White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis.

Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.

Alanine transaminase is predominantly increased in the active phase of anti-HMGCR myopathy.

Autoantibodies against 3­hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and the signal recognition particle (SRP) are representative antibodies causing immune-mediated necrotizing myopathies (IMNM), called as anti-HMGCR and anti-SRP myopathies, respectively. Here, we analyzed the differences in routine blood test results between 56 anti-HMGCR and 77 anti-SRP myopathy patients. A higher alanine transaminase (ALT) level and a lower aspartate transaminase (AST)/ALT ratio were observed in anti-HMGCR myopathy patients [ALT, 265.7 ±â€¯213.3 U/L (mean ± standard deviation); AST/ALT ratio, 0.88 ±â€¯0.32] than in anti-SRP-myopathy patients (ALT, 179.3 ±â€¯111.2 U/L, p < 0.05; AST/ALT ratio, 1.28 ±â€¯0.40, p < 0.01). In the active phase, anti-HMGCR myopathy often showed ALT predominance, whereas anti-SRP myopathy often showed AST predominance. In addition, there were differences in erythrocyte sedimentation rate (ESR), total cholesterol (TChol) level, and high-density lipoprotein (HDL) level between anti-HMGCR and anti-SRP myopathies (ESR: HMGCR, 24.4 ±â€¯20.8 mm/1 h; SRP, 35.7 ±â€¯26.7 mm/1 h, p = 0.0334; TChol: HMGCR, 226.7 ±â€¯36.6 mg/dL; SRP, 207.6 ±â€¯40.8 mg/dL, p = 0.0163; HDL: HMGCR, 58.4 ±â€¯13.9 mg/dL; SRP, 46.2 ±â€¯17.3 mg/dL, p < 0.01). Additional studies on the differences in routine blood test results may further reveal the pathomechanisms of IMNM.

Anti-LGI1 Encephalitis Developing Immunoglobulin Responsive Orthostatic Hypotension after Remission.

Anti-leucine-rich glioma-inactivated 1 (LGI1) antibody is associated with limbic encephalitis. We herein report a patient with anti-LGI1 encephalitis who developed severe orthostatic hypotension (OH) responsive to immunoglobulin therapy five years after developing symptoms of encephalitis. A 71-year-old man presented with amnesia caused by limbic encephalitis. The symptoms of encephalitis improved partially without any immunotherapy. Five years later, he developed severe OH, and anti-LGI1 antibody was positive. The catecholamine dynamics indicated that the central autonomic nervous system was the lesion of his OH. Intravenous immunoglobulin therapy improved the OH. This case suggests that anti-LGI1 antibody can be associated with severe OH.

Reliability of fiber tracking measurements in diffusion tensor imaging for longitudinal study.

UNLABELLED: The statistical reliability of diffusion property measurements was evaluated in ten healthy subjects using deterministic fiber tracking to localize tracts affected in motor neuron disease: corticospinal tract (CST), uncinate fasciculus (UNC), and the corpus callosum in its entirety (CC), and its genu (GE), motor (CCM), and splenium (SP) fibers separately. Measurements of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda(1)), transverse diffusivity (lambda( perpendicular)), and volume of voxels containing fibers (VV) were obtained within each tract. To assess intra-rater and inter-rater reliability, two raters carried out fiber tracking five times on each scan. Scan-rescan and longitudinal reliability were assessed in a subset of four subjects who had six scans, with two sets of three scans separated by 1 year. The statistical reliability of repeated measurements was evaluated using intraclass correlation coefficients (ICC) and coefficients of variation (CV). Spatial agreement of tract shape was assessed using the kappa (kappa) statistic. RESULTS: Repeated same-scan fiber tracking evaluations showed good geometric alignment (intra-rater kappa >0.90, inter-rater kappa >0.76) and reliable diffusion property measurements (intra-rater ICC >0.92, inter-rater ICC >0.77). FA, MD, and lambda( perpendicular) were highly reliable with repeated scans on different days, up to a year apart (ICC >0.8). VV also exhibited good reliability, but with higher CVs. We were unable to demonstrate reproducibility of lambda(1). Longitudinal reliability after one year was improved by averaging measurements from multiple scans at each time point. Fiber tracking provides a reliable tool for the longitudinal evaluation of white matter diffusion properties.

Diffusion tensor tract-specific analysis of the uncinate fasciculus in patients with amyotrophic lateral sclerosis.

INTRODUCTION: The uncinate fasciculus (UF) consists of core fibers connecting the frontal and temporal lobes and is considered to be related to cognitive/behavioral function. Using diffusion tensor tractography, we quantitatively evaluated changes in fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) of the UF by tract-specific analysis to evaluate the damage of the UF in patients with amyotrophic lateral sclerosis (ALS). METHODS: We obtained diffusion tensor images of 15 patients with ALS and 9 age-matched volunteers. RESULTS: Patients with ALS showed significantly lower mean FA (P = 0.029) compared with controls. No significant difference was seen in mean ADC. CONCLUSION: The results suggest that damage of the UF in patients with ALS can be quantitatively evaluated with FA.

Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjögren syndrome.

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessively inherited neurodegenerative disorder characterized by cerebellar ataxia, cataracts, mental retardation, and progressive myopathy. Recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum (ER) resident cochaperone, were identified as a major cause of MSS. We here report four novel mutations in SIL1, including the first missense substitution p.Leu457Pro described in MSS. In addition, we excluded three functional candidate genes, HSPA5, HYOU1, and AARS, as causative genes in SIL1 mutation-negative patients. To understand the mechanisms of disturbed SIL1 function, we studied the subcellular localization of the missense mutant Leu457Pro protein in COS-1 cells. Moreover, we studied a mutant protein lacking the putative C-terminal ER retrieval signal. In contrast to the wild-type protein's localization to ER and Golgi apparatus, both mutant proteins formed aggregates within the ER depending on the expression level. These data imply that aggregation of mutant proteins may contribute to MSS pathogenesis. The genetic background of a subgroup of patients with MSS remains uncovered.

Differences in after-effect between monophasic and biphasic high-frequency rTMS of the human motor cortex.

OBJECTIVE: To study differences in the long-term after-effect between high-frequency, monophasic and biphasic repetitive transcranial magnetic stimulation (rTMS). METHODS: Ten hertz rTMS was delivered over the left primary motor cortex and motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle. To probe motor cortex excitability we recorded MEPs at several timings before, during and after several types of conditioning rTMSs. We also recorded F-waves to probe spinal excitability changes. Thousand pulses were given in total, with a train of 10 Hz, 100 pulses delivered every minute (ten trains for 10min). The intensity was fixed at 90% active motor threshold (AMT) or 90% resting motor threshold (RMT) for both monophasic and biphasic rTMS. In addition, we performed a monophasic rTMS experiment using a fixed intensity of 90% RMT for biphasic pulses. RESULTS: At 90% AMT, MEPs were enhanced for a few minutes after both monophasic and biphasic rTMS. On the other hand, at 90% RMT, a larger and longer enhancement of MEPs was evoked after monophasic rTMS than after biphasic rTMS. Monophasic rTMS at an intensity adjusted to biphasic 90% RMT elicited a great enhancement similar to that after monophasic rTMS at monophasic 90% RMT. Neither F-wave amplitude nor its occurrence rate was significantly altered by 90% RMT monophasic rTMS. CONCLUSIONS: These results suggest that enhancement after rTMS occurs at the motor cortex. Monophasic rTMS has a stronger after-effect on motor cortical excitability than biphasic rTMS. This is probably because monophasic pulses preferentially activate a relatively uniform population of neurons oriented in the same direction and their effects summate more readily than biphasic rTMS activating differently oriented neurons at slight different timings altogether. SIGNIFICANCE: The present results suggest that when using rTMS as a therapeutic tool or in research fields, the waveforms of magnetic pulses may affect the results profoundly.

Anti-TIF1-γ antibody and cancer-associated myositis: A clinicohistopathologic study.

OBJECTIVE: We aimed to analyze the clinical and histopathologic features of cancer-associated myositis (CAM) in relation to anti-transcriptional intermediary factor 1 γ antibody (anti-TIF1-γ-Ab), a marker of cancer association. METHODS: We retrospectively studied 349 patients with idiopathic inflammatory myopathies (IIMs), including 284 patients with pretreatment biopsy samples available. For the classification of IIMs, the European Neuromuscular Center criteria were applied. Patients with CAM with (anti-TIF1-γ-Ab[+] CAM) and without anti-TIF1-γ-Ab (anti-TIF1-γ-Ab[-] CAM) were compared with patients with IIM without cancers within and beyond 3 years of myositis diagnosis. RESULTS: Cancer was detected in 75 patients, of whom 36 (48%) were positive for anti-TIF1-γ-Ab. In anti-TIF1-γ-Ab(+) patients with CAM, cancers were detected within 1 year of myositis diagnosis in 35 (97%) and before 1 year of myositis diagnosis in 1. All the anti-TIF1-γ-Ab(+) patients with CAM satisfied the dermatomyositis (DM) criteria, including 2 possible DM sine dermatitis cases, and were characterized histologically by the presence of perifascicular atrophy, vacuolated fibers (VFs), and dense C5b-9 deposits on capillaries (dC5b-9). In contrast, 39 anti-TIF1-γ-Ab(-) patients with CAM were classified into various subgroups, and characterized by a higher frequency of necrotizing autoimmune myopathy (NAM). Notably, all 7 patients with CAM classified into the NAM subgroup were anti-TIF1-γ-Ab(-) and exhibited no dC5b-9 or VFs. CONCLUSIONS: CAM includes clinicohistopathologically heterogeneous disease entities. Among CAM entities, anti-TIF1-γ-Ab(+) CAM has characteristically shown a close temporal association with cancer detection and the histopathologic findings of dC5b-9 and VFs, and CAM with NAM is a subset of anti-TIF1-γ-Ab(-) CAM.

Quantitative evaluation of the pyramidal tract segmented by diffusion tensor tractography: feasibility study in patients with amyotrophic lateral sclerosis.

PURPOSE: Diffusion tensor imaging can evaluate the cerebral white matter quantitatively using fractional anisotropy (FA) and also can extract a certain tract by tractography, but these two have been used separately and not combined. The purpose of this study was to assess the clinical feasibility of ROI analysis using diffusion tensor tractography (DTT) in patients with amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: Sixteen patients with ALS (9 limb-onset type, 7 bulbar-onset type) and nine age-matched volunteers were studied. DTT of the corticobulbar tract (DTT-CBT) and corticospinal tract (DTT-CST) were visualized by free software (dTV/VOLUME-ONE). Regions-of-interest (ROIs) were semi-automatically placed on the tracts defined by DTT methods, and FA values within the ROIs were measured. RESULTS: Mean FA values of ALS patients in the ROIs along the DTT-CST (bulbar-onset: 0.574, limb-onset: 0.594) were significantly lower than those of controls (DTT-CST: 0.629) (p<0.05). The mean FA of DTT-CBT of the bulbar-onset type (0.509) was significantly lower than that of the limb-onset type (0.558) and that of volunteers (0.561). CONCLUSION: DTT could segmentate certain white matter tracts and evaluate them quantitatively. It could depict the subtle changes between subtypes of ALS as well as the changes between the patients and volunteers.

[Magnetic resonance imaging in patients of amyotrophic lateral sclerosis with and without dementia].

Classic magnetic resonance imaging (MRI) findings in patients with amyotrophic lateral sclerosis (ALS) are subtle, but some findings have been reported such as signal changes in the primary motor cortex and the corticospinal tract (CST). Only a few reports have discussed MRI findings of ALS with dementia (ALS-D), in which frontotemporal atrophy and hyperintensity in subcortical white matter of bilateral temporal tips have been reported. Recent development of diffusion tensor imaging (DTI) techniques allows us to extract specific white matter tracts and to analyze them quantitatively, i.e. we can visualize the CST and can also measure its integrity using DTI parameters such as fractional anisotropy (FA) or apparent diffusion coefficient (ADC). In patients with ALS, general decrease in FA and increase in ADC in the CST have been reported. In patients with ALS-D, several authors detected decrease in fractional anisotropy in the corpus callosum, the thalamus, frontal/parietal/temporal, the cingulate gyrus, and the uncinate fasciculus in addition to the CST. Voxel based morphometry or statistical analysis of imaging are the newly developed methods which enable to make objective and reliable imaging analysis based on automated procedure using standardized database. We also presented several researches using these techniques. In this article, we reviewed classic imaging findings and recent development of MRI including DTI and statistical imaging analysis in patients with ALS/ALS-D.

[Objective markers for upper motor neuron involvement in amyotrophic lateral sclerosis].

A reliable objective marker of upper motor neuron (UMN) involvement is critical for early diagnosis and monitoring disease course in patients with amyotrophic lateral sclerosis (ALS). Lower motor neuron (LMN) involvement can be identified by electromyography, whereas UMN dysfunction has been currently distinguished solely by neurological examination. In the search for diagnostic tests to evaluate UMN involvement in ALS, numerous reports on new markers using neurophysiological and imaging techniques are accumulating. Transcranial magnetic stimulation evaluates the neurophysiological integrity of UMN. Although the diagnostic reliability and sensitivity of various parameters of central motor conduction measurement differ, central motor conduction time measurement using brainstem stimulation is potentially useful for determining UMN dysfunction by distinguishing lesions above the pyramidal decussation. MR-based techniques also have the potential to be used as diagnostic markers and are continuously improving as a modality to pursue early diagnosis and monitoring of the disease progression. Conventional MRI reveals hyperintensity along the corticospinal tract, hypointensity in the motor cortex, and atrophy of the precentral gyrus. There is a lack of agreement regarding sensitivity and specificity in detecting UMN abnormalities. Recent advances in magnetizing transfer imaging (MTI) provide more sensitive and accurate detection of corticospinal tract abnormality than conventional MRI. Reduction in N-acetyl-aspartate by proton magnetic spectroscopy in the motor cortex or the brainstem of the patients with ALS is reported with different techniques. Its diagnostic value in clinical assessment is uncertain and remains to be established. Diffusion tensor imaging (DTI) reveals the structural integrity of neuronal fibers, and has great diagnostic promise for ALS. It shows reduced diffusion anisotropy in the corticospinal tract with good correlation with physiological index, reflecting UMN pathology. Diffusion tensor tractography allows for visualization and evaluation of corticospinal and corticobulbar tract dysfunction individually in patients with ALS. Although many of these new approaches do not yet reach clinical significance, they have been extensively explored in objective evaluation of upper motor function in patients with ALS. Further investigation is needed to determine and to compare the utility of various neurophysiological and neuroimaging markers.

The effects of cerebellar stimulation on the motor cortical excitability in neurological disorders: a review.

The cerebellum regulates execution of skilled movements through neural connections with the primary motor cortex. A main projection from the cerebellum to the primary motor cortex is a disynaptic excitatory pathway relayed at the ventral thalamus. This dentatothalamocortical pathway receives inhibitory inputs from Purkinje cells of the cerebellar cortex. These pathways (cerebellothalamocortical pathways) have been characterized extensively using cellular approaches in animals. Advances in non-invasive transcranial activation of neural structures using electrical and magnetic stimulation have allowed us to investigate these neural connections in humans. This review summarizes various studies of the cerebellothalamocortical pathway in humans using current transcranial electrical and magnetic stimulation techniques. We studied effects on motor cortical excitability elicited by electrical or magnetic stimulation over the cerebellum by recording surface electromyographic (EMG) responses from the first dorsal interosseous (FDI) muscle. Magnetic stimuli were given with a round or figure eight coil (test stimulation) for primary motor cortical activation. For cerebellar stimulation, we gave high-voltage electrical stimuli or magnetic stimuli through a cone-shaped coil ipsilateral to the surface EMG recording (conditioning stimulation). We examined effects of interstimulus intervals (ISIs) with randomized condition-test paradigm, using a test stimulus given preceded by a conditioning stimulus by ISIs of several milliseconds. We demonstrated significant gain of EMG responses at an ISI of 3 ms (facilitatory effect) and reduced responses starting at 5 ms, which lasted 3-7 ms (inhibitory effect). We applied this method to patients with ataxia and showed that the inhibitory effect was only absent in patients with a lesion at cerebellar efferent pathways or dentatothalamocortical pathway. These results imply that this method activates the unilateral cerebellar structures. We confirmed facilitatory and inhibitory natures of cerebellothalamocortical pathways in humans. We can differentiate ataxia attributable to somewhere in the cerebello-thalamo-cortical pathways from that caused by other pathways.

Interhemispheric transmission of visuomotor information for motor implementation.

Using transcranial magnetic stimulation (TMS), we addressed the contribution of both hemispheres to the visuomotor control of each hand. The subjects had to press one of two buttons as quickly as possible after the go-signal. A precue preceding this conveyed full, partial or no advance information (hand and/or button), such that reaction time (RT) shortened with increasing amount of information. We gave TMS over each hemisphere at various time intervals (100-350 ms) after the go-signal and before the expected onset of response, and measured its effect on RT, movement time (MT) and error rate. At short intervals (100-200 ms), left hemisphere TMS delayed RT and prolonged MT of both hands, while right hemisphere TMS delayed RT only of the right hand, without affecting error rates. At long intervals (250-350 ms), TMS produced slightly more pronounced RT delays of the contralateral hand. RT was delayed more if the precues were less informative. The results suggest the importance of interhemispheric transmission of visuomotor information for motor implementation. The right hemisphere may play a role mainly in calculating target and effector information, determining RT, while the left hemisphere may play a role in elaborating the motor program and determining MT.

Effects of motor cortical stimulation on the excitability of contralateral motor and sensory cortices.

Single pulses of transcranial magnetic stimulation (TMS) were applied to the right hemisphere over either the hand sensory area, the hand motor area (M1), ventral premotor area (vPM), dorsolateral prefrontal cortex, or 10 cm away from head (sham stimulation) in order to test the effect on motor evoked potentials (MEPs) elicited by single pulse TMS or transcranial electrical stimulus (TES) over the left M1 or the somatosensory evoked potential (SEP) elicited by an electrical stimulus to the right median nerve. The interstimulus intervals (ISIs) for MEP experiments were 50, 100, 150, 200, 300 and 400 ms, with those for SEP experiments being adjusted for the impulse conduction time from the wrist to the cortex. TMS over the right M1 reduced MEPs elicited by TMS of the left motor cortex at ISIs of 50-150 ms, whereas MEPs produced by TES were unaffected. TMS over M1 and vPM facilitated the contralateral cortical median nerve SEPs at an ISI of 100-200 ms, whereas it had no effect on tibial nerve SEPs or paired median nerve stimulation SEP. Based on these results, we conclude that at around 150-ms intervals, TMS over the motor areas (M1 and vPM) reduces the excitability of the contralateral motor area. This has a secondary effect of enhancing the responsiveness of the sensory cortex through cortico-cortical connections.