Kay L. Double

Brain iron pathways and their relevance to Parkinson's disease

A central role of iron in the pathogenesis of Parkinsons disease (PD), due to its increase in substantia nigra pars compacta dopaminergic neurons and reactive microglia and its capacity to enhance production of toxic reactive oxygen radicals, has been discussed for many years. Recent transcranial ultrasound findings and the observation of the ability of iron to induce aggregation and toxicity of alpha-synuclein have reinforced the critical role of iron in the pathogenesis of nigrostriatal injury. Presently the mechanisms involved in the disturbances of iron metabolism in PD remain obscure. In this review we summarize evidence from recent studies suggesting disturbances of iron metabolism in PD at possibly different levels including iron uptake, storage, intracellular metabolism, release and post-transcriptional control. Moreover we outline that the interaction of iron with other molecules, especially alpha-synuclein, may contribute to the process of neurodegeneration. Because many neurodegenerative diseases show increased accumulation of iron at the site of neurodegeneration, it is believed that maintenance of cellular iron homeostasis is crucial for the viability of neurons.

The Relevance of Iron in the Pathogenesis of Parkinson's Disease

Abstract: Investigations that revealed increased levels of iron in postmortem brains from patients with Parkinsons disease (PD) as compared to those from individuals not suffering from neurological disorders are reported. The chemical natures in which iron predominates in the brain and the relevance of neuromelanin for neuronal iron binding are discussed. Major findings have been that iron levels increase with the severity of neuropathological changes in PD, presumably due to increased transport through the blood‐brain barrier in late stages of parkinsonism. Glial iron is mainly stored as ferric iron in ferritin, while neuronal iron is predominantly bound to neuromelanin. Iron overload may induce progressive degeneration of nigrostriatal neurons by facilitating the formation of reactive biological intermediates, including reactive oxygen species, and the formation of cytotoxic protein aggregates. There are indications that iron‐mediated neuronal death in PD proceeds retrogradely. These results are also discussed with respect to their relevance for disease progression in relation to cytotoxic α‐synuclein protofibril formation.

Regional specificity of brain atrophy in Huntington's disease

The present study analyzes the relationship between cortical and subcortical brain volumes in patients with Huntingtons disease. The brains of seven patients with a clinical diagnosis and positive family history of Huntingtons disease and 12 controls were collected at autopsy with consent from relatives. Detailed clinical assessments were available for all study subjects with genotype confirmation for patients with Huntingtons disease. Volume analysis of the brain on serial 3-mm coronal slices was performed as previously described. All patients with Huntingtons disease exhibited significant brain atrophy resulting from volume reductions in both cortical and subcortical grey matter. Atrophy of the cortex was relatively uniform, although the medial temporal lobe structures were spared. The caudate nucleus and putamen were strikingly reduced in all cases and this atrophy correlated with the severity of cortical atrophy, suggesting an associated disease process. The rate of cortical but not subcortical atrophy correlated with CAG repeat numbers. Loss of frontal white matter correlated with both cortical and striatal atrophy. Age of onset of chorea correlated with the amount of subcortical atrophy, while duration of chorea correlated negatively with atrophy of the white matter. These results suggest a more widespread and global disease process in patients with Huntingtons disease.

Topography of brain atrophy during normal aging and alzheimer's disease

The present study investigated the effect of age on total and regional brain volumes and compared age-associated changes in 20 healthy controls with those observed in 12 patients with Alzheimers disease (AD). Weights and volumes of the whole brain and cerebrum, as well as the fractional volumes of the frontal, temporal, and parieto-occipital cortices, medial temporal structures, deep brain structures, and white matter were measured. Males had larger and heavier brains than females of comparable age. A small decline in brain volume with age was found (approximately 2 ml per year), but only within the white matter. In comparison, no further loss of white matter occurred in AD; however, the cerebral cortex was significantly reduced in volume, with the greatest loss from the medial temporal structures. This loss was related to disease progression; greater proportional loss was associated with more rapid decline in older patients. This study suggests that significant brain atrophy is not a consequence of advancing age. In addition, it suggests a regional specificity of damage in AD.

Brain iron pathways and their relevance to Parkinson's disease: Brain iron pathways and Parkinson's disease

A central role of iron in the pathogenesis of Parkinsons disease (PD), due to its increase in substantia nigra pars compacta dopaminergic neurons and reactive microglia and its capacity to enhance production of toxic reactive oxygen radicals, has been discussed for many years. Recent transcranial ultrasound findings and the observation of the ability of iron to induce aggregation and toxicity of α‐synuclein have reinforced the critical role of iron in the pathogenesis of nigrostriatal injury. Presently the mechanisms involved in the disturbances of iron metabolism in PD remain obscure. In this review we summarize evidence from recent studies suggesting disturbances of iron metabolism in PD at possibly different levels including iron uptake, storage, intracellular metabolism, release and post‐transcriptional control. Moreover we outline that the interaction of iron with other molecules, especially α‐synuclein, may contribute to the process of neurodegeneration. Because many neurodegenerative diseases show increased accumulation of iron at the site of neurodegeneration, it is believed that maintenance of cellular iron homeostasis is crucial for the viability of neurons.

Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum

Summary. The aim of this study was to compare dopamine receptor binding affinities of all currently approved dopamine receptor agonist treatments for Parkinson’s disease (PD) in human brain tissue. α-Dihydroergocryptine and lisuride displayed higher comparative affinities (Ki=35.4 and 56.7 nM, respectively) for D1 receptors, than the D1/D2 dopamine agonist pergolide (Ki=447 nM). The second generation non-ergot dopamine receptors agonists pramipexole and ropinirole demonstrated no affinity for D1 receptors at concentrations up to 10−4 M. The ergoline dopamine agonists cabergoline and lisuride displayed the highest affinities for the D2 receptor (Ki=0.61 and 0.95 nM, respectively). Surprisingly, the second generation non-ergot dopamine receptors agonists pramipexole and ropinirole only weakly inhibited binding to D2 receptors (Ki=79.5 and 98.7 µM, respectively using [3H]spiperone). Interestingly we also found that the affinities of cabergoline (Ki=1.27 nM), lisuride (Ki=1.08 nM) and pergolide (Ki=0.86 nM) for the D3 receptor subtype were comparable to that of pramipexole (Ki=0.97 nM). The present results thus support the hypothesis that the antiparkinsonian effect of dopamine receptor agonists is mediated by a more complex interactions with dopamine receptor subtypes than currently believed.

In vitro studies of ferritin iron release and neurotoxicity.

Abstract: The increase in brain iron associated with several neurodegenerative diseases may lead to an increased production of free radicals via the Fenton reaction. Intracellular iron is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core. The neurotoxin 6‐hydroxydopamine (6‐OHDA) releases iron from the ferritin core by reducing it to the ferrous form. Iron release induced by 6‐OHDA and structurally related compounds and two other dopaminergic neurotoxins, 1‐methyl‐4‐phenylpyridinium iodide (MPP+) and 1‐trichloromethyl‐1,2,3,4‐tetrahydro‐β‐carboline (TaClo), were compared, to identify the structural characteristics important for such release. 1,2,4‐Trihydroxybenzene (THB) was most effective in releasing ferritin‐bound iron, followed by 6‐OHDA, dopamine, catechol, and hydroquinone. Resorcinol, MPP+, and TaClo were ineffective. The ability to release iron was associated with a low oxidation potential. It is proposed that a low oxidation potential and an ortho‐dihydroxyphenyl structure are important in the mechanism by which ferritin iron is mobilized. In the presence of ferritin, both 6‐OHDA and THB strongly stimulated lipid peroxidation, an effect abolished by the addition of the iron chelator deferoxamine. These results suggest that ferritin iron release contributes to free radical‐induced cell damage in vivo.

Iron-binding characteristics of neuromelanin of the human substantia nigra

The vulnerability of the dopaminergic neurons of the substantia nigra (SN) in Parkinsons disease has been related to the presence of the pigment neuromelanin (NM) in these neurons. It is hypothesised that NM may act as an endogenous storage molecule for iron, an interaction suggested to influence free radical production. The current study quantified and characterised the interaction between NM and iron. Iron-binding studies demonstrated that both NM and synthetically-produced dopamine melanin contain equivalent numbers of high and low-affinity binding sites for iron but that the affinity of NM for iron is higher than that of synthetic melanin. Quantification of the total iron content in iron-loaded NM and synthetic melanin demonstrated that the iron-binding capacity of NM is 10-fold greater than that of the model melanin. This data was in agreement with the larger iron cluster size demonstrated by Mössbauer spectroscopy in the native pigment compared with the synthetic melanin. These findings are consistent with the hypothesis that NM may act as an endogenous iron-binding molecule in dopaminergic neurons of the SN in the human brain. The interaction between NM and iron has implications for disorders such as Parkinsons disease where an increase in iron in the SN is associated with increased indices of oxidative stress.

Structural characteristics of human substantia nigra neuromelanin and synthetic dopamine melanins

Abstract: Neuromelanin (NM) is a complex polymer pigment foundprimarily in the dopaminergic neurons of the human substantia nigra. Thestructure of NM is only partially characterized, and its synthesis pathwayremains unknown. We used nuclear magnetic and infrared spectroscopy to examinethe structure of human NM isolated from the substantia nigra compared withsynthetic dopamine melanins. Biochemical analyses were used to investigateproteinaceous and dopaminergic components in these samples. Following acidhydrolysis of NM samples, small amounts of DOPA, dopamine, and a variety ofamino acids were measured. These findings suggest a peptide component in NMstructure. NM also appears to contain a variety of unidentified structuralcomponents possibly derived from the oxidation of dopamine. Human NM differsstructurally from synthetic dopamine melanin, but both human and synthetic NMinclude an aromatic backbone. It is interesting that both human NM andsynthetic melanin also contain a large proportion of aliphatic structures. Ourresults suggest that NM is a more complex pigment than synthetic dopaminemelanin formed via dopamine autoxidation alone.

Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson’s disease

The neuropathological substrate of dementia in patients with Parkinsons disease is still under debate, particularly in patients with insufficient alternate neuropathology for other degenerative dementias. In patients with pure Lewy body Parkinsons disease, previous post-mortem studies have shown that dopaminergic and cholinergic regulatory projection systems degenerate, but the exact pathways that may explain the development of dementia in patients with Parkinsons disease remain unclear. Studies in rodents suggest that both the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways may functionally interact to regulate certain aspects of cognition, however, whether such an interaction occurs in humans is still poorly understood. In this study, we performed stereological analyses of the A9 and A10 dopaminergic neurons and Ch1, Ch2 and Ch4 cholinergic neurons located in the basal forebrain, along with an assessment of α-synuclein pathology in these regions and in the hippocampus of six demented and five non-demented patients with Parkinsons disease and five age-matched control individuals with no signs of neurological disease. Moreover, we measured choline acetyltransferase activity in the hippocampus and frontal cortex of eight demented and eight non-demented patients with Parkinsons disease, as well as in the same areas of eight age-matched controls. All patients with Parkinsons disease exhibited a similar 80-85% loss of pigmented A9 dopaminergic neurons, whereas patients with Parkinsons disease dementia presented an additional loss in the lateral part of A10 dopaminergic neurons as well as Ch4 nucleus basalis neurons. In contrast, medial A10 dopaminergic neurons and Ch1 and Ch2 cholinergic septal neurons were largely spared. Despite variable Ch4 cell loss, cortical but not hippocampal cholinergic activity was consistently reduced in all patients with Parkinsons disease, suggesting significant dysfunction in cortical cholinergic pathways before frank neuronal degeneration. Patients with Parkinsons disease dementia were differentiated by a significant reduction in hippocampal cholinergic activity, by a significant loss of non-pigmented lateral A10 dopaminergic neurons and Ch4 cholinergic neurons (30 and 55% cell loss, respectively, compared with neuronal preservation in control subjects), and by an increase in the severity of α-synuclein pathology in the basal forebrain and hippocampus. Overall, these results point to increasing α-synuclein deposition and hippocampal dysfunction in a setting of more widespread degeneration of cortical dopaminergic and cholinergic pathways as contributing to the dementia occurring in patients with pure Parkinsons disease. Furthermore, our findings support the concept that α-synuclein deposition is associated with significant neuronal dysfunction in the absence of frank neuronal loss in Parkinsons disease.