Iron In Basal Ganglia Research Articles

Lifestyle, biological, and genetic factors related to brain iron accumulation across adulthood

Iron is necessary for many neurobiological mechanisms, but its overaccumulation can be harmful. Factors triggering age-related brain iron accumulation remain largely unknown and longitudinal data are insufficient. We examined associations between brain iron load and accumulation and, blood markers of iron metabolism, cardiovascular health, lifestyle factors (smoking, alcohol use, physical activity, diet), and ApoE status using longitudinal data from the IronAge study (n = 208, age = 20–79, mean follow-up time = 2.75 years). Iron in cortex and basal ganglia was estimated with magnetic resonance imaging using quantitative susceptibility mapping (QSM). Our results showed that (1) higher peripheral iron levels (i.e., composite score of blood iron markers) were related to greater iron load in the basal ganglia; (2) healthier diet was related to higher iron levels in the cortex and basal ganglia, although for the latter the association was significant only in younger adults (age = 20–39); (3) worsening cardiovascular health was related to increased iron accumulation; (4) younger ApoE ε4 carriers accumulated more iron in basal ganglia than younger non-carriers. Our results demonstrate that modifiable factors, including lifestyle, cardiovascular, and physiological ones, are linked to age-related brain iron content and accumulation, contributing novel information on potential targets for interventions in preventing brain iron-overload.

Is Mitochondrial DNA Copy Number from Human Blood Associated with Iron Deposits in the Brain?

Iron overload is implicated in mitochondrial dysfunction. Some iron and mitochondria-related measures show sex differences. It is unclear whether mitochondrial DNA copy number (mtDNAcn) from blood associated with iron depositions in the brain or liver and whether the relationship differs by sex. In this population-based study, we find that among community-dwelling adults, lower mtDNAcn assessed in blood is associated with higher brain iron in basal ganglia and hippocampus and more liver fat, and not with brain volumes or liver iron. Interestingly, the association between mtDNAcn and brain iron in basal ganglia is prominent in men. Our observations lead to the hypothesis that mechanisms connecting mitochondrial dysfunction and iron overload may differ between brain and liver and differ by sex.

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage.

Higher nigral iron has been reported in Parkinson's disease (PD). The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PDDN ) and 87 drug-treated (PDDT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PDDN and PDDT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. Compared to controls, PDDN had lower iron in the substantia nigra (P=0.018), caudate nucleus (P=0.038), and globus pallidus (P=0.01) but not in the putamen or red nucleus. In contrast, PDDT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PDDN . Iron in the nigra increased with disease duration (PDE > PDDN [P=0.001], PDM > PDE [P=0.045]) except for PDM versus PDL (P=0.226). Levodopa usage was associated with higher (P=0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P=0.030). Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation. © 2022 International Parkinson and Movement Disorder Society.

Neuropsychological profile associated to PKAN in its initial phase: a case series report

ABSTRACT Pantothenase kinase-associated neurodegeneration (PKAN) is characterized by an abnormal accumulation of iron in basal ganglia and progressing varied extrapyramidal clinical symptoms. There are few studies on the cognitive symptoms and their development. The aim of this study is to explore the neuropsychological profile of PKAN patients in the initial stages of the disorder, when there are relatively fewer motor limitations. we present a full neuropsychological examination of three female cases (two early and one late onset). perception and spatial cognition were within normal range. Performance on other tasks were mixed, except for primary impairments in inhibition, flexibility, and cognitive fluency, which were consistent across cases. unlike most previous studies which report adults with major motor impairment, we present cases of young participants with minor motor difficulties. The results of the neuropsychological assessment – potentially less confounded by poor motor functioning during examination – are compatible with impairments in the fronto-subcortical circuits in the early phases of the disease. This could explain frequent misdiagnoses (e.g., with attention deficit hyperactivity disorder) in initial referrals.

Age-related magnetic susceptibility changes in deep grey matter and cerebral cortex of normal young and middle-aged adults depicted by whole brain analysis.

Iron accumulates in brain tissue in healthy subjects during aging. Our goal was to conduct a detailed analysis of iron deposition patterns in the cerebral deep grey matter and cortex using region-based and whole-brain analyses of brain magnetic susceptibility. Brain MRI was performed in 95 healthy individuals aged between 21 and 58 years on a 3T scanner. MRI protocol included T1-weighted (T1W) magnetization-prepared rapid acquisition with gradient echo images and 3D flow-compensated multi-echo gradient-echo images for quantitative susceptibility mapping (QSM). In the region-based analysis, QSM and T1W images entered an automated multi-atlas segmentation pipeline and regional mean bulk susceptibility values were calculated. The whole-brain analysis included a non-linear transformation of QSM images to the standard MNI template. For the whole-brain analysis voxel-wise maps of linear regression slopes β and P values were calculated. Regional masks of cortical voxels with a significant association between susceptibility and age were created and further analyzed. In cortical regions, the highest increase of susceptibility values with age was found in areas involved in motor functions (precentral and postcentral areas, premotor cortex), in cognitive processing (prefrontal cortex, superior temporal gyrus, insula, precuneus), and visual processing (occipital gyri, cuneus, posterior cingulum, fusiform, calcarine and lingual gyrus). Thalamic susceptibility increased until the fourth decade and decreased thereafter with the exception of the pulvinar where susceptibility increase was observed throughout the adult lifespan. Deep grey matter structures with the highest increase of susceptibility values with age included the red nucleus, putamen, substantia nigra, dentate nucleus, external globus pallidus, caudate nucleus, and the subthalamic nucleus in decreasing order. Accumulation of iron in basal ganglia follows a linear pattern whereas in the thalamus, pulvinar, precentral cortex, and precuneus, it follows a quadratic or exponential pattern. Age-related changes of iron content are different in the pulvinar and the rest of the thalamus as well as in internal and external globus pallidus. In the cortex, areas involved in motor and cognitive functions and visual processing show the highest iron increase with aging. We suggest that the departure from normal patterns of regional brain iron trajectories during aging may be helpful in the detection of subtle neurodegenerative and neuroinflammatory processes.

Neurodegeneration with Brain Iron Accumulation and a Brief Report of the Disease in Iran.

Neurodegeneration with brain iron accumulation (NBIA) is a term used for a group of hereditary neurological disorders with abnormal accumulation of iron in basal ganglia. It is clinically and genetically heterogeneous with symptoms such as dystonia, dysarthria, Parkinsonism, intellectual disability, and spasticity. The age at onset and rate of progression are variable among individuals. Current therapies are exclusively symptomatic and unable to hinder the disease progression. Approximately 16 genes have been identified and affiliated to such condition with different functions such as iron metabolism (only two genes: Ferritin Light Chain (FTL) Ceruloplasmin (CP)), lipid metabolism, lysosomal functions, and autophagy process, but some functions have remained unknown so far. Subgroups of NBIA are categorized based on the mutant genes. Although in the last 10 years, the development of whole-exome sequencing (WES) technology has promoted the identification of disease-causing genes, there seem to be some unknown genes and our knowledge about the molecular aspects and pathogenesis of NBIA is not complete yet. There is currently no comprehensive study about the NBIA in Iran; however, one of the latest discovered NBIA genes, GTP-binding protein 2 (GTPBP2), has been identified in an Iranian family, and there are some patients who have genetically remained unknown.

Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) subjects suffer from a variety of cognitive complaints indicating that the central nervous system plays a role in its pathophysiology. Recently, the ratio T1w/T2w has been used to study changes in tissue myelin and/or iron levels in neurodegenerative diseases such as multiple sclerosis and schizophrenia. In this study, we applied the T1w/T2w method to detect changes in tissue microstructure in ME/CFS patients relative to healthy controls. We mapped the T1w/T2w signal intensity values in the whole brain for forty-five ME/CFS patients who met Fukuda criteria and twenty-seven healthy controls and applied both region- and voxel-based quantification. We also performed interaction-with-group regressions with clinical measures to test for T1w/T2w relationships that are abnormal in ME/CFS at the population level. Region-based analysis showed significantly elevated T1w/T2w values (increased myelin and/or iron) in ME/CFS in both white matter (WM) and subcortical grey matter. The voxel-based group comparison with sub-millimetre resolution voxels detected very significant clusters with increased T1w/T2w in ME/CFS, mostly in subcortical grey matter, but also in brainstem and projection WM tracts. No areas with decreased T1w/T2w were found in either analysis. ME/CFS T1w/T2w regressions with heart-rate variability, cognitive performance, respiration rate and physical well-being were abnormal in both gray and white matter foci. Our study demonstrates that the T1w/T2w approach is very sensitive and shows increases in myelin and/or iron in WM and basal ganglia in ME/CFS.

A pilot trial of deferiprone in pantothenate kinase-associated neurodegeneration patients.

Pantothenate kinase-associated neurodegeneration (PKAN) is the most common form of neurodegeneration with brain iron accumulation, it is an autosomal recessive disease due to mutation in PANK 2 on chromosome 20, which causes the accumulation of iron in basal ganglia and production of free radicals that cause degeneration of the cells. Deferiprone is an iron chelator that was used in treatment of thalassemia patients, it can cross the blood-brain barrier and reverse the iron deposition in the brain. Five patients with genetically confirmed PKAN received 15 mg/kg deferiprone twice daily. All patients were examined at baseline, 12 and 18 months and magnetic resonance imaging (MRI) was done at the baseline and after 18 months. In our study qualitative evaluation of MRI showed that deferiprone was able to reduce the iron load in globus pallidus of all the patients and the results of clinical rating scales show that in four patients, there is an improvement in the first 12 months. The results of our paper show that deferiprone can prevent the progression of the disease.

Magnetic susceptibility of brain iron is associated with childhood spatial IQ

Iron is an essential micronutrient for healthy brain function and development. Because of the importance of iron in the brain, iron deficiency results in widespread and lasting effects on behavior and cognition. We measured iron in the basal ganglia of young children using a novel MRI method, quantitative susceptibility mapping, and examined the association of brain iron with age and cognitive performance. Participants were a community sample of 39 young children recruited from pediatric primary care who were participating in a 5-year longitudinal study of child brain development and anxiety disorders. The children were ages 7 to 11years old (mean age: 9.5years old) at the time of the quantitative susceptibility mapping scan. The differential abilities scale was administered when the children were 6years old to provide a measure of general intelligence and verbal (receptive and expressive), non-verbal, and spatial performance. Magnetic susceptibility values, which are linearly related to iron concentration in iron-rich areas, were extracted from regions of interest within iron-rich deep gray matter nuclei from the basal ganglia, including the caudate, putamen, substantia nigra, globus pallidus, and thalamus. Controlling for scan age, there was a significant positive association between iron in the basal ganglia and spatial IQ, with this effect being driven by iron in the right caudate We also replicated previous findings of a significant positive association between iron in the bilateral basal ganglia and age. Our finding of a positive association between spatial IQ and mean iron in the basal ganglia, and in the caudate specifically, suggests that iron content in specific regions of the iron-rich deep nuclei of the basal ganglia influences spatial intelligence. This provides a potential neurobiological mechanism linking deficits in spatial abilities reported in children who were severely iron deficient as infants to decreased iron within the caudate.

The role of iron in gray matter degeneration in Huntington's disease: a magnetic resonance imaging study.

In Huntington's disease, iron accumulation in basal ganglia accompanies neuronal loss. However, if iron content changes with disease progression and how it relates to gray matter atrophy is not clear yet. We explored iron content in basal ganglia and cortex and its relationship with gray matter volume in 77 mutation carriers [19 presymptomatic, 8 with soft symptoms (SS), and 50 early-stage patients) and 73 matched-controls by T2*relaxometry and T1-weighted imaging on a 3T scanner. The ANCOVA model showed that iron accumulates in the caudate in presymptomatic subjects (P = 0.004) and remains relatively stable along disease stages in this nucleus; while increases in putamen and globus pallidus (P < 0.05). Volume instead decreases in basal ganglia, starting from the caudate (P < 0.0001) and extending to the putamen and globus pallidus (P ≤ 0.001). The longer the disease duration and the higher the CAG repeats, the higher the iron accumulation and the smaller the volume. In the cortex, iron decreases in parieto-occipital areas in SS (P < 0.027); extending to premotor and parieto-temporo-occipital areas in patients (P < 0.003); while volume declines in frontoparietal and temporal areas in presymptomatic (P < 0.023) and SS (P < 0.045), and extends throughout the cortex, with the exception of anterior frontal regions, in patients (P < 0.023). There is an inverse correlation between volume and iron levels in putamen, globus pallidus and the anterior cingulate; and a direct correlation in cortical structures (SMA-sensoriomotor and temporo-occipital). Iron homeostasis is affected in the disease; however, there appear to be differences in the role played by iron in basal ganglia and in cortex.