Responsible research practices could be more strongly endorsed by Australian university codes of research conduct.

BACKGROUND: This study aimed to investigate how strongly Australian university codes of research conduct endorse responsible research practices. METHODS: Codes of research conduct from 25 Australian universities active in health and medical research were obtained from public websites, and audited against 19 questions to assess how strongly they (1) defined research integrity, research quality, and research misconduct, (2) required research to be approved by an appropriate ethics committee, (3) endorsed 9 responsible research practices, and (4) discouraged 5 questionable research practices. RESULTS: Overall, a median of 10 (IQR 9 to 12) of 19 practices covered in the questions were mentioned, weakly endorsed, or strongly endorsed. Five to 8 of 9 responsible research practices were mentioned, weakly, or strongly endorsed, and 3 questionable research practices were discouraged. Results are stratified by Group of Eight (n = 8) and other (n = 17) universities. Specifically, (1) 6 (75%) Group of Eight and 11 (65%) other codes of research conduct defined research integrity, 4 (50%) and 8 (47%) defined research quality, and 7 (88%) and 16 (94%) defined research misconduct. (2) All codes required ethics approval for human and animal research. (3) All codes required conflicts of interest to be declared, but there was variability in how strongly other research practices were endorsed. The most commonly endorsed practices were ensuring researcher training in research integrity [8 (100%) and 16 (94%)] and making study data publicly available [6 (75%) and 12 (71%)]. The least commonly endorsed practices were making analysis code publicly available [0 (0%) and 0 (0%)] and registering analysis protocols [0 (0%) and 1 (6%)]. (4) Most codes discouraged fabricating data [5 (63%) and 15 (88%)], selectively deleting or modifying data [5 (63%) and 15 (88%)], and selective reporting of results [3 (38%) and 15 (88%)]. No codes discouraged p-hacking or hypothesising after results are known. CONCLUSIONS: Responsible research practices could be more strongly endorsed by Australian university codes of research conduct. Our findings may not be generalisable to smaller universities, or those not active in health and medical research.

A Century of Progress on Wilson Disease and the Enduring Challenges of Genetics, Diagnosis, and Treatment.

Wilson disease (WD) is a rare, inherited metabolic disorder manifested with varying clinical presentations including hepatic, neurological, psychiatric, and ophthalmological features, often in combination. Causative mutations in the ATP7B gene result in copper accumulation in hepatocytes and/or neurons, but clinical diagnosis remains challenging. Diagnosis is complicated by mild, non-specific presentations, mutations exerting no clear effect on protein function, and inconclusive laboratory tests, particularly regarding serum ceruloplasmin levels. As early diagnosis and effective treatment are crucial to prevent progressive damage, we report here on the establishment of a global collaboration of researchers, clinicians, and patient advocacy groups to identify and address the outstanding challenges posed by WD.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Co-deposition of SOD1, TDP-43 and p62 proteinopathies in ALS: evidence for multifaceted pathways underlying neurodegeneration.

Multiple neurotoxic proteinopathies co-exist within vulnerable neuronal populations in all major neurodegenerative diseases. Interactions between these pathologies may modulate disease progression, suggesting they may constitute targets for disease-modifying treatments aiming to slow or halt neurodegeneration. Pairwise interactions between superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and ubiquitin-binding protein 62/sequestosome 1 (p62) proteinopathies have been reported in multiple transgenic cellular and animal models of amyotrophic lateral sclerosis (ALS), however corresponding examination of these relationships in patient tissues is lacking. Further, the coalescence of all three proteinopathies has not been studied in vitro or in vivo to date. These data are essential to guide therapeutic development and enhance the translation of relevant therapies into the clinic. Our group recently profiled SOD1 proteinopathy in post-mortem spinal cord tissues from familial and sporadic ALS cases, demonstrating an abundance of structurally-disordered (dis)SOD1 conformers which become mislocalized within these vulnerable neurons compared with those of aged controls. To explore any relationships between this, and other, ALS-linked proteinopathies, we profiled TDP-43 and p62 within spinal cord motor neurons of the same post-mortem tissue cohort using multiplexed immunofluorescence and immunohistochemistry. We identified distinct patterns of SOD1, TDP43 and p62 co-deposition and subcellular mislocalization between motor neurons of familial and sporadic ALS cases, which we primarily attribute to SOD1 gene status. Our data demonstrate co-deposition of p62 with mutant and wild-type disSOD1 and phosphorylated TDP-43 in familial and sporadic ALS spinal cord motor neurons, consistent with attempts by p62 to mitigate SOD1 and TDP-43 deposition. Wild-type SOD1 and TDP-43 co-deposition was also frequently observed in ALS cases lacking SOD1 mutations. Finally, alterations to the subcellular localization of the three proteins were tightly correlated, suggesting close relationships between the regulatory mechanisms governing the subcellular compartmentalization of these proteins. Our study is the first to profile spatial relationships between SOD1, TDP-43 and p62 pathologies in post-mortem spinal cord motor neurons of ALS patients, previously only studied in vitro. Our findings suggest interactions between these three key ALS-linked proteins are likely to modulate the formation of their respective proteinopathies, and perhaps the rate of motor neuron degeneration, in ALS patients.

Empirical evidence for biometal dysregulation in Parkinson's disease from a systematic review and Bradford Hill analysis.

The Bradford Hill model evaluates the causal inference of one variable on another by assessing whether evidence of the suspected causal variable aligns with a set of nine criteria proposed by Bradford Hill, each representing fundamental tenets of a causal relationship. The aim of this study was to use the Bradford Hill model of causation to assess the level of empirical evidence supporting our hypotheses that alterations to iron and copper levels, and iron- and copper-associated proteins and genes, contribute to Parkinson's disease etiology. We conducted a systematic review of all available articles published to September 2019 in four online databases. 8437 articles matching search criteria were screened for pre-defined inclusion and exclusion criteria. 181 studies met study criteria and were subsequently evaluated for study quality using established quality assessment tools. Studies meeting criteria for moderate to high quality of study design (n = 155) were analyzed according to the Bradford Hill model of causation. Evidence from studies considered of high quality (n = 73) supported a causal role for iron dysregulation in Parkinson's disease. A causal role for copper dysregulation in Parkinson's disease was also supported by high quality studies, although substantially fewer studies investigated copper in this disorder (n = 25) compared with iron. The available evidence supports an etiological role for iron and copper dysregulation in Parkinson's disease, substantiating current clinical trials of therapeutic interventions targeting alterations in brain levels of these metals in Parkinson's disease.

Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord.

Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases. Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development.

A brief history of brain iron accumulation in Parkinson disease and related disorders.

Iron has a long and storied history in Parkinson disease and related disorders. This essential micronutrient is critical for normal brain function, but abnormal brain iron accumulation has been associated with extrapyramidal disease for a century. Precisely why, how, and when iron is implicated in neuronal death remains the subject of investigation. In this article, we review the history of iron in movement disorders, from the first observations in the early twentieth century to recent efforts that view extrapyramidal iron as a novel therapeutic target and diagnostic indicator.

Native Separation and Metallation Analysis of SOD1 Protein from the Human Central Nervous System: a Methodological Workflow.

Studies of the metal content of metalloproteins in tissues from the human central nervous system (CNS) can be compromised by preparative techniques which alter levels of, or interactions between, metals and the protein of interest within a complex mixture. We developed a methodological workflow combining size exclusion chromatography, native isoelectric focusing, and either proton or synchrotron X-ray fluorescence within electrophoresis gels to analyze the endogenous metal content of copper-zinc superoxide dismutase (SOD1) purified from minimal amounts (<20 mg) of post-mortem human brain and spinal cord tissue. Abnormal metallation and aggregation of SOD1 are suspected to play a role in amyotrophic lateral sclerosis and Parkinson's disease, but data describing SOD1 metal occupancy in human tissues have not previously been reported. Validating our novel approach, we demonstrated step-by-step metal preservation, preserved SOD1 activity, and substantial enrichment of SOD1 protein versus confounding metalloproteins. We analyzed tissues from nine healthy individuals and five CNS regions (occipital cortex, substantia nigra, locus coeruleus, dorsal spinal cord, and ventral spinal cord). We found that Cu and Zn were bound to SOD1 in a ratio of 1.12 ± 0.28, a ratio very close to the expected value of 1. Our methodological workflow can be applied to the study of endogenous native SOD1 in a pathological context and adapted to a range of metalloproteins from human tissues and other sources.

Measurement of the adult human midbrain with transcranial ultrasound.

BACKGROUND: Transcranial sonography is increasingly used to aid clinical diagnoses of movement disorders, for example, to identify an enlarged area of substantia nigra echogenicity in patients with Parkinson's disease. OBJECTIVE: The current study investigated characteristics of the midbrain at the anatomical plane for quantification of substantia nigra echogenicity. METHODS: Area of substantia nigra echogenicity, cross-sectional area of the midbrain, and interpeduncular angle were quantified in two groups of adults aged 18-50 years: 47 healthy non-drug-using controls (control group) and 22 individuals with a history of methamphetamine use (methamphetamine group), a cohort with a high prevalence of enlarged substantia nigra echogenicity and thus risk of Parkinson's disease. RESULTS: In the control group, cross-sectional area of the midbrain (4.47±0.44 cm2) and interpeduncular angle were unaffected by age, sex, or image acquisition side. In the methamphetamine group, cross-sectional midbrain area (4.72±0.60 cm2) and area of substantia nigra echogenicity were enlarged compared to the control group, and the enlargement was sex-dependent (larger in males than females). Whole midbrain area and interpeduncular angle were found to be weak predictors of area of substantia nigra echogenicity after accounting for group and sex. CONCLUSIONS: History of methamphetamine use is associated with an enlarged midbrain and area of substantia nigra echogenicity, and the abnormality is more pronounced in males than females. Thus, males may be more susceptible to methamphetamine-induced changes to the brainstem, and risk of Parkinson's disease, than females.

Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic.

Cu/Zn superoxide dismutase (SOD1) is a frontline antioxidant enzyme catalysing superoxide breakdown and is important for most forms of eukaryotic life. The evolution of aerobic respiration by mitochondria increased cellular production of superoxide, resulting in an increased reliance upon SOD1. Consistent with the importance of SOD1 for cellular health, many human diseases of the central nervous system involve perturbations in SOD1 biology. But far from providing a simple demonstration of how disease arises from SOD1 loss-of-function, attempts to elucidate pathways by which atypical SOD1 biology leads to neurodegeneration have revealed unexpectedly complex molecular characteristics delineating healthy, functional SOD1 protein from that which likely contributes to central nervous system disease. This review summarises current understanding of SOD1 biology from SOD1 genetics through to protein function and stability.

Meta-Analysis of Copper and Iron in Parkinson's Disease Brain and Biofluids.

BACKGROUND: Variations in study quality and design complicate interpretation of the clinical significance of consistently reported changes in copper and iron levels in human Parkinson's disease brain and biofluids. METHODS: We systematically searched literature databases for quantitative reports of biometal levels in the degenerating substantia nigra (SN), CSF, serum, and plasma in Parkinson's disease compared with healthy age-matched controls and assessed the quality of these publications. The primary outcomes of our analysis confirmed SN copper and iron levels are decreased and increased, respectively, in the Parkinson's disease brain. We applied a novel Quality Assessment Scale for Human Tissue to categorize the quality of individual studies and investigated the effects of study quality on our outcomes. We undertook a random-effects meta-analysis and meta-regression subgroup analysis. RESULTS: In the 18 eligible studies identified (211 Parkinson's disease, 215 control cases), SN copper levels were significantly lower (d, -2.00; 95% CI, -2.81 to -1.19; P < 0.001), and iron levels were significantly higher (d, 1.31; 95% CI, 0.38-2.24; P < 0.01) in Parkinson's disease. No changes were detected in CSF, serum, or plasma for any metals (29 studies; 2443 Parkinson's disease and 2183 control cases) except serum iron, which was lower in Parkinson's disease (14 studies; 1177 Parkinson's disease and 1447 control cases). CONCLUSIONS: Reductions in copper levels and elevations in iron were confirmed as characteristic of the degenerating SN of Parkinson's disease. Iron in serum was also changed, but in the opposite direction to that in the SN and to a lesser extent. © 2019 International Parkinson and Movement Disorder Society.

Simultaneous structural and elemental nano-imaging of human brain tissue.

Examining chemical and structural characteristics of micro-features in complex tissue matrices is essential for understanding biological systems. Advances in multimodal chemical and structural imaging using synchrotron radiation have overcome many issues in correlative imaging, enabling the characterization of distinct microfeatures at nanoscale resolution in ex vivo tissues. We present a nanoscale imaging method that pairs X-ray ptychography and X-ray fluorescence microscopy (XFM) to simultaneously examine structural features and quantify elemental content of microfeatures in complex ex vivo tissues. We examined the neuropathological microfeatures Lewy bodies, aggregations of superoxide dismutase 1 (SOD1) and neuromelanin in human post-mortem Parkinson's disease tissue. Although biometals play essential roles in normal neuronal biochemistry, their dyshomeostasis is implicated in Parkinson's disease aetiology. Here we show that Lewy bodies and SOD1 aggregates have distinct elemental fingerprints yet are similar in structure, whilst neuromelanin exhibits different elemental composition and a distinct, disordered structure. The unique approach we describe is applicable to the structural and chemical characterization of a wide range of complex biological tissues at previously unprecedented levels of detail.

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease.

Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.

Expression of tyrosine hydroxylase isoforms and phosphorylation at serine 40 in the human nigrostriatal system in Parkinson's disease.

Tyrosine hydroxylase is the key enzyme controlling the synthesis of the catecholamines including dopamine. The breakdown of dopamine into toxic compounds has been suggested to have a key role in the degeneration of the dopaminergic neurons in Parkinson's disease. Humans are unique in containing four isoforms of tyrosine hydroxylase, but understanding of the role of these isoforms under normal conditions and in disease states is limited. The aim of this work was to determine the level and distribution of the four human isoforms in tissues from healthy controls and patients with Parkinson's disease. The results show that isoform 1 and isoform 2 are the major tyrosine hydroxylase isoforms in human brain, but that tyrosine hydroxylase isoform 2 is more abundant in the substantia nigra than the tyrosine hydroxylase isoform 1. The two minor isoforms, isoform 3 and isoform 4, are expressed at a proportionally higher level in the terminal field regions (caudate and putamen) compared to the substantia nigra. There was a selective loss of tyrosine hydroxylase isoform 1 in Parkinson's disease compared to age-matched controls and a corresponding increase in the proportion of tyrosine hydroxylase isoform 2. Phosphorylation of serine 40 was significantly increased in caudate, putamen and ventral tegmental area, but not in the substantia nigra, in Parkinson's disease brain. These results show a selective sparing of tyrosine hydroxylase isoform 2 in Parkinson's disease. Isoform 2 exhibits a reduced capacity for activation compared to isoform 1, which may account for the selective sparing of cells expressing isoform 2 in Parkinson's disease. Surviving neurons in Parkinson's disease brain exhibit a substantial increase in tyrosine hydroxylase phosphorylation consistent with a compensatory mechanism of increased dopamine synthesis in the terminal field regions.

Levels of glial cell line-derived neurotrophic factor are decreased, but fibroblast growth factor 2 and cerebral dopamine neurotrophic factor are increased in the hippocampus in Parkinson's disease.

Growth factors can facilitate hippocampus-based learning and memory and are potential targets for treatment of cognitive dysfunction via their neuroprotective and neurorestorative effects. Dementia is common in Parkinson's disease (PD), but treatment options are limited. We aimed to determine if levels of growth factors are altered in the hippocampus of patients with PD, and if such alterations are associated with PD pathology. Enzyme-linked immunosorbent assays were used to quantify seven growth factors in fresh frozen hippocampus from 10 PD and nine age-matched control brains. Western blotting and immunohistochemistry were used to explore cellular and inflammatory changes that may be associated with growth factor alterations. In the PD hippocampus, protein levels of glial cell line-derived neurotrophic factor were significantly decreased, despite no evidence of neuronal loss. In contrast, protein levels of fibroblast growth factor 2 and cerebral dopamine neurotrophic factor were significantly increased in PD compared to controls. Levels of the growth factors epidermal growth factor, heparin-binding epidermal growth factor, brain-derived neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor did not differ between groups. Our data demonstrate changes in specific growth factors in the hippocampus of the PD brain, which potentially represent targets for modification to help attenuate cognitive decline in PD. These data also suggest that multiple growth factors and direction of change needs to be considered when approaching growth factors as a potential treatment for cognitive decline.

Reduction in IGF1 mRNA in the Human Subependymal Zone During Aging.

The cell proliferation marker, Ki67 and the immature neuron marker, doublecortin are both expressed in the major human neurogenic niche, the subependymal zone (SEZ), but expression progressively decreases across the adult lifespan (PMID: 27932973). In contrast, transcript levels of several mitogens (transforming growth factor α, epidermal growth factor and fibroblast growth factor 2) do not decline with age in the human SEZ, suggesting that other growth factors may contribute to the reduced neurogenic potential. While insulin like growth factor 1 (IGF1) regulates neurogenesis throughout aging in the mouse brain, the extent to which IGF1 and IGF family members change with age and relate to adult neurogenesis markers in the human SEZ has not yet been determined. We used quantitative polymerase chain reaction to examine gene expression of seven IGF family members [IGF1, IGF1 receptor, insulin receptor and high-affinity IGF binding proteins (IGFBPs) 2, 3, 4 and 5] in the human SEZ across the adult lifespan (n=50, 21-103 years). We found that only IGF1 expression significantly decreased with increasing age. IGFBP2 and IGFBP4 expression positively correlated with Ki67 mRNA. IGF1 expression positively correlated with doublecortin mRNA, whereas IGFBP2 expression negatively correlated with doublecortin mRNA. Our results suggest IGF family members are local regulators of neurogenesis and indicate that the age-related reduction in IGF1 mRNA may limit new neuron production by restricting neuronal differentiation in the human SEZ.

Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain.

Elevated iron and decreased copper levels are cardinal features of the degenerating substantia nigra pars compacta in the Parkinson's disease brain. Both of these redox-active metals, and fellow transition metals manganese and zinc, are found at high concentrations within the midbrain and participate in a range of unique biological reactions. We examined the total metal content and cellular compartmentalisation of manganese, iron, copper and zinc in the degenerating substantia nigra, disease-affected but non-degenerating fusiform gyrus, and unaffected occipital cortex in the post mortem Parkinson's disease brain compared with age-matched controls. An expected increase in iron and a decrease in copper concentration was isolated to the soluble cellular fraction, encompassing both interstitial and cytosolic metals and metal-binding proteins, rather than the membrane-associated or insoluble fractions. Manganese and zinc levels did not differ between experimental groups. Altered Fe and Cu levels were unrelated to Braak pathological staging in our cases of late-stage (Braak stage V and VI) disease. The data supports our hypothesis that regional alterations in Fe and Cu, and in proteins that utilise these metals, contribute to the regional selectively of neuronal vulnerability in this disorder.

Evidence for reduced neurogenesis in the aging human hippocampus despite stable stem cell markers.

Reduced neurogenesis in the aging mammalian hippocampus has been linked to cognitive deficits and increased risk of dementia. We utilized postmortem human hippocampal tissue from 26 subjects aged 18-88 years to investigate changes in expression of six genes representing different stages of neurogenesis across the healthy adult lifespan. Progressive and significant decreases in mRNA levels of the proliferation marker Ki67 (MKI67) and the immature neuronal marker doublecortin (DCX) were found in the healthy human hippocampus over the lifespan. In contrast, expression of genes for the stem cell marker glial fibrillary acidic protein delta and the neuronal progenitor marker eomesodermin was unchanged with age. These data are consistent with a persistence of the hippocampal stem cell population with age. Age-associated expression of the proliferation and immature neuron markers MKI67 and DCX, respectively, was unrelated, suggesting that neurogenesis-associated processes are independently altered at these points in the development from stem cell to neuron. These data are the first to demonstrate normal age-related decreases at specific stages of adult human hippocampal neurogenesis.

Excessive early-life dietary exposure: a potential source of elevated brain iron and a risk factor for Parkinson's disease.

Iron accumulates gradually in the ageing brain. In Parkinson's disease, iron deposition within the substantia nigra is further increased, contributing to a heightened pro-oxidant environment in dopaminergic neurons. We hypothesise that individuals in high-income countries, where cereals and infant formulae have historically been fortified with iron, experience increased early-life iron exposure that predisposes them to age-related iron accumulation in the brain. Combined with genetic factors that limit iron regulatory capacity and/or dopamine metabolism, this may increase the risk of Parkinson's diseases. We propose to (a) validate a retrospective biomarker of iron exposure in children; (b) translate this biomarker to adults; (c) integrate it with in vivo brain iron in Parkinson's disease; and (d) longitudinally examine the relationships between early-life iron exposure and metabolism, brain iron deposition and Parkinson's disease risk. This approach will provide empirical evidence to support therapeutically addressing brain iron deposition in Parkinson's diseases and produce a potential biomarker of Parkinson's disease risk in preclinical individuals.