Abstract Iron is an essential element necessary for energy production, DNA and neurotransmitter synthesis, myelination and phospholipid metabolism. Neurodegeneration with brain iron accumulation ...(NBIA) involves several genetic disorders, two of which, aceruloplasminemia and neuroferritinopathy, are caused by mutations in genes directly involved in iron metabolic pathway, and others, such as pantothenate-kinase 2, phospholipase-A2 and fatty acid 2-hydroxylase associated neurodegeneration, are caused by mutations in genes coding for proteins involved in phospholipid metabolism. Phospholipids are major constituents of myelin and iron accumulation has been linked to myelin derangements. Another group of NBIAs is caused by mutations in lysosomal enzymes or transporters such as ATP13A2, mucolipin-1 and possibly also β-galactosidase and α-fucosidase. Increased cellular iron uptake in these diseases may be caused by impaired recycling of iron which normally involves lysosomes. Abnormal iron utilization by mitochondria, as has been proposed in Friedreich's ataxia, is another possible mechanism of iron accumulation. Other, more common degenerative movement disorders, such as Parkinson's disease, Huntington's disease, multiple system atrophy and progressive supranuclear palsy also exhibit increased brain iron content. Finally, brain iron deficiency has been implicated in restless legs syndrome. This review provides an update on recent findings related to genetics, pathogenic mechanisms, diagnosis, and treatment of movement disorders associated with dysregulation of brain iron. We also propose a new classification of NBIAs.
•Briefly introduce the biochemical underpinnings of brain iron accumulation in PD.•Overview the advancements in iron-sensitive MRI technologies.•Summarize and discuss the role of QSM as a biomarker ...in PD.•Specify the value of QSM in the neurosurgery in PD.•Outline the translational concerning and future perspective.
Parkinson's disease (PD) is a common neurodegenerative disease, and apart from a few rare genetic causes, its pathogenesis remains largely unclear. Recent scientific interest has been captured by the involvement of iron biochemistry and the disruption of iron homeostasis, particularly within the brain regions specifically affected in PD. The advent of Quantitative Susceptibility Mapping (QSM) has enabled non-invasive quantification of brain iron in vivo by MRI, which has contributed to the understanding of iron-associated pathogenesis and has the potential for the development of iron-based biomarkers in PD. This review elucidates the biochemical underpinnings of brain iron accumulation, details advancements in iron-sensitive MRI technologies, and discusses the role of QSM as a biomarker of iron deposition in PD. Despite considerable progress, several challenges impede its clinical application after a decade of QSM studies. The initiation of multi-site research is warranted for developing robust, interpretable, and disease-specific biomarkers for monitoring PD disease progression.
Impaired cellular homeostasis of metals, particularly of Cu, Fe and Mn may trigger neurodegeneration through various mechanisms, notably induction of oxidative stress, promotion of α-synuclein ...aggregation and fibril formation, activation of microglial cells leading to inflammation and impaired production of metalloproteins. In this article we review available studies concerning Fe, Cu and Mn in Parkinson's disease and Wilson's disease. In Parkinson's disease local dysregulation of iron metabolism in the substantia nigra (SN) seems to be related to neurodegeneration with an increase in SN iron concentration, accompanied by decreased SN Cu and ceruloplasmin concentrations and increased free Cu concentrations and decreased ferroxidase activity in the cerebrospinal fluid. Available data in Wilson's disease suggest that substantial increases in CNS Cu concentrations persist for a long time during chelating treatment and that local accumulation of Fe in certain brain nuclei may occur during the course of the disease. Consequences for chelating treatment strategies are discussed.
Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include ...reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson's disease, Friedreich's disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood-brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.
Trace elements, such as iron, copper, manganese, and calcium, which are essential constituents necessary for cellular homeostasis, become toxic when present in excess quantities. In this article, we ...describe disorders arising from endogenous dysregulation of metal homeostasis leading to their tissue accumulation. Although subgroups of these diseases lead to regional brain metal accumulation, mostly in globus pallidus, which is susceptible to accumulate divalent metal ions, other subgroups cause systemic metal accumulation affecting the whole brain, liver, and other parenchymal organs. The latter group comprises Wilson disease, manganese transporter deficiency, and aceruloplasminemia and responds favorably to chelation treatment.
The effect of dopaminergic medication on speech has rarely been examined in early-stage Parkinson's disease (PD) and the respective literature is inconclusive and limited by inappropriate design with ...lack of PD control group. The study aims to examine the short-term effect of dopaminergic medication on speech in PD using patients with good motor responsiveness to levodopa challenge compared to a control group of PD patients with poor motor responsiveness. A total of 60 early-stage PD patients were investigated before (OFF) and after (ON) acute levodopa challenge and compared to 30 age-matched healthy controls. PD patients were categorised into two clinical subgroups (PD responders vs. PD nonresponders) according to the comparison of their motor performance based on movement disorder society-unified Parkinson's disease rating scale, part III. Seven distinctive parameters of hypokinetic dysarthria were examined using quantitative acoustic analysis. We observed increased monopitch (p > 0.01), aggravated monoloudness (p > 0.05) and longer duration of stop consonants (p > 0.05) in PD compared to healthy controls, confirming the presence of hypokinetic dysarthria in early PD. No speech alterations from OFF to ON state were revealed in any of the two PD groups and speech dimensions investigated including monopitch, monoloudness, imprecise consonants, harsh voice, slow sequential motion rates, articulation rate, or inappropriate silences, although a subgroup of PD responders manifested obvious improvement in motor function after levodopa intake (p > 0.001). Since the short-term usage of levodopa does not easily affect voice and speech performance in PD, speech assessment may provide a medication state-independent motor biomarker of PD.
Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to
grow considerably. In addition to the core syndromes of pantothenate kinase-associated ...neurodegeneration (PKAN,
NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified
(including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened
and new age-dependent presentations are being described. There is also growing recognition of overlap between the different
NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis
which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed
cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative
disorders such as Parkinson’s disease (PD) and Alzheimer’s disease. Until we disentangle the various NBIA genes and
their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic.
Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in
neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize
therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and
molecular underpinnings of the NBIA syndromes.
Wilson’s disease (WD) is an inherited metabolic disorder related to disturbances of copper metabolism, and predominantly presents with liver and neuropsychiatric symptoms. In most cases it can be ...successfully treated with anti-copper agents, and both liver function and neuropsychiatric symptoms typically improve. Treatment guidelines for WD include recommendations for anti-copper treatment as well as for the treatment of liver failure symptoms. Recently, recommendations for treatment of the neurological symptoms of WD have also been proposed. Although most WD patients present with psychiatric symptoms at some stage of the disease, currently there are no guidelines for the treatment of the psychiatric manifestations. Treatment of the psychiatric symptoms of WD is often guided by general psychiatric experience, which typically glosses over the specificity of WD, and can result in severe neurological and/or hepatic complications. Here we review and discuss the possible treatments available for the mood disturbances, psychosis, behavioral and cognitive disorders that can occur in WD, as well as their efficacy.
In this prospective longitudinal study, we quantified regional brain volume and susceptibility changes during the first two years after the diagnosis of multiple sclerosis (MS) and identified their ...association with cerebrospinal fluid (CSF) markers at baseline. Seventy patients underwent MRI (T1 and susceptibility weighted images processed to quantitative susceptibility maps, QSM) with neurological examination at the diagnosis and after two years. In CSF obtained at baseline, the levels of oxidative stress, products of lipid peroxidation, and neurofilaments light chain (NfL) were determined. Brain volumetry and QSM were compared with a group of 58 healthy controls. In MS patients, regional atrophy was identified in the striatum, thalamus, and substantia nigra. Magnetic susceptibility increased in the striatum, globus pallidus, and dentate and decreased in the thalamus. Compared to controls, MS patients developed greater atrophy of the thalamus, and a greater increase in susceptibility in the caudate, putamen, globus pallidus and a decrease in the thalamus. Of the multiple calculated correlations, only the decrease in brain parenchymal fraction, total white matter, and thalamic volume in MS patients negatively correlated with increased NfL in CSF. Additionally, negative correlation was found between QSM value in the substantia nigra and peroxiredoxin-2, and QSM value in the dentate and lipid peroxidation levels.
Background:
Early diagnosis and treatment of patients with multiple sclerosis (MS) are associated with better outcomes; however, diagnostic delays remain a major problem.
Objective:
Describe the ...prevalence, determinants and consequences of delayed diagnoses.
Methods:
This single-centre ambispective study analysed 146 adult relapsing-remitting MS patients (2016–2021) for frequency and determinants of diagnostic delays and their associations with clinical, cognitive, imaging and biochemical measures.
Results:
Diagnostic delays were identified in 77 patients (52.7%), including 42 (28.7%) physician-dependent cases and 35 (24.0%) patient-dependent cases. Diagnosis was delayed in 22 (15.1%) patients because of misdiagnosis by a neurologist. A longer diagnostic delay was associated with trends towards greater Expanded Disability Status Scale (EDSS) scores (B = 0.03; p = 0.034) and greater z-score of the blood neurofilament light chain (B = 0.35; p = 0.031) at the time of diagnosis. Compared with patients diagnosed at their first clinical relapse, patients with a history of >1 relapse at diagnosis (n = 63; 43.2%) had a trend towards greater EDSS scores (B = 0.06; p = 0.006) and number of total (B = 0.13; p = 0.040) and periventricular (B = 0.06; p = 0.039) brain lesions.
Conclusion:
Diagnostic delays in MS are common, often determined by early misdiagnosis and associated with greater disease burden.
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