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Neurobiology of Disease Jul 2024Multiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although...
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.
Topics: Humans; Multiple System Atrophy; Iron; Male; Aged; Female; Middle Aged; alpha-Synuclein; Brain; Aged, 80 and over; Oligodendroglia
PubMed: 38761956
DOI: 10.1016/j.nbd.2024.106535 -
Journal of Neurology, Neurosurgery, and... May 2024The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of...
BACKGROUND
The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD.
METHODS
Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2-3 weeks, and 18F-Choline-PET was performed immediately after.
RESULTS
The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions.
CONCLUSION
BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.
PubMed: 38760152
DOI: 10.1136/jnnp-2023-332967 -
Journal of Alzheimer's Disease : JAD 2024Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer's disease (AD) by many years. No study has evaluated the...
BACKGROUND
Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer's disease (AD) by many years. No study has evaluated the free water of patients with AD using gray matter-based spatial statistics.
OBJECTIVE
The aim of this study was to explore cortical microstructural changes within the gray matter in AD by using free water imaging with gray matter-based spatial statistics.
METHODS
Seventy-one participants underwent multi-shell diffusion magnetic resonance imaging, 11C-Pittsburgh compound B positron emission tomography, and neuropsychological evaluations. The patients were divided into two groups: healthy controls (n = 40) and the AD spectrum group (n = 31). Differences between the groups were analyzed using voxel-based morphometry, diffusion tensor imaging, and free water imaging with gray matter-based spatial statistics.
RESULTS
Voxel-based morphometry analysis revealed gray matter volume loss in the hippocampus of patients with AD spectrum compared to that in controls. Furthermore, patients with AD spectrum exhibited significantly greater free water, mean diffusivity, and radial diffusivity in the limbic areas, precuneus, frontal lobe, temporal lobe, right putamen, and cerebellum than did the healthy controls. Overall, the effect sizes of free water were greater than those of mean diffusivity and radial diffusivity, and the larger effect sizes of free water were thought to be strongly correlated with AD pathology.
CONCLUSIONS
This study demonstrates the utility of applying voxel-based morphometry, gray matter-based spatial statistics, free water imaging and diffusion tensor imaging to assess AD pathology and detect changes in gray matter.
Topics: Humans; Alzheimer Disease; Male; Female; Gray Matter; Aged; Positron-Emission Tomography; Diffusion Tensor Imaging; Aniline Compounds; Thiazoles; Neuropsychological Tests; Water; Diffusion Magnetic Resonance Imaging; Middle Aged; Brain; Aged, 80 and over; Image Processing, Computer-Assisted
PubMed: 38759008
DOI: 10.3233/JAD-231416 -
Brain Imaging and Behavior May 2024Quantitative susceptibility mapping (QSM) is an MRI technique that accurately measures iron concentration in brain tissues. This meta-analysis synthesized evidence from... (Review)
Review
Quantitative susceptibility mapping (QSM) is an MRI technique that accurately measures iron concentration in brain tissues. This meta-analysis synthesized evidence from 30 studies that used QSM to quantify the iron levels in the putamen. The PRISMA statement was adhered to when conducting the systematic reviews and meta-analyses. We conducted a meta-analysis using a random-effects model, as well as subgroup analyses (disease type, geographic region, field strength, coil, disease type, age, and sex) and sensitivity analysis. A total of 1247 patients and 1035 controls were included in the study. Pooled results showed a standardized mean difference (SMD) of 0.41 (95% CI 0.19 to 0.64), with the strongest effect seen in Alzheimer's disease (AD) at 1.01 (95% CI 0.50 to 1.52). Relapsing-remitting multiple sclerosis (RRMS) also showed increased putaminal iron at 0.37 (95% CI 0.177 to 0.58). No significant differences were observed in Parkinson's disease (PD). No significant differences were found between subgroups based on geographic region, field strength, coil, disease type, age, and sex. The studies revealed significant heterogeneity, with field strength as the primary source, while other factors, such as disease type, location, age, sex, and coil type, may have contributed. The sensitivity analysis showed that these factors did not have a significant influence on the overall results. In summary, this meta-analysis supports abnormalities in putaminal iron content across different diseases with neurodegeneration, especially AD and RRMS, as measured by QSM. This highlights the potential of QSM as an imaging biomarker to better understand disease mechanisms involving disturbances in brain iron homeostasis.
PubMed: 38758278
DOI: 10.1007/s11682-024-00895-6 -
Movement Disorders Clinical Practice May 2024The G2019S leucine-rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological...
BACKGROUND
The G2019S leucine-rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological findings associated with this mutation have thus far been varied but are most often associated with Lewy body (LB) pathology.
OBJECTIVE
Describe a case of clinical Parkinson's disease with levodopa responsiveness found to have LRRK2 mutations and the absence of Lewy bodies.
METHOD
We present an 89-year-old man with a 10-year history of slowly progressive parkinsonism suspected to be secondary to Parkinson's disease.
RESULTS
Neuropathological evaluation revealed nigral degeneration without Lewy bodies or Lewy neurites, but there were frequent tau-immunopositive neurites and astrocytes in the putamen and substantia nigra, neocortical glial tau positive astrocytes associated with aging-related tau astrogliopathy (ARTAG), as well as neurofibrillary tangles, beta amyloid plaques, and amyloid angiopathy typical of advanced Alzheimer's disease. G2019S LRRK2 homozygous mutations were found.
CONCLUSION
This case illustrates that levodopa-responsive clinical PD caused by G2019S LRRK2 mutations can occur without Lewy bodies.
PubMed: 38757351
DOI: 10.1002/mdc3.14068 -
Journal of Gambling Studies May 2024The role of dopamine in the pathophysiology of gambling disorder (GD) remains incompletely understood, with disparate research findings concerning presynaptic and...
The role of dopamine in the pathophysiology of gambling disorder (GD) remains incompletely understood, with disparate research findings concerning presynaptic and postsynaptic structures and dopaminergic synthesis. The aim of this study was to investigate potential correlations between striatal dopamine transporter (DAT) lateralization and asymmetry index, as assessed by I-FP-CIT SPECT, and temperamental traits, as measured by Cloninger's Temperament and Character Inventory (TCI), in GD subjects. Significant associations were found between DAT binding asymmetries in the caudate and putamen and the temperamental dimensions of harm avoidance and novelty seeking. Specifically, high novelty seeking scores correlated with increased DAT binding in the left caudate relative to the right, whereas higher harm avoidance scores corresponded to increased DAT binding in the right putamen relative to the left. These observations potentially imply that the asymmetry in DAT expression in the basal ganglia could be an outcome of hemispheric asymmetry in emotional processing and behavioural guidance. In summary, our study provides evidence supporting the relationship between DAT asymmetries, temperamental dimensions and GD. Future investigations could be directed towards examining postsynaptic receptors to gain a more comprehensive understanding of dopamine's influence within the basal ganglia circuit in disordered gambling. If confirmed in larger cohorts, these findings could have substantial implications for the tailoring of individualized neuromodulation therapies in the treatment of behavioural addictions.
PubMed: 38755422
DOI: 10.1007/s10899-024-10311-9 -
Brain, Behavior, and Immunity Jul 2024Cognitive impairment in Parkinson's disease is considered an indicator of the prodromal stages of this condition, occurring prior to the onset of classic and...
Cognitive impairment in Parkinson's disease is considered an indicator of the prodromal stages of this condition, occurring prior to the onset of classic and pathognomonic motor symptoms. Among other factors, neuroinflammation is increasingly recognized as a potential mediator of this neurodegenerative process, and glial cells are directly involved. However, the use of neurotrophic factors is associated with neuroprotection and cognitive improvements. Among all those factors, insulin-like growth factor 1 (IGF-1) has attracted considerable attention. In this study, we aimed to investigate the effect of IGF-1 gene therapy in an early animal model of 6-hydroxidopamine (6-OHDA)- induced parkinsonism. For this purpose, we employed male Wistar rats. The animals were first divided into two groups according to the bilateral injection into de Caudate Putamen unit (CPu):(a) VEH group (vehicle solution) and (b) 6-OHDA group (neurotoxic solution). After that, the animals in each group were divided, according to the bilateral injection into the dorsal hippocampus, in a control group (who received a control virus RAd-DSRed) and an experimental group (who received a therapeutic virus (RAd-IGF1). After three weeks of exposure to 6-OHDA, our study showed that IGF-1 gene therapy improved cognitive deficits related to short-term and spatial working memory, it also increased expression levels of tyrosine hydroxylase in the CPu. In addition, the therapy resulted in significant changes in several parameters (area, perimeter, roundness, ramification, and skeleton ́s analyses) related to microglia and astrocyte phenotypes, particularly in the CPu and dorsal hippocampal areas. Our data support the use of IGF-1 as a therapeutic molecule for future gene transfer interventions, that will contribute to a better understanding of the mechanisms correlating cognitive function and inflammatory process.
Topics: Animals; Male; Insulin-Like Growth Factor I; Rats; Rats, Wistar; Genetic Therapy; Disease Models, Animal; Spatial Memory; Memory Disorders; Parkinsonian Disorders; Oxidopamine; Inflammation; Dopaminergic Neurons; Hippocampus; Dopamine
PubMed: 38750702
DOI: 10.1016/j.bbi.2024.05.013 -
Research Square Apr 2024The study aim was to determine whether associations of antenatal maternal anaemia with smaller corpus callosum, putamen, and caudate nucleus volumes previously described...
BACKGROUND
The study aim was to determine whether associations of antenatal maternal anaemia with smaller corpus callosum, putamen, and caudate nucleus volumes previously described in children at age 2-3 years persist to age 6-7 years in the Drakenstein Child Health Study (DCHS).
METHODS
This neuroimaging sub-study was nested within the DCHS, a South African population-based birth cohort. Pregnant women were enrolled (2012-2015) and mother-child dyads were followed prospectively. A sub-group of children had magnetic resonance imaging at 6-7 years of age (2018-2022). Mothers had haemoglobin measurements during pregnancy and a proportion of children were tested postnatally. Maternal anaemia (haemoglobin<11g/dL) and child anaemia were classified using WHO and local guidelines. Linear modeling was used to investigate associations between antenatal maternal anaemia status, maternal haemoglobin concentrations, and regional child brain volumes. Models included potential confounders and were conducted with and without child anaemia to assess the relative roles of antenatal versus postnatal anaemia.
RESULTS
Overall, 157 children ( [] age of 75.54 [4.77] months; 84 [53.50%] male) were born to mothers with antenatal haemoglobin data. The prevalence of maternal anaemia during pregnancy was 31.85% (50/157). In adjusted models, maternal anaemia status was associated with smaller volumes of the total corpus callosum (adjusted percentage difference, -6.77%; =0.003), left caudate nucleus (adjusted percentage difference, -5.98%, =0.005), and right caudate nucleus (adjusted percentage difference, -6.12%; =0.003). Continuous maternal haemoglobin was positively associated with total corpus callosum (=0.239 [CI: 0.10 to 0.38]; <0.001) and caudate nucleus (=0.165 [CI: 0.02 to 0.31]; =0.027) volumes. In a sub-group (=89) with child haemoglobin data ( [] age of 76.06[4.84]), the prevalence of antenatal maternal anaemia and postnatal child anaemia was 38.20% (34/89) and 47.19% (42/89), respectively. There was no association between maternal and child anaemia (c = 0.799; =0.372), and child anaemia did not contribute to regional brain volume differences associated with maternal anaemia.
CONCLUSIONS
Associations between maternal anaemia and regional child brain volumes previously reported at 2-3 years of age were consistent and persisted to 6-7 years of age. Findings support the importance of optimizing antenatal maternal health and reinforce these brain regions as a future research focus on intervention outcomes.
PubMed: 38746172
DOI: 10.21203/rs.3.rs-4281448/v1 -
Endocrinology, Diabetes & Metabolism... Apr 2024Hemichorea-hemiballismus (HCHB) syndrome is a syndrome characterized by choreic movements which are irregular, nonrepetitive, and random movements, and ballismus which...
SUMMARY
Hemichorea-hemiballismus (HCHB) syndrome is a syndrome characterized by choreic movements which are irregular, nonrepetitive, and random movements, and ballismus which are spontaneous and violent movements. HCHB syndrome with a metabolic cause is a rare presentation that can be precipitated by uncontrolled diabetes. Presented here is a case of HCHB syndrome with right-sided neuroimaging findings and contralateral chorea due to uncontrolled type 2 diabetes mellitus. This patient was found to be obtunded with a blood glucose of greater than 500 mg/dL by EMS. After the administration of insulin, she was able to answer clarifying questions of noncompliance with her antihyperglycemic medications. She had a computed tomography without contrast of the head which showed hyperdense lesions in the right caudate nucleus and putamen consistent with HCHB syndrome. She was started on treatment for nonketotic hyperglycemia with insulin. As her mentation improved, she was able to cooperate with physical examination, which revealed irregular and violent movements in the left upper and lower extremities. Her hemichorea and hemiballismus improved with strict glycemic control, and she was able to be discharged to a skilled nursing facility for further rehabilitation. She would later have repeated hospitalizations for poor glycemic control, and repeat neuroimaging would reveal the resolution of hyperdensities after 4 months. HCHB syndrome due to uncontrolled diabetes has been termed diabetic striatopathy and is characterized by poor glycemic control, unilateral striatal hyperdensity on CT imaging, and contralateral choreic movements. Diabetic striatopathy remains a poorly understood disease, and the exact pathophysiologic mechanism has not been definitively elucidated.
LEARNING POINTS
Diabetic striatopathy is a relatively new term for metabolic etiology of hemichorea-hemiballismus syndrome and was coined in 2009. The triad for diabetic striatopathy is poor glycemic control, unilateral striatal hyperdensity on CT imaging, and contralateral choreic movements. Multiple etiologies have been suggested for the cause of diabetic striatopathy including petechial hemorrhage, mineral deposition, myelin destruction, and infarction with reactive astrocytosis; however, the exact mechanism has yet to be determined. Antidopaminergic medications may be used to control the choreic movements of diabetic striatopathy; however, the mainstay of treatment is glycemic control, often with insulin therapy.
PubMed: 38744315
DOI: 10.1530/EDM-23-0082 -
Clinical Neuroradiology May 2024Children with congenital heart diseases (CHDs) have an increased risk of developing neurologic deficits, even in the absence of apparent brain pathology. The aim of this...
BACKGROUND AND OBJECTIVES
Children with congenital heart diseases (CHDs) have an increased risk of developing neurologic deficits, even in the absence of apparent brain pathology. The aim of this work was to compare quantitative macro- and microstructural properties of subcortical gray matter structures of pediatric CHD patients with normal appearing brain magnetic resonance imaging to healthy controls.
METHODS
We retrospectively reviewed children with coarctation of the aorta (COA) and hypoplastic left heart syndrome (HLHS) admitted to our hospital. We identified 24 pediatric CHD patients (17 COA, 7 HLHS) with normal-appearing brain MRI. Using an atlas-based approach, the volume and apparent diffusion coefficient (ADC) were determined for the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, cerebral white matter, cerebral cortex, and brainstem. Multivariate statistics were used to compare the extracted values to reference values from 100 typically developing children without any known cardiac or neurological diseases.
RESULTS
Multivariate analysis of covariance using the regional ADC and volume values as dependent variables and age and sex as co-variates revealed a significant difference between pediatric CHD patients and healthy controls (p < 0.001). Post-hoc comparisons demonstrated significantly reduced brain volumes in most subcortical brain regions investigated and elevated ADC values in the thalamus for children with CHD. No significant differences were found comparing children with COA and HLHS.
CONCLUSIONS
Despite normal appearing brain MRI, children with CHD exhibit wide-spread macro-structural and regional micro-structural differences of subcortical brain structures compared to healthy controls, which could negatively impact neurodevelopment, leading to neurological deficits in childhood and beyond.
PubMed: 38743101
DOI: 10.1007/s00062-024-01417-z