Cerebral atrophy in multiple system atrophy by MRI

Cranial magnetic resonance images (MRI) of the cerebral areas of 40 patients with multiple system atrophy (MSA) and of 61 age-matched controls were analyzed. The cerebral area of MSA patients was 131. 95+/-15.89 cm(2) (mean+/-S.D.), which was significantly smaller than that of normal controls at 149.01+/-10.93 cm(2) (P<0.0001). All 23 MSA cases subjected to the MRI study over a 1-year period showed progressive cerebral atrophy, and the atrophy rate was 2.46+/-1. 66%/year. There were no significant differences within the MSA subtypes or between gender. The progression of cerebral atrophy in MSA correlated more with duration (r=-0.634) than age (r=-0.421). We conclude that MRI findings throughout the course of MSA suggest progressive cerebral atrophy, which is common in all subtypes and reflects duration of the disease rather than age.     

Alpha-synuclein inclusions in amygdala in the brains of patients with the parkinsonism-dementia complex of Guam

We investigated by immunohistochemistry the deposition of alpha-synuclein in the brains of deceased patients with the parkinsonism-dementia complex (PDC) of Guam. Five of 13 PDC brains showed numerous alpha-synuclein positive neuronal inclusions and abnormal neurites, chiefly in the amygdala. Similar alpha-synuclein positive lesions were observed, although to a lesser extent, in the entorhinal cortex and the dorsal vagal nucleus. No alpha-synuclein positive inclusions were observed in motor cortex or locus coeruleus, and only a small number of positive inclusions were found in the Sommer's sector, temporal cortex, or substantia nigra. Some of the alpha-synuclein positive inclusions were reminiscent of cortical Lewy bodies (LB), but many of those in the amygdala coexisted with tau-positive pretangles and/or neurofibrillary tangles (NFT) within the same neurons. In these neurons, tau-positive shells encapsulated alpha-synuclein positive central cores or irregularly shaped alpha-synuclein-positive deposition intermingled with pretangles/NFT. Thus, the present study suggests that a common mechanism may govern aggregation of alpha-synuclein and tau in the amygdala, and that aggregation of alpha-synuclein may play some role in the neurodegenerative process of a tauopathy (i.e. PDC) in which Abeta deposition is virtually absent.     

Serial diffusion-weighted imaging in MELAS

Clinical features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) resemble those of cerebral infarcts, but the pathogenesis of infarct-like lesions is not fully understood. To characterise these infarct-like lesions, we studied two patients with MELAS using diffusion-weighted (DWI) MRI before and after stroke-like episodes and measured the apparent diffusion coefficient (ADC) in the new infarct-like lesions. These gave high signal on DWI and had much higher ADC than normal-appearing regions. The ADC remained high even 30 days after a stroke-like episode then decreased in lesions, with or without abnormality as shown by conventional MRI. We speculate that early elevation of ADC in the acute or subacute phase reflects vasogenic rather than cytotoxic edema. The ADC of the lesions, which disappeared almost completely with clinical improvement, returned to normal levels, which may reflect tissue recovery without severe damage. To our knowledge, this is the first study of DWI in MELAS. Received: 13 September 1999/Accepted: 7 January 2000     

Cerebral oximetry for the detection of cerebral ischemia during temporary carotid artery occlusion

The near-infrared spectroscopy cerebral oximeter was assessed as a monitoring device for detecting and/or predicting cerebral ischemia during carotid endarterectomy (CEA) and the balloon occlusion test in 24 patients, 12 males and 12 females aged 28 to 77 years (mean 59.9 years). Tolerance testing of complete internal carotid artery (ICA) occlusion by balloon inflation for 20 minutes was performed in nine patients (cerebral aneurysm 6, neck tumor 3) and CEA was performed in 15 patients. The probe of the cerebral oximeter was placed on the forehead of the affected side and regional cerebral oxygen saturation (rSO2) was monitored continuously during all procedures. Stump pressure was measured just after ICA occlusion. Collateral circulation detected by digital subtraction angiography was classified into three groups: good, moderate, or poor. Stump pressure was 41-90 mmHg (mean 61.3 mmHg) in the good collateral circulation group, 40-43 mmHg (41.5 mmHg) in the moderate group, and 14-30 mmHg (23.8 mmHg) in the poor group. Change in rSO2 after ICA occlusion was +3.5(-)-4.2% (mean -1.6%) in the good collateral circulation group, -1.2(-)-6.6% (-3.2%) in the moderate group, and -2.4(-)-10.2% (-6.6%) in the poor group. Changes in rSO2 were significantly different between the good and poor collateral circulation groups (p < 0.01). A greater than 5% fall in rSO2 was observed in 0 of 15 patients in the good collateral circulation group, one of five in the moderate group, and three of four in the poor group. The cerebral oximeter is a useful, real-time, non-invasive method to measure brain oxygenation during CEA, skull base surgery, or other procedures which need to evaluate brain ischemia. A fall of greater than 10% from the rSO2 baseline value is dangerous, but less than 5% is safe.     

Inhibitors on an elastase-like enzyme activity catalyzing Suc-Ala-Ala-Pro-Leu-pNA amidolysis in human seminal plasma

The behavior of some proteinase inhibitors toward the Suc-Ala-Ala-Pro-Leu-pNA amidolytic enzyme activity in human seminal plasma (HSP) was tested. [(2S, 3R)-3-Amino-2-hydroxy-5-methyl-hexanoyl]L-valyl-L-valyl-L-aspartic acid (Amastatin) and 3-[1-[(2-(hydroxymethyl)- -pyrolidinyl)-2-methylpropyl]-carbamoyl] octanohydroxamic acid (Actinonin) showed strong inhibitory effects. No inhibition of this present enzyme activity was seen with anti-human serum (whole), anti-human leukocyte elastase, phenyl-methyl sulfonyl fluoride, Elastatinal, ethyeneglycol bis(beta-aminoethyl ethyl)N,N,N:N'-tetra acetic acid, and [L-3-trans-ethoxycarbonyl-oxirane-2-carbonyl]1-L-leucine(3-methylbutyl)a mido (E-64). No relation was observed between human pancreatic elastase antigen and the Suc-Ala-Ala-Pro-Leu-pNA amidolytic enzyme enzyme activity in HSP. Two peaks of Suc-Ala-Ala-Leu-Pro-pNA amidolytic enzyme activity were separated by Cellulofine GCL-2000 gel filtration and these activities were completely abolished by addition of Amastatin. Suc-Ala-Ala-Pro-Leu-pNA amidolytic enzyme activity in HSP is not an elastase-like metalloproteinase but is rather an acyl amidase-like leucine aminopeptidase.     

The management of medial ligament tears in patients with combined anterior cruciate and medial ligament lesions

The management of patients with combined medial collateral (MCL) and anterior cruciate (ACL) rupture remains controversial. We studied 25 such patients who elected to have the ACL lesion treated conservatively; 14 underwent MCL repair with early mobilization and 11 were treated with immobilization for two weeks. The mean follow up was 5.9 years (2 to 11). There was no difference in the clinical assessment of ligamentous laxity, KT-1000 measurements or Tegner activity scores between the two groups but there were significantly higher Lysholm function scores in the operated group.

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Résumé Le traitement optimal des cas associant des lésions du ligament croisé antérieur (ACL) à des lésions médiales collatérales (MCL) est controversé. Nous avons réalisé une étude sur le suivi du traitement de telles lésions dans le but d’évaluer si le traitement opératoire des déchirures de MCL peut apporter une amélioration des résultats fonctionnels pour des patients choisissant de ne pas subir une reconstruction de ACL. Notre étude portait sur 14 patients ayant subi une reconstruction du MCL et 11 patients traités sans opération. Nous n’avons pas observé de différences significatives entre les deux groupes pour les tests de relachement manuel, ni pour les mesures KT-1000, ni pour les niveaux d’activité de Tegner. En revanche les patients du groupe opératoire ont obtenu un meilleur score fonctionnel de Lysholm.

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Accepted: 7 December 1999     

Age-specific effects of noradrenergic alpha-2 agonist clonidine on the development of amygdaloid kindling in developing rats

The effects of clonidine on the development of amygdaloid kindling were studied in rats of various ages (14, 21, 28 and 70 postnatal days). Administration of clonidine (0.2, 0.5 mg/kg i.p.) caused a significant retardation of kindling development in the 28-day-old rats as well as in the adult rats, whereas, in the 14-day-old rats, the development of kindling was significantly facilitated by clonidine. No significant effect of clonidine was observed in the 21-day-old rats. These results indicate that in rats the effects of clonidine on the development of amygdaloid kindling vary during development.     

Characterization of mouse Ire1 alpha: cloning, mRNA localization in the brain and functional analysis in a neural cell line

In yeast, an endoplasmic reticulum (ER)-associated protein, Ire1p, is believed to initiate the unfolded protein response (UPR), that is responsible for protein folding in the ER under stressed conditions. Two mammalian homologs of Ire1p have been identified, Ire1 alpha and Ire1 beta. We have previously reported that familial Alzheimer's disease linked presenilin-1 variants downregulate the signaling pathway of the UPR by affecting the phosphorylation of Ire1 alpha. In the present study, we cloned the mouse homolog of Ire1 alpha for generating genetically modified mice. Ire1 alpha was ubiquitously expressed in all mouse tissues examined, and was expressed preferentially in neuronal cells in mouse brain. This led us to investigate the effects of the downregulation of the UPR on the survival of neuronal cells under conditions of ER stress. Morphological and biochemical studies using a dominant-negative form of mouse Ire1 alpha have revealed that cell death caused by ER stress can be attributed to apoptosis, and that the downregulation of the UPR enhances the apoptotic process in the mouse neuroblastoma cell line, Neuro2a. Our results indicate that genetically modified mice such as transgenic mice with a dominant-negative form of Ire1 alpha might provide further understanding of the pathogenic mechanisms of Alzheimer's disease and other neurodegenerative disorders.