Alzheimer type II astrocytic changes following sub-acute exposure to manganese and its prevention by antioxidant treatment

Hazell, Alan S.; Normandin, Louise; Norenberg, Michael D.; Kennedy, G.; Yi, Jae Hyuk

doi:10.1016/j.neulet.2005.11.064

Cited by 72 publications

(54 citation statements)

References 17 publications

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“…Moreover, Alzheimer type II astrocytes, a common abnormality in HE that has been interpreted as a sign of astrocyte swelling, may indeed correspond to cellular damage and loss of cellular shape caused by oxidative stress, rather than intracellular edema. 30 A recent hypothesis has proposed that in patients with small-vessel disease, leakage of toxic plasma components through an impaired blood-brain barrier at the level of disturbed microvasculature causes secondary interstitial edema and injury to axons, myelin, and glial cells. This injury can lead to neuropsychological decline and eventually result in dementia.…”

Section: Discussionmentioning

confidence: 99%

Decreased white matter lesion volume and improved cognitive function after liver transplantation

et al. 2007

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Focal T2-weighted white matter lesions (WML) on brain magnetic resonance imaging (MRI), mimicking those seen in cerebrovascular small-vessel disease described in patients with persistent hepatic encephalopathy, decreased in volume with the improvement of hepatic encephalopathy. This outcome has been interpreted as a decrease in the edema that it is proposed to be involved in the pathogenesis of hepatic encephalopathy. We designed a study to further investigate potential changes in focal WML in the brains of patients with cirrhosis following liver transplantation and to study the relationship between these changes and overall cognitive function. We used MRI to measure the volume of supratentorial focal WML and a neuropsychological examination to assess cognitive function before and after liver transplantation in 27 patients with cirrhosis without signs of overt hepatic encephalopathy. Baseline MRI identified focal T2-weighted lesions in 19 patients (70.3%). The presence of WML was associated with older age but not with vascular risk factors, severity of liver function, or psychometric tests. A significant reduction in lesion volume was observed after liver transplantation (from a median of 1.306 cm 3 to 0.671 cm 3 , P ‫؍‬ 0.001). This decrease correlated with an improvement in an index of global cognitive function (r ‫؍‬ ؊0.663; P < 0.001). This evolution indicates that lesion volume is partially related to a reversible type of tissue damage, which is compatible with brain edema. F ocal white matter lesions (WML) secondary to cerebrovascular small-vessel disease are commonly found in the general population over 60 years of age. 1 In a previous report, we described focal brain WML on T2-weighted images in patients with hepatic encephalopathy (HE). 2 This abnormality, which is radiologically indistinguishable from the features of small-vessel disease or normal aging, was partially reversible with improvements in HE. This evolution pattern contrasts with what occurs in focal WML attributable to small-vessel disease or brain aging, which remain stable or progress in number and size over time, but never decrease. [3][4][5] The most plausible explanation for decreasing the volume of WML with improvement of HE is a decrease in the edema component of WML.There is a large body of evidence indicating an increase in the amount of water in the brain of patients with liver cirrhosis that is related to the development of HE. 6 The most accepted hypothesis for this low-grade brain edema is that astrocytic accumulation of glutamine induces edema as a result of ammonia detoxification. This hypothesis is supported by experimental data showing astrocyte swelling and changes in brain organic osmolytes in models of HE, 7 and by brain proton magnetic resonance spectroscopy studies in patients with liver cirrhosis, which consistently show increases in the glutamine/glutamate signal accompanied by myoinositol depletion, 8

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Section: Discussionmentioning

confidence: 99%

Decreased white matter lesion volume and improved cognitive function after liver transplantation

et al. 2007

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“…Moreover, Alzheimer type II astrocytes, a common abnormality in HE that was interpreted as a sign of astrocyte swelling, may correspond indeed to cellular damage and lose of cellular shape caused by oxidative stress, instead of intracellular edema. 113 Another proposed explanation is that exposure of the brain to ammonia results in reduced expression of genes coding for key astrocytic proteins, such as the structural glial fibrillary acidic protein (GFAP), a cytoplasmatic filamentous protein that constitutes a major integral part of the cellular component in mature astrocytes. 114,115 Reduced expression of GFAP induces morphologic changes in astrocytes, favoring diffusivity in the extracellular space.…”

Section: Dwimentioning

confidence: 99%

MR Imaging Findings in Hepatic Encephalopathy

Rovira¹,

Alonso²,

Córdoba³

2008

AJNR Am J Neuroradiol

306

218

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SUMMARY:The term hepatic encephalopathy (HE) includes a spectrum of neuropsychiatric abnormalities occurring in patients with liver dysfunction. Most cases are associated with cirrhosis and portal hypertension or portal-systemic shunts, but the condition can also be seen in patients with acute liver failure and, rarely, with portal-systemic bypass and no associated intrinsic hepatocellular disease. Although HE is a clinical condition, several neuroimaging techniques, particularly MR imaging, may eventually be useful for the diagnosis because they can identify and measure the consequences of central nervous system (CNS) increase in substances that under normal circumstances, are efficiently metabolized by the liver. Classic MR imaging abnormalities include high signal intensity in the globus pallidum on T1-weighted images, likely a reflection of increased tissue concentrations of manganese, and an elevated glutamine/glutamate peak coupled with decreased myo-inositol and choline signals on proton MR spectroscopy, representing disturbances in cell-volume homeostasis secondary to brain hyperammonemia. Recent data have shown that white matter abnormalities, also related to increased CNS ammonia concentration, can also be detected with several MR imaging techniques such as magnetization transfer ratio measurements, fast fluid-attenuated inversion recovery sequences, and diffusion-weighted images. All these MR imaging abnormalities, which return to normal with restoration of liver function, probably reflect the presence of mild diffuse brain edema, which seems to play an essential role in the pathogenesis of HE. It is likely that MR imaging will be increasingly used to evaluate the mechanisms involved in the pathogenesis of HE and to assess the effects of therapeutic measures focused on correcting brain edema in these patients. Hepatic encephalopathy (HE) reflects a spectrum of neuropsychiatric abnormalities occurring in patients with liver dysfunction. Most cases are associated with cirrhosis and portal hypertension or portal-systemic shunts, but the condition can also be seen in patients with acute liver failure and, rarely, with portal-systemic bypass and no associated intrinsic hepatocellular disease.1,2 The most common clinical pattern in these patients is the development of confusion or coma precipitated by gastrointestinal bleeding, acute superimposed hepatitis, or concomitant infection in a previously asymptomatic patient with cirrhosis. The neurologic manifestations are mainly due to shunt of blood arising from the portal venous bed into the systemic circulation and are reversible once the liver function abnormality or precipitating factor has been corrected. HE can be classified according to the underlying liver disease and the evolution of the neurologic manifestations (Table 1). Clinical FeaturesClinically, HE manifests as a neuropsychiatric syndrome encompassing a wide spectrum of mental and motor disorders.2,3 The changes in mental status range from subtle cognitive dysfunction to severe coma, whereas the...

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“…Early studies lacked detailed information on treatment and biomarkers, and other drugs were coadministered, thus potentially confounding the results. Recent work (Hazell et al 2006) has also shown that the Mn chelator 1,2-cyclohexylenedinitrilotetraacetic acid (CDTA) blocked the development of pathological changes in glial cells of rats treated with MnCl2PAS-Na, an antitubercular and antiinflammatory drug, has also been suggested to be useful in occupational manganism (Jiang et al 2006;Ky et al 1992), but the patient with the longest follow-up was also previously treated with CaNa2EDTA (Jiang et al 2006). PAS-Na has been reported to actually increase brain Mn concentrations in MnCl2 poisoned rodents (Sánchez et al 1995).…”

Section: Treatmentmentioning

confidence: 99%

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

et al. 2009

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Abstract:The purpose of this review is to highlight recent advances in the neuropathology associated with Mn exposures. We commence with a discussion on occupational manganism and clinical aspects of the disorder. This is followed by novel considerations on Mn transport (see also chapter by Yokel, this volume), advancing new hypotheses on the involvement of several transporters in Mn entry into the brain. This is followed by a brief description of the effects of Mn on neurotransmitter systems that are putative modulators of dopamine (DA) biology (the primary target of Mn neurotoxicity), as well as its effects on mitochondrial dysfunction and disruption of cellular energy metabolism. Next, we discuss inflammatory activation of glia in neuronal injury and how disruption of synaptic transmission and glial-neuronal communication may serve as underlying mechanisms of Mn-induced neurodegeneration commensurate with the cross-talk between glia and neurons. We conclude with a discussion on therapeutic aspects of Mn exposure. Emphasis is directed at treatment modalities and the utility of chelators in attenuating the neurodegenerative sequelae of exposure to Mn. For additional reading on several topics inherent to this review as well as others, the reader may wish to consult Aschner and Dorman (Toxicological Review 25:147-154, 2007) and Bowman et al. (Metals and neurodegeneration, 2009).

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Alzheimer type II astrocytic changes following sub-acute exposure to manganese and its prevention by antioxidant treatment

Cited by 72 publications

References 17 publications

Decreased white matter lesion volume and improved cognitive function after liver transplantation

Decreased white matter lesion volume and improved cognitive function after liver transplantation

MR Imaging Findings in Hepatic Encephalopathy

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

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