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Nature Communications Jul 2023The ability to use blood to predict the outcomes of Parkinson's disease, including disease progression and cognitive and motor complications, would be of significant...
The ability to use blood to predict the outcomes of Parkinson's disease, including disease progression and cognitive and motor complications, would be of significant clinical value. We undertook bulk RNA sequencing from the caudate and putamen of postmortem Parkinson's disease (n = 35) and control (n = 40) striatum, and compared molecular profiles with clinical features and bulk RNA sequencing data obtained from antemortem peripheral blood. Cognitive and motor complications of Parkinson's disease were associated with molecular changes in the caudate (stress response) and putamen (endothelial pathways) respectively. Later and earlier-onset Parkinson's disease were molecularly distinct, and disease duration was associated with changes in caudate (oligodendrocyte development) and putamen (cellular senescence), respectively. Transcriptome patterns in the postmortem Parkinson's disease brain were also evident in antemortem peripheral blood, and correlated with clinical features of the disease. Together, these findings identify molecular signatures in Parkinson's disease patients' brain and blood of potential pathophysiologic and prognostic importance.
Topics: Humans; Parkinson Disease; Transcriptome; Brain; Corpus Striatum; Putamen
PubMed: 37407548
DOI: 10.1038/s41467-023-39652-6 -
The Journal of Neuroscience : the... Sep 2022In nonhuman primates, major input to the striatum originates from ipsilateral cortex and thalamus. The striatum is a target also of crossed corticostriatal (CSt)...
In nonhuman primates, major input to the striatum originates from ipsilateral cortex and thalamus. The striatum is a target also of crossed corticostriatal (CSt) projections from the contralateral hemisphere, which have been so far somewhat neglected. In the present study, based on neural tracer injections in different parts of the striatum in macaques of either sex, we analyzed and compared qualitatively and quantitatively the distribution of labeled CSt cells in the two hemispheres. The results showed that crossed CSt projections to the caudate and the putamen can be relatively robust (up to 30% of total labeled cells). The origin of the direct and the crossed CSt projections was not symmetrical as the crossed ones originated almost exclusively from motor, prefrontal, and cingulate areas and not from parietal and temporal areas. Furthermore, there were several cases in which the contribution of contralateral areas tended to equal that of the ipsilateral ones. The present study is the first detailed description of this anatomic pathway of the macaque brain and provides the substrate for bilateral distribution of motor, motivational, and cognitive signals for reinforcement learning and selection of actions or action sequences, and for learning compensatory motor strategies after cortical stroke. In nonhuman primates the striatum is a target of projections originating from the contralateral hemisphere (crossed CSt projections), which have been so far poorly investigated. The present study analyzed qualitatively and quantitatively in the macaque brain the origin of the crossed CSt projections compared with those originating from the ipsilateral hemisphere. The results showed that crossed CSt projections originate mostly from frontal and rostral cingulate areas and in some cases their contribution tended to equal that from ipsilateral areas. These projections could provide the substrate for bilateral distribution of motor, motivational, and cognitive signals for reinforcement learning and action selection, and for learning compensatory motor strategies after cortical stroke.
Topics: Animals; Brain Mapping; Corpus Striatum; Macaca; Neural Pathways; Putamen; Stroke
PubMed: 35953294
DOI: 10.1523/JNEUROSCI.0071-22.2022 -
Biological Psychiatry Jan 2023Psychosis is a defining feature of schizophrenia and highly prevalent in bipolar disorder. Notably, individuals with these illnesses also have major disruptions in sleep...
BACKGROUND
Psychosis is a defining feature of schizophrenia and highly prevalent in bipolar disorder. Notably, individuals with these illnesses also have major disruptions in sleep and circadian rhythms, and disturbances of sleep and circadian rhythms can precipitate or exacerbate psychotic symptoms. Psychosis is associated with the striatum, though to our knowledge, no study to date has directly measured molecular rhythms and determined how they are altered in the striatum of subjects with psychosis.
METHODS
We performed RNA sequencing and both differential expression and rhythmicity analyses to investigate diurnal alterations in gene expression in human postmortem striatal subregions (nucleus accumbens, caudate, and putamen) in subjects with psychosis (n = 36) relative to unaffected comparison subjects (n = 36).
RESULTS
Across regions, we found differential expression of immune-related transcripts and a substantial loss of rhythmicity in core circadian clock genes in subjects with psychosis. In the nucleus accumbens, mitochondrial-related transcripts had decreased expression in subjects with psychosis, but only in those who died at night. Additionally, we found a loss of rhythmicity in small nucleolar RNAs and a gain of rhythmicity in glutamatergic signaling in the nucleus accumbens of subjects with psychosis. Between-region comparisons indicated that rhythmicity in the caudate and putamen was far more similar in subjects with psychosis than in matched comparison subjects.
CONCLUSIONS
Together, these findings reveal differential and rhythmic gene expression differences across the striatum that may contribute to striatal dysfunction and psychosis in psychotic disorders.
Topics: Humans; Psychotic Disorders; Circadian Rhythm; Corpus Striatum; Putamen; Gene Expression
PubMed: 36302706
DOI: 10.1016/j.biopsych.2022.08.013 -
Neuroscience and Biobehavioral Reviews Oct 2022The dorsolateral striatum plays a critical role in the acquisition and expression of stimulus-response habits that are learned in experimental laboratories. Here, we use... (Meta-Analysis)
Meta-Analysis Review
The dorsolateral striatum plays a critical role in the acquisition and expression of stimulus-response habits that are learned in experimental laboratories. Here, we use meta-analytic procedures to contrast the neural circuits activated by laboratory-acquired habits with those activated by stimulus-response behaviours acquired in everyday-life. We confirmed that newly learned habits rely more on the anterior putamen with activation extending into caudate and nucleus accumbens. Motor and associative components of everyday-life habits were identified. We found that motor-dominant stimulus-response associations developed outside the laboratory primarily engaged posterior dorsal putamen, supplementary motor area (SMA) and cerebellum. Importantly, associative components were also represented in the posterior putamen. Thus, common neural representations for both naturalistic and laboratory-based habits were found in the left posterior and right anterior putamen. These findings suggest a partial common striatal substrate for habitual actions that are performed predominantly by stimulus-response associations represented in the posterior striatum. The overlapping neural substrates for laboratory and everyday-life habits supports the use of both methods for the analysis of habitual behaviour.
Topics: Corpus Striatum; Habits; Humans; Laboratories; Magnetic Resonance Imaging; Putamen
PubMed: 35963543
DOI: 10.1016/j.neubiorev.2022.104826 -
Brain : a Journal of Neurology Apr 2022The striatal dopaminergic deficit in Parkinson's disease exhibits a typical pattern, extending from the caudal and dorsal putamen at onset to its more rostral region as...
The striatal dopaminergic deficit in Parkinson's disease exhibits a typical pattern, extending from the caudal and dorsal putamen at onset to its more rostral region as the disease progresses. Clinically, upper-limb onset of cardinal motor features is the rule. Thus, according to current understanding of striatal somatotopy (i.e. the lower limb is dorsal to the upper limb) the assumed pattern of early dorsal striatal dopaminergic denervation in Parkinson's disease does not fit with an upper-limb onset. We have examined the topography of putaminal denervation in a cohort of 23 recently diagnosed de novo Parkinson's disease patients and 19 age-/gender-matched healthy subjects assessed clinically and by 18F-DOPA PET; 15 patients were re-assessed after 2 years. There was a net upper-limb predominance of motor features at onset. Caudal denervation of the putamen was confirmed in both the more- and less-affected hemispheres and corresponding hemibodies. Spatial covariance analysis of the most affected hemisphere revealed a pattern of 18F-DOPA uptake rate deficit that suggested focal dopamine loss starting in the posterolateral and intermediate putamen. Functional MRI group-activation maps during a self-paced motor task were used to represent the somatotopy of the putamen and were then used to characterize the decline in 18F-DOPA uptake rate in the upper- and lower-limb territories. This showed a predominant decrement in both hemispheres, which correlated significantly with severity of bradykinesia. A more detailed spatial analysis revealed a dorsoventral linear gradient of 18F-DOPA uptake rate in Parkinson's disease patients, with the highest putamen denervation in the caudal intermediate subregion (dorsoventral plane) compared to healthy subjects. The latter area coincides with the functional representation of the upper limb. Clinical motor assessment at 2-year follow-up showed modest worsening of parkinsonism in the primarily affected side and more noticeable increases in the upper limb in the less-affected side. Concomitantly, 18F-DOPA uptake rate in the less-affected putamen mimicked that recognized on the most-affected side. Our findings suggest that early dopaminergic denervation in Parkinson's disease follows a somatotopically related pattern, starting with the upper-limb representation in the putamen and progressing over a 2-year period in the less-affected hemisphere. These changes correlate well with the clinical presentation and evolution of motor features. Recognition of a precise somatotopic onset of nigrostriatal denervation may help to better understand the onset and progression of dopaminergic neurodegeneration in Parkinson's disease and eventually monitor the impact of putative therapies.
Topics: Child, Preschool; Corpus Striatum; Denervation; Dihydroxyphenylalanine; Dopamine; Humans; Parkinson Disease; Putamen
PubMed: 35349639
DOI: 10.1093/brain/awab378 -
Movement Disorders : Official Journal... Sep 2023It has been suggested that the loss of nigrostriatal dopaminergic axon terminals occurs before the loss of dopaminergic neurons in the substantia nigra (SN) in...
BACKGROUND
It has been suggested that the loss of nigrostriatal dopaminergic axon terminals occurs before the loss of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease (PD). This study aimed to use free-water imaging to evaluate microstructural changes in the dorsoposterior putamen (DPP) of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) patients, which is considered a prodromal stage of synucleinopathies.
METHODS
Free water values in the DPP, dorsoanterior putamen (DAP), and posterior SN were compared between the healthy controls (n = 48), iRBD (n = 43) and PD (n = 47) patients. In iRBD patients, the relationships between baseline and longitudinal free water values and clinical manifestations or dopamine transporter (DAT) striatal binding ratio (SBR) were analyzed.
RESULTS
Free water values were significantly higher in the DPP and posterior substantia nigra (pSN), but not in the DAP, in the iRBD and PD groups than in controls. In iRBD patients, free water values in the DPP were progressively increased and correlated with the progression of clinical manifestations and the striatal DAT SBR. Baseline free water in the DPP was negatively correlated with striatal DAT SBR and hyposmia and positively correlated with motor deficits.
CONCLUSIONS
This study demonstrates that free water values in the DPP are increased cross-sectionally and longitudinally and associated with clinical manifestations and the function of the dopaminergic system in the prodromal stage of synucleinopathies. Our findings indicate that free-water imaging of the DPP has the potential to be a valid marker of early diagnosis and progression of synucleinopathies. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; REM Sleep Behavior Disorder; Putamen; Synucleinopathies; Prodromal Symptoms; Parkinson Disease; Dopamine; Water
PubMed: 37342973
DOI: 10.1002/mds.29499 -
Biological Psychiatry Jul 2024Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year.
METHODS
We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants.
RESULTS
We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume.
CONCLUSIONS
Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.
Topics: Tourette Syndrome; Humans; Genome-Wide Association Study; Male; Female; Quantitative Trait Loci; Chromosomes, Human, Pair 5; Child; Genetic Predisposition to Disease; Putamen; Brain; Adolescent; RNA, Long Noncoding
PubMed: 36738982
DOI: 10.1016/j.biopsych.2023.01.023 -
European Radiology Jul 2020The present study aims to investigate structural and functional connectivity (SC and FC) in cerebello-cerebral circuit in idiopathic generalized epilepsy (IGE).
PURPOSE
The present study aims to investigate structural and functional connectivity (SC and FC) in cerebello-cerebral circuit in idiopathic generalized epilepsy (IGE).
METHODS
Diffusion tensor imaging and resting-state imaging data were collected from 57 patients with IGE and 66 controls in the present study. First, we performed bidirectional probabilistic fiber tracking between cerebellum and cerebral cortex, consisting of cerebellar efferent and afferent fibers. Then, strength of structural connectivity (SCS), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were extracted and compared between groups. Finally, cerebellar FC with cerebral cortex was evaluated with seeding at dentate nucleus. Between-group comparisons were performed using t tests with a significant level setting at p < 0.05 with threshold-free cluster enhancement correction.
RESULTS
The patients with IGE showed decreased SCS in cerebellar efferent fibers to sensorimotor cortex in anterior corona radiate and increased SCS in efferent fibers to occipital cortex in posterior corona radiata. The SCS in cerebellar afferent fibers in corticospinal tract from frontal and in retrolenticular part of the internal capsule from occipital cortices were increased in IGE, and SCS in afferent fibers in posterior limb of internal capsule from parietal cortex was decreased. Decreased FA and increased MD and RD were observed in cerebello-cerebral tracts. Besides, decreased cerebellar FC with putamen and motor cortex was observed in IGE.
CONCLUSION
The patients with IGE demonstrated distinct alterations in efferent and afferent pathways between cerebellum and different cerebral cortices, which might be the pathological anatomical basis for cerebellar modulation effect on epileptic activities and contribute to motor deficits.
KEY POINTS
• IGE showed decreased SCS in cerebellar efferent fibers to the sensorimotor cortex and increased SCS in efferent fibers to the occipital cortex. • Patients demonstrated increased SCS in cerebellar afferent fibers from the frontal and the occipital cortex and decreased SCS in afferent fibers from parietal cortex. • Decreased FC between motor-related regions and dentate nucleus was observed in IGE.
Topics: Adult; Brain Mapping; Cerebellum; Cerebral Cortex; Diffusion Magnetic Resonance Imaging; Epilepsy, Generalized; Female; Humans; Internal Capsule; Male; Putamen; Pyramidal Tracts; Young Adult
PubMed: 32125514
DOI: 10.1007/s00330-020-06674-3 -
Addiction Biology Mar 2021The gray matter volume (GMV) of the putamen has been reported to be regulated by kinectin 1 gene (KTN1). As a hub of the dopaminergic circuit, the putamen is widely...
The gray matter volume (GMV) of the putamen has been reported to be regulated by kinectin 1 gene (KTN1). As a hub of the dopaminergic circuit, the putamen is widely implicated in the etiological processes of substance use disorders (SUD). Here, we aimed to identify robust and reliable associations between KTN1 SNPs and SUD across multiple samples. We examined the associations between SUD and KTN1 SNPs in four independent population-based or family-based samples (n = 10,209). The potential regulatory effects of the risk alleles on the putamen GMVs, the effects of alcohol, nicotine, marijuana and cocaine on KTN1 mRNA expression, and the relationship between KTN1 mRNA expression and SUD were explored. We found that a total of 23 SNPs were associated with SUD across at least two independent samples (1.4 × 10 ≤ p ≤ 0.049), including one SNP (rs12895072) across three samples (8.8 × 10 ≤ p ≤ 0.049). Four other SNPs were significantly or suggestively associated with SUD only in European-Australians (4.8 × 10 ≤ p ≤ 0.058). All of the SUD-risk alleles of these 27 SNPs increased (β > 0) the putamen GMVs and represented major alleles (f > 0.5) in Europeans. Twenty-two SNPs were potentially biologically functional. Alcohol, nicotine and cocaine significantly affected the KTN1 mRNA expression, and the KTN1 mRNA was differentially expressed between nicotine or cocaine dependent and control subjects. We concluded that there was a replicable and robust relationship among the KTN1 variants, KTN1 mRNA expression, putamen GMVs, molecular effects of substances, and SUD, suggesting that some risk KTN1 alleles might increase kinectin 1 expression in the putamen, altering putamen structures and functions, and leading to SUD.
Topics: Alcoholism; Alleles; Australia; Comorbidity; Female; Genetic Predisposition to Disease; Gray Matter; Humans; Male; Marijuana Abuse; Membrane Proteins; Polymorphism, Single Nucleotide; Putamen; RNA, Messenger; Substance-Related Disorders; Tobacco Use Disorder; White People
PubMed: 32115811
DOI: 10.1111/adb.12888 -
NeuroImage. Clinical 2022Cortical (e.g., Broca's area and Wernicke's area) and subcortical (e.g., putamen) language-related areas and executive control areas (e.g., inferior frontal gyrus (IFG),...
BACKGROUND AND HYPOTHESIS
Cortical (e.g., Broca's area and Wernicke's area) and subcortical (e.g., putamen) language-related areas and executive control areas (e.g., inferior frontal gyrus (IFG), dorsolateral prefrontal cortex (DLPFC)) show functional and structural dysconnectivity in long-term psychosis. We examined whether resting-state basal perfusion levels revealed selective pathophysiology (likely hypo- and hyper-activation) of language-related and executive areas in first-episode psychosis (FEP).
STUDY DESIGN
Basal resting-state perfusion was measured using pseudo-continuous Arterial Spin Labeling (pcASL). Relative cerebral blood flow (rCBF) was compared between 32 FEP and 34 matched healthy comparison (HC) individuals. Structural and functional MRI scans were acquired using a 3T Prisma scanner during the same session.
STUDY RESULTS
Whole-brain comparison of resting rCBF identified 8 clusters with significant between-group differences. Reduced rCBF was found in executive control areas in left and right IFG, right DLPFC, and right parietal cortex. Increased rCBF was found in left and right temporal cortex (including Wernicke's area), and left and right putamen. A positive correlation was observed between auditory hallucination severity and rCBF in the left putamen.
CONCLUSIONS
To the degree that perfusion implies activation, language and auditory processing areas in bilateral temporal lobe and putamen showed pathological hyper-activity, and cognitive control areas (IFG, DLPFC, right parietal) showed pathological hypo-activity in FEP at rest. Pathological basal activity was present across the range of symptom severity, suggesting it may be a common underlying pathology for psychosis that may be targeted with non-invasive brain stimulation to normalize resting activity levels.
Topics: Humans; Psychotic Disorders; Language; Brain Mapping; Temporal Lobe; Hallucinations; Magnetic Resonance Imaging
PubMed: 36451364
DOI: 10.1016/j.nicl.2022.103261