCR to measure PMP22 mRNA levels. Results were also correlated with impairment in CMT1A, as measured by the validated CMT Neuropathy Score. Most, but not all patients with CMT1A, had elevated PMP22 levels in myelin compared with the controls. The levels of PMP22 in CMT1A were highly variable, but not in HNPP or the controls. However, there was no correlation between neurological disabilities and the level of over-expression of PMP22 protein or mRNA in patients with CMT1A. The extra copy of PMP22 in CMT1A results in disruption of the tightly regulated expression of PMP22. Thus, variability of PMP22 levels, rather than absolute level of PMP22, may play an important role in the pathogenesis of CMT1A.

Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy

2009-06-24

Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41–46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings—findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.

Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

2009-06-24

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with l-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.

Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I

2009-06-24

In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3–36 months). The frequency of striatal injury is significantly less in patients diagnosed as asymptomatic newborns by newborn screening. Most previous studies have focused on the onset and mechanism of striatal injury, whereas little is known about neuroradiological abnormalities in pre-symptomatically diagnosed patients and about dynamic changes of extrastriatal abnormalities. Thus, the major aim of the present retrospective study was to improve our understanding of striatal and extrastriatal abnormalities in affected individuals including those diagnosed by newborn screening. To this end, we systematically analysed magnetic resonance imagings (MRIs) in 38 patients with glutaric aciduria type I diagnosed before or after the manifestation of neurological symptoms. To identify brain regions that are susceptible to cerebral injury during acute encephalopathic crises, we compared the frequency of magnetic resonance abnormalities in patients with and without such crises. Major specific changes after encephalopathic crises were found in the putamen (P < 0.001), nucleus caudatus (P < 0.001), globus pallidus (P = 0.012) and ventricles (P = 0.001). Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in both groups (P = 0.544) suggesting that isolated pallidal abnormalities are not induced by acute crises––in contrast to striatal abnormalities. The manifestation of motor disability was associated with signal abnormalities in putamen, caudate, pallidum and ventricles. In addition, we found a large number of extrastriatal abnormalities in patients with and without preceding encephalophatic crises. These abnormalities include widening of anterior temporal and sylvian CSF spaces, pseudocysts, signal changes of substantia nigra, nucleus dentatus, thalamus, tractus tegmentalis centralis and supratentorial white matter as well as signs of delayed maturation (myelination and gyral pattern). In contrast to the striatum, extrastriatal abnormalities were variable and could regress or even normalize with time. This includes widening of sylvian fissures, delayed maturation, pallidal signal changes and pseudocysts. Based on these results, we hypothesize that neuroradiological abnormalities and neurological symptoms in glutaric aciduria type I can be explained by overlaying episodes of cerebral alterations including maturational delay of the brain in utero, acute striatal injury during a vulnerable period in infancy and chronic progressive changes that may continue lifelong. This may have widespread consequences for the pathophysiological understanding of this disease, long-term outcomes and therapeutic considerations.

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease

2009-06-24

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12–12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant -synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5–6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.

Gene expression profiling of substantia nigra dopamine neurons: further insights into Parkinson's disease pathology

2009-06-24

Parkinson's disease is caused by a progressive loss of the midbrain dopamine (DA) neurons in the substantia nigra pars compacta. Although the main cause of Parkinson's disease remains unknown, there is increasing evidence that it is a complex disorder caused by a combination of genetic and environmental factors, which affect key signalling pathways in substantia nigra DA neurons. Insights into pathogenesis of Parkinson's disease stem from in vitro and in vivo models and from postmortem analyses. Recent technological developments have added a new dimension to this research by determining gene expression profiles using high throughput microarray assays. However, many of the studies reported to date were based on whole midbrain dissections, which included cells other than DA neurons. Here, we have used laser microdissection to isolate single DA neurons from the substantia nigra pars compacta of controls and subjects with idiopathic Parkinson's disease matched for age and postmortem interval followed by microarrays to analyse gene expression profiling. Our data confirm a dysregulation of several functional groups of genes involved in the Parkinson's disease pathogenesis. In particular, we found prominent down-regulation of members of the PARK gene family and dysregulation of multiple genes associated with programmed cell death and survival. In addition, genes for neurotransmitter and ion channel receptors were also deregulated, supporting the view that alterations in electrical activity might influence DA neuron function. Our data provide a ‘molecular fingerprint identity’ of late–stage Parkinson's disease DA neurons that will advance our understanding of the molecular pathology of this disease.

Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death

2009-06-24

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by prominent autonomic failure with ataxia and/or parkinsonism. The leading cause of death in MSA is sudden death. We have shown that the early development of autonomic failure is an independent risk factor for sudden death. The depletion of sympathetic preganglionic neurons in the spinal intermediolateral cell column (IML) and its afferent medullary catecholaminergic and serotonergic neurons has been proposed to be partly responsible for autonomic failure in MSA. In this study, we investigated whether the depletion of neurons in any of these autonomic neuron groups contributes to sudden death in MSA. Out of 52 autopsy-proven patients with MSA, we selected 12 individuals who had died within 3.5 years after disease onset to define the accurate levels of slices and identify early neuropathological changes of autonomic nuclei in MSA. Four patients succumbed to sudden death and eight patients died through established causes. Serial 10 µm sections were obtained from the 8th segment of the thoracic cord and the rostral medulla oblongata. Sections from the medulla oblongata were immunostained for thyrosine hydroxylase and tryptophan hydroxylase. The total cell number in the five sections was computed for comparison. Compared with the control, the MSA group showed a marked depletion of neurons in the IML (38.0 ± 7.1 versus 75.2 ± 7.6 cells, P < 0.001), thyrosine hydroxylase-immunoreactive neurons in the ventrolateral medulla (VLM) (17.4 ± 5.1 versus 72.8 ± 13.6 cells, P < 0.01) and tryptophan hydroxylase-immunoreactive neurons in the VLM (15.6 ± 9.2 versus 60.8 ± 17.0 cells, P < 0.01), nucleus raphe obscurus (19.3 ± 4.4 versus 75.3 ± 8.6 cells, P < 0.001), nucleus raphe pallidus (2.1 ± 2.7 versus 9.0 ± 3.4 cells, P < 0.03), and arcuate nucleus (0.4 ± 0.8 versus 2.3 ± 1.5 cells, P < 0.05). Moreover, in patients who succumbed to sudden death, when compared with patients who had established causes of death, we found a marked depletion of tryptophan hydroxylase-immunoreactive neurons in the VLM (7.3 ± 3.5 versus 21.8 ± 6.5 cells, P < 0.02) and nucleus raphe obscurus (15.0 ± 2.0 versus 22.5 ± 2.1 cells, P < 0.01). The results indicate that the spinal IML and medullary catecholaminergic and serotonergic systems are involved even in the early stages of MSA, and the dysfunction of the medullary serotonergic system regulating cardiovascular and respiratory systems could be responsible for sudden death in patients with MSA.

Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease

2009-06-24

It has been established for a long time that brain glucose metabolism is impaired in Alzheimer's disease. Recent studies have demonstrated that impaired brain glucose metabolism precedes the appearance of clinical symptoms, implying its active role in the development of Alzheimer's disease. However, the molecular mechanism by which this impairment contributes to the disease is not known. In this study, we demonstrated that protein O-GlcNAcylation, a common post-translational modification of nucleocytoplasmic proteins with β-N-acetyl-glucosamine and a process regulated by glucose metabolism, was markedly decreased in Alzheimer's disease cerebrum. More importantly, the decrease in O-GlcNAc correlated negatively with phosphorylation at most phosphorylation sites of tau protein, which is known to play a crucial role in the neurofibrillary degeneration of Alzheimer's disease. We also found that hyperphosphorylated tau contained 4-fold less O-GlcNAc than non-hyperphosphorylated tau, demonstrating for the first time an inverse relationship between O-GlcNAcylation and phosphorylation of tau in the human brain. Downregulation of O-GlcNAcylation by knockdown of O-GlcNAc transferase with small hairpin RNA led to increased phosphorylation of tau in HEK-293 cells. Inhibition of the hexosamine biosynthesis pathway in rat brain resulted in decreased O-GlcNAcylation and increased phosphorylation of tau, which resembled changes of O-GlcNAcylation and phosphorylation of tau in rodent brains with decreased glucose metabolism induced by fasting, but not those in rat brains when protein phosphatase 2A was inhibited. Comparison of tau phosphorylation patterns under various conditions suggests that abnormal tau hyperphosphorylation in Alzheimer's disease brain may result from downregulation of both O-GlcNAcylation and protein phosphatase 2A. These findings suggest that impaired brain glucose metabolism leads to abnormal hyperphosphorylation of tau and neurofibrillary degeneration via downregulation of tau O-GlcNAcylation in Alzheimer's disease. Thus, restoration of brain tau O-GlcNAcylation and protein phosphatase 2A activity may offer promising therapeutic targets for treating Alzheimer's disease.

The neural correlates of verbal short-term memory in Alzheimer's disease: an fMRI study

Peters, F., Collette, F., Degueldre, C., Sterpenich, V., Majerus, S., Salmon, E. — 2009-06-24

Although many studies have shown diminished performance in verbal short-term memory tasks in Alzheimer's disease, few studies have explored the neural correlates of impaired verbal short-term memory in Alzheimer's disease patients. In this fMRI study, we examined alterations in brain activation patterns during a verbal short-term memory recognition task, by differentiating encoding and retrieval phases. Sixteen mild Alzheimer's disease patients and 16 elderly controls were presented with lists of four words followed, after a few seconds, by a probe word. Participants had to judge whether the probe matched one of the items of the memory list. In both groups, the short-term memory task elicited a distributed fronto-parieto-temporal activation that encompassed bilateral inferior frontal, insular, supplementary motor, precentral and postcentral areas, consistent with previous studies of verbal short-term memory in young subjects. Most notably, Alzheimer's disease patients showed reduced activation in several regions during the encoding phase, including the bilateral middle frontal and the left inferior frontal gyri (associated with executive control processes) as well as the transverse temporal gyri (associated with phonological processing). During the recognition phase, we found decreased activation in the left supramarginal gyrus and the right middle frontal gyrus in Alzheimer's disease patients compared with healthy seniors, possibly related to deficits in manipulation and decision processes for phonological information. At the same time, Alzheimer's disease patients showed increased activation in several brain areas, including the left parahippocampus and hippocampus, suggesting that Alzheimer's disease patients may recruit alternative recognition mechanisms when performing a short-term memory task. Overall, our results indicate that Alzheimer's disease patients show differences in the functional networks underlying memory over short delays, mostly in brain areas known to support phonological processing or executive functioning.

Anterior thalamic lesions stop synaptic plasticity in retrosplenial cortex slices: expanding the pathology of diencephalic amnesia

2009-06-24

Recent, convergent evidence places the anterior thalamic nuclei at the heart of diencephalic amnesia. However, the reasons for the severe memory loss in diencephalic amnesia remain unknown. A potential clue comes from the dense, reciprocal connections between the anterior thalamic nuclei and retrosplenial cortex, another region vital for memory. We now report a loss of synaptic plasticity [long-term depression (LTD)] in rat retrosplenial cortex slices months following an anterior thalamic lesion. The loss of LTD was lamina-specific, occurring only in superficial layers of the cortex and was associated with a decrease in GABA_A-mediated inhibitory transmission. As retrosplenial cortex is itself vital for memory, this distal lesion effect will amplify the impact of anterior thalamic lesions. These findings not only provide novel insights into the functional pathology of diencephalic amnesia and have implications for the aetiology of the posterior cingulate hypoactivity in Alzheimer's disease, but also show how distal changes in plasticity could contribute to diaschisis.

Increased binding to 5-HT1A and 5-HT2A receptors is associated with large vessel infarction and relative preservation of cognition

2009-06-24

Vascular dementia accounts for ~15–20% of all dementias. In addition, a significant subset of people with Alzheimer's disease have concurrent cerebrovascular disease. Vascular dementia is caused by different cerebrovascular morphological abnormalities including large artery territory infarction (multi-infarct vascular dementia) and sub-cortical ischaemic vascular dementia. Despite this distinction, there is a lack of studies examining the neurochemistry of individual vascular dementia subtypes. Serotonin is believed to play an important role in cognition, and serotonin receptors may provide a novel target for future anti-dementia therapeutics. This study aimed to determine levels of two serotonin receptors in subtypes of vascular dementia and relate any changes to cognition. We have determined, using saturation radioligand binding, the binding parameters (affinity and maximal binding) of (³H)-WAY 100635 binding to 5-HT_1A receptors and (³H)-ketanserin binding to 5-HT_2A receptors in post-mortem tissue from the frontal and temporal cortices of patients with either multi-infarct vascular dementia, sub-cortical ischaemic vascular dementia, mixed Alzheimer's disease/vascular dementia or stroke no dementia (SND). 5-HT_1A and 5-HT_2A receptor binding was significantly increased in the temporal cortex of patients with either multi-infarct vascular dementia or SND, compared to age-matched controls. 5-HT_1A receptor maximal binding in the temporal cortex was also positively correlated with cognition as determined by Mini-Mental State Examination (MMSE) and Cambridge Assessment of Mental Health for the Elderly scores (CAMCOG). These results reveal an important distinction between the neurochemistry of multi-infarct vascular dementia/SND and sub-cortical ischaemic vascular dementia, suggesting that pharmacological manipulation of serotonin offers the possibility to develop novel therapies for stroke and multi-infarct vascular dementia patients. The results also highlight the importance of the cortical 5-HT_1A receptor in mediating cognition.

Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage

2009-06-24

The term cortical spreading depolarization (CSD) describes a wave of mass neuronal depolarization associated with net influx of cations and water. Clusters of prolonged CSDs were measured time-locked to progressive ischaemic damage in human cortex. CSD induces tone alterations in resistance vessels, causing either transient hyperperfusion (physiological haemodynamic response) in healthy tissue; or hypoperfusion [inverse haemodynamic response = cortical spreading ischaemia (CSI)] in tissue at risk for progressive damage, which has so far only been shown experimentally. Here, we performed a prospective, multicentre study in 13 patients with aneurysmal subarachnoid haemorrhage, using novel subdural opto-electrode technology for simultaneous laser-Doppler flowmetry (LDF) and direct current-electrocorticography, combined with measurements of tissue partial pressure of oxygen (ptiO₂). Regional cerebral blood flow and electrocorticography were simultaneously recorded in 417 CSDs. Isolated CSDs occurred in 12 patients and were associated with either physiological, absent or inverse haemodynamic responses. Whereas the physiological haemodynamic response caused tissue hyperoxia, the inverse response led to tissue hypoxia. Clusters of prolonged CSDs were measured in five patients in close proximity to structural brain damage as assessed by neuroimaging. Clusters were associated with CSD-induced spreading hypoperfusions, which were significantly longer in duration (up to 144 min) than those of isolated CSDs. Thus, oxygen depletion caused by the inverse haemodynamic response may contribute to the establishment of clusters of prolonged CSDs and lesion progression. Combined electrocorticography and perfusion monitoring also revealed a characteristic vascular signature that might be used for non-invasive detection of CSD. Low-frequency vascular fluctuations (LF-VF) (f < 0.1 Hz), detectable by functional imaging methods, are determined by the brain's resting neuronal activity. CSD provides a depolarization block of the resting activity, recorded electrophysiologically as spreading depression of high-frequency-electrocorticography activity. Accordingly, we observed a spreading suppression of LF-VF, which accompanied spreading depression of high-frequency-electrocorticography activity, independently of whether CSD was associated with a physiological, absent or inverse haemodynamic response. Spreading suppressions of LF-VF thus allow the differentiation of progressive ischaemia and repair phases in a fashion similar to that shown previously for spreading depressions of high-frequency-electrocorticography activity. In conclusion, it is suggested that (i) CSI is a novel human disease mechanism associated with lesion development and a potential target for therapeutic intervention in stroke; and that (ii) prolonged spreading suppressions of LF-VF are a novel ‘functional marker’ for progressive ischaemia.

Reduced medial temporal lobe functionality in stroke patients: a functional magnetic resonance imaging study

Snaphaan, L., Rijpkema, M., Uden, I. v., Fernandez, G., de Leeuw, F.-E. — 2009-06-24

Stroke is a leading cause of disability, not only because of motor limitations, but also because of the frequent occurrence of post-stroke cognitive impairment. This is illustrated by the fact that the risk of post-stroke dementia is reportedly higher than a recurrent stroke. The loss of subcortical and cortical functions in the post-stroke cognitive dysfunction spectrum is usually well explained by the size and location of the infarction. However, this does not apply for post-stroke memory dysfunction (especially episodic memory dysfunction), as there is almost never an infarction in the medial temporal lobe. Involvement of the medial temporal lobe in post-stroke memory dysfunction seems likely since this structure is essential for memory encoding and retrieval. For a proper episodic memory function, the medial temporal lobe depends on intact connections with virtually the whole brain. Disconnection from other brain areas due to the infarction could lead to a reduced medial temporal lobe function and the attendant reduced episodic memory function. We investigated medial temporal lobe functionality in 28 ‘first-ever’ stroke patients and 22 healthy controls with the aid of functional magnetic resonance imaging. Stroke patients with a reduced episodic memory function 6–8 weeks after infarction had reduced medial temporal lobe functionality. Post-stroke reduced medial temporal lobe functionality may be responsible for the frequent observation of impaired post-stroke episodic memory function. Insight into this mechanism could be helpful in identifying which stroke patients may be at increased risk for developing post-stroke dementia and those who could benefit from early cognitive rehabilitation.

Implicit representation and explicit detection of features in patients with hemispatial neglect

Van Vleet, T. M., Robertson, L. C. — 2009-06-24

Despite profound inattention to the side of space opposite a brain lesion in patients with unilateral neglect, priming studies demonstrate that undetected stimuli are capable of influencing subsequent behaviour. However, the nature of implicit processing of neglected stimuli is poorly understood. In the current study, we examined implicit processing in five patients with neglect using both visual search and priming methods. A psychophysical staircase method varying time of presentation was first used to establish a high (75%) and low (25%) detection probability for targets in both a feature and a conjunction search array. The arrays were then used in a priming task to examine how a difference in the level of overt detection of a feature or a conjunction presented in neglected space influenced subsequent discrimination speed to a single probe presented at fixation. The results showed that priming effects with feature primes were independent of their explicit detection rates (high versus low), but priming effects with conjunction primes reflected the pattern of explicit detection. These findings are discussed as they relate to availability versus accessibility of neglected stimuli.

Changes in cortical grey matter density associated with long-standing retinal visual field defects

2009-06-24

Retinal lesions caused by eye diseases such as glaucoma and age-related macular degeneration can, over time, eliminate stimulation of parts of the visual cortex. This could lead to degeneration of inactive cortical neuronal tissue, but this has not been established in humans. Here, we used magnetic resonance imaging to assess the effects of prolonged sensory deprivation in human visual cortex. High-resolution anatomical magnetic resonance images were obtained in subjects with foveal (age-related macular degeneration) and peripheral (glaucoma) retinal lesions as well as age-matched controls. Comparison of grey matter between patient and control groups revealed density reductions in the approximate retinal lesion projection zones in visual cortex. This indicates that long-term cortical deprivation, due to retinal lesions acquired later in life, is associated with retinotopic-specific neuronal degeneration of visual cortex. Such degeneration could interfere with therapeutic strategies such as the future application of artificial retinal implants to overcome lesion-induced visual impairment.

About the role of visual field defects in pure alexia

2009-06-24

Pure alexia is an acquired reading disorder characterized by a disproportionate prolongation of reading time as a function of word length. Although the vast majority of cases reported in the literature show a right-sided visual defect, little is known about the contribution of this low-level visual impairment to their reading difficulties. The present study was aimed at investigating this issue by comparing eye movement patterns during text reading in six patients with pure alexia with those of six patients with hemianopic dyslexia showing similar right-sided visual field defects. We found that the role of the field defect in the reading difficulties of pure alexics was highly deficit-specific. While the amplitude of rightward saccades during text reading seems largely determined by the restricted visual field, other visuo-motor impairments—particularly the pronounced increases in fixation frequency and viewing time as a function of word length—may have little to do with their visual field defect. In addition, subtracting the lesions of the hemianopic dyslexics from those found in pure alexics revealed the largest group differences in posterior parts of the left fusiform gyrus, occipito-temporal sulcus and inferior temporal gyrus. These regions included the coordinate assigned to the centre of the visual word form area in healthy adults, which provides further evidence for a relation between pure alexia and a damaged visual word form area. Finally, we propose a list of three criteria that may improve the differential diagnosis of pure alexia and allow appropriate therapy recommendations.

Neural processing of spoken words in specific language impairment and dyslexia

Helenius, P., Parviainen, T., Paetau, R., Salmelin, R. — 2009-06-24

Young adults with a history of specific language impairment (SLI) differ from reading-impaired (dyslexic) individuals in terms of limited vocabulary and poor verbal short-term memory. Phonological short-term memory has been shown to play a significant role in learning new words. We investigated the neural signatures of auditory word recognition and word repetition in young adults with SLI, dyslexia and normal language development using magnetoencephalography. The stimuli were 7-8 letter spoken real words and pseudo-words. They evoked a transient peak at 100 ms (N100m) followed by longer-lasting activation peaking around 400 ms (N400m) in the left and right superior temporal cortex. Both word repetition (first vs. immediately following second presentation) and lexicality (words vs. pseudowords) modulated the N400m response. An effect of lexicality was detected about 400 ms onwards as activation culminated for words but continued for pseudo-words. This effect was more pronounced in the left than right hemisphere in the control subjects. The left hemisphere lexicality effect was also present in the dyslexic adults, but it was non-significant in the subjects with SLI, possibly reflecting their limited vocabulary. The N400m activation between 200 and 700 ms was attenuated by the immediate repetition of words and pseudo-words in both hemispheres. In SLI adults the repetition effect evaluated at 200–400 ms was abnormally weak. This finding suggests impaired short-term maintenance of linguistic activation that underlies word recognition. Furthermore, the size of the repetition effect decreased from control subjects through dyslexics to SLIs, i.e. when advancing from milder to more severe language impairment. The unusually rapid decay of speech-evoked activation could have a detrimental role on vocabulary growth in children with SLI.

Enhanced activation of the left inferior frontal gyrus in deaf and dyslexic adults during rhyming

MacSweeney, M., Brammer, M. J., Waters, D., Goswami, U. — 2009-06-24

Hearing developmental dyslexics and profoundly deaf individuals both have difficulties processing the internal structure of words (phonological processing) and learning to read. In hearing non-impaired readers, the development of phonological representations depends on audition. In hearing dyslexics, many argue, auditory processes may be impaired. In congenitally profoundly deaf individuals, auditory speech processing is essentially absent. Two separate literatures have previously reported enhanced activation in the left inferior frontal gyrus in both deaf and dyslexic adults when contrasted with hearing non-dyslexics during reading or phonological tasks. Here, we used a rhyme judgement task to compare adults from these two special populations to a hearing non-dyslexic control group. All groups were matched on non-verbal intelligence quotient, reading age and rhyme performance. Picture stimuli were used since this requires participants to generate their own phonological representations, rather than have them partially provided via text. By testing well-matched groups of participants on the same task, we aimed to establish whether previous literatures reporting differences between individuals with and without phonological processing difficulties have identified the same regions of differential activation in these two distinct populations. The data indicate greater activation in the deaf and dyslexic groups than in the hearing non-dyslexic group across a large portion of the left inferior frontal gyrus. This includes the pars triangularis, extending superiorly into the middle frontal gyrus and posteriorly to include the pars opercularis, and the junction with the ventral precentral gyrus. Within the left inferior frontal gyrus, there was variability between the two groups with phonological processing difficulties. The superior posterior tip of the left pars opercularis, extending into the precentral gyrus, was activated to a greater extent by deaf than dyslexic participants, whereas the superior posterior portion of the pars triangularis extending into the ventral pars opercularis, was activated to a greater extent by dyslexic than deaf participants. Whether these regions play differing roles in compensating for poor phonological processing is not clear. However, we argue that our main finding of greater inferior frontal gyrus activation in both groups with phonological processing difficulties in contrast to controls suggests greater reliance on the articulatory component of speech during phonological processing when auditory processes are absent (deaf group) or impaired (dyslexic group). Thus, the brain appears to develop a similar solution to a processing problem that has different antecedents in these two populations.

Neural correlates of pragmatic language comprehension in autism spectrum disorders

2009-06-24

Difficulties with pragmatic aspects of communication are universal across individuals with autism spectrum disorders (ASDs). Here we focused on an aspect of pragmatic language comprehension that is relevant to social interaction in daily life: the integration of speaker characteristics inferred from the voice with the content of a message. Using functional magnetic resonance imaging (fMRI), we examined the neural correlates of the integration of voice-based inferences about the speaker's age, gender or social background, and sentence content in adults with ASD and matched control participants. Relative to the control group, the ASD group showed increased activation in right inferior frontal gyrus (RIFG; Brodmann area 47) for speaker-incongruent sentences compared to speaker-congruent sentences. Given that both groups performed behaviourally at a similar level on a debriefing interview outside the scanner, the increased activation in RIFG for the ASD group was interpreted as being compensatory in nature. It presumably reflects spill-over processing from the language dominant left hemisphere due to higher task demands faced by the participants with ASD when integrating speaker characteristics and the content of a spoken sentence. Furthermore, only the control group showed decreased activation for speaker-incongruent relative to speaker-congruent sentences in right ventral medial prefrontal cortex (vMPFC; Brodmann area 10), including right anterior cingulate cortex (ACC; Brodmann area 24/32). Since vMPFC is involved in self-referential processing related to judgments and inferences about self and others, the absence of such a modulation in vMPFC activation in the ASD group possibly points to atypical default self-referential mental activity in ASD. Our results show that in ASD compensatory mechanisms are necessary in implicit, low-level inferential processes in spoken language understanding. This indicates that pragmatic language problems in ASD are not restricted to high-level inferential processes, but encompass the most basic aspects of pragmatic language processing.

Hemispheric competence for auditory spatial representation

Spierer, L., Bellmann-Thiran, A., Maeder, P., Murray, M. M., Clarke, S. — 2009-06-24

Sound localization relies on the analysis of interaural time and intensity differences, as well as attenuation patterns by the outer ear. We investigated the relative contributions of interaural time and intensity difference cues to sound localization by testing 60 healthy subjects: 25 with focal left and 25 with focal right hemispheric brain damage. Group and single-case behavioural analyses, as well as anatomo-clinical correlations, confirmed that deficits were more frequent and much more severe after right than left hemispheric lesions and for the processing of interaural time than intensity difference cues. For spatial processing based on interaural time difference cues, different error types were evident in the individual data. Deficits in discriminating between neighbouring positions occurred in both hemispaces after focal right hemispheric brain damage, but were restricted to the contralesional hemispace after focal left hemispheric brain damage. Alloacusis (perceptual shifts across the midline) occurred only after focal right hemispheric brain damage and was associated with minor or severe deficits in position discrimination. During spatial processing based on interaural intensity cues, deficits were less severe in the right hemispheric brain damage than left hemispheric brain damage group and no alloacusis occurred. These results, matched to anatomical data, suggest the existence of a binaural sound localization system predominantly based on interaural time difference cues and primarily supported by the right hemisphere. More generally, our data suggest that two distinct mechanisms contribute to: (i) the precise computation of spatial coordinates allowing spatial comparison within the contralateral hemispace for the left hemisphere and the whole space for the right hemisphere; and (ii) the building up of global auditory spatial representations in right temporo-parietal cortices.

Evaluation of evoked potentials to dyadic tones after cochlear implantation

2009-06-24

Auditory evoked potentials are tools widely used to assess auditory cortex functions in clinical context. However, in cochlear implant users, electrophysiological measures are challenging due to implant-created artefacts in the EEG. Here, we used independent component analysis to reduce cochlear implant-related artefacts in event-related EEGs of cochlear implant users (n = 12), which allowed detailed spatio-temporal evaluation of auditory evoked potentials by means of dipole source analysis. The present study examined hemispheric asymmetries of auditory evoked potentials to musical sounds in cochlear implant users to evaluate the effect of this type of implantation on neuronal activity. In particular, implant users were presented with two dyadic tonal intervals in an active oddball design and in a passive listening condition. Principally, the results show that independent component analysis is an efficient approach that enables the study of neurophysiological mechanisms of restored auditory function in cochlear implant users. Moreover, our data indicate altered hemispheric asymmetries for dyadic tone processing in implant users compared with listeners with normal hearing (n = 12). We conclude that the evaluation of auditory evoked potentials are of major relevance to understanding auditory cortex function after cochlear implantation and could be of substantial clinical value by indicating the maturation/reorganization of the auditory system after implantation.

Encoding of human action in Broca's area

2009-06-24

Broca's area has been considered, for over a century, as the brain centre responsible for speech production. Modern neuroimaging and neuropsychological evidence have suggested a wider functional role is played by this area. In addition to the evidence that it is involved in syntactical analysis, mathematical calculation and music processing, it has recently been shown that Broca's area may play some role in language comprehension and, more generally, in understanding actions of other individuals. As shown by functional magnetic resonance imaging, Broca's area is one of the cortical areas activated by hand/mouth action observation and it has been proposed that it may form a crucial node of a human mirror-neuron system. If, on the one hand, neuroimaging studies use a correlational approach which cannot offer a final proof for such claims, available neuropsychological data fail to offer a conclusive demonstration for two main reasons: (i) they use tasks taxing both language and action systems; and (ii) they rarely consider the possibility that Broca's aphasics may also be affected by some form of apraxia. We administered a novel action comprehension test—with almost no linguistic requirements—on selected frontal aphasic patients lacking apraxic symptoms. Patients, as well as matched controls, were shown short movies of human actions or of physical events. Their task consisted of ordering, in a temporal sequence, four pictures taken from each movie and randomly presented on the computer screen. Patient's performance showed a specific dissociation in their ability to re-order pictures of human actions (impaired) with respect to physical events (spared). Our study provides a demonstration that frontal aphasics, not affected by apraxia, are specifically impaired in their capability to correctly encode observed human actions.

Another way to understand

Freund, H.-J. — 2009-06-24

Erratum

2009-06-24

Subcortical damage and white matter disconnection associated with non-fluent speech

Bonilha, L., Fridriksson, J. — 2009-05-24

Clinical features and natural history of neuroferritinopathy caused by the 458dupA FTL mutation

2009-05-24

Can CBT substantially change grey matter volume in chronic fatigue syndrome?

Bramsen, I. — 2009-05-24

Reply to: can CBT substantially change grey matter volume in chronic fatigue syndrome?

2009-05-24

Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study

VanDenBrink, A. M., Duncker, D. J., Saxena, P. R. — 2009-05-24

Reply to: Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study

Schoonman, G. G., Ferrari, M. D. — 2009-05-24

Ravel's last illness: a unifying hypothesis

Warren, J. D., Rohrer, J. D. — 2009-05-24

Editorial

Compston, A. — 2009-05-24

Evaluation and management of gliomas of the anterior visual pathways, by N. R. Miller, W. J. Iliff and W. R. Green (From the Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD, USA) Brain 1974: 97; 743-754; and The biological and clinical behaviour of pilocytic astrocytomas of the optic pathways, by Adam Borit and Edward P. Richardson Jr (From the CS Kubik Laboratory for Neuropathology of the Department of Pathology and the Neurology service of the Massachusetts General Hospital, the Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, and the Departments of Neurology-Neuropathology, Ophthalmology and Pathology, Harvard Medical School, Boston, MA, USA) Brain 1982: 105; 161-187.

Compston, A. — 2009-05-24

Recovery from spinal cord injury: regeneration, plasticity and rehabilitation

Fawcett, J. W. — 2009-05-24

Morphing voxels: the hype around structural imaging of headache patients

May, A. — 2009-05-24

Neuroimaging analysis using structural data has begun to provide insights into the pathophysiology of headache syndromes. Several independent studies have suggested a decrease in grey matter in pain-transmitting areas in migraine patients. Most of these data are discussed as damage or loss of brain grey matter, reinforcing the idea of migraine as a progressive disease. However, given what we know about the nature of morphometric changes detectable by the methods we have to date, this interpretation is highly speculative and not supported by the data. It is likely that these changes are the consequence and not the cause of the respective headache syndromes, as they are probably not irreversible and only mirror the proportion or duration of pain suffered. Moreover, structural changes are not headache specific and have to be seen in the light of a wealth of pain studies using these methods. The studies in cluster headache patients prompted the use of stereotactic stimulation of the hypothalamic target point identified by functional and structural neuroimaging. Due to the nature of the methods used and due to a high anatomical variance it is more than questionable to use this point as a definite answer to the source of the headache in clusters and even more so when it is uncritically used in individuals. We need a way to study each patient individually using the functional imaging method with the highest spatial and temporal resolution available to enable us to target the seed point for deep brain stimulation on this individual basis. One of the major future challenges is to understand the behavioural consequences and cellular mechanisms underlying neuroanatomic changes in pain and headache.

Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury

2009-05-24

Locomotor training on treadmills can improve recovery of stepping in spinal cord injured animals and patients. Likewise, lesioned rats treated with antibodies against the myelin associated neurite growth inhibitory protein, Nogo-A, showed increased regeneration, neuronal reorganization and behavioural improvements. A detailed kinematic analysis showed that the hindlimb kinematic patterns that developed in anti-Nogo-A antibody treated versus treadmill trained spinal cord injured rats were significantly different. The synchronous combined treatment group did not show synergistic effects. This lack of synergistic effects could not be explained by an increase in pain perception, sprouting of calcitonin gene-related peptide (CGRP) positive fibres or by interference of locomotor training with anti-Nogo-A antibody induced regeneration and sprouting of descending fibre tracts. The differential mechanisms leading to behavioural recovery during task-specific training and in regeneration or plasticity enhancing therapies have to be taken into account in designing combinatorial therapies so that their potential positive interactive effects can be fully expressed.

Sensory capacity of reinnervated skin after redirection of amputated upper limb nerves to the chest

Marasco, P. D., Schultz, A. E., Kuiken, T. A. — 2009-05-24

Targeted reinnervation is a new neural-machine interface that has been developed to help improve the function of new-generation prosthetic limbs. Targeted reinnervation is a surgical procedure that takes the nerves that once innervated a severed limb and redirects them to proximal muscle and skin sites. The sensory afferents of the redirected nerves reinnervate the skin overlying the transfer site. This creates a sensory expression of the missing limb in the amputee's reinnervated skin. When these individuals are touched on this reinnervated skin they feel as though they are being touched on their missing limb. Targeted reinnervation takes nerves that once served the hand, a skin region of high functional importance, and redirects them to less functionally relevant skin areas adjacent to the amputation site. In an effort to better understand the sensory capacity of the reinnervated target skin following this procedure, we examined grating orientation thresholds and point localization thresholds on two amputees who had undergone the targeted reinnervation surgery. Grating orientation thresholds and point localization thresholds were also measured on the contralateral normal skin of the targeted reinnervation amputees and on analogous sites in able-bodied controls. Grating orientation thresholds for the reinnervated skin of the targeted reinnervation amputees were found to be similar to normal ranges for both the amputees’ contralateral skin and also for the control population. Point localization thresholds for these amputees were found to be lower for their reinnervated skin than for their contralateral skin. Reinnervated point localization thresholds values were also lower in comparison to homologous chest sites on the control population. Mechanisms appear to be in place to maximize re-established touch input in targeted reinnervation amputees. It seems that sound sensory function is provided to the denervated skin of the residual limb when connected to afferent pathways once serving highly functionally relevant regions of the brain. This suggests that tactile interface devices could be used to give a physiologically appropriate sense of touch to a prosthetic limb, which would likely help with better functional utilization of the prosthetic device and possibly help to more effectively integrate the device with the user's self-image.

Polysialic acid glycomimetics promote myelination and functional recovery after peripheral nerve injury in mice

2009-05-24

2,8 Polysialic acid (PSA) is a carbohydrate attached to the glycoprotein backbone of the neural cell adhesion molecule (NCAM) and implicated in nervous system development and repair. Here, we investigated whether PSA can improve functional recovery after peripheral nerve lesion in adult mice. We applied a functional PSA mimicking peptide or a control peptide in a polyethylene cuff used to surgically reconnect the severed stumps of the femoral nerve before it bifurcates into the motor and sensory branches. Using video-based motion analysis to monitor motor recovery over a 3 month postoperative period, we observed a better functional outcome in the PSA mimetic-treated than in control mice receiving a control peptide or phosphate buffered saline. Retrograde tracing of regenerated motoneurons and morphometric analyses showed that motoneuron survival, motoneuron soma size and axonal diameters were not affected by treatment with the PSA mimetic. However, remyelination of regenerated axons distal to the injury site was considerably improved by the PSA mimetic indicating that effects on Schwann cells in the denervated nerve may underlie the functional effects seen in motor recovery. In line with this notion was the observation that the PSA mimetic enhanced the elongation of Schwann cell processes and Schwann cell proliferation in vitro, when compared with the control peptide. Moreover, Schwann cell proliferation in vivo was enhanced in both motor and sensory branches of the femoral nerve by application of the PSA mimetic. These effects were likely mediated by NCAM through its interaction with the fibroblast growth factor receptor (FGFR), since they were not observed when the PSA mimetic was applied to NCAM-deficient Schwann cells, and since application of two different FGFR inhibitors reduced process elongation from Schwann cells in vitro. Our results indicate the potential of PSA mimetics as therapeutic agents promoting motor recovery and myelination after peripheral nerve injury.

Motor cortex stimulation for the treatment of refractory peripheral neuropathic pain

2009-05-24

Epidural motor cortex stimulation (MCS) has been proposed as a treatment for chronic, drug-resistant neuropathic pain of various origins. Regarding pain syndromes due to peripheral nerve lesion, only case series have previously been reported. We present the results of the first randomized controlled trial using chronic MCS in this indication. Sixteen patients were included with pain origin as follows: trigeminal neuralgia (n = 4), brachial plexus lesion (n = 4), neurofibromatosis type-1 (n = 3), upper limb amputation (n = 2), herpes zoster ophthalmicus (n = 1), atypical orofacial pain secondary to dental extraction (n = 1) and traumatic nerve trunk transection in a lower limb (n = 1). A quadripolar lead was implanted, under radiological and electrophysiological guidance, for epidural cortical stimulation. A randomized crossover trial was performed between 1 and 3 months postoperative, during which the stimulator was alternatively switched ‘on’ and ‘off’ for 1 month, followed by an open phase during which the stimulator was switched ‘on’ in all patients. Clinical assessment was performed up to 1 year after implantation and was based on the following evaluations: visual analogue scale (VAS), brief pain inventory, McGill Pain questionnaire, sickness impact profile and medication quantification scale. The crossover trial included 13 patients and showed a reduction of the McGill Pain questionnaire-pain rating index (P = 0.0166, Wilcoxon test) and McGill Pain questionnaire sensory subscore (P = 0.01) when the stimulator was switched ‘on’ compared to the ‘off-stimulation’ condition. However, these differences did not persist after adjustment for multiple comparisons. In the 12 patients who completed the open study, the VAS and sickness impact profile scores varied significantly in the follow-up and were reduced at 9–12 months postoperative, compared to the preoperative baseline. At final examination, the mean rate of pain relief on VAS scores was 48% (individual results ranging from 0% to 95%) and MCS efficacy was considered as good or satisfactory in 60% of the patients. Pain relief after 1 year tended to correlate with pain scores at 1 month postoperative, but not with age, pain duration or location, preoperative pain scores or sensory-motor status. Although the results of the crossover trial were slightly negative, which may have been due to carry-over effects from the operative and immediate postoperative phases, observations made during the open trial were in favour of a real efficacy of MCS in peripheral neuropathic pain. Analgesic effects were obtained on the sensory-discriminative rather than on the affective aspect of pain. These results suggest that the indication of MCS might be extended to various types of refractory, chronic peripheral pain beyond trigeminal neuropathic pain.

Bilateral widespread mechanical pain sensitivity in carpal tunnel syndrome: evidence of central processing in unilateral neuropathy

2009-05-24

The aim of this study was to investigate whether bilateral widespread pressure hypersensitivity exists in patients with unilateral carpal tunnel syndrome. A total of 20 females with carpal tunnel syndrome (aged 22–60 years), and 20 healthy matched females (aged 21–60 years old) were recruited. Pressure pain thresholds were assessed bilaterally over median, ulnar, and radial nerve trunks, the C5–C6 zygapophyseal joint, the carpal tunnel and the tibialis anterior muscle in a blinded design. The results showed that pressure pain threshold levels were significantly decreased bilaterally over the median, ulnar, and radial nerve trunks, the carpal tunnel, the C5–C6 zygapophyseal joint, and the tibialis anterior muscle in patients with unilateral carpal tunnel syndrome as compared to healthy controls (all, P < 0.001). Pressure pain threshold was negatively correlated to both hand pain intensity and duration of symptoms (all, P < 0.001). Our findings revealed bilateral widespread pressure hypersensitivity in subjects with carpal tunnel syndrome, which suggest that widespread central sensitization is involved in patients with unilateral carpal tunnel syndrome. The generalized decrease in pressure pain thresholds associated with pain intensity and duration of symptoms supports a role of the peripheral drive to initiate and maintain central sensitization. Nevertheless, both central and peripheral sensitization mechanisms are probably involved at the same time in carpal tunnel syndrome.

Selective adenosine A2a receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemia

2009-05-24

Adenosine is a potent biological mediator, the concentration of which increases dramatically following brain ischaemia. During ischaemia, adenosine is in a concentration range (µM) that stimulates all four adenosine receptor subtypes (A₁, A_2A, A_2B and A₃). In recent years, evidence has indicated that the A_2A receptor subtype is of critical importance in stroke. We have previously shown that 24 h after medial cerebral artery occlusion (MCAo), A_2A receptors up-regulate on neurons and microglia of ischaemic striatum and cortex and that subchronically administered adenosine A_2A receptor antagonists protect against brain damage and neurological deficit and reduce activation of p38 mitogen-activated protein kinase (MAPK) in microglial cells. The mechanisms by which A_2A receptors are noxious during ischaemia still remain elusive. The objective of the present study was to investigate whether the adenosine A_2A antagonist SCH58261 affects JNK and MEK1/ERK MAPK activation. A further aim was to investigate cell types expressing activated JNK and MEK1/ERK MAPK after ischaemia. We hereby report that the selective adenosine A_2A receptor antagonist, SCH58261, administered subchronically (0.01 mg/kg i.p) 5 min, 6 and 20 h after MCAo in male Wistar rats, reduced JNK MAPK activation (immunoblot analysis: phospho-JNK54 isoform by 81% and phospho-JNK46 isoform by 60%) in the ischaemic striatum. Twenty-four hours after MCAo, the Olig2 transcription factor of oligodendroglial progenitor cells and mature oligodendrocytes was highly expressed in cell bodies in the ischaemic striatum. Immunofluorescence staining showed that JNK MAPK is maximally expressed in Olig2-stained oligodendrocytes and in a few NeuN stained neurons. Striatal cell fractioning into nuclear and extra-nuclear fractions demonstrated the presence of Olig2 transcription factor and JNK MAPK in both fractions. The A_2A antagonist reduced striatal Olig 2 transcription factor (immunoblot analysis: by 55%) and prevented myelin disorganization, assessed by myelin-associated glycoprotein staining. Twenty-four hours after MCAo, ERK1/2 MAPK was highly activated in the ischaemic striatum, mostly in microglia, while it was reduced in the ischaemic cortex. The A_2A antagonist did not affect activation of the ERK1/2 pathway. The efficacy of A_2A receptor antagonism in reducing activation of JNK MAPK in oligodendrocytes suggests a mechanism of protection consisting of scarring oligodendrocyte inhibitory molecules that can hinder myelin reconstitution and neuron functionality.

The effect of N-acetyl-aspartyl-glutamate and N-acetyl-aspartate on white matter oligodendrocytes

Kolodziejczyk, K., Hamilton, N. B., Wade, A., Karadottir, R., Attwell, D. — 2009-05-24

Elevations of the levels of N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) are associated with myelin loss in the leucodystrophies Canavan's disease and Pelizaeus-Merzbacher-like disease. NAAG and NAA can activate and antagonize neuronal N-methyl-D-aspartate (NMDA) receptors, and also act on group II metabotropic glutamate receptors. Oligodendrocytes and their precursors have recently been shown to express NMDA receptors, and activation of these receptors in ischaemia leads to the death of oligodendrocyte precursors and the loss of myelin. This raises the possibility that the failure to develop myelin, or demyelination, occurring in the leucodystrophies could reflect an action of NAAG or NAA on oligodendrocyte NMDA receptors. However, since the putative subunit composition of NMDA receptors on oligodendrocytes differs from that of neuronal NMDA receptors, the effects of NAAG and NAA on them are unknown. We show that NAAG, but not NAA, evokes an inward membrane current in cerebellar white matter oligodendrocytes, which is reduced by NMDA receptor block (but not by block of metabotropic glutamate receptors). The size of the current evoked by NAAG, relative to that evoked by NMDA, was much smaller in oligodendrocytes than in neurons, and NAAG induced a rise in [Ca²⁺]_i in neurons but not in oligodendrocytes. These differences in the effect of NAAG on oligodendrocytes and neurons may reflect the aforementioned difference in receptor subunit composition. In addition, as a major part of the response in oligodendrocytes was blocked by tetrodotoxin (TTX), much of the NAAG-evoked current in oligodendrocytes is a secondary consequence of activating neuronal NMDA receptors. Six hours exposure to 1 mM NAAG did not lead to the death of cells in the white matter. We conclude that an action of NAAG on oligodendrocyte NMDA receptors is unlikely to be a major contributor to white matter damage in the leucodystrophies.

Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death

2009-05-24

Although inhibition of the epidermal growth factor receptor is a plausible therapy for malignant gliomas that, in vitro, enhances apoptosis, the results of clinical trials have been disappointing. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates starvation signals and generates adaptive responses that aim at the maintenance of energy homeostasis. Antagonism of mTOR has been suggested as a strategy to augment the efficacy of epidermal growth factor receptor inhibition by interfering with deregulated signalling cascades downstream of Akt. Here we compared effects of antagonism of mTOR utilizing rapamycin or a small hairpin RNA-mediated gene silencing to those of epidermal growth factor receptor inhibition or combined inhibition of epidermal growth factor receptor and mTOR in human malignant glioma cells. In contrast to epidermal growth factor receptor inhibition, mTOR antagonism neither induced cell death nor enhanced apoptosis induced by CD95 ligand or chemotherapeutic drugs. However, mTOR inhibition mimicked the hypoxia-protective effects of epidermal growth factor receptor inhibition by maintaining adenosine triphosphate levels. These in vitro experiments thus challenge the current view of mTOR as a downstream target of Akt that mediates antiapoptotic stimuli. Under the conditions of the tumour microenvironment, metabolic effects of inhibition of epidermal growth factor receptor, Akt and mTOR may adversely affect outcome by protecting the hypoxic tumour cell fraction.

Pilocytic astrocytoma of the optic pathway: a tumour deriving from radial glia cells with a specific gene signature

2009-05-24

Pilocytic astrocytomas are WHO grade I gliomas that occur predominantly in childhood. They share features of both astroglial and oligodendroglial lineages. These tumours affect preferentially the cerebellum (benign clinical course) and the optic pathway, especially the hypothalamo–chiasmatic region (poor prognosis). Understanding the molecular basis responsible for the aggressive behaviour of hypothalamo–chiasmatic pilocytic astrocytomas is a prerequisite to setting up new molecular targeted therapies. We used the microarray technique to compare the transcriptional profiles of five hypothalamo–chiasmatic and six cerebellar pilocytic astrocytomas. Validation of the microarray results and comparison of the tumours with normal developing tissue was done by quantitative real-time PCR and immunohistochemistry. Results demonstrate that cerebellar and hypothalamo–chiasmatic pilocytic astrocytomas are two genetically distinct and topography-dependent entities. Numerous genes upregulated in hypothalamo–chiasmatic pilocytic astrocytomas also increased in the developing chiasm, suggesting that developmental genes mirror the cell of origin whereas migrative, adhesive and proliferative genes reflect infiltrative properties of these tumours. Of particular interest, NOTCH2, a gene expressed in radial glia and involved in gliomagenesis, was upregulated in hypothalamo–chiasmatic pilocytic astrocytomas. In order to find progenitor cells that could give rise to hypothalamo-chiasmatic pilocytic astrocytomas, we performed a morphological study of the hypothalamo–chiasmatic region and identified, in the floor of the third ventricle, a unique population of vimentin- and glial fibrillary acidic protein-positive cells highly suggestive of radial glia cells. Therefore, pilocytic astrocytomas of the hypothalamo–chiasmatic region should be considered as a distinct entity which probably originates from a unique population of cells with radial glia phenotype.

Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis

2009-05-24

Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture ≥10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients’ total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA⁺CD62L cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and B-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions (Clinical Trials. Gov NCT00079768).

Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease

Vissing, J., Duno, M., Schwartz, M., Haller, R. G. — 2009-05-24

Over 100 mutations in the myophosphorylase gene, which cause McArdle disease, are known. All these mutations have resulted in a complete block of muscle glycogenolysis, and accordingly, no genotype–phenotype correlation has been identified in this condition. We evaluated physiologic and genetic features of two patients with a variant form of McArdle disease, associated with unusually high exercise capacity. Physiologic findings were compared to those in 47 patients with typical McArdle disease, and 17 healthy subjects. Subjects performed an ischaemic forearm exercise test to assess lactate and ammonia production. Peak oxidative capacity (VO2max) and cardiac output were determined, using cycle ergometry as the exercise modality. The two patients with atypical McArdle disease carried common mutations on one allele (R50X and G205S), and novel splice mutations in introns 3 [IVS3-26A>G (c.425-26A>G)] and 5 [IVS5-601G>A (c.856-601G>A)] on the other allele. Plasma lactate after ischaemic exercise decreased in all typical McArdle patients, but increased in the two atypical McArdle patients (10% of that in healthy subjects). Peak workload and oxidative capacity were 2-fold higher in patients with atypical McArdle disease compared to typical McArdle patients. Oxygen uptake, relative to cardiac output, was severely impaired in the 47 patients with typical McArdle disease, and partially normalized in the milder affected McArdle patients. These findings identify the first distinct genotype-phenotype relationship in McArdle disease, and indicate that minimal myophosphorylase activity ameliorates the typical McArdle disease phenotype by augmenting muscle oxidative capacity. The milder form of McArdle disease provides important clues to the level of functional myophosphorylase needed to support muscle oxidative metabolism.

Recessive twinkle mutations cause severe epileptic encephalopathy

Lonnqvist, T., Paetau, A., Valanne, L., Pihko, H. — 2009-05-24

The C10orf2 gene encodes the mitochondrial DNA helicase Twinkle, which is one of the proteins important for mitochondrial DNA maintenance. Dominant mutations cause multiple mitochondrial DNA deletions and progressive external ophthalmoplegia, but recent findings associate recessive mutations with mitochondrial DNA depletion and encephalopathy or hepatoencephalopathy. The latter clinical phenotypes resemble those associated with recessive POLG1 mutations. We have previously described patients with infantile onset spinocerebellar ataxia (MIM271245) caused either by homozygous (Y508C) or compound heterozygous (Y508C and A318T) Twinkle mutations. Our earlier reports focused on the spinocerebellar degeneration, but the 20-year follow-up of 23 patients has shown that refractory status epilepticus, migraine-like headaches and severe psychiatric symptoms are also pathognomonic for the disease. All adolescent patients have experienced phases of severe migraine, and seven patients had antipsychotic medication. Epilepsia partialis continua occurred in 15 patients leading to generalized epileptic statuses in 13 of them. Eight of these patients have died. Valproate treatment was initiated on two patients, but had to be discontinued because of a severe elevation of liver enzymes. The patients recovered, and we have not used valproate in infantile onset spinocerebellar ataxia since. The first status epilepticus manifested between 15 and 34 years of age in the homozygotes, and at 2 and 4 years in the compound heterozygotes. The epileptic statuses lasted from several days to weeks. Focal, stroke-like lesions were seen in magnetic resonance imaging, but in infantile onset spinocerebellar ataxia these lesions showed no predilection. They varied from resolving small cortical to large hemispheric oedematous lesions, which reached from cerebral cortex to basal ganglia and thalamus and caused permanent necrotic damage and brain atrophy. Brain atrophy with focal laminar cortical necrosis and hippocampal damage was confirmed on neuropathological examination. The objective of our study was to describe the development and progression of encephalopathy in infantile onset spinocerebellar ataxia syndrome, and compare the pathognomonic features with those in other mitochondrial encephalopathies.

Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females

2009-05-24

Mutations in the X-linked aristaless-related homeobox gene (ARX) have been linked to structural brain anomalies as well as multiple neurocognitive deficits. The generation of Arx-deficient mice revealed several morphological anomalies, resembling those observed in patients and an interneuron migration defect but perinatal lethality precluded analyses of later phenotypes. Interestingly, many of the neurological phenotypes observed in patients with various ARX mutations can be attributed, in part, to interneuron dysfunction. To directly test this possibility, mice carrying a floxed Arx allele were generated and crossed to Dlx5/6^CRE-IRES-GFP(Dlx5/6^CIG) mice, conditionally deleting Arx from ganglionic eminence derived neurons including cortical interneurons. We now report that Arx^–/y;Dlx5/6^CIG (male) mice exhibit a variety of seizure types beginning in early-life, including seizures that behaviourally and electroencephalographically resembles infantile spasms, and show evolution through development. Thus, this represents a new genetic model of a malignant form of paediatric epilepsy, with some characteristics resembling infantile spasms, caused by mutations in a known infantile spasms gene. Unexpectedly, approximately half of the female mice carrying a single mutant Arx allele (Arx^–/+;Dlx5/6^CIG) also developed seizures. We also found that a subset of human female carriers have seizures and neurocognitive deficits. In summary, we have identified a previously unrecognized patient population with neurological deficits attributed to ARX mutations that are recapitulated in our mouse model. Furthermore, we show that perturbation of interneuron subpopulations is an important mechanism underling the pathogenesis of developmental epilepsy in both hemizygous males and carrier females. Given the frequency of ARX mutations in patients with infantile spasms and related disorders, our data unveil a new model for further understanding the pathogenesis of these disorders.

Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study

2009-05-24

A population-based, cross-sectional study was performed in southeast Norway, between January 2002 and February 2008, to identify subjects with hereditary ataxia and hereditary spastic paraplegia, and to estimate the prevalence of these disorders. Patients were recruited through colleagues, families, searches in computerized hospital archives and the National Patients’ Association for Hereditary Ataxia and Spastic Paraplegia. Strict criteria were used for inclusion of familial and isolated subjects. A project neurologist examined all index subjects and clinical and genetic data were registered. The source population on January 1, 2008 was 2.63 million and the prevalence day was set as February 1, 2008. One hundred seventy-one subjects from 87 unrelated families with hereditary ataxia and 194 subjects from 65 unrelated families with hereditary spastic paraplegia were included. The total prevalence was estimated at 13.9/100 000. Hereditary ataxia prevalence in the region was estimated at 6.5/100 000: 4.2/100 000 for autosomal-dominant and 2.3/100 000 for autosomal recessive, 0.15/100 000 for Friedreich's ataxia and 0.4/100 000 for ataxia telangiectasia. Hereditary spastic paraplegia prevalence was 7.4/100 000: 5.5/100 000 for autosomal dominant-hereditary spastic paraplegia, 0.6/100 000 for autosomal recessive-hereditary spastic paraplegia and 1.3/100 000 for isolated subjects. Marked differences were found in the frequencies of hereditary ataxia subtypes compared with other countries, while those of the most common autosomal dominant-hereditary spastic paraplegia genotypes, SPG4, SPG3 and SPG31, were similar to those previously reported. Clear variations between age groups and counties were observed, but no gender differences. Mean age on prevalence day was 48 years, mean age at onset was 24 years. We present the largest population study performed on hereditary ataxia and hereditary spastic paraplegia prevalence and report a higher prevalence than expected. Better inclusion criteria and multiple search strategies may explain the observed differences.

CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5

2009-05-24

Thirty-four different loci for hereditary spastic paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with ‘pure’ forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7- hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon–intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic paraplegia index patients, manifesting either a pure (n = 52) or a complex form (n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 ± 12.1 years (range 4–47 years). After a mean disease duration of 28.3 ± 13.4 years (10–58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% (n = 6/82) in our series of autosomal recessive hereditary spastic paraplegia families and 3.3% (n = 3/90) in our series of sporadic pure spastic paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic paraplegia determinism.

Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain

2009-05-24

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant small-vessel disease of the brain caused by mutations in the NOTCH3 receptor. The highly stereotyped nature of the mutations, which alter the number of cysteine residues within the epidermal growth factor-like repeats (EGFR), predicts that all mutations share common mechanisms. Prior in vitro assays and genetic studies in the mouse support the hypothesis that common mutations do not compromise canonical Notch3 function but instead convey a non-physiological and deleterious activity to the receptor through the unpaired cysteine residue. Intriguingly, in vitro studies predict that mutations located in the Delta/Serrate/LAG-2 ligand binding domain-(EGFR10-11) may result in a loss of Notch3 receptor function. However, the in vivo relevance and functional significance of this with respect to the pathogenic mechanisms and clinical expression of the disease remain largely unexplored. To ascertain, in vivo, the functional significance of EGFR10-11 mutations, we generated transgenic mice with one representative mutation (C428S) in EGFR10 of Notch3. These mice, like those with a common R90C mutation, developed characteristic arterial accumulation of Notch3 protein and granular osmiophilic material upon aging. By introducing the mutant C428S transgene into a Notch3 null background, we found that, unlike the R90C mutant protein, the C428S mutant protein has lost wild-type Notch3 activity and exhibited mild dominant-negative activity in three different biological settings. From a large prospectively recruited cohort of 176 CADASIL patients, we identified 10 patients, from five distinct pedigrees carrying a mutation in EGFR10 or 11. These mutations were associated with significantly higher Mini-Mental State Examination and Mattis Dementia Rating Scale scores (P < 0.05), when compared with common mutations. Additionally, we found a strong effect of this genotype on the burden of white matter hyperintensities (P < 0.01). Collectively, these results highlight distinctive functional and phenotypic features of EGFR10-11 mutations relative to the common CADASIL mutations. Our findings are compatible with the hypothesis that EGFR10-11 mutations cause the disease through the same gain of novel function as the common mutations, and lead us to propose that reduced Notch3 signalling acts as a modifier of the CADASIL phenotype.

Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)

2009-05-24

Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's disease. The zebrafish Parkin protein is 62% identical to its human counterpart with 78% identity in functionally relevant regions. The parkin gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of parkin knockdown appears to be specific for dopaminergic neurons. Notably, parkin knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinson's Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of parkin knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.

Functional compensation of motor function in pre-symptomatic Huntington's disease

2009-05-24

Involuntary choreiform movements are a clinical hallmark of Huntington's disease. Studies in clinically affected patients suggest a shift of motor activations to parietal cortices in response to progressive neurodegeneration. Here, we studied pre-symptomatic gene carriers to examine the compensatory mechanisms that underlie the phenomenon of retained motor function in the presence of degenerative change. Fifteen pre-symptomatic gene carriers and 12 matched controls performed button presses paced by a metronome at either 0.5 or 2 Hz with four fingers of the right hand whilst being scanned with functional magnetic resonance imaging. Subjects pressed buttons either in the order of a previously learnt 10-item finger sequence, from left to right, or kept still. Error rates ranged from 2% to 7% in the pre-symptomatic gene carriers and from 0.5% to 4% in controls, depending on the condition. No significant difference in task performance was found between groups for any of the conditions. Activations in the supplementary motor area (SMA) and superior parietal lobe differed with gene status. Compared with healthy controls, gene carriers showed greater activations of left caudal SMA with all movement conditions. Activations correlated with increasing speed of movement were greater the closer the gene carriers were to estimated clinical diagnosis, defined by the onset of unequivocal motor signs. Activations associated with increased movement complexity (i.e. with the pre-learnt 10-item sequence) decreased in the rostral SMA with nearing diagnostic onset. The left superior parietal lobe showed reduced activation with increased movement complexity in gene carriers compared with controls, and in the right superior parietal lobe showed greater activations with all but the most demanding movements. We identified a complex pattern of motor compensation in pre-symptomatic gene carriers. The results show that preclinical compensation goes beyond a simple shift of activity from premotor to parietal regions involving multiple compensatory mechanisms in executive and cognitive motor areas. Critically, the pattern of motor compensation is flexible depending on the actual task demands on motor control.

Not on the face alone: perception of contextualized face expressions in Huntington's disease

2009-05-24

Numerous studies have demonstrated that Huntington's disease mutation-carriers have deficient explicit recognition of isolated facial expressions. There are no studies, however, which have investigated the recognition of facial expressions embedded within an emotional body and scene context. Real life facial expressions are typically embedded in contexts which may dramatically change the emotion recognized in the face. Moreover, a recent study showed that the magnitude of the contextual bias is modulated by the similarity between the actual expression of the presented face and the facial expression that would typically fit the context, e.g. disgust faces are more similar to anger than to sadness faces and, consequently, are more strongly influenced by contexts expressing anger than by contexts expressing sadness. Since context effects on facial expression perception are not explicitly controlled, their pattern serves as an implicit measure of the processing of facial expressions. In this study we took advantage of the face-in-context design to compare explicit recognition of face-expressions by Huntington's disease mutation-carriers, with evidence for processing the expressions deriving from implicit measures. In an initial experiment we presented a group of 21 Huntington's disease mutation-carriers with standard tests of face-expression recognition. Relative to controls, they displayed deficits in recognizing disgust and anger faces despite intact recognition of these emotions from non-facial images. In a subsequent experiment, we embedded the disgust faces on images of people conveying sadness and anger as expressed by body language and additional paraphernalia. In addition, sadness and anger faces were embedded on context images conveying disgust. In both cases participants were instructed to categorize the facial expressions, ignoring the context. Despite the deficient explicit recognition of isolated disgust and anger faces, the perception of the emotions expressed by the faces was affected by context in Huntington's disease mutation-carriers in a similar manner as in control participants. Specifically, they displayed the same sensitivity to face–context pairings. These findings suggest that, despite their impaired explicit recognition of facial expressions, Huntington's disease mutation-carriers display relatively preserved processing of the same facial configurations when embedded in context. The results also show intact utilization of the information elicited by contextual cues about faces expressing disgust even when the actually presented face expresses a different emotion. Overall, our findings shed light on the nature of the deficit in facial expression recognition in Huntington's disease mutation-carriers as well as underscore the importance of context in emotion perception.

The neural basis of tool use

Goldenberg, G., Spatt, J. — 2009-05-24

Misuse of tools and objects by patients with left brain damage is generally recognized as a manifestation of apraxia, caused by parietal lobe damage. The use of tools and objects can, however, be subdivided in several components. The purpose of our study was to find out which of these are dependent on parietal lobe function. Thirty-eight patients with left brain damage and aphasia were examined using tests to assess the retrieval of functional knowledge from semantic memory (Functional Associations), mechanical problem solving (Novel Tools) and use of everyday tools and objects (Common Tools). Voxel-wise analysis of magnetic resonance images revealed two regions where lesions had a significant impact on the test results. One extended rostrally from the central region and ventrally through the middle frontal cortex to the dorsal margin of the inferior frontal gyrus. The other reached dorsally and caudally from the supramarginal gyrus, through the inferior, to superior parietal lobe. Whereas the frontal lesions had an adverse influence on all experimental tests as well as on the subtests of the Aachen Aphasia test, parietal lesions impaired Novel and Common Tools, but did not have an adverse effect on the Functional Associates. An association between Functional Associations and temporal lesions became apparent when patients with only a selective deficit in the test were considered, but did not show up in the whole group analysis. The parietal influence was as strong for the selection as for the use of either novel or common tools, although choice of appropriate manual configuration and movements was more important for use than for selection. We conclude that the contribution of the parietal lobe to tool use concerns general principles of tool use rather than knowledge about the prototypical use of common tools and objects, and the comprehension of mechanical interactions of the tool with other tools, recipients or material rather than the selection of grip formation and manual movements.

Defining Meyer's loop-temporal lobe resections, visual field deficits and diffusion tensor tractography

2009-05-24

Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyer's loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyer's loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T₁-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyer's loop to the temporal pole was 24–43 mm (mean 34 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was –15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyer's loop to the temporal pole was 24–47 mm (mean 35 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was –11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyer's loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyer's loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patient's risk of postoperative VFDs following anterior temporal lobe resection.

Prism adaptation reverses the local processing bias in patients with right temporo-parietal junction lesions

Bultitude, J. H., Rafal, R. D., List, A. — 2009-05-24

Lesions to the right temporo-parietal cortex commonly result in hemispatial neglect. Lesions to the same area are also associated with hyperattention to local details of a scene and difficulty perceiving the global structure. This local processing bias is an important factor contributing to neglect and may contribute to the higher prevalence of the disorder following right compared with left hemisphere strokes. In recent years, visuomotor adaptation to rightward-shifting prisms has been introduced as a promising treatment for hemispatial neglect. Explanations for these improvements have generally described a leftward realignment of attention, however, the present investigation provides evidence that prism adaptation reduces the local processing bias. Five patients with right temporal-parietal junction lesions were asked to identify the global or local levels of hierarchical figures before and after visuomotor adaptation to rightward-shifting prisms. Prior to prism adaptation the patients had difficulty ignoring the local elements when identifying the global component. Following prism adaptation, however, this pattern was reversed, with greater global interference during local level identification. The results suggest that prism adaptation may improve non-spatially lateralized deficits that contribute to the neglect syndrome.

The muddle of embodiment

le Fanu, J. — 2009-05-24

Editorial

Compston, A. — 2009-05-06

Traumatic intradural avulsion of the nerve roots of the brachial plexus, by Patrick Taylor (from the Division of Neurological Surgery, Department of Surgery, University of California at Los Angeles and the Wadsworth Veterans Administration Hospital Los Angeles). Brain 1962: 85; 579-602.

Compston, A. — 2009-05-06

Duet for one, Almeida Theatre, London (January 22nd to March 14th 2009)

Cornwell, J. — 2009-05-06

Multiple sclerosis and vitamin D: don't (yet) blame it on the sunshine

Stewart, G. — 2009-05-06

The retina in Parkinson's disease

Archibald, N. K., Clarke, M. P., Mosimann, U. P., Burn, D. J. — 2009-05-06

As a more complete picture of the clinical phenotype of Parkinson's disease emerges, non-motor symptoms have become increasingly studied. Prominent among these non-motor phenomena are mood disturbance, cognitive decline and dementia, sleep disorders, hyposmia and autonomic failure. In addition, visual symptoms are common, ranging from complaints of dry eyes and reading difficulties, through to perceptual disturbances (feelings of presence and passage) and complex visual hallucinations. Such visual symptoms are a considerable cause of morbidity in Parkinson's disease and, with respect to visual hallucinations, are an important predictor of cognitive decline as well as institutional care and mortality. Evidence exists of visual dysfunction at several levels of the visual pathway in Parkinson's disease. This includes psychophysical, electrophysiological and morphological evidence of disruption of retinal structure and function, in addition to disorders of ‘higher’ (cortical) visual processing. In this review, we will draw together work from animal and human studies in an attempt to provide an insight into how Parkinson's disease affects the retina and how these changes might contribute to the visual symptoms experienced by patients.

Immunomodulatory effects of Vitamin D in multiple sclerosis

Correale, J., Ysrraelit, M. C., Gaitan, M. I. — 2009-05-06

Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A protective effect of Vitamin D on multiple sclerosis is supported by the reduced risk associated with sun exposure and use of Vitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of multiple sclerosis. In this study, we measured 1,25 (OH)₂ Vitamin D and 25 (OH) Vitamin D levels in multiple sclerosis patients separated into different clinical subgroups according to disease status. In addition, direct effects of 1,25 (OH)₂ Vitamin D on ex vivo CD4+ T cells and myelin-peptide specific T cell lines were investigated to gain more insight into putative regulatory mechanisms in the disease pathogenesis. One hundred and thirty-two Hispanic patients with clinically definite multiple sclerosis were studied, 58 with relapsing remitting multiple sclerosis during remission, 34 during relapse and 40 primary progressive multiple sclerosis cases. Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gender served as controls. Levels of 25(OH)D₃ and 1,25(OH)₂D₃, measured by ELISA were significantly lower in relapsing–remitting patients than in controls. In addition, levels in patients suffering relapse were lower than during remissions. In contrast, primary progressive patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)₂D₃. Moreover, activated Vitamin D enhanced the development of IL-10 producing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, Vitamin D receptor expression was induced by 1,25(OH)₂D₃ in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH)D₃ into biologically active 1,25(OH)₂D₃, since T cells express 1-hydroxylase constitutively. Finally, 1,25(OH)₂D₃ also increased the expression and biological activity of indoleamine 2,3-dioxygenase, mediating significant increase in the number of CD4+CD25+ T regulatory cells. Collectively, these data suggest that 1,25(OH)₂D₃ plays an important role in T cell homeostasis during the course of multiple sclerosis, thus making correction of its deficiency may be useful during treatment of the disease.

Mitochondrial changes within axons in multiple sclerosis

2009-05-06

Multiple sclerosis is the most common cause of non-traumatic neurological impairment in young adults. An energy deficient state has been implicated in the degeneration of axons, the pathological correlate of disease progression, in multiple sclerosis. Mitochondria are the most efficient producers of energy and play an important role in calcium homeostasis. We analysed the density and function of mitochondria using immunohistochemistry and histochemistry, respectively, in chronic active and inactive lesions in progressive multiple sclerosis. As shown before in acute pattern III and Balo's lesions, the mitochondrial respiratory chain complex IV activity is reduced despite the presence of mitochondria in demyelinated axons with amyloid precursor protein accumulation, which are predominantly located at the active edge of chronic active lesions. Furthermore, the strong non-phosphorylated neurofilament (SMI32) reactivity was associated with a significant reduction in complex IV activity and mitochondria within demyelinated axons. The complex IV defect associated with axonal injury may be mediated by soluble products of innate immunity, as suggested by an inverse correlation between complex IV activity and macrophage/microglial density in chronic lesions. However, in inactive areas of chronic multiple sclerosis lesions the mitochondrial respiratory chain complex IV activity and mitochondrial mass, judged by porin immunoreactivity, are increased within approximately half of large (>2.5 µm diameter) chronically demyelinated axons compared with large myelinated axons in the brain and spinal cord. The axon-specific mitochondrial docking protein (syntaphilin) and phosphorylated neurofilament-H were increased in chronic lesions. The lack of complex IV activity in a proportion of Na⁺/K⁺ ATPase -1 positive demyelinated axons supports axonal dysfunction as a contributor to neurological impairment and disease progression. Furthermore, in vitro studies show that inhibition of complex IV augments glutamate-mediated axonal injury (amyloid precursor protein and SMI32 reactivity). Our findings have important implications for both axonal degeneration and dysfunction during the progressive stage of multiple sclerosis.

The relation between inflammation and neurodegeneration in multiple sclerosis brains

2009-05-06

Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.

Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease

2009-05-06

The pathological substrate of progressive disability in multiple sclerosis is hypothesized to be axonal loss. Differences in the demographic, pathological and radiological features of patients with primary progressive compared with secondary progressive multiple sclerosis raise the question as to whether they actually represent separate clinical entities. So far, large pathological studies comparing axonal damage between primary progressive and secondary progressive multiple sclerosis have not been reported. In this clinico-pathological study we examined the cervical spinal cord in patients with primary and secondary progressive multiple sclerosis. Human cervical spinal cord was derived at autopsy from 54 patients (17 primary progressive, 30 secondary progressive and 7 controls). Tissue was stained immunohistochemically and examined to determine: (i) the number of surviving corticospinal tract axons; (ii) the extent of grey and white matter demyelination; (iii) the degree of inflammation inside and outside of lesions; and (iv) the relationship between demyelination and axonal loss. Associated clinical data was used to calculate expanded disability status scale for each patient preceding death. Motor disability in the primary progressive and secondary progressive groups was similar preceding death. Secondary progressive multiple sclerosis patients showed considerably more extensive demyelination of both the white and grey matter of the cervical spinal cord. The total number of corticospinal axons was equally low in primary progressive and secondary progressive multiple sclerosis groups versus controls. The reduction of axonal density in demyelinated regions compared to normal appearing white matter was significantly more extensive in primary progressive versus secondary progressive patients (33% reduction versus 16% reduction, P < 0.001). These findings suggest axonal loss is the pathological substrate of progressive disability in both primary progressive and secondary progressive multiple sclerosis with a common plaque-centred mechanism. More extensive axonal loss within areas of demyelination in primary progressive multiple sclerosis could explain high levels of axonal loss observed in these patients despite low levels of demyelination.

Sensorimotor dysfunction in multiple sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord

2009-05-06

The human spinal cord contains segregated sensory and motor pathways that have been difficult to quantify using conventional magnetic resonance imaging (MRI) techniques. Multiple sclerosis is characterized by both focal and spatially diffuse spinal cord lesions with heterogeneous pathologies that have limited attempts at linking MRI and behaviour. We used a novel magnetization-transfer-weighted imaging approach to quantify damage to spinal white matter columns and tested its association with sensorimotor impairment. We studied 42 participants with multiple sclerosis who each underwent MRI at 3 Tesla and quantitative tests of sensorimotor function. We measured cerebrospinal-fluid-normalized magnetization-transfer signals in the dorsal and lateral columns and grey matter of the cervical cord. We also measured brain lesion volume, cervical spinal cord lesion number and cross-sectional area, vibration sensation, strength, walking velocity and standing balance. We used linear regression to assess the relationship between sensorimotor impairment and MRI abnormalities. We found that the dorsal column cerebrospinal-fluid-normalized magnetization-transfer signal specifically correlated with vibration sensation (R = 0.58, P < 0.001) and the lateral column signal with strength (R = –0.45, P = 0.003). Spinal cord signal measures also correlated with walking and balance dysfunction. A stepwise multiple regression showed that the dorsal column signal and diagnosis subtype alone explained a significant portion of the variance in sensation (R² = 0.54, P < 0.001), whereas the lateral column signal and diagnosis subtype explained a significant portion of the variance in strength (R² = 0.30, P < 0.001). These results help to understand the anatomic basis of sensorimotor disability in multiple sclerosis and have implications for testing the effects of neuroprotective and reparative interventions.

In vivo measurement of axon diameter distribution in the corpus callosum of rat brain

Barazany, D., Basser, P. J., Assaf, Y. — 2009-05-06

Here, we present the first in vivo non-invasive measurement of the axon diameter distribution in the rat corpus callosum. Previously, this measurement was only possible using invasive histological methods. The axon diameter, along with other physical properties, such as the intra-axonal resistance, membrane resistance and capacitance etc. helps determine many important functional properties of nerves, such as their conduction velocity. In this work, we provide a novel magnetic resonance imaging method called AxCaliber, which can resolve the distinct signatures of trapped water molecules diffusing within axons as well as water molecules diffusing freely within the extra-axonal space. Using a series of diffusion weighted magnetic resonance imaging brain scans, we can reliably infer both the distribution of axon diameters and the volume fraction of these axons within each white matter voxel. We were able to verify the known microstructural variation along the corpus callosum of the rat from the anterior (genu) to posterior (splenium) regions. AxCaliber yields a narrow distribution centered ~1 µm in the genu and splenium and much broader distributions centered ~3 µm in the body of the corpus callosum. The axon diameter distribution found by AxCaliber is generally broader than those usually obtained by histology. One factor contributing to this difference is the significant tissue shrinkage that results from histological preparation. To that end, AxCaliber might provide a better estimate of the in vivo morphology of white matter. Being a magnetic resonance imaging based methodology, AxCaliber has the potential to be used in human scanners for morphological studies of white matter in normal and abnormal development, and white matter related diseases.

Differing roles for members of the phospholipase A2 superfamily in experimental autoimmune encephalomyelitis

2009-05-06

The phospholipase A₂ (PLA₂) superfamily hydrolyzes phospholipids to release free fatty acids and lysophospholipids, some of which can mediate inflammation and demyelination, hallmarks of the CNS autoimmune disease multiple sclerosis. The expression of two of the intracellular PLA₂s (cPLA₂ GIVA and iPLA₂ GVIA) and two of the secreted PLA₂s (sPLA₂ GIIA and sPLA₂ GV) are increased in different stages of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We show using small molecule inhibitors, that cPLA₂ GIVA plays a role in the onset, and iPLA₂ GVIA in the onset and progression of EAE. We also show a potential role for sPLA₂ in the later remission phase. These studies demonstrate that selective inhibition of iPLA₂ can ameliorate disease progression when treatment is started before or after the onset of symptoms. The effects of these inhibitors on lesion burden, chemokine and cytokine expression as well as on the lipid profile provide insights into their potential modes of action. iPLA₂ is also expressed by macrophages and other immune cells in multiple sclerosis lesions. Our results therefore suggest that iPLA₂ might be an excellent target to block for the treatment of CNS autoimmune diseases, such as multiple sclerosis.

CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery

2009-05-06

Rasmussen encephalitis (RE) is a rare neurological disorder of childhood characterized by uni-hemispheric inflammation, progressive neurological deficits and intractable focal epilepsy. Destruction of neurons and astrocytes by cytotoxic CD8 T cells has been proposed as a pathogenic mechanism underlying this enigmatic disorder. We tested this hypothesis by analysing the clonal composition and T-cell receptor (TCR) repertoire of CD4+ and CD8+ T cells using complementarity determining region 3 (CDR3) spectratyping from peripheral blood and corresponding CNS specimens. Severe perturbations of the TCR repertoire were found in brain infiltrates from all specimens (n = 5). Clonal expansions, as evidenced by peripheral blood analysis (n = 14), belonged to the CD8+ T-cell subset, while CD4+ cells showed normal distributions. Some of those expansions were analysed in the respective CNS specimens by histochemistry. The stainings showed Vβ specific T cells containing the cytotoxic molecule granzyme B and lying in close appositions to NeuN+ neurons and GFAP+ astrocytes. Analysis of corresponding CNS/blood specimens revealed overlapping but also CNS-restricted expansions of certain TCR clonotypes suggesting expansions of T cells within the target organ itself. Longitudinal analysis of peripheral blood samples (n = 5) demonstrated dominance but also longitudinal persistence of specific CD8 T-cell clones over time. The Vβ/Jβ usage, length of the CDR3, and biochemical characteristics of the CDR3 amino acids suggested high similarities putatively related to common driving antigen(s) without shared clones. Taken together, our data strongly support the hypothesis of an antigen-driven MHC class-I restricted, CD8+ T cell-mediated attack against neurons and astrocytes in the CNS dominating the pathogenesis in RE.

Differential immune cell dynamics in the CNS cause CD4+ T cell compartmentalization

2009-05-06

In the course of autoimmune CNS inflammation, inflammatory infiltrates form characteristic perivascular lymphocyte cuffs by mechanisms that are not yet well understood. Here, intravital two-photon imaging of the brain in anesthetized mice, with experimental autoimmune encephalomyelitis, revealed the highly dynamic nature of perivascular immune cells, refuting suggestions that vessel cuffs are the result of limited lymphocyte motility in the CNS. On the contrary, vessel-associated lymphocyte motility is an actively promoted mechanism which can be blocked by CXCR4 antagonism. In vivo interference with CXCR4 in experimental autoimmune encephalomyelitis disrupted dynamic vessel cuffs and resulted in tissue-invasive migration. CXCR4-mediated perivascular lymphocyte movement along CNS vessels was a key feature of CD4⁺ T cell subsets in contrast to random motility of CD8⁺ T cells, indicating a dominant role of the perivascular area primarily for CD4⁺ T cells. Our results visualize dynamic T cell motility in the CNS and demonstrate differential CXCR4-mediated compartmentalization of CD4⁺ T-cell motility within the healthy and diseased CNS.

Kynurenine pathway inhibition reduces central nervous system inflammation in a model of human African trypanosomiasis

Rodgers, J., Stone, T. W., Barrett, M. P., Bradley, B., Kennedy, P. G. E. — 2009-05-06

Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasites Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense, and is a major cause of systemic and neurological disability throughout sub-Saharan Africa. Following early-stage disease, the trypanosomes cross the blood–brain barrier to invade the central nervous system leading to the encephalitic, or late stage, infection. Treatment of human African trypanosomiasis currently relies on a limited number of highly toxic drugs, but untreated, is invariably fatal. Melarsoprol, a trivalent arsenical, is the only drug that can be used to cure both forms of the infection once the central nervous system has become involved, but unfortunately, this drug induces an extremely severe post-treatment reactive encephalopathy (PTRE) in up to 10% of treated patients, half of whom die from this complication. Since it is unlikely that any new and less toxic drug will be developed for treatment of human African trypanosomiasis in the near future, increasing attention is now being focussed on the potential use of existing compounds, either alone or in combination chemotherapy, for improved efficacy and safety. The kynurenine pathway is the major pathway in the metabolism of tryptophan. A number of the catabolites produced along this pathway show neurotoxic or neuroprotective activities, and their role in the generation of central nervous system inflammation is well documented. In the current study, Ro-61-8048, a high affinity kynurenine-3-monooxygenase inhibitor, was used to determine the effect of manipulating the kynurenine pathway in a highly reproducible mouse model of human African trypanosomiasis. It was found that Ro-61-8048 treatment had no significant effect (P = 0.4445) on the severity of the neuroinflammatory pathology in mice during the early central nervous system stage of the disease when only a low level of inflammation was present. However, a significant (P = 0.0284) reduction in the severity of the neuroinflammatory response was detected when the inhibitor was administered in animals exhibiting the more severe, late central nervous system stage, of the infection. In vitro assays showed that Ro-61-8048 had no direct effect on trypanosome proliferation suggesting that the anti-inflammatory action is due to a direct effect of the inhibitor on the host cells and not a secondary response to parasite destruction. These findings demonstrate that kynurenine pathway catabolites are involved in the generation of the more severe inflammatory reaction associated with the late central nervous system stages of the disease and suggest that Ro-61-8048 or a similar drug may prove to be beneficial in preventing or ameliorating the PTRE when administered as an adjunct to conventional trypanocidal chemotherapy.

Restoration of hand function in a rat model of repair of brachial plexus injury

Ibrahim, A. G., Kirkwood, P. A., Raisman, G., Li, Y. — 2009-05-06

The incurability of spinal cord injury and subcortical strokes is due to the inability of nerve fibres to regenerate. One of the clearest clinical situations where failure of regeneration leads to a permanent functional deficit is avulsion of the brachial plexus. In current practice, surgical re-implantation of avulsed spinal roots provides a degree of motor recovery, but the patients neither recover sensation nor the use of the hand. In the present rat study, we show that transplantation of cultured adult olfactory ensheathing cells restores the sensory input needed for a complex, goal-directed fore-paw function and re-establishes synaptic transmission to the spinal grey matter and cuneate nucleus by providing a bridge for regeneration of severed dorsal root fibres into the spinal cord. Success in a first application of human olfactory ensheathing cells in clinical brachial plexus injury would open the way to the wider field of brain and spinal cord injuries.

The amusic brain: in tune, out of key, and unaware

Peretz, I., Brattico, E., Jarvenpaa, M., Tervaniemi, M. — 2009-05-06

Like language, music engagement is universal, complex and present early in life. However, ~4% of the general population experiences a lifelong deficit in music perception that cannot be explained by hearing loss, brain damage, intellectual deficiencies or lack of exposure. This musical disorder, commonly known as tone-deafness and now termed congenital amusia, affects mostly the melodic pitch dimension. Congenital amusia is hereditary and is associated with abnormal grey and white matter in the auditory cortex and the inferior frontal cortex. In order to relate these anatomical anomalies to the behavioural expression of the disorder, we measured the electrical brain activity of amusic subjects and matched controls while they monitored melodies for the presence of pitch anomalies. Contrary to current reports, we show that the amusic brain can track quarter-tone pitch differences, exhibiting an early right-lateralized negative brain response. This suggests near-normal neural processing of musical pitch incongruities in congenital amusia. It is important because it reveals that the amusic brain is equipped with the essential neural circuitry to perceive fine-grained pitch differences. What distinguishes the amusic from the normal brain is the limited awareness of this ability and the lack of responsiveness to the semitone changes that violate musical keys. These findings suggest that, in the amusic brain, the neural pitch representation cannot make contact with musical pitch knowledge along the auditory-frontal neural pathway.

The clinical profile of right temporal lobe atrophy

2009-05-06

Frontotemporal lobar degeneration is currently associated with three syndromic variants. Disorders of speech and language figure prominently in two of the three variants, and are associated with left-sided frontotemporal atrophy. The detailed characterization of these syndromes contrasts with the relative paucity of information relating to frontotemporal lobar degeneration primarily affecting the right cerebral hemisphere. The objective of this study was to identify the clinical profile associated with asymmetrical, predominantly right-sided, temporal lobe atrophy. Twenty patients with predominant right temporal lobe atrophy were identified on the basis of blinded visual assessment of the MRI scans. The severity of right temporal lobe atrophy was quantified using volumetric analysis of the whole temporal lobes, the amygdala and the hippocampus. Profiles of cognitive function, behavioural and personality changes were obtained on each patient. The pattern of atrophy and the clinical features were compared with those observed in a group of patients with semantic dementia and predominant left-sided temporal lobe atrophy. The mean right temporal lobe volume in the right temporal lobe atrophy group was reduced by 37%, with the mean left temporal lobe volume reduced by 19%. There was marked atrophy of the right hippocampus and right amygdala, with mean volumes reduced by 41 and 51%, respectively (left hippocampus and amygdala volumes were reduced by 18 and 33%, respectively). The most prominent cognitive deficits were impairment of episodic memory and getting lost. Prosopagnosia was a symptom in right temporal lobe atrophy patients. These patients also exhibited a variety of behavioural symptoms including social disinhibition, depression and aggressive behaviour. Nearly all behavioural disorders were more prevalent in the right temporal lobe atrophy patient group than the semantic dementia group. Symptoms particular to the right temporal lobe atrophy patient group included hyper-religiosity, visual hallucinations and cross-modal sensory experiences. The combination of clinical features associated with predominant right temporal lobe atrophy differs significantly from those associated with the other syndromes associated with focal degeneration of the frontal and temporal lobes and it is, therefore, proposed that this right temporal variant should be considered a separate syndromic variant of frontotemporal lobar degeneration.

A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia

Torralva, T., Roca, M., Gleichgerrcht, E., Bekinschtein, T., Manes, F. — 2009-05-06

Traditional cognitive tests may not be sensitive for the early detection of executive and social cognitive impairments in the behavioural variant of frontotemporal dementia. The aim of this study was to detect specific executive and social cognitive deficits in patients with early behavioural variant frontotemporal dementia using a battery of tests previously shown to be sensitive to frontal lobe dysfunction. Behavioural variant frontotemporal dementia patients and paired controls were assessed with a complete standard neuropsychological battery evaluating attention, memory, visuospatial abilities, language and executive functions. All participants were then assessed with our Executive and Social Cognition Battery, which included Theory of Mind tests (Mind in the Eyes, Faux Pas), the Hotel Task, Multiple Errands Task-hospital version and the Iowa Gambling Task for complex decision-making. Patients were divided into two groups according to their Addenbrooke's Cognitive Examination scores, a measure of general cognitive status. Low Addenbrooke's Cognitive Examination patients differed from controls on most tasks of the standard battery and the Executive and Social Cognition Battery. While high Addenbrooke's Cognitive Examination patients did not differ from controls on most traditional neuropsychological tests, significant differences were found between this high-functioning behavioural variant of frontotemporal dementia group and controls on most measures of our Executive and Social Cognition Battery. Our results suggest that the Executive and Social Cognition Battery used in this study is more sensitive in detecting executive and social cognitive impairment deficits in early behavioural variant of frontotemporal dementia than the classical cognitive measures.

Episodic memory loss is related to hippocampal-mediated {beta}-amyloid deposition in elderly subjects

2009-05-06

Although β-amyloid (Aβ) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via ‘Pittsburgh Compound-B’ (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Aβ and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Aβ deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Aβ deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Aβ-induced hippocampus atrophy.

Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study

2009-05-06

Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the ‘tauopathies’, which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Aβ pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Aβ, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Aβ was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.

Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation

2009-05-06

Alzheimer's disease neuropathology is characterized by neuronal death, amyloid β-peptide deposits and neurofibrillary tangles composed of paired helical filaments of tau protein. Although crucial for our understanding of the pathogenesis of Alzheimer's disease, the molecular mechanisms linking amyloid β-peptide and paired helical filaments remain unknown. Here, we show that amyloid β-peptide-induced nitro-oxidative damage promotes the nitrotyrosination of the glycolytic enzyme triosephosphate isomerase in human neuroblastoma cells. Consequently, nitro-triosephosphate isomerase was found to be present in brain slides from double transgenic mice overexpressing human amyloid precursor protein and presenilin 1, and in Alzheimer's disease patients. Higher levels of nitro-triosephosphate isomerase (P < 0.05) were detected, by Western blot, in immunoprecipitates from hippocampus (9 individuals) and frontal cortex (13 individuals) of Alzheimer's disease patients, compared with healthy subjects (4 and 9 individuals, respectively). Triosephosphate isomerase nitrotyrosination decreases the glycolytic flow. Moreover, during its isomerase activity, it triggers the production of the highly neurotoxic methylglyoxal (n = 4; P < 0.05). The bioinformatics simulation of the nitration of tyrosines 164 and 208, close to the catalytic centre, fits with a reduced isomerase activity. Human embryonic kidney (HEK) cells overexpressing double mutant triosephosphate isomerase (Tyr164 and 208 by Phe164 and 208) showed high methylglyoxal production. This finding correlates with the widespread glycation immunostaining in Alzheimer's disease cortex and hippocampus from double transgenic mice overexpressing amyloid precursor protein and presenilin 1. Furthermore, nitro-triosephosphate isomerase formed large β-sheet aggregates in vitro and in vivo, as demonstrated by turbidometric analysis and electron microscopy. Transmission electron microscopy (TEM) and atomic force microscopy studies have demonstrated that nitro-triosephosphate isomerase binds tau monomers and induces tau aggregation to form paired helical filaments, the characteristic intracellular hallmark of Alzheimer's disease brains. Our results link oxidative stress, the main etiopathogenic mechanism in sporadic Alzheimer's disease, via the production of peroxynitrite and nitrotyrosination of triosephosphate isomerase, to amyloid β-peptide-induced toxicity and tau pathology.

Clinical field-strength MRI of amyloid plaques induced by low-level cholesterol feeding in rabbits

2009-05-06

Two significant barriers have limited the development of effective treatment of Alzheimer's disease. First, for many cases the aetiology is unknown and likely multi-factorial. Among these factors, hypercholesterolemia is a known risk predictor and has been linked to the formation of β-amyloid plaques, a pathological hallmark this disease. Second, standardized diagnostic tools are unable to definitively diagnose this disease prior to death; hence new diagnostic tools are urgently needed. Magnetic resonance imaging (MRI) using high field-strength scanners has shown promise for direct visualization of β-amyloid plaques, allowing in vivo longitudinal tracking of disease progression in mouse models. Here, we present a new rabbit model for studying the relationship between cholesterol and Alzheimer's disease development and new tools for direct visualization of β-amyloid plaques using clinical field-strength MRI. New Zealand white rabbits were fed either a low-level (0.125–0.25% w/w) cholesterol diet (n = 5) or normal chow (n = 4) for 27 months. High-resolution (66 x 66 x 100 µm³; scan time = 96 min) ex vivo MRI of brains was performed using a 3-Tesla (T) MR scanner interfaced with customized gradient and radiofrequency coils. β-Amyloid-42 immunostaining and Prussian blue iron staining were performed on brain sections and MR and histological images were manually registered. MRI revealed distinct signal voids throughout the brains of cholesterol-fed rabbits, whereas minimal voids were seen in control rabbit brains. These voids corresponded directly to small clusters of extracellular β-amyloid-positive plaques, which were consistently identified as iron-loaded (the presumed source of MR contrast). Plaques were typically located in the hippocampus, parahippocampal gyrus, striatum, hypothalamus and thalamus. Quantitative analysis of the number of histologically positive β-amyloid plaques (P < 0.0001) and MR-positive signal voids (P < 0.05) found in cholesterol-fed and control rabbit brains corroborated our qualitative observations. In conclusion, long-term, low-level cholesterol feeding was sufficient to promote the formation of extracellular β-amyloid plaque formation in rabbits, supporting the integral role of cholesterol in the aetiology of Alzheimer's disease. We also present the first evidence that MRI is capable of detecting iron-associated β-amyloid plaques in a rabbit model of Alzheimer's disease and have advanced the sensitivity of MRI for plaque detection to a new level, allowing clinical field-strength scanners to be employed. We believe extension of these technologies to an in vivo setting in rabbits is feasible and that our results support future work exploring the role of MRI as a leading imaging tool for this debilitating and life-threatening disease.

Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease

2009-05-06

The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial ¹¹C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources—ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm³ by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm³/year) < amnestic mild cognitive impairment (2.5 cm³/year) < Alzheimer's disease (7.7 cm³/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = –0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =–0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =–0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.

Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naive Parkinson's disease

2009-05-06

The D₃ dopamine (DA) receptor is a member of the D₂-like DA receptor family. While the D₂ receptor is abundant especially in motor-regions of the striatum, the D₃ receptor shows a relative abundance in limbic regions and globus pallidus. This receptor is of current interest in neurology because of its potential involvement in psychiatric and motor complications in Parkinson's disease and the possibility that dopamine D₃-preferring agonist therapy might delay progression of the disorder. Preclinical data indicate that striatal levels of the D₃ (but not the D₂) DA receptor are decreased following lesion of nigrostriatal DA neurons; at present, there are no in vivo data on this receptor subtype in Parkinson's disease. The objective of this positron emission tomography study was to compare [¹¹C]-(+)-PHNO (D₃ versus D₂ preferring) and [¹¹C]raclopride (D₃ = D₂) binding in brain of non-depressed, non-demented, dopaminergic drug-naïve patients with early-stage Parkinson's disease (n = 10), relative to matched-controls (n = 9). Parkinson's disease was associated with a trend for bilaterally decreased [¹¹C]-(+)-PHNO (but not [¹¹C]raclopride) binding in the D₃-rich ventral striatum (–11%, P = 0.07) and significantly decreased binding in globus pallidus (–42%, P = 0.02). In contrast, in the primarily D₂-populated putamen, both [¹¹C]-(+)-PHNO (25%, P = 0.02) and [¹¹C]raclopride (25%, P < 0.01) binding were similarly increased, especially on the side contra-lateral to the symptoms. In the midbrain, presumably containing D₃ receptors localized to the substantia nigra, [¹¹C]-(+)-PHNO binding was normal. Decreased [¹¹C]-(+)-PHNO to [¹¹C]raclopride ratio correlated with motor deficits and lowered-mood (P < 0.02). Our imaging data suggest that brain DA neuron loss in the human causes region-specific differential changes in DA D₂ and D₃ receptors with D₃ receptor ‘downregulation’ possibly related to some motor and mood problems in Parkinson disease. D₃ receptor levels might be a determinant vulnerability factor underlying side-effects associated with treatment; hence, these initial findings provide valuable baseline information to understand the role of D₃ receptors in response to Parkinson's disease medication.

Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study

2009-05-06

Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson's disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson's disease patients with impulse control disorders. We describe results of a [¹¹C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson's disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson's disease patients may provide a model into the pathophysiology of this disorder.

Do parkinsonian patients have trouble telling lies? The neurobiological basis of deceptive behaviour

2009-05-06

Parkinson's disease is a common neurodegenerative disorder with both motor symptoms and cognitive deficits such as executive dysfunction. Over the past 100 years, a growing body of literature has suggested that patients with Parkinson's disease have characteristic personality traits such as industriousness, seriousness and inflexibility. They have also been described as ‘honest’, indicating that they have a tendency not to deceive others. However, these personality traits may actually be associated with dysfunction of specific brain regions affected by the disease. In the present study, we show that patients with Parkinson's disease are indeed ‘honest’, and that this personality trait might be derived from dysfunction of the prefrontal cortex. Using a novel cognitive task, we confirmed that patients with Parkinson's disease (n = 32) had difficulty making deceptive responses relative to healthy controls (n = 20). Also, using resting-state ¹⁸F-fluorodeoxyglucose PET, we showed that this difficulty was significantly correlated with prefrontal hypometabolism. Our results are the first to demonstrate that the ostensible honesty found in patients with Parkinson's disease has a neurobiological basis, and they provide direct neuropsychological evidence of the brain mechanisms crucial for human deceptive behaviour.

Hubris syndrome: An acquired personality disorder? A study of US Presidents and UK Prime Ministers over the last 100 years

Owen, D., Davidson, J. — 2009-05-06

Fit to decide?

Coles, A., Coles, A. — 2009-05-06