Organophosphate pesticide exposure and neurodegeneration.

Organophosphate pesticides (OPs) are used extensively throughout the world. The main sources of contamination for humans are dietary ingestion and occupational exposures. The major concerns related to OP exposure are delayed effects following high level exposures as well as the impact of low level exposures during the lifespan which are suggested to be a risk factor for nervous system chronic diseases. Both high and low level exposures may have a particularly high impact in population subgroups such as aged or genetically vulnerable populations. Apart from the principle action of OPs which involves inhibition of the acetylcholinesterase (AChE) enzyme, several molecular targets, such as hormones; neurotransmitters; neurotrophic factors; enzymes related to the metabolism of beta amyloid protein as well as inflammatory changes have been identified for OP compounds. Here we review the main neurological and/or cognitive deficits described and the experimental and epidemiological relationships found between pesticide exposure and Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS) diseases. This report also focuses on possible individual differences making groups resilient or vulnerable to these toxicants. A critical discussion of the evidence obtained from experimental models and possible sources of bias in epidemiological studies is included. In particular this review aims to discuss common targets and pathways identified which may underlie the functional deficits associated with both pesticide exposure and neurodegeneration.

Role of manganese in neurodegenerative diseases.

Manganese (Mn) is an essential ubiquitous trace element that is required for normal growth, development and cellular homeostasis. Exposure to high Mn levels causes a clinical disease characterized by extrapyramidal symptom resembling idiopathic Parkinson's disease (IPD). The present review focuses on the role of various transporters in maintaining brain Mn homeostasis along with recent methodological advances in real-time measurements of intracellular Mn levels. We also provide an overview on the role for Mn in IPD, discussing the similarities (and differences) between manganism and IPD, and the relationship between α-synuclein and Mn-related protein aggregation, as well as mitochondrial dysfunction, Mn and PD. Additional sections of the review discuss the link between Mn and Huntington's disease (HD), with emphasis on huntingtin function and the potential role for altered Mn homeostasis and toxicity in HD. We conclude with a brief survey on the potential role of Mn in the etiologies of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and prion disease. Where possible, we discuss the mechanistic commonalities inherent to Mn-induced neurotoxicity and neurodegenerative disorders.

Manganese and its role in Parkinson's disease: from transport to neuropathology.

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).

On the track of the white tiger: pigmentation could be linked to prion diseases, and location explains why.

Certain rodent pigmentation mutants spontaneously develop brain spongiform changes. It is hypothesized that animals, and possibly humans, characterized by certain pigmentation gene variants could be more susceptible to prion diseases, which are characterized by this type of neuropathology. This hypothesis could be explained by the common location of the prion protein and several important pigmentation genes in the same chromosome. This common location can promote the joint transfer of both pigmentary and prion protein genes to the progeny. Pigmentation genes could also play a role in regulating protein folding and aggregation. Understanding the relationship between pigmentation genes and prion genes could lead to identify pigmentation variants at higher risk of prion diseases and understand the etiopathogenesis of these still invariably lethal disorders.

Pigmentation genes link Parkinson's disease to melanoma, opening a window on both etiologies.

Melanomas occur more frequently among subjects with Parkinson's disease (PD) and a biological explanation for this epidemiological observation is lacking. It is also well-known that pigmentation genes play an important role in the development of melanomas. It is therefore suggested that the link between both diseases resides in genes that regulate pigmentation. Among these, those involved in the synthesis of dopamine and related compounds as melanin appear to be the most plausible candidates. Whilst it is known that individuals with fair phototypes have an increased risk for melanoma, this hypothesis suggests that the same applies to Parkinson's disease. It is therefore postulated that the accurate analysis of the phototype could be used to identify subjects at higher risk for both diseases, possibly allowing preventative interventions (photoprotective, nutritional, occupational) and prediction of risk in childhood. Another possible implication of this hypothesis is that therapeutic strategies targeting melanogenesis could maintain or perhaps restore the physiological concentrations of neuromelanin in the substantia nigra and achieve protection against neuronal loss in subjects at risk of developing PD.

Follow-up of patients affected by manganese-induced Parkinsonism after treatment with CaNa2EDTA.

In the period of 1998-2004, seven workers affected by manganese-induced Parkinsonism were diagnosed, studied and treated with CaNa2EDTA at our Occupational Health Ward. Biological markers, as well as magnetic resonance imaging and clinical examinations, were used to assess the disease trend. Those workers still employed were immediately removed from exposure. Our results seem to confirm that very good clinical, biological and neuroradiological results can be obtained by timely removal from exposure and chelating treatment, and that amelioration can persist in time. Manganism is, however, a severe condition that can also progress independent of further exposure. Therefore, chelating treatment can be a great aid in overt manganism, but particular attention must be paid to primary prevention, as this disease should now be totally preventable and definitely merits eradication.

Motor neuron disease and optic neuropathy after acute exposure to a methanol-containing solvent mixture.

A 34-years-old floor-layer developed optic neuropathy and motor neuron disease after being accidentally exposed to a solvent mixture containing methanol and other substances. Optic neuropathy is a complication of methanol poisoning, but the onset of a motor neuron disorder resembling amyotrophic lateral sclerosis after the exposure to these substances has not been previously described. The temporal onset of the clinical symptoms, biological plausibility, young age of the patient and absence of neurological disorders in the family history raises suspicion of a possible causative relationship.

Manganese intoxication: the cause of an inexplicable epileptic syndrome in a 3 year old child.

Excess manganese (Mn) can cause several neurotoxic effects, however only a few studies have reported epileptic syndromes related to manganese intoxication. We describe an epileptic syndrome due to manganese intoxication in a 3 year old male child. His blood manganese was elevated, but no other abnormal values or toxic substances were found in blood or urine. The electroencephalogram (EEG) showed a picture of progressive encephalopathy, while brain magnetic resonance was normal. The patient's conditions rapidly worsened to epileptic status despite the use of antiepileptic drugs. Chelating treatment with CaNa(2)EDTA was initiated to remove excess manganese and promptly succeeded in reverting epileptic symptoms. Concurrently, manganese blood levels and electroencephalogram progressively normalized. Thereafter it has been possible to discontinue antiepileptic treatment, and the patient remains in excellent conditions without any treatment.

T1-weighted hyperintensity in basal ganglia at brain magnetic resonance imaging: are different pathologies sharing a common mechanism?

Basal ganglia bilateral symmetric hyperintensity in T1-weighted sequences at magnetic resonance imaging (MRI) is recognized to be due to the presence of manganese deposits. This abnormal finding has been reported in occupational exposures, liver cirrhosis and total parenteral nutrition with unbalanced solutions. However, the same imaging is often observed "by chance" in brain MRIs of patients not belonging to these groups. In order to better understand which are the clinical conditions coexisting with such findings, we decided to study systematically patients which showed this kind of imaging, focusing on their manganese and iron status, as it is known that these two metals have similar properties and that iron-deficiency can competitively increase manganese absorption. The 20 patients studied underwent clinical evaluation and the following laboratory tests: whole blood iron and manganese, hemoglobin, plasma iron, transferrin and ferritin. The neuroradiologic evaluation was integrated by pallidal index calculation, in order to provide a semi-quantitative esteem of the hyperintensity. The patients could be classified into four subgroups: Parkinsonism, anemia, cirrhosis, central nervous system tumors. In 18 out of 20 cases, we found abnormalities in iron and/or manganese-related values. Particularly, iron-deficiency seems to be frequent among patients showing brain MRI abnormalities compatible with manganese deposits in basal ganglia. This observation suggests that iron-deficiency could be an important risk factor for manganese-induced neurotoxicity and should, therefore, be accurately considered and treated.