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International Journal of Molecular... Sep 2015Putamen atrophy and its long-term progress during disease course were recently shown in patients with multiple sclerosis (MS). Here we investigated retrospectively the...
Putamen atrophy and its long-term progress during disease course were recently shown in patients with multiple sclerosis (MS). Here we investigated retrospectively the time point of atrophy onset in patients with relapsing-remitting MS (RRMS). 68 patients with RRMS and 26 healthy controls (HC) were admitted to 3T MRI in a cross-sectional study. We quantitatively analyzed the putamen volume of individual patients in relation to disease duration by correcting for age and intracranial volume (ICV). Patient's relative putamen volume (RPV), expressed in percent of ICV, was significantly reduced compared to HC. Based on the correlation between RPV and age, we computed the age-corrected RPV deviation (ΔRPV) from HC. Patients showed significantly negative ΔRPV. Interestingly, the age-corrected ΔRPV depended logarithmically on disease duration: Directly after first symptom manifestation, patients already showed a reduced RPV followed by a further degressive volumetric decline. This means that atrophy progression was stronger in the first than in later years of disease. Putamen atrophy starts directly after initial symptom manifestation or even years before, and progresses in a degressive manner. Due to its important role in neurological functions, early detection of putamen atrophy seems necessary. High-resolution structural MRI allows monitoring of disease course.
Topics: Adult; Aged; Atrophy; Cross-Sectional Studies; Disease Progression; Female; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Putamen; Young Adult
PubMed: 26404239
DOI: 10.3390/ijms161023195 -
Annals of Neurology Mar 2020Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now...
OBJECTIVE
Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system.
METHODS
This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen.
RESULTS
A group-by-brain region interaction effect (F = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06).
INTERPRETATION
This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338.
Topics: Autoradiography; Case-Control Studies; Early Diagnosis; Female; Functional Neuroimaging; Humans; Locus Coeruleus; Male; Membrane Glycoproteins; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Positron-Emission Tomography; Putamen; Pyridines; Pyrrolidines; Red Nucleus; Substantia Nigra; Synapses
PubMed: 31953875
DOI: 10.1002/ana.25682 -
ELife Jun 2021Human reproduction is controlled by ~2000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here, we report the discovery and characterization of additional...
Human reproduction is controlled by ~2000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here, we report the discovery and characterization of additional ~150,000-200,000 GnRH-synthesizing cells in the human basal ganglia and basal forebrain. Nearly all extrahypothalamic GnRH neurons expressed the cholinergic marker enzyme choline acetyltransferase. Similarly, hypothalamic GnRH neurons were also cholinergic both in embryonic and adult human brains. Whole-transcriptome analysis of cholinergic interneurons and medium spiny projection neurons laser-microdissected from the human putamen showed selective expression of and autoreceptors in the cholinergic cell population and uncovered the detailed transcriptome profile and molecular connectome of these two cell types. Higher-order non-reproductive functions regulated by GnRH under physiological conditions in the human basal ganglia and basal forebrain require clarification. The role and changes of GnRH/GnRHR1 signaling in neurodegenerative disorders affecting cholinergic neurocircuitries, including Parkinson's and Alzheimer's diseases, need to be explored.
Topics: Adult; Basal Forebrain; Basal Ganglia; Cells, Cultured; Choline O-Acetyltransferase; Female; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neurons; Putamen; Transcriptome
PubMed: 34128468
DOI: 10.7554/eLife.67714 -
CNS Neuroscience & Therapeutics Dec 2022To develop an automatic method of classification for parkinsonian variant of multiple system atrophy (MSA-P) and Idiopathic Parkinson's disease (IPD) in early to...
AIMS
To develop an automatic method of classification for parkinsonian variant of multiple system atrophy (MSA-P) and Idiopathic Parkinson's disease (IPD) in early to moderately advanced stages based on multimodal striatal alterations and identify the striatal neuromarkers for distinction.
METHODS
77 IPD and 75 MSA-P patients underwent 3.0 T multimodal MRI comprising susceptibility-weighted imaging, resting-state functional magnetic resonance imaging, T1-weighted imaging, and diffusion tensor imaging. Iron-radiomic features, volumes, functional and diffusion scalars of bilateral 10 striatal subregions were calculated and provided to the support vector machine for classification RESULTS: A combination of iron-radiomic features, function, diffusion, and volumetric measures optimally distinguished IPD and MSA-P in the testing dataset (accuracy 0.911 and area under the receiver operating characteristic curves [AUC] 0.927). The diagnostic performance further improved when incorporating clinical variables into the multimodal model (accuracy 0.934 and AUC 0.953). The most crucial factor for classification was the functional activity of the left dorsolateral putamen.
CONCLUSION
The machine learning algorithm applied to multimodal striatal dysfunction depicted dorsal striatum and supervening prefrontal lobe and cerebellar dysfunction through the frontostriatal and cerebello-striatal connections and facilitated accurate classification between IPD and MSA-P. The dorsolateral putamen was the most valuable neuromarker for the classification.
Topics: Humans; Multiple System Atrophy; Parkinson Disease; Diffusion Tensor Imaging; Putamen; Magnetic Resonance Imaging; Iron; Diagnosis, Differential
PubMed: 36047435
DOI: 10.1111/cns.13959 -
Neurology(R) Neuroimmunology &... Nov 2019To identify the top brain regions affected by MS-specific atrophy (i.e., atrophy in excess of normal aging) and to test whether normal aging and MS-specific atrophy...
OBJECTIVE
To identify the top brain regions affected by MS-specific atrophy (i.e., atrophy in excess of normal aging) and to test whether normal aging and MS-specific atrophy increase or decrease in these regions with age.
METHODS
Six hundred fifty subjects (2,790 MRI time points) were analyzed: 520 subjects with relapse-onset MS from a 5-year prospective cohort with annual standardized 1-mm 3D T1-weighted images (3DT1s; 2,483 MRIs) and 130 healthy controls with longitudinal 3DT1s (307 MRIs). Rates of change in all FreeSurfer regions (v5.3) and Structural Image Evaluation Using Normalization of Atrophy (SIENA) were estimated with mixed-effects models. All FreeSurfer regions were ranked by the MS-specific atrophy slope/standard error ratio (β/SE). In the top regions, age was added as an effect modifier to test whether MS-specific atrophy varied by age.
RESULTS
The top-ranked regions were all gray matter structures. For SIENA, normal aging increased from 0.01%/y at age 30 years to -0.31%/y at age 60 years (-0.11% ± 0.032%/decade, < 0.01), whereas MS-specific atrophy decreased from -0.38%/y at age 30 years to -0.12%/y at age 60 years (0.09% ± 0.035%/decade, = 0.01). Similarly, in the thalamus, normal aging increased from -0.15%/y at age 30 years to -0.62%/y at age 60 years (-0.16% ± 0.079%/decade, < 0.05), and MS-specific atrophy decreased from -0.59%/y at age 30 years to -0.05%/y at age 60 years (0.18% ± 0.08%/decade, < 0.05). In the putamen and caudate, normal aging and MS-specific atrophy did not vary by age.
CONCLUSIONS
For SIENA and thalamic atrophy, the contribution of normal aging increases with age, but does not change in the putamen and caudate. This may have substantial implications to understand the biology of brain atrophy in MS.
Topics: Adult; Aged; Aging; Atrophy; Brain Diseases; Caudate Nucleus; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Prospective Studies; Putamen; Thalamus
PubMed: 32330116
DOI: 10.1212/NXI.0000000000000616 -
The Journal of Comparative Neurology Mar 2021Sex steroid hormones such as 17β-estradiol (estradiol) regulate neuronal function by binding to estrogen receptors (ERs), including ERα and GPER1, and through...
Estrogen receptor alpha, G-protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region-specific differences across the rat caudate-putamen, nucleus accumbens core and shell.
Sex steroid hormones such as 17β-estradiol (estradiol) regulate neuronal function by binding to estrogen receptors (ERs), including ERα and GPER1, and through differential production via the enzyme aromatase. ERs and aromatase are expressed across the nervous system, including in the striatal brain regions. These regions, comprising the nucleus accumbens core, shell, and caudate-putamen, are instrumental for a wide-range of functions and disorders that show sex differences in phenotype and/or incidence. Sex-specific estrogen action is an integral component for generating these sex differences. A distinctive feature of the striatal regions is that in adulthood neurons exclusively express membrane but not nuclear ERs. This long-standing finding dominates models of estrogen action in striatal regions. However, the developmental etiology of ER and aromatase cellular expression in female and male striatum is unknown. This omission in knowledge is important to address, as developmental stage influences cellular estrogenic mechanisms. Thus, ERα, GPER1, and aromatase cellular immunoreactivity was assessed in perinatal, prepubertal, and adult female and male rats. We tested the hypothesis that ERα, GPER1, and aromatase exhibits sex, region, and age-specific differences, including nuclear expression. ERα exhibits nuclear expression in all three striatal regions before adulthood and disappears in a region- and sex-specific time-course. Cellular GPER1 expression decreases during development in a region- but not sex-specific time-course, resulting in extranuclear expression by adulthood. Somatic aromatase expression presents at prepuberty and increases by adulthood in a region- but not sex-specific time-course. These data indicate that developmental period exerts critical sex-specific influences on striatal cellular estrogenic mechanisms.
Topics: Animals; Caudate Nucleus; Estrogen Receptor alpha; Female; Male; Nucleus Accumbens; Putamen; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Sex Characteristics
PubMed: 32632943
DOI: 10.1002/cne.24978 -
Movement Disorders : Official Journal... Apr 2017Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by...
BACKGROUND
Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome pathology includes dystrophic white matter and intranuclear inclusions in neurons and astrocytes. We previously demonstrated that the transport of iron into the brain is altered in fragile X-associated tremor/ataxia syndrome; therefore, we also expect an alteration of iron metabolism in brain areas related to motor control. Iron is essential for cell metabolism, but uncomplexed iron leads to oxidative stress and contributes to the development of neurodegenerative diseases. We investigated a potential iron modification in the putamen - a structure that participates in motor learning and performance - in fragile X-associated tremor/ataxia syndrome.
METHODS
We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome and 9 control cases to study iron localization using Perl's method, and iron-binding proteins using immunostaining.
RESULTS
We found increased iron deposition in neuronal and glial cells in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron.
CONCLUSIONS
Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome. © 2017 International Parkinson and Movement Disorder Society.
Topics: Astrocytes; Ataxia; Case-Control Studies; Cerebellum; Ceruloplasmin; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Iron; Male; Putamen; Transferrin; Tremor
PubMed: 28233916
DOI: 10.1002/mds.26902 -
BMC Genomic Data Oct 2021Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive actions, that presents the involvement of the cortico-striatal areas. The...
BACKGROUND
Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive actions, that presents the involvement of the cortico-striatal areas. The contribution of environmental risk factors to OCD development suggests that epigenetic mechanisms may contribute to its pathophysiology. DNA methylation changes and gene expression were evaluated in post-mortem brain tissues of the cortical (anterior cingulate gyrus and orbitofrontal cortex) and ventral striatum (nucleus accumbens, caudate nucleus and putamen) areas from eight OCD patients and eight matched controls.
RESULTS
There were no differentially methylated CpG (cytosine-phosphate-guanine) sites (DMSs) in any brain area, nevertheless gene modules generated from CpG sites and protein-protein-interaction (PPI) showed enriched gene modules for all brain areas between OCD cases and controls. All brain areas but nucleus accumbens presented a predominantly hypomethylation pattern for the differentially methylated regions (DMRs). Although there were common transcriptional factors that targeted these DMRs, their targeted differentially expressed genes were different among all brain areas. The protein-protein interaction network based on methylation and gene expression data reported that all brain areas were enriched for G-protein signaling pathway, immune response, apoptosis and synapse biological processes but each brain area also presented enrichment of specific signaling pathways. Finally, OCD patients and controls did not present significant DNA methylation age differences.
CONCLUSIONS
DNA methylation changes in brain areas involved with OCD, especially those involved with genes related to synaptic plasticity and the immune system could mediate the action of genetic and environmental factors associated with OCD.
Topics: Aged; Brain; Caudate Nucleus; CpG Islands; DNA Methylation; Female; Gyrus Cinguli; Humans; Immune System; Immunity; Male; Neuronal Plasticity; Nucleus Accumbens; Obsessive-Compulsive Disorder; Prefrontal Cortex; Putamen
PubMed: 34717534
DOI: 10.1186/s12863-021-00993-0 -
Cells Apr 2023The volume reduction of the gray matter structures in patients with Alzheimer's disease is often accompanied by an asymmetric increase in the number of white matter...
The volume reduction of the gray matter structures in patients with Alzheimer's disease is often accompanied by an asymmetric increase in the number of white matter fibers located close to these structures. The present study aims to investigate the white matter structure changes in the motor basal ganglia in Alzheimer's disease patients compared to healthy controls using diffusion tensor imaging. The amounts of tracts, tract length, tract volume, quantitative anisotropy, and general fractional anisotropy were measured in ten patients with Alzheimer's disease and ten healthy controls. A significant decrease in the number of tracts and general fractional anisotropy was found in patients with Alzheimer's disease compared to controls in the right caudate nucleus, while an increase was found in the left and the right putamen. Further, a significant decrease in the structural volume of the left and the right putamen was observed. An increase in the white matter diffusion tensor imaging parameters in patients with Alzheimer's disease was observed only in the putamen bilaterally. The right caudate showed a decrease in both the diffusion tensor imaging parameters and the volume in Alzheimer's disease patients. The right pallidum showed an increase in the diffusion tensor imaging parameters but a decrease in volume in Alzheimer's disease patients.
Topics: Humans; Diffusion Tensor Imaging; Alzheimer Disease; White Matter; Gray Matter; Putamen
PubMed: 37174620
DOI: 10.3390/cells12091220 -
Head & Face Medicine Aug 2023Eggshell peptides (EP) majorly contribute to rapid bone building in chicks, wherefore this paper investigated their potential for stimulating osteogenesis in vitro. In...
Eggshell peptides (EP) majorly contribute to rapid bone building in chicks, wherefore this paper investigated their potential for stimulating osteogenesis in vitro. In this study, the effects of EP, also called putamen ovi peptides and a combination of hyaluronic acid with EP in cell culture medium were tested towards proliferation, differentiation, gene expression and mineralization of bovine osteoprogenitors and primary human osteoblasts. The influence of EP at concentrations of 0.005 g/L, 0.5 g/L and 0.5 g/L with 0.25% hyaluronic acid was analyzed using immunocytochemical staining of bone-specific matrix proteins, namely collagen type I, osteonectin, osteopontin and osteocalcin, to prove osteoblastic differentiation. Additionally, Richardson-staining was performed. All tests revealed a superior osteoblastic differentiation with EP at 0.5 g/L after 5 days of cultivation. Hyaluronic acid alone showed controversial results and partially constrained osteoblastic differentiation in combination with EP to a level as low as for pure EP at 0.005 g/L. Of particular interest is the osteoblast-typical mineralization, as an important indicator of bone formation, which was measured indirectly via the calcium concentration after cultivation over 4 weeks. The mineralization showed an increase by a factor of 286 during the cultivation of primary human osteoblasts with hyaluronic acid and EP. Meanwhile, cell cultures treated with EP (0.5 g/L) only showed an 80-fold increase in calcium concentration.The influence of EP (0.5 g/L) on primary human osteoblasts was investigated by gene expression after 2 weeks of cultivation. Microarray and qRT-PCR analysis showed a strongly increased expression of main important genes in bone formation, bone regeneration and the physiological bone remodelling processes. Namely, BMP 2, osteopontin and the matrix metalloproteinases 1 and 9, were present during in vitro osteoprogenitor culture with EP. By explicitly underlining the potential of eggshell peptides for stimulating osteogenesis, as well as emphasizing complex and controversial interaction with hyaluronan, this manuscript is relevant for developing new functionalized biomaterials for bone regeneration.
Topics: Animals; Cattle; Humans; Osteopontin; Hyaluronic Acid; Calcium; Putamen; Peptides; Osteogenesis; Cell Differentiation; Osteocalcin; Osteoblasts; Cells, Cultured
PubMed: 37553683
DOI: 10.1186/s13005-023-00380-3