Thalamic Local Field Potentials and Closed-Loop Deep Brain Stimulation in Orthostatic Tremor.

BACKGROUND: Orthostatic tremor (OT) is a rare movement disorder characterized by a feeling of unsteadiness and a high-frequency tremor in the legs (13-18 Hz) relieved by sitting or walking. OBJECTIVES: The aims were to study the brain electrophysiology captured chronically in a person with medication-refractory OT while standing and walking and in the semi-recumbent position using bilateral ventral intermedius nucleus deep brain stimulation (DBS) (Medtronic Percept PC) and to describe the clinical use of closed-loop DBS. METHODS: A sensing survey was used to capture baseline local field potentials (LFPs) while standing. Livestreamed LFPs were synchronized with data collected from two accelerometers (legs) and gait analysis during OFF stimulation and continuous and closed-loop DBS. RESULTS: Strong oscillatory coupling between thalamic LFP and leg tremor with significant coherence at 14.65 Hz was found during weight-bearing. Single-threshold adaptive DBS (sensing at this frequency) was superior to continuous stimulation in reducing tremor and stimulation-related gait ataxia. CONCLUSIONS: This study provides new insights into both the pathophysiology and management of OT. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Disease-modifying therapies for Parkinson disease: lessons from multiple sclerosis.

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs.

Four-Repeat Tau Seeding in the Skin of Patients With Progressive Supranuclear Palsy.

This study discusses 4-repeat tau seeding in the skin of patients with progressive supranuclear palsy.

Genome-wide association study of copy number variations in Parkinson's disease.

Objective: Our study investigates the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD. Methods: We applied a sliding window approach to perform CNV-GWAS and conducted genome-wide burden analyses on CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium. Results: We identified 14 genome-wide significant CNV loci associated with PD, including one deletion and 13 duplications. Among these, duplications in 7q22.1, 11q12.3 and 7q33 displayed the highest effect. Two significant duplications overlapped with PD-related genes SNCA and VPS13C, but none overlapped with recent significant SNP-based GWAS findings. Five duplications included genes associated with neurological disease, and four overlapping genes were dosage-sensitive and intolerant to loss-of-function variants. Enriched pathways included neurodegeneration, steroid hormone biosynthesis, and lipid metabolism. In early-onset cases, four loci were significantly associated with EOPD, including three known duplications and one novel deletion in PRKN. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. Interpretation: This is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden in EOPD, primarily driven by the PRKN gene, warranting further investigation.

Exercise Habits in People with Parkinson's: A Multinational Survey.

BACKGROUND: Exercise has been demonstrated to result in improvements in physical function, cognition, and quality of life in People with Parkinson's (PwP) but its adoption is variable. OBJECTIVES: To investigate exercise preferences, levels, influencing factors among a diverse Parkinson's disease (PD) population, to understand exercise adoption patterns and plan informed interventions. METHODS: A cross-sectional survey collected data through online platforms and paper-based methods. The Exercise Index (ExI) calculated exercise level based on frequency and duration. RESULTS: Of 2976 PwP, 40.6% exercised regularly, 38.3% occasionally, and 21.2% did not exercise. The overall mean ExI was 18.99 ± 12.37. Factors associated with high exercise levels included exercising in groups (ExI 24-26), weightlifting (ExI 27 (highest)), using muscle-building equipment (ExI 25-26), and exercising at home following an app (ExI 26). A positive trend between ExI and varied exercise groups, locations, types, and equipment was observed. No expected benefit from exercise achieved the lowest ExI (8). Having at least two exercise-promoting factors, a bachelor's degree or higher, receiving exercise advice at initial visits, and aged ≤40 years at PD onset were strong predictors of exercise (adjust OR = 7.814; 6.981; 4.170; 3.565). Falls and "other" most troublesome PD symptoms were negative predictors (aOR = 0.359; 0.466). Barriers to exercise did not predict the odds of exercise. CONCLUSIONS: The study shows that PwP's exercise behavior is influenced by their exercise belief, age at PD onset, doctor's advice at initial visits, education level, symptoms, and exercise-promoting factors. High exercise levels were associated with certain types of exercises and exercising in groups.

Lateralized Subthalamic Stimulation for Axial Dysfunction in Parkinson's Disease: Exploratory Outcomes and Open-Label Extension.

BACKGROUND: A randomized trial suggested that reducing left-sided subthalamic stimulation amplitude could improve axial dysfunction. OBJECTIVES: To explore open-label tolerability and associations between trial outcomes and asymmetry data. METHODS: We collected adverse events in trial participants treated with open-label lateralized settings for ≥3 months. We explored associations between trial outcomes, location of stimulation and motor asymmetry. RESULTS: 14/17 participants tolerated unilateral amplitude reduction (left-sided = 10, right-sided = 4). Two hundred eighty-four left-sided and 1113 right-sided stimulated voxels were associated with faster gait velocity, 81 left-sided and 22 right-sided stimulated voxels were associated with slower gait velocity. Amplitude reduction contralateral to shorter step length was associated with 2.4-point reduction in axial MDS-UPDRS. Reduction contralateral to longer step length was associated with 10-point increase in MDS-UPDRS. CONCLUSIONS: Left-sided amplitude reduction is potentially more tolerable than right-sided amplitude reduction. Right-sided more than left-sided stimulation could be associated with faster gait velocity. Shortened step length might reflect contralateral overstimulation.

CSF α-Synuclein Seed Amplification Assay in Patients With Atypical Parkinsonian Disorders.

BACKGROUND AND OBJECTIVES: There is no disease-modifying treatment of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), 2 disorders characterized by their striking phenotypic, and, in CBS, pathologic heterogeneity. Seed amplification assays (SAAs) could enable the detection of neuropathologic processes, such as α-synuclein (αSyn) copathology, that affect the success of future disease-modifying treatment strategies. The primary objective was to assess possible αSyn copathology in CBS and PSP, as detected in CSF using an αSyn SAA (αSyn-SAA). Secondary objectives were to evaluate the association of αSyn-SAA positivity with other biomarkers including of Alzheimer disease (AD), and with clinical presentation. We hypothesized that αSyn-SAA positivity would be detectable in CBS and PSP and that it would be associated with AD biomarker positivity and ß-amyloid (Aß) 42 levels, neurodegeneration as assessed by neurofilament light chain (NfL) levels, and symptoms associated with synucleinopathies. METHODS: This cross-sectional observational study included patients clinically diagnosed with CBS and PSP who underwent a lumbar puncture between 2012 and 2021 (Toronto Western Hospital, Canada). CSF was tested for αSyn-SAA positivity, AD biomarkers, and NfL levels. Clinical data were derived from medical records. RESULTS: We tested the CSF of 40 patients with CBS (19 female patients, 65.9 ± 8.6 years) and 28 with PSP (13 female patients, 72.5 ± 8.7 years old), mostly White (n = 50) or Asian (n = 14). αSyn-SAA positivity was observed in 35.9% patients with CBS and 28.6% with PSP. In young-onset, but not late-onset patients, αSyn-SAA positivity and AD positivity were associated (odds ratio [OR] 8.8, 95% CI 1.2-82.6, p < 0.05). A multivariable linear regression analysis showed a significant interaction of αSyn-SAA status by age at onset on CSF Aß42 levels (ß = 0.3 ± 0.1, p < 0.05). Indeed, age at onset was positively related to Aß42 levels only in αSyn-SAA-positive patients, as shown by slope comparison. A logistic regression analysis also suggested that REM sleep behavior disorder was associated with αSyn-SAA positivity (OR 60.2, 95% CI 5.2-1,965.8; p < 0.01). DISCUSSION: We detected a frequency of αSyn-SAA positivity in CBS and PSP in line with pathologic studies, highlighting the usefulness of SAAs for in vivo detection of otherwise undetectable neuropathologic processes. Our results also suggest that AD status (specifically low Aß42) and older age at onset may contribute to αSyn-SAA positivity. This opens new perspectives for the stratification of patients in clinical trials.

Severe Acute Motor Exacerbations (SAME) across Metabolic, Developmental and Genetic Disorders.

Acute presentation of severe motor disorders is a diagnostic and management challenge. We define severe acute motor exacerbations (SAME) as acute/subacute motor symptoms that persist for hours-to-days with a severity that compromise vital signs (temperature, breath, and heart rate) and bulbar function (swallowing/dysphagia). Phenomenology includes dystonia, choreoathetosis, combined movement disorders, weakness, and hemiplegic attacks. SAME can develop in diverse diseases and can be preceded by triggers or catabolic states. Recent descriptions of SAME in complex neurodevelopmental and epileptic encephalopathies have broadened appreciation of this presentation beyond inborn errors of metabolism. A high degree of clinical suspicion is required to identify appropriately targeted investigations and management. We conducted a comprehensive literature analysis of etiologies. Reported triggers are described and classified as per pathophysiological mechanism. A video of six cases displaying multiple SAME with diverse outcomes is provided. We identified 50 different conditions that manifest SAME, some associated with developmental regression. Etiologies include disorders of metabolism: energy substrate, amino acids, complex molecules, vitamins/cofactors, minerals, and neurotransmitters/synaptic vesicle cycling. Non-metabolic neurodegenerative and genetic disorders that present with movement disorders and epilepsy can additionally manifest SAME. A limited number of triggers are grouped here, together with an approach to investigations and general management strategies. Several neurogenetic and neurometabolic disorders manifest SAME. Identifying triggers can help in certain cases narrow the differential diagnosis and guide the expeditious application of targeted therapies to minimize adverse developmental and neurological consequences. This process may inform pathogenesis and eventually improve our understanding of the mechanisms that lead to the development of SAME. © 2024 International Parkinson and Movement Disorder Society.

Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association of Body Mass Index and Parkinson Disease: A Bidirectional Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

Levodopa-responsive dystonia, parkinsonism, and treatment-resistant schizoaffective disorder in Williams syndrome.

BACKGROUND: Williams syndrome (WS; chromosome 7q11.23 deletion) is a rare, multisystemic, neurodevelopmental disorder with variable penetrance and expressivity. Although movement and psychiatric disorders are known to occur in individuals with WS, parkinsonism, dystonia, and treatment-resistant schizoaffective disorder have not been formally described. METHODS: We present two unrelated cases of adults with molecularly confirmed WS and typical histories of developmental delays, intellectual/learning disabilities, and treatment-responsive anxiety/mood disorder who developed similar noteworthy neuropsychiatric expressions. We reviewed detailed neuropsychiatric histories, laboratory investigations, neuroimaging, and treatment responses and compared data for the two cases. RESULTS: Both individuals developed treatment-resistant schizoaffective disorder in adulthood requiring multiple trials of antipsychotic treatments. While on clozapine, both patients developed parkinsonism and generalized dystonia with truncal involvement that responded to trials of low-dose levodopa without exacerbating underlying psychotic or affective symptoms. CONCLUSION: This report illustrates the novel occurrence of levodopa-responsive movement disorders and treatment-resistant schizoaffective disorder in individuals with WS, adding to the expanding neuropsychiatric phenotypes, and highlighting potential shared underlying mechanisms. The observed treatment response suggests that levodopa, in relatively low doses, may be safe and useful in ameliorating presumed antipsychotic-associated parkinsonism and tardive dystonia in WS.

Ageing-related tau astrogliopathy severely affecting the substantia nigra.

AIMS: Astrocytic tau pathology is a major feature of tauopathies and ageing-related tau astrogliopathy (ARTAG). The substantia nigra (SN) is one of the important degenerative areas in tauopathies with parkinsonism. Nigral tau pathology is usually reported as neuronal predominant with less prominent astrocytic involvement. We aimed to identify cases with prominent astrocytic tau pathology in the SN. METHODS: We use the term nigral tau-astrogliopathy (NITAG) to describe cases showing an unusually high density of ARTAG with less neuronal tau pathology in the SN. We collected clinical information and studied the distribution of tau pathology, morphological features and immunostaining profiles in three cases. RESULTS: Three cases, all males with parkinsonism, were identified with the following clinicopathological diagnoses: (i) atypical parkinsonism with tau pathology reminiscent to that in postencephalitic parkinsonism (69-year-old); (ii) multiple system atrophy (73-year-old); (iii) traumatic encephalopathy syndrome/chronic traumatic encephalopathy (84-year-old). Double-labelling immunofluorescence confirmed co-localization of GFAP and phosphorylated tau in affected astrocytes. Staining profiles of NITAG revealed immunopositivity for various phosphorylated tau antibodies. Some astrocytic tau lesions were also seen in other brainstem regions and cerebral grey matter. CONCLUSIONS: We propose NITAG is a rare neuropathological feature, and not a distinct disease entity, in the frame of multiple system ARTAG, represented by abundant tau-positive astrocytes in various brain regions but having the highest density in the SN. The concept of NITAG allows the stratification of cases with various background pathologies to understand its relevance and contribution to neuronal dysfunction.

SNCA and TPPP transcripts increase in oligodendroglial cytoplasmic inclusions in multiple system atrophy.

Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of α-syn accumulation in GCIs is unclear, in particular whether abnormal α-syn aggregates result from the abnormal elevation of endogenous α-syn expression in MSA or ingested from the neuronal source. Tubulin polymerization promoting protein (TPPP) has been reported to play a crucial role in developing GCI pathology. Here, the total cell body, nucleus, and cytoplasmic area density of SNCA and TPPP transcripts in neurons and oligodendrocytes with and without various α-syn pathologies in the pontine base in autopsy cases of MSA (n = 4) and controls (n = 2) were evaluated using RNAscope with immunofluorescence. Single-nucleus RNA-sequencing data for TPPP was evaluated using control frontal cortex (n = 3). SNCA and TPPP transcripts were present in the nucleus and cytoplasm of oligodendrocytes in both controls and diseased, with higher area density in GCIs and glial nuclear inclusions in MSA. Area densities of SNCA and TPPP transcripts were lower in neurons showing cytoplasmic inclusions in MSA. Indeed, TPPP transcripts were unexpectedly found in neurons, while the anti-TPPP antibody failed to detect immunoreactivity. Single-nucleus RNA-sequencing revealed significant TPPP transcript expression predominantly in oligodendrocytes, but also in excitatory and inhibitory neurons. This study addressed the unclear origin of accumulated α-syn in GCIs, proposing that the elevation of SNCA transcripts may supply templates for misfolded α-syn. In addition, the parallel behavior of TPPP and SNCA transcripts in GCI development highlights their potential synergistic contribution to inclusion formation. In conclusion, this study advances our understanding of MSA pathogenesis, offers insights into the dynamics of SNCA and TPPP transcripts in inclusion formation, and proposes regulating their transcripts for future molecular therapy to MSA.

Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria.

BACKGROUND: Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. OBJECTIVE: The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. METHODS: Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. RESULTS: We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout). CONCLUSIONS: The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The why and how of the SynNerGe criteria of Parkinson´s disease.

In pursuit of early therapeutic interventions for Parkinson's disease, the proposed SynNeurGe classification system integrates α-synuclein pathology (S), neurodegeneration evidence (N), and pathogenic gene variants (G). This approach aims to address the disease's complexity and biological diversity. It suggests categorizing patients based on the presence or absence of α-synuclein pathology in tissues or cerebrospinal fluid, neurodegeneration indicators from specific imaging techniques, and identification of pathogenic gene variants associated with Parkinson's disease. The proposed system emphasizes the future need for precision medicine and aims to facilitate both basic and clinical research toward disease-modifying therapies. However, the authors stress that initial implementation should be confined to research settings, considering ethical implications and current limitations. Prospective validation of these criteria is deemed necessary to ensure their efficacy and ethical application in clinical practice.

Cellular iron deposition patterns predict clinical subtypes of multiple system atrophy.

BACKGROUND: Multiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although neurotoxic effects of brain iron deposition and its relationship with α-synuclein pathology have been demonstrated, the exact role of iron dysregulation in MSA pathogenesis is unknown. Therefore, advancing the understanding of iron dysregulation at the cellular level is critical, especially in relation to α-synuclein cytopathology. METHODS: Iron burden in subcortical and brainstem regions were histologically mapped in human post-mortem brains of 4 MSA-parkinsonian (MSA-P), 4 MSA-cerebellar (MSA-C), and 1 MSA case with both parkinsonian and cerebellar features. We then performed the first cell type-specific evaluation of pathological iron deposition in α-synuclein-affected and -unaffected cells of the globus pallidus, putamen, and the substantia nigra, regions of highest iron concentration, using a combination of iron staining with immunolabelling. Selective regional and cellular vulnerability patterns of iron deposition were compared between disease subtypes. In 7 MSA cases, expression of key iron- and closely related oxygen-homeostatic genes were examined. RESULTS: MSA-P and MSA-C showed different patterns of regional iron burden across the pathology-related systems. We identified subcortical microglia to predominantly accumulate iron, which was more distinct in MSA-P. MSA-C showed relatively heterogenous iron accumulation, with greater or similar deposition in astroglia. Iron deposition was also found outside cellular bodies. Cellular iron burden associated with oligodendrocytic, and not neuronal, α-synuclein cytopathology. Gene expression analysis revealed dysregulation of oxygen homeostatic genes, rather than of cellular iron. Importantly, hierarchal cluster analysis revealed the pattern of cellular vulnerability to iron accumulation, distinctly to α-synuclein pathology load in the subtype-related systems, to distinguish MSA subtypes. CONCLUSIONS: Our comprehensive evaluation of iron deposition in MSA brains identified distinct regional, and for the first time, cellular distribution of iron deposition in MSA-P and MSA-C and revealed cellular vulnerability patterns to iron deposition as a novel neuropathological characteristic that predicts MSA clinical subtypes. Our findings suggest distinct iron-related pathomechanisms in MSA clinical subtypes that are therefore not a consequence of a uniform down-stream pathway to α-synuclein pathology, and inform current efforts in iron chelation therapies at the disease and cellular-specific levels.