Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis.
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We report a middle-aged woman with a novel transthyretin (TTR) variant, Leu12Pro. She had extensive amyloid deposition in the leptomeninges and liver as well as the involvement of the heart and peripheral nervous system which characterizes familial amyloid polyneuropathy caused by variant TTR. Clinical features attributed to her leptomeningeal amyloid included radiculopathy, central hypoventilation, recurrent subarachnoid haemorrhage, depression, seizures and periods of decreased consciousness. MRI showed a marked enhancement throughout her meninges and ependyma, and TTR amyloid deposition was confirmed by meningeal biopsy. The simultaneous presence of extensive visceral amyloid and clinically significant deposits affecting both the peripheral and central nervous system extends the spectrum of amyloid-related disease associated with TTR mutations. The unusual association of severe peripheral neuropathy with symptoms of leptomeningeal amyloid indicates that leptomeningeal amyloidosis should be considered part of the syndrome of TTR-related familial amyloid polyneuropathy. (+info)
Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study.
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Metalloproteinases have been implicated in the pathogenesis of multiple sclerosis. We report longitudinal serum levels of gelatinase B and of the tissue inhibitors of matrix metalloproteinases (TIMP), TIMP-1 and TIMP-2, in 21 patients with relapsing multiple sclerosis. Patients had monthly clinical and gadolinium-enhanced MRI follow-up for 10 months. Longitudinal samples in nine healthy controls and cross-sectional samples from 12 patients with inflammatory CNS disease and 15 patients with other neurological diseases were used for comparison. Average serum gelatinase B, TIMP-1 and TIMP-2 levels were significantly higher in multiple sclerosis patients and those with other neurological diseases than in healthy controls. In the patients with multiple sclerosis, gelatinase B levels were significantly higher during clinical relapse compared with periods of clinical stability. Multiple sclerosis patients with high mean serum gelatinase B levels had significantly more T1-weighted gadolinium-enhancing MRI lesions than those with mean levels within the control range. TIMP-1 levels were not different during relapse and between relapses. There was a trend for TIMP-2 levels to be lower during relapse compared with non-relapse periods. For similar levels of serum gelatinase B, associated TIMP-1 levels were significantly lower and TIMP-2 levels significantly higher in multiple sclerosis patients compared with the inflammatory CNS control group. We propose that an abnormality in the inhibitory response to metalloproteinases may play an aetiological role in the chronicity of multiple sclerosis. (+info)
Language processing is strongly left lateralized in both sexes. Evidence from functional MRI.
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Functional MRI (fMRI) was used to examine gender effects on brain activation during a language comprehension task. A large number of subjects (50 women and 50 men) was studied to maximize the statistical power to detect subtle differences between the sexes. To estimate the specificity of findings related to sex differences, parallel analyses were performed on two groups of randomly assigned subjects. Men and women showed very similar, strongly left lateralized activation patterns. Voxel-wise tests for group differences in overall activation patterns demonstrated no significant differences between women and men. In further analyses, group differences were examined by region of interest and by hemisphere. No differences were found between the sexes in lateralization of activity in any region of interest or in intrahemispheric cortical activation patterns. These data argue against substantive differences between men and women in the large-scale neural organization of language processes. (+info)
Blind smell: brain activation induced by an undetected air-borne chemical.
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EEG and behavioural evidence suggests that air-borne chemicals can affect the nervous system without being consciously detected. EEG and behaviour, however, do not specify which brain structures are involved in chemical sensing that occurs below a threshold of conscious detection. Here we used functional MRI to localize brain activation induced by high and low concentrations of the air-borne compound oestra-1,3,5(10),16-tetraen-3yl acetate. Following presentations of both concentrations, eight of eight subjects reported verbally that they could not detect any odour (P = 0.004). Forced choice detection performed during the presentations revealed above-chance detection of the high concentration, but no better than chance detection of the low concentration compound. Both concentrations induced significant brain activation, primarily in the anterior medial thalamus and inferior frontal gyrus. Activation in the inferior frontal gyrus during the high concentration condition was significantly greater in the right than in the left hemisphere (P = 0.03). A trend towards greater thalamic activation was observed for the high concentration than the low concentration compound (P = 0.08). These findings localize human brain activation that was induced by an undetectable air-borne chemical (the low concentration compound). (+info)
Characterization of nodular neuronal heterotopia in children.
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Neuronal heterotopia are seen in various pathologies and are associated with intractable epilepsy. We examined brain tissue from four children with subcortical or periventricular nodular heterotopia of different aetiologies: one with severe epilepsy following focal brain trauma at 17 weeks gestation, one with hemimegalencephaly and intractable epilepsy, one with focal cortical dysplasia and intractable epilepsy, and one dysmorphic term infant with associated hydrocephalus and polymicrogyria. The connectivity of nodules was investigated using histological and carbocyanine dye (DiI) tracing techniques. DiI crystal placement adjacent to heterotopic nodules revealed numerous DiI-labelled fibres within a 2-3 mm radius of the crystals. Although we observed labelled fibres closely surrounding nodules, the majority did not penetrate them. Placement of DiI crystals within nodules also identified a limited number of projections out of the nodules and in one case there was evidence for connectivity between adjacent nodules. The cellular and neurochemical composition of nodules was also examined using immunohistochemistry for calretinin and neuropeptide Y (NPY), which are normally expressed in GABAergic cortical interneurons. Within heterotopic nodules from all cases, numerous calretinin-positive neurons were identified, along with a few cell bodies and many processes positive for NPY. Calretinin-positive neurons within nodules were less morphologically complex than those in the cortex, which may reflect incomplete differentiation into an inhibitory neuronal phenotype. There were also abnormal clusters of calretinin-positive cells in the overlying cortical plate, indicating that the migratory defect which produces heterotopic nodules also affects development of the cortex itself. Thus, heterotopic nodules consisting of multiple neuronal cell types are associated with malformation in the overlying cortical plate, and have limited connectivity with other brain regions. This abnormal development of connectivity may affect neuronal maturation and consequently the balance of excitation and inhibition in neuronal circuits, leading to their epileptogenic potential. (+info)
Infratentorial atrophy on magnetic resonance imaging and disability in multiple sclerosis.
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Loss of tissue volume in the central nervous system may provide an index of fixed neurological dysfunction in multiple sclerosis. Recent magnetic resonance studies have shown a modest relationship between clinical disability rating scores and transverse sectional area of the cervical spinal cord. To explore further the relationship between atrophy and disability in multiple sclerosis, we estimated the volumes of infratentorial structures from MRIs in a cross-sectional study of 41 patients, 21 with relapsing-remitting multiple sclerosis and 20 with secondary progressive multiple sclerosis. We used the Cavalieri method of modern design stereology with point counting to estimate the volume of brainstem, cerebellum and upper cervical spinal cord from three-dimensional MRIs acquired with an MPRAGE (Magnetization-prepared Rapid Acquisition Gradient Echo) sequence. The volume of the upper (C1-C3) cervical spinal cord was significantly correlated with a composite spinal cord score derived from the appropriate Functional Scale scores of the Expanded Disability Status Scale (r = -0.50, P < 0.01). The cerebellar (r = 0.49, P < 0.01) and brainstem (r = 0.34, P < 0.05) volumes correlated with the Scripp's Neurological Disability Rating Scale scores. The upper cervical cord volumes (r = -0.39, P < 0.01), but not the brainstem or cerebellar volumes, were significantly associated with disease duration. MRI-estimated structural volumes may provide a simple index of axonal and/or myelin loss, the presumed pathological substrates of irreversible impairment and disability in multiple sclerosis. (+info)
Brain activation during maintenance of standing postures in humans.
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The regulatory mechanism of bipedal standing in humans remains to be elucidated. We investigated neural substrates for maintaining standing postures in humans using PET with our mobile gantry PET system. Normal volunteers were instructed to adopt several postures: supine with eyes open toward a target; standing with feet together and eyes open or eyes closed; and standing on one foot or with two feet in a tandem relationship with eyes open toward the target. Compared with the supine posture, standing with feet together activated the cerebellar anterior lobe and the right visual cortex (Brodmann area 18/19), and standing on one foot increased cerebral blood flow in the cerebellar anterior vermis and the posterior lobe lateral cortex ipsilateral to the weight-bearing side. Standing in tandem was accompanied by activation within the visual association cortex, the anterior and posterior vermis as well as within the midbrain. Standing with eyes closed activated the prefrontal cortex (Brodmann area 8/9). Our findings confirmed that the cerebellar vermis efferent system plays an important role in maintenance of standing posture and suggested that the visual association cortex may subserve regulating postural equilibrium while standing. (+info)
Selective horizontal dysmetropsia following prestriate lesion.
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We describe a patient (P.S.) who, following a right prestriate lesion, reported that objects in the left visual field appeared distorted and smaller than those on the right. Other aspects of visual processing were remarkably unaffected. We carried out a series of size comparison tests using simple or complex stimuli and requiring different types of behavioural responses. We found that P.S. significantly underestimated the size of stimuli presented in her left visual field. When comparison tasks involved stimuli placed along the vertical axis or in the right visual field, P.S. performed well. The vertical and horizontal components of size distortion were found to be differentially affected. We conclude that size processing may be dissociated from other aspects of visual processing, such as form or colour processing, and depends critically on part of the occipital, prestriate areas (Brodmann areas 18-19). (+info)