中央前回质子磁共振波谱在肌萎缩侧索硬化患者临床病情评估中的价值

目的 以质子磁共振波谱(1H-MRS)研究肌萎缩侧索硬化(ALS)的上运动神经元病损情况,以期探寻一种评估病情和疾病进程的指标.方法 对110例ALS和24例下运动神经元综合征(LMNS)患者以及89名健康志愿者进行双侧中央前回单体素1H-MRS检查.以上运动神经元受损体征和反射评分、ALS功能评估量表(ALS-FRS)和APPEL ALS量表(AARS)定量评定患者临床症状和体征.结果 与对照组(1.62±0.18)相比,LMNS患者(1.60±0.17)的NAA/Cr无改变,但ALS患者(1.40±0.25)与两组相比均明显降低(与对照组比较,t=-5.007,P=0.000;与LMNS组比较,t=-2.660,P=0.009);在不同分级的ALS患者中,确诊ALS患者较拟诊ALS者和可能ALS者降低更为明显(与拟诊组比较,t=-2.626,P=0.010;与可能组比较,t=-2.537,P=0.013).结合ALS患者临床表现进一步分析发现,上运动神经元体征明显的患者其NAA/Cr较不明显的患者降低更为明显,差异有统计学意义(t=-2.827,P=0.006),相关分析显示,NAA/Cr与患者的反射评分、ALS-FRS、AARS及其各分项均存在显著相关性(P＜0.05).结论 ALS中央前回1H-MRS检测在一定程度上反映患者上运动神经元受损情况,可作为评估患者病情程度的一项临床指标,但其对该病早期诊断和鉴别诊断的价值有限.     

Signal loss in the motor cortex on magnetic resonance images in amyotrophic lateral sclerosis

Three of 7 patients with amyotrophic lateral sclerosis had bilateral signal loss confined to the motor cortex on T2-weighted magnetic resonance images. None of the control subjects had this abnormality. Although not present in every patient, this finding might reflect the primary pathological process of the motor cortex in amyotrophic lateral sclerosis.     

Double magnetic stimulation of the motor cortex in amyotrophic lateral sclerosis

Objectives: To study the motor cortex circuitry and the motor interhemispheric influences with double magnetic stimulation in patients affected by amystrophic lateral sclerosis.Methods: We investigated the motor cortex in 21 amyotrophic lateral sclerosis patients (ALS, 10 with bulbar and 11 with spinal onset) with double magnetic stimulation (one shock in each hand area) with 2, 4, 6, 11 and 15 ms delay between shocks and paired magnetic stimulation (both shocks in the same area), with 4, 15, 25, 35, 55, 85, 100, 155, 200 and 255 ms delays, and compared the results with those obtained in normal subjects.Results: Double magnetic stimulation showed reduced interhemispheric facilitatory influences (maximal at 4 ms delay between shocks) when the test shock was applied on the left hemisphere in all patients; whereas no significant differences were observed compared to control (P>0.05) when it was applied on the right hemisphere in both forms. Inhibitory effects (maximal at 11 ms delay between shocks) were reduced in all patients for both hemispheres (P<0.05). Paired magnetic stimulations showed decreased inhibitory influences at 100–155 ms delay between shocks. Compared to control, the difference was significant in bulbar (P<0.05) and spinal onset, but not between onset forms (P>0.05). Inhibitory effects recorded with a short delay between shocks (4 ms) were not significantly modified in both forms of onset (P>0.05) as compared to control. There were no facilitatory influences at 15 and 35 ms delays between shocks.Conclusions: The results suggest that under these test conditions inhibition and facilitation were reduced in the motor cortex in ALS. As inhibitory effects were affected differently, two distinct cortical circuitries could be involved for short and long delays. As GABA neurons altered in ALS have been identified as a subpopulation reactive to parvalbumin, and since only inhibitory effects recorded with long delay between shocks were impaired in ALS, we suggest that this subpopulation of GABA neurons may be involved in the genesis of inhibitory effects recorded with a long delay between shocks.     

The motor cortex and amyotrophic lateral sclerosis

On theoretical grounds, abnormalities of the motor cortex in patients with amyotrophic lateral sclerosis (ALS) could lead to anterograde ("dying-forward") transneuronal degeneration of the anterior horn cells as suggested by Charcot. Conversely, retrograde ("dying-back") degeneration of the corticospinal tracts could affect the motor cortex. Evidence derived from clinical, neuropathological, static, and functional imaging, and physiological studies, favors the occurrence of anterograde degeneration. It is hypothesized that transneuronal degeneration in ALS is an active excitotoxic process in which live but dysfunctional corticomotoneurons, originating in the primary motor cortex, drive the anterior horn cell into metabolic deficit. When this is marked, it will result in more rapid and widespread loss of lower motor neurons. In contrast, slow loss of corticomotoneurons, as occurs in primary lateral sclerosis (PLS), precludes excitotoxic drive and is incompatible with anterograde degeneration. Preservation of slow-conducting non-M1 direct pathways in PLS is not associated with excitotoxicity, and anterior horn cells survive for long periods of time.     

Neuronophagia in the motor cortex in amyotrophic lateral sclerosis

This study was designed to identify which phagocytic cells in the cerebral cortex of amyotrophic lateral sclerosis (ALS) patients are involved in the process of neurono-phagia. For this purpose a number of single and double immunocytochemical stains were carried out on five ALS cases which were selected on the basis of the presence of degenerative and phagocytic phenomena in the cerebral cortex. The cortical degenerative process is mainly present in the third and fifth layers and is not restricted to the fifth layer which contains the cell bodies of the Betz cells. The present study indicates that a number of cells are involved in the process of phagocytosis in ALS. Resident macro-phages (from microglial or perivascular origin) and astrocytes seem to play an immunologically-mediated role in the disappearance of neurons. Some of the cells involved in the degenerative process, i.e. rounded macrophages and microglia, expressed major histocompatibility class II antigen. The phagocytic cells in neuronophagia were phenotypically identical to perivascular macrophages and not to microglia. Therefore, the process of phagocytosis of neurons appears to be primarily the task of the perivascularly located macrophage.     

Changes in motor cortex inhibition over time in patients with amyotrophic lateral sclerosis

Abnormal balance between intracortical inhibitory and excitatory mechanisms has been found to contribute to the genesis of motor cortex hyperexcitability in amyotrophic lateral sclerosis (ALS), but data are lacking on the role of these abnormalities in the pathophysiology of the disease. We evaluated the resting motor threshold (RMT), the cortical silent period (CSP) to single-pulse transcranial magnetic stimulation (TMS), early intracortical inhibition (ICI), early intracortical facilitation (ICF) and late ICI to paired-pulse TMS in 40 patients with ALS. These parameters were correlated with disease duration and clinical features. They were also monitored over time in selected patients.The main abnormal TMS findings were: (a). reduced or even absent early and late ICI; six out of 9 patients, with normal early ICI at the first recording, developed abnormal ICI after several months; (b). reduced cortical silent period duration with increasing TMS intensity. ICF and RMT were not affected. Impairment of early and late ICI correlated significantly with disease duration, the diagnostic categories and the clinical evidence of upper motor neuron involvement.The alteration of different cortical inhibitory functions seems to take place with disease progression, rather than being the primary event in the pathogenesis of ALS. The impaired inhibition is considered as being due to both depletion of specific subpopulations of intracortical GABAergic neurons and mechanisms involved in motor cortex reorganization following progressive neuronal loss. Clarification of the importance of these factors in the pathogenesis of the disease may have diagnostic and therapeutic implications.     

Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients

Summary We examined patterns of neuronal degeneration in the motor cortex of amyotrophic lateral selerosis (ALS) patients using traditional cell stains and several histochemical markers including neurofilament, parvalbumin, NADPH-diaphorase, ubiquitin, Alz-50 and tau. Three grades of ALS (mild, moderate, severe) were defined based on the extent of Betz cell depletion. Non-phosphorylated neurofilament immunoreactive cortical pyramidal neurons and non-pyramidal parvalbumin local circuit neurons were significantly depleted in all grades of ALS. In contrast, NADPH-diaphorase neurons and Alz-50-positive neurons were quantitatively preserved despite reduced NADPH-diaphorase cellular staining and dendritic pruning. The density of ubiquitin-positive structures in the middle and deep layers of the motor cortex was increased in all cases. Axonal tau immunoreactivity was not altered. These histochemical results suggest that cortical degeneration in ALS is distinctive from other neurodegenerative diseases affecting cerebral cortex. Unlike Huntington's disease, both pyramidal and local cortical neurons are affected in ALS; unlike Alzheimer's disease, alteration of the neuronal cytoskeleton is not prominent. The unique pattern of neuronal degeneration found in ALS motor cortex is consistent with non-N-methyl-Dxxx-aspartate glutamate receptor-mediated cytotoxicity.Supported in part by a Muscular Dystrophy Association Research Development grant     

Functional magnetic resonance imaging of human motor unit fasciculation in amyotrophic lateral sclerosis

A novel diffusion‐weighted magnetic resonance imaging protocol sensitive to contraction of individual skeletal motor units was developed. We applied this technique to the lower limb muscles of 4 patients with confirmed amyotrophic lateral sclerosis (ALS) and 6 healthy controls. A 3‐minute scan revealed florid fasciculation in ALS patients, involving both superficial and deep muscles, and at a frequency higher than in healthy controls. This novel imaging technique reveals hitherto unobtainable information on human motor unit structure and function, which may allow earlier diagnosis and recruitment to clinical trials. ANN NEUROL 2019;85:455–459.     

Proton magnetic resonance spectroscopy in multiple sclerosis

Regional in vivo proton magnetic resonance spectroscopy provides quantitative data on selected chemical constituents of brain. We imaged 16 volunteers with clinically definite multiple sclerosis on a 1.5 tesla magnetic resonance scanner to define plaque-containing volumes of interest, and obtained localized water-suppressed proton spectra using a stimulated echo sequence. Twenty-five of 40 plaque-containing regions provided spectra of adequate quality. Of these, 8 spectra from 6 subjects were consistent with the presence of cholesterol or fatty acids; the remainder were similar to those obtained from white matter of normal volunteers. This early experience with regional proton spectroscopy suggests that individual plaques are distinct. These differences likely reflect dynamic stages of the evolution of the demyelinative process not previously accessible to in vivo investigation.     

Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy

BACKGROUND: Clinical assessment is insensitive to the degree of cerebral involvement in amyotrophic lateral sclerosis (ALS). Regional brain concentrations N-acetylaspartylglutamate (NAA) plus myo-inositol (Ins), as measured by magnetic resonance spectroscopy, are respectively decreased and increased, suggesting that these compounds may provide a biomarker of the degree of cerebral involvement in ALS. OBJECTIVE: To test the hypothesis that the NAA/Ins ratio may provide an index of cerebral involvement in patients with ALS. DESIGN: High-field (3.0-T) magnetic resonance spectroscopy was performed to determine the NAA/creatine plus phosphocreatine (NAA/Cr), NAA/choline (NAA/Cho), Ins/Cr, and NAA/Ins ratios in the motor cortex. PARTICIPANTS: Seventeen patients with ALS and 15 healthy control subjects were studied. RESULTS: In patients with ALS, the greatest abnormality was a 22% decrease in NAA/Ins (71% sensitivity and 93% specificity, P = .001); Ins/Cr was increased 18% (88% sensitivity and 53% specificity, P = .04), NAA/Cr was decreased 10% (88% sensitivity and 47% specificity, P = .04), and NAA/Cho was decreased 14% (53% sensitivity and 87% specificity, P = .047). Correlation of the ALS Functional Rating Scale with NAA/Ins approached statistical significance (R = 0.43, P = .07). CONCLUSION: The NAA/Ins ratio may provide a meaningful biomarker in ALS given its optimal sensitivity and specificity profile.     

磁共振波谱检测肌萎缩侧索硬化的上运动神经元损害

目的探讨质子磁共振波谱(proton magnetic resonance spectroscopy,1 H-MRS)检测肌萎缩侧索硬化(amyotrophic lateral sclerosis,ALS)的上运动神经元损害(upper motor neuron,UMN)的特点和诊断准确性。方法收集ALS患者31例和健康对照32名,采用1 H-MRS检测脑中央前回皮质下、内囊后肢和大脑脚感兴趣区代谢产物N-乙酰天冬氨酸(NAA)、胆碱(Cho)、肌酸(Cr)的水平,计算NAA/Cr、NAA/(Cho+Cr)、Cho/Cr比值,采用受试者工作特征(receiver operating characteristic,ROC)曲线分析1 H-MRS对ALS患者UMN损害的诊断价值。结果 ALS患者各锥体束走行部位和部位组合的NAA/Cr和NAA/(Cho+Cr)较对照组显著降低(P0.05)。NAA比值预测ALS的UMN损害的ROC曲线下面积(area under the curve,AUC)为0.67~0.91,其中内囊后肢、大脑脚两部位的平均NAA/(Cho+Cr)和三部位的平均NAA/(Cho+Cr)的AUC、灵敏度、特异度分别为0.91、0.828、0.906和0.90、0.769、0.875。结论 1 H-MRS可检出ALS患者锥体束走行的生化代谢异常,是评估ALS的UMN损害的客观影像学指标,其诊断准确性中等,多水平检测和综合指标的选择有助于提高其诊断效力。     

1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis.

1H-magnetic resonance spectroscopy (MRS) is potentially a powerful tool for the investigation of the chemicals of the brain in vivo in health and disease. Levels of N-acetyl-aspartate (NAA) in the motor cortex and brainstem of patients with amyotrophic lateral sclerosis (ALS) have been reported to be reduced by up to 68%, and in one report the level of glutamate in the brainstem was increased by 58%. We studied levels of metabolites in the cerebral cortex and brainstem of 20 ALS patients and 14 age-matched controls with a 1.5 Tesla Picker magnet using MRS. We used the same spectra for determining both the area of the metabolite peaks expressed as a ratio of the area of the creatine (Cr) peak, and the absolute concentrations using the Provencher LC model. These produced different results. With the LC model, the NAA content of the motor cortex of ALS patients was reduced by 7.7% (P=0.015), and that of the brainstem was reduced by 21.5% (P=0.035), compared with controls. The degree of reduction of NAA was related to the severity of upper motor neuron abnormalities. No effect of treatment with anti-glutamate agents on NAA concentration could be detected. Concentrations of other metabolites were not affected in ALS. It appears that MRS is a technique that is still in development, and that further refinement is required before it can be used to understand disease mechanisms and investigate treatment in ALS.     

肌萎缩侧索硬化38例弥散张量成像及磁共振波谱表现

目的 研究肌萎缩侧索硬化(ALS)的弥散张量成像(DTI)和磁共振波谱(MRS)特点,并对ALs的病理生理机制进行初步探讨.方法 ALS患者38例,单纯下运动神经元受累疾病患者8例,混合型颈椎病5例和健康对照34名,行常规头颅MRI、DTI和1H-MRS测定.结果 21%(8/38)的ALS患者可见T2 FLAIR序列双侧锥体束走行异常高信号,强度高于皮质灰质.ALS组和健康对照组相比,中央前回(ALS组0.492±0.059,健康对照组0.552 4-0.045,F=17.150,P<0.01)、内囊后肢(分别为0.679 ±0.048、0.727±0.031,F=19.481,P<0.01)、大脑脚(左侧0.740±0.038、0.761±0.024,F=4.290;右侧0.720±0.044、0.746±0.034,F=3.264,均P<0.01)的部分各向异性(FA值)显著降低;ALS组上述部位的N-乙酰大冬氨酸/肌酸(NAA/Cr)值和健康对照组相比亦存在显著降低.AKS组各部位FA值降低百分率分别为10.9%、6.6%、2.8%～3.5%,以中央前回处最为显著;内囊前肢、枕叶处的FA值亦有不同程度降低.结论 DTI和MRS枪测不仪有助于ALS患者:运动神经元高位受累的确认和ALS的诊断和鉴别诊断,而且还可促进对ALS病理机制和病损分布的了解.     

Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex

Glutamate transport is critical for synaptic inactivation of glutamate and prevention of excitotoxicity. The following four glutamate transporters have been identified in human brain: EAAT1, EAAT2, EAAT3, and EAAT4. Deficient glutamate transport has been identified in the motor cortex and the spinal cord of tissue from amyotrophic lateral sclerosis (ALS) patients. The defect appears to be due to a selective loss of the astroglial specific glutamate transporter protein EAAT2. In these studies we sought to extend our understanding of glutamate transporters in ALS by examining the mRNA for each transporter subtype in ALS motor cortex. All tissue was matched for age and postmortem delay. There was no quantitative change in mRNA for EAAT1, EAAT2, or EAAT3 in ALS motor cortex, even in patients with a large loss of EAAT2 protein (95% decrease compared with control) and decreased tissue glutamate transport (73% decrease compared with control). These studies suggest that the dramatic abnormalities in EAAT2 may be due to translational or post- translational processes.     

Immunocytochemical and ultrastructural studies of the motor cortex in amyotrophic lateral sclerosis

This report concerns an immunocytochemical and ultrastructural study of the motor cortices of 11 patients with amyotrophic lateral sclerosis (ALS). Specimens from 12 normal individuals served as controls. Antibodies against phosphorylated neurofilament (PNF; 200 kDa), ubiquitin, glial fibrillary acidic protein (GFAP) and phosphorylated tau protein were used. The pyramidal cells of layer III of all ALS patients were stained, with varying intensities, by the antibody to PNF. By contrast, Betz cells reacted less frequently with this antibody. Staining for GFAP was noted in numerous astrocytes in layer III and at the transition between white matter and motor cortex of most patients. Ubiquitin-positive inclusions were only occasionally seen in Betz cell and pyramidal cell of layer V. These observations indicate that alterations of the motor cortex occur first in the pyramidal cells of layer III rather than in Betz cells. Pyramidal cells and Betz cells were not stained by the antibody to phosphorylated tau protein. In controls, pyramidal cells and Betz cells were less frequently stained with the anti-neurofilament antibody than those from ALS patients. Immunoreactivity of GFAP in layer III and at the junction of white matter and motor cortex was observed in only one patient. Ultrastructural examination revealed that the Betz cells of some ALS patients had Bunina bodies (BB), Lewy body-like inclusions (LBI) and skein-like inclusions (SI), as well as bundles of filaments that were thicker than neurofilaments; some of these filaments appeared to be constricted. The incidence of these inclusions was lower than that seen in anterior horn neurons. Cytoplasmic inclusions such as BB, LBI, and SI were not observed in any of the controls. Our findings suggest that the cytopathology of upper motor neurons is similar to that of lower motor neurons and that the changes seen in Betz cells appear to be a reflection of the lower motor neuron alterations.Supported by a research grant for New Drug Development in ALS from the Ministry of Health and Welfare of Japan     

Golgi apparatus of the motor neurons in patients with amyotrophic lateral sclerosis and in mice models of amyotrophic lateral sclerosis

We examined the Golgi apparatus (GA) of motor neurons of patients with ALS and in mice models of ALS by immunohistological method using antiserum against MG160 and against components of the trans‐Golgi network (TGN46). The GA of half of the remaining spinal cord motor neurons of patients with sporadic ALS showed fragmentation, where the GA were dispersed or fragmented into numerous small, isolated elements. The GA of Betz cells in sporadic ALS were fragmented similar to that of anterior horn cells, and the GA of spinal cord motor neurons of those with familial ALS and of those with ALS with basophilic inclusions were fragmented or diminished. The GA in the majority of the motor neurons contained Bunina bodies, basophilic inclusions and superoxide dismutase 1 (SOD1)‐positive aggregates were fragmented. The motor neurons in transgenic mice expressing G93A mutation of the SOD1 gene showed the fragmentation of the GA months before the onset of paralysis. These findings suggest that the fragmentation of GA may be related to the neuronal degeneration in patients with ALS.     

Proton magnetic resonance spectroscopy of the striatum in Parkinson's disease patients with motor response fluctuations

We have performed proton magnetic resonance spectroscopy centred on the putamen contralateral to the worst affected side in 10 patients with idiopathic Parkinson's disease (PD) and motor response fluctuations and seven age matched healthy controls. In PD, there was striking reduction in the N-acetylaspartate (NAA) and creatine and NAA/choline ratios compared to controls. This pilot study provides in vivo evidence of striatal neuronal dysfunction in PD and further studies are in progress to establish if the observed changes are due to the disease process itself or due to chronic levodopa therapy.