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Frontiers in Neuroscience 2020Selective loss of dopaminergic neurons and diminished putamen gray matter volume (GMV) represents a central feature of Parkinson's disease (PD). Recent studies have...
BACKGROUND
Selective loss of dopaminergic neurons and diminished putamen gray matter volume (GMV) represents a central feature of Parkinson's disease (PD). Recent studies have reported specific effects of kinectin 1 gene () variants on the putamen GMV.
OBJECTIVE
To examine the relationship of variants, mRNA expression in the putamen and substantia nigra pars compacta (SNc), putamen GMV, and PD.
METHODS
We examined the associations between PD and a total of 1847 imputed single nucleotide polymorphisms (SNPs) in one discovery sample [2,000 subjects with PD vs. 1,986 healthy controls (HC)], and confirmed the nominally significant associations ( < 0.05) in two replication samples (900 PD vs. 867 HC, and 940 PD vs. 801 HC, respectively). The regulatory effects of risk variants on the mRNA expression in putamen and SNc and the putamen GMV were tested. We also quantified the expression levels of mRNA in the putamen and/or SNc for comparison between PD and HC in five independent cohorts.
RESULTS
Six replicable and two non-replicable -PD associations were identified (0.009 ≤ ≤ 0.049). The major alleles of five SNPs, including rs12880292, rs8017172, rs17253792, rs945270, and rs4144657, significantly increased risk for PD (0.020 ≤ ≤ 0.049) and putamen GMVs (19.08 ≤ β ≤ 60.38; 2.82 ≤ Z ≤ 15.03; 5.0 × 10 ≤ ≤ 0.018). The risk alleles of five SNPs, including rs8017172, rs17253792, rs945270, rs4144657, and rs1188184 also significantly increased the mRNA expression in the putamen or SNc (0.021 ≤ ≤ 0.046). The mRNA was abundant in the putamen and/or SNc across five independent cohorts and differentially expressed in the SNc between PD and HC in one cohort ( = 0.047).
CONCLUSION
There was a consistent, significant, replicable, and robust positive relationship among the variants, PD risk, mRNA expression in putamen, and putamen volumes, and a modest relation between PD risk and mRNA expression in SNc, suggesting that may play a functional role in the development of PD.
PubMed: 32655362
DOI: 10.3389/fnins.2020.00651 -
Movement Disorders : Official Journal... Sep 2023Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant...
BACKGROUND
Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood.
OBJECTIVE
To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD.
METHODS
Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively.
RESULTS
Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load.
CONCLUSIONS
In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Substantia Nigra; Corpus Striatum; Putamen; Dopamine; Lewy Body Disease
PubMed: 37347552
DOI: 10.1002/mds.29510 -
Neuroscience Letters Sep 2020Parkinson's disease (PD) is the most widespread movement disorder with a prevalence of 1 in 1000 individuals above 60 years of age. Until now, understanding the... (Review)
Review
Parkinson's disease (PD) is the most widespread movement disorder with a prevalence of 1 in 1000 individuals above 60 years of age. Until now, understanding the pathological mechanisms of PD to translate them into therapy has remained a high research priority. In this review, we highlight evidence describing the involvement of microglial dysfunction in PD. Thereafter, we provide current knowledge suggesting that the substantia nigra pars compacta and putamen, compared to other brain regions, show a reduced microglial density, as well as altered morphological and functional properties in homeostatic conditions, while presenting dystrophic features associated with aging. Further, we describe that this defective microglial programing emerges as early as the second postnatal week, persists until adulthood and impacts negatively on their transcriptional pattern and provision of local trophic support. We emphasize the role of α-synuclein oligomers as a major dysfunctional signal underlining microglial-mediated phenotypic switch and adaptive response contributing to neurodegeneration. Moreover, we explore available avenues should microglia be considered as target for neuroprotective or restorative strategies including preventing the aggregation of α-synuclein protofibrils formation. However, we provide a note of caution regarding the success of microglial-targeted PD strategies, using minocycline as an example. In conclusion, we discuss putative neuroprotective agents that were unsuccessful in previous trials but could be reconsidered by focusing on the stage of microglial-dependent pathogenic events during PD in suitable cohorts of patients.
Topics: Animals; Humans; Microglia; Parkinson Disease; Pars Compacta; Phenotype; Putamen
PubMed: 32561452
DOI: 10.1016/j.neulet.2020.135164 -
Neurology International Mar 2021Although the putamen has a significant role in reward-seeking and motivated behaviors, including eating and food-seeking, minorities' diminished returns (MDRs) suggest...
INTRODUCTION
Although the putamen has a significant role in reward-seeking and motivated behaviors, including eating and food-seeking, minorities' diminished returns (MDRs) suggest that individual-level risk and protective factors have weaker effects for Non-Hispanic Black than Non-Hispanic White individuals. However, limited research is available on the relevance of MDRs in terms of the role of putamen functional connectivity on body mass index (BMI).
PURPOSE
Building on the MDRs framework and conceptualizing race and socioeconomic status (SES) indicators as social constructs, we explored racial and SES differences in the associations between putamen functional connectivity to the salience network and children's BMI.
METHODS
For this cross-sectional study, we used functional magnetic resonance imaging (fMRI) data of 6473 9-10-year-old Non-Hispanic Black and Non-Hispanic White children from the Adolescent Brain Cognitive Development (ABCD) study. The primary independent variable was putamen functional connectivity to the salience network, measured by fMRI. The primary outcome was the children's BMI. Age, sex, neighborhood income, and family structure were the covariates. Race, family structure, parental education, and household income were potential moderators. For data analysis, we used mixed-effect models in the overall sample and by race.
RESULTS
Higher right putamen functional connectivity to the salience network was associated with higher BMI in Non-Hispanic White children. The same association was missing for Non-Hispanic Black children. While there was no overall association in the pooled sample, a significant interaction was found, suggesting that the association between right putamen functional connectivity to the salience network and children's BMI was modified by race. Compared to Non-Hispanic White children, Non-Hispanic Black children showed a weaker association between right putamen functional connectivity to the salience network and BMI. While parental education and household income did not moderate our association of interest, marital status altered the associations between putamen functional connectivity to the salience network and children's BMI. These patterns were observed for right but not left putamen. Other/Mixed Race children also showed a pattern similar to Non-Hispanic Black children.
CONCLUSIONS
The association between right putamen functional connectivity to the salience network and children's BMI may depend on race and marital status but not parental education and household income. While right putamen functional connectivity to the salience network is associated with Non-Hispanic White children's BMI, Non-Hispanic Black children' BMI remains high regardless of their putamen functional connectivity to the salience network. This finding is in line with MDRs, which attributes diminished effects of individual-risk and protective factors for Non-Hispanic Black children to racism, stratification, and segregation.
PubMed: 33806587
DOI: 10.3390/neurolint13010009 -
Movement Disorders : Official Journal... Jan 2022Dopamine transporter single photon-emission computed tomography (DAT-SPECT) is the strongest risk factor for phenoconversion in patients with idiopathic rapid eye...
BACKGROUND
Dopamine transporter single photon-emission computed tomography (DAT-SPECT) is the strongest risk factor for phenoconversion in patients with idiopathic rapid eye movement (REM)-sleep behavior disorder (iRBD). However, it might be used as a second-line stratification tool in clinical trials, because it is expensive and mini-invasive.
OBJECTIVE
Aim of the study is to investigate whether other cost-effective and non-invasive biomarkers may be proposed as first-line stratification tools.
METHODS
Forty-seven consecutive iRBD patients (68.53 ± 7.16 years, 40 males) underwent baseline clinical and neuropsychological assessment, olfaction test, resting electroencephalogram (EEG), and DAT-SPECT. All patients underwent 6 month-based clinical follow-up to investigate the emergence of parkinsonism and/or dementia. Survival analysis and Cox regression were used to estimate conversion risk.
RESULTS
Seventeen patients developed an overt synucleinopathy (eight Parkinsonism and nine dementia) 32.8 ± 22 months after diagnosis. The strongest risk factors were putamen specific to non-displaceable binding ratio (SBR) (hazard ratio [HR], 7.3), attention/working memory cognitive function (NPS-AT/WM) (HR, 5.9), EEG occipital mean frequency (HR, 2.7) and clinical motor assessment (HR, 2.3). On multivariate Cox-regression analysis, only putamen SBR and NPS-AT/WM significantly contributed to the model (HR, 6.2, 95% confidence interval [CI], 1.9-19.8). At post-hoc analysis, the trail-making test B (TMT-B) was the single most efficient first-line stratification tool that allowed to reduce the number of eligible subjects to 76.6% (sensitivity 1, specificity 0.37). Combining TMT-B and DAT-SPECT further reduced the sample to 66% (sensitivity 0.88, specificity 0.47).
CONCLUSION
The TMT-B seems to be a cost-effective and efficient first-line screening tool, to be used to select patients that deserve DAT-SPECT as second-line screening tool for disease-modifying clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Aged; Female; Humans; Male; Middle Aged; Parkinsonian Disorders; Putamen; REM Sleep Behavior Disorder; Synucleinopathies; Tomography, Emission-Computed, Single-Photon
PubMed: 34533239
DOI: 10.1002/mds.28785 -
Psychoneuroendocrinology Feb 2022Acute stress is associated with a shift from goal-directed to habitual behavior. This stress-induced preference for habitual behavior has been suggested as a potential...
Acute stress is associated with a shift from goal-directed to habitual behavior. This stress-induced preference for habitual behavior has been suggested as a potential mechanism by which binge eating disorder (BED) patients succumb to eating large amounts of high-caloric foods in an uncontrolled manner (i.e., binge episodes). While in healthy subjects the balance between goal-directed and habitual behavior is subserved by the anterior cingulate cortex (ACC), insular cortex, orbitofrontal cortex (OFC), anterior caudate nucleus, and posterior putamen, the brain mechanism that underlies this (possibly amplified) stress-induced behavioral shift in BED patients is currently unknown. In the current study, 76 participants (38 BED, 38 healthy controls (HCs)) learned six stimulus-response-outcome associations in a well-established instrumental learning task. Subsequently, three outcomes were selectively devalued, after which participants underwent either a stress induction procedure (Maastricht Acute Stress Test; MAST) or a no-stress control procedure. Next, the balance between goal-directed and habitual behavior was assessed during functional magnetic resonance imaging. Findings show that the balance between goal-directed and habitual behavior was associated with activity in the ACC, insula, and OFC in no-stress HCs. Although stress and BED did not modulate the balance between goal-directed and habitual behavior, BED participants displayed a smaller difference in putamen activation between trials probing goal-directed and habitual behavior compared with HCs when using a ROI approach. We conclude that putamen activity differences between BED and HC could reflect changes in monitoring of response accuracy or reward value, albeit perhaps not sufficiently to induce a measurable shift from goal-directed to habitual behavior. Future research could clarify potential boundary conditions of stress-induced shifts in instrumental behavior in BED patients.
Topics: Binge-Eating Disorder; Conditioning, Operant; Goals; Humans; Motivation; Putamen
PubMed: 34839081
DOI: 10.1016/j.psyneuen.2021.105596 -
Epilepsy Research Nov 2020Cortical and subcortical grey matter (GM) morphometric changes have been demonstrated Temporal Lobe Epilepsy (TLE) or Idiopathic Generalized Epilepsies (IGE). Hot Water...
BACKGROUND
Cortical and subcortical grey matter (GM) morphometric changes have been demonstrated Temporal Lobe Epilepsy (TLE) or Idiopathic Generalized Epilepsies (IGE). Hot Water Epilepsy (HWE) has not hitherto been studied in these perspectives.
PURPOSE
To investigate the cortical and subcortical grey matter in subjects with HWE in terms of thickness, volume, and surface area using Surface-Based Morphometry (SBM). To assess relationships of SBM-derived metrics with clinical variables.
MATERIALS AND METHODS
Ninety-nine people with HWE and 50 age-matched healthy controls underwent high resolution volumetric MRI brain. These were processed with FreeSurfer to obtain SBM parameters i:e cortical thickness, cortical volume, and Cortical surface area. Volumes of seven subcortical GM structures (hippocampus, globus pallidus, nucleus ambiguous(NA), caudate nucleus, putamen, thalamus, and amygdala) were computed. Intergroup morphometric differences and their correlation with epilepsy-specific clinical variables were calculated.
RESULTS
SBM revealed a global reduction in bihemispheric cortical thickness and left hemispheric cortical volume. Besides, a regional difference in the morphometric measures was noted in temporo-limbic, parietal, pre-cuneus, and the cingulate region. Reduced volume of thalami and left caudate alongside an increased volume of the bilateral amygdala, bilateral nucleus ambiguous (NA), right caudate, and putamen was the other cardinal observation.
CONCLUSION
HWE subjects show alterations in the morphometry of the cortical ribbon and the subcortical grey matter. The temporal semiology, 'reflex nature' pathophysiology correlates involvement of temporo-limbic structures/somatosensory cortex, while the involvement of structures like pre-cuneus, posterior cingulate, and frontal regions are in agreement with functional networks related loss of awareness. That bilateral amygdala swelling occurs in HWE is a novel observation and may signal that it could be a distinct variant of Mesial TLE.
Topics: Adolescent; Adult; Aged; Brain Mapping; Cerebral Cortex; Child; Epilepsy; Epilepsy, Generalized; Epilepsy, Temporal Lobe; Female; Gray Matter; Hippocampus; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Putamen; Water; Young Adult
PubMed: 32846313
DOI: 10.1016/j.eplepsyres.2020.106436 -
NeuroImage Jul 2021A wide homology between human and macaque striatum is often assumed as in both the striatum is involved in cognition, emotion and executive functions. However,... (Comparative Study)
Comparative Study
A wide homology between human and macaque striatum is often assumed as in both the striatum is involved in cognition, emotion and executive functions. However, differences in functional and structural organization between human and macaque striatum may reveal evolutionary divergence and shed light on human vulnerability to neuropsychiatric diseases. For instance, dopaminergic dysfunction of the human striatum is considered to be a pathophysiological underpinning of different disorders, such as Parkinson's disease (PD) and schizophrenia (SCZ). Previous investigations have found a wide similarity in structural connectivity of the striatum between human and macaque, leaving the cross-species comparison of its functional organization unknown. In this study, resting-state functional connectivity (RSFC) derived striatal parcels were compared based on their homologous cortico-striatal connectivity. The goal here was to identify striatal parcels whose connectivity is human-specific compared to macaque parcels. Functional parcellation revealed that the human striatum was split into dorsal, dorsomedial, and rostral caudate and ventral, central, and caudal putamen, while the macaque striatum was divided into dorsal, and rostral caudate and rostral, and caudal putamen. Cross-species comparison indicated dissimilar cortico-striatal RSFC of the topographically similar dorsal caudate. We probed clinical relevance of the striatal clusters by examining differences in their cortico-striatal RSFC and gray matter (GM) volume between patients (with PD and SCZ) and healthy controls. We found abnormal RSFC not only between dorsal caudate, but also between rostral caudate, ventral, central and caudal putamen and widespread cortical regions for both PD and SCZ patients. Also, we observed significant structural atrophy in rostral caudate, ventral and central putamen for both PD and SCZ while atrophy in the dorsal caudate was specific to PD. Taken together, our cross-species comparative results revealed shared and human-specific RSFC of different striatal clusters reinforcing the complex organization and function of the striatum. In addition, we provided a testable hypothesis that abnormalities in a region with human-specific connectivity, i.e., dorsal caudate, might be associated with neuropsychiatric disorders.
Topics: Adult; Aged; Animals; Caudate Nucleus; Cerebral Cortex; Connectome; Datasets as Topic; Female; Humans; Macaca; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net; Parkinson Disease; Putamen; Schizophrenia; Species Specificity; Young Adult
PubMed: 33819611
DOI: 10.1016/j.neuroimage.2021.118006 -
Psychiatry Research. Neuroimaging Oct 2023Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) present similarly with bradykinesia, tremor, rigidity, and cognitive...
Striatal and thalamic automatic segmentation, morphology, and clinical correlates in Parkinsonism: Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.
Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) present similarly with bradykinesia, tremor, rigidity, and cognitive impairments. Neuroimaging studies have found differential changes in the nigrostriatal pathway in these disorders, however whether the volume and shape of specific regions within this pathway can distinguish between atypical Parkinsonian disorders remains to be determined. This paper investigates striatal and thalamic volume and morphology as distinguishing biomarkers, and their relationship to neuropsychiatric symptoms. Automatic segmentation to calculate volume and shape analysis of the caudate nucleus, putamen, and thalamus were performed in 18 PD patients, 12 MSA, 15 PSP, and 20 healthy controls, then correlated with clinical measures. PSP bilateral thalami and right putamen were significantly smaller than controls, but not MSA or PD. The left caudate and putamen significantly correlated with the Neuropsychiatric Inventory total score. Bilateral thalamus, caudate, and left putamen had significantly different morphology between groups, driven by differences between PSP and healthy controls. This study demonstrated that PSP patient striatal and thalamic volume and shape are significantly different when compared with controls. Parkinsonian disorders could not be differentiated on volumetry or morphology, however there are trends for volumetric and morphological changes associated with PD, MSA, and PSP.
Topics: Humans; Parkinson Disease; Supranuclear Palsy, Progressive; Multiple System Atrophy; Parkinsonian Disorders; Thalamus
PubMed: 37806261
DOI: 10.1016/j.pscychresns.2023.111719 -
Nature Neuroscience Oct 2020Time perception and prediction errors are essential for everyday life. We hypothesized that their putative shared circuitry in the striatum might enable these two...
Time perception and prediction errors are essential for everyday life. We hypothesized that their putative shared circuitry in the striatum might enable these two functions to interact. We show that positive and negative prediction errors bias time perception by increasing and decreasing perceived time, respectively. Imaging and behavioral modeling identify this interaction to occur in the putamen. Depending on context, this interaction may have beneficial or adverse effects.
Topics: Adult; Brain; Brain Mapping; Choice Behavior; Discrimination, Psychological; Female; Gyrus Cinguli; Humans; Magnetic Resonance Imaging; Male; Prefrontal Cortex; Putamen; Time Perception; Young Adult
PubMed: 32839618
DOI: 10.1038/s41593-020-0698-3