Burden of non-motor symptoms in unclear parkinsonism and tremor : A study with [I-123]FP-CIT SPECT

Background: Non-motor symptoms (NMSs) are clearly more prevalent in Parkinson's disease (PD) patients compared to healthy individuals. However, NMSs are also common in the elderly and other neurological conditions, and thus, it is not known whether NMSs could be used to differentiate PD from parkinsonism/tremor without dopamine deficiency. Methods: We prospectively evaluated NMSs immediately before brain dopamine transporter (DAT) [I-123]FP-CIT SPECT scanning in 193 patients with unclear parkinsonism/tremor. According to the clinical follow-up and imaging results, 84 patients had PD. NMSs and their correlations with striatal DAT binding were investigated in PD patients and in parkinsonism/tremor patients with normal dopamine function. Results: Total NMS burden, anxiety or depression did not differ between PD patients and patients with normal DAT binding. DAT-normal patients reported more perception-related (p = 0.045) and attention/memory-related NMSs than PD patients (p <0.001). Total NMS score did not correlate with striatal DAT binding in either group. Conclusions: In clinically uncertain cases, the total NMS burden cannot be used as a tool in distinguishing PD patients from patients with non-dopaminergic parkinsonism/tremor. Clinical screening of NMSs appears equally important in all patients with parkinsonism.Peer reviewe

Etuaivoidentiteetillisten ihmisen monikykyisistä kantasoluista johdettujen astrosyyttien tuottaminen

Astrosyytit ovat hermoston tukisoluja, joiden toiminnalliset ja morfologiset ominaisuudet vaihtelevat eri aivoalueilla. Astrosyyttien ominaisuuksien vaihtelun on todettu olevan erityisen suurta ihmisen aivoissa. Ihmisen pluripotentit kantasolut (hPS-solut) mahdollistavat astroglian monimuotoisuutta säätelevien mekanismien tutkimisen. Olemme luoneet menetelmän, joka tuottaa hPS-soluista ihmisen etuaivojen astrosyyttejä, ja kuvanneet tuotettujen astrosyyttien erityispiirteitä. Määritimme hPS-soluista erilaistettujen solujen geenien ilmentymisprofiilin päivänä 0 (D0), neuronaalisen induktion jälkeen D12 sekä solujen kasvutekijöillä monistamisen jälkeen D30 ja D60. Astrosyyttien lopullinen määräytyminen toteutettiin siliaarisella neurotrofisella tekijällä (ciliary neurotrophic factor; CNTF) ja D95-ikäisien astrosyyttien osoitettiin ilmentävän lähes 100 prosenttisesti yleisesti käytössä olevia astrosyyttimarkkereita. Erilaistamisen aikana tehty geeniprofilointi vahvisti solujen etuaivojen identiteetin. Kuvasimme solunsisäisen kalsiumkuvantamisen avulla, että erilaistamamme astrosyytit olivat elinkykyisiä ja antoivat toiminnallisia vasteita ATP:lle. Lisäksi määritimme astrosyyttien perustehtävää eli kykyä säädellä immuunivasteita aivoissa tutkimalla niistä erittyvien sytokiinien määriä. Totesimme D95-astrosyyttien viljelynesteessä merkittäviä pitoisuuksia MCP-1- ja TIMP-2-proteiinia yhteneväisesti näitä proteiineja ilmentävien geenien kohonneisiin mRNA-määriin. Astrosyyttien erilaistamismenetelmä oli toistettavissa usealla hPSC-linjalla, ja tutkimuksemme osoitti, että erilaistamamme etuaivojen astrosyytit tarjoavat uudenlaisen keinon sekä astrosyyttien soluspesifisten ominaisuuksien että yhteisviljelmissä muiden hermoston solujen kanssa hermoston solujen yhteisvaikutusten tutkimiseen. Potilaskohtaisista hPS-soluista erilaistettujen astrosyyttien avulla voidaan selvittää ihmisen astrosyyttien toimintaa myös sairaustiloissa

Generation of the Human Pluripotent Stem-Cell-Derived Astrocyte Model with Forebrain Identity

Astrocytes form functionally and morphologically distinct populations of cells with brainregion-specific properties. Human pluripotent stem cells (hPSCs) offer possibilities to generate astroglia for studies investigating mechanisms governing the emergence of astrocytic diversity. We established a method to generate human astrocytes from hPSCs with forebrain patterning and final specification with ciliary neurotrophic factor (CNTF). Transcriptome profiling and gene enrichment analysis monitored the sequential expression of genes determining astrocyte differentiation and confirmed activation of forebrain differentiation pathways at Day 30 (D30) and D60 of differentiation in vitro. More than 90% of astrocytes aged D95 in vitro co-expressed the astrocytic markers glial fibrillary acidic protein (GFAP) and S100 beta. Intracellular calcium responses to ATP indicated differentiation of the functional astrocyte population with constitutive monocyte chemoattractant protein-1 (MCP-1/CCL2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) expression. The method was reproducible across several hPSC lines, and the data demonstrated the usefulness of forebrain astrocyte modeling in research investigating forebrain pathology.Peer reviewe

Individual parkinsonian motor signs and striatal dopamine transporter deficiency: a study with [I-123]FP-CIT SPECT

IntroductionTotal parkinsonian motor symptom severity correlates with presynaptic striatal dopamine function in patients with Parkinson's disease. There is a lack of studies that have investigated the associations between parkinsonian motor signs and striatal dopaminergic deficiency in patients with parkinsonism of an unknown origin. Identification of specific motor signs associated with the highest likelihood of striatal dopamine deficiency could aid the differential diagnostics of parkinsonian and tremor syndromes.MethodsIn this cross-sectional clinical and imaging study, detailed motor examinations were performed for 221 patients with parkinsonism or tremor of an unknown origin immediately before dopamine transporter (DAT) [I-123]FP-CIT SPECT imaging. Region-of-interest and voxel-based methods were used to investigate striatal DAT deficiency in relation to individual motor signs.ResultsUpper extremity rigidity and facial expression were the only motor signs that differentiated patients with normal and abnormal striatal DAT function. The presence of any upper extremity rigidity showed the highest likelihood of DAT deficiency (OR 4.79, 95% CI 1.56-14.75, P=0.006) followed by reduced facial expression (OR 2.14, 95% CI 1.14-4.00, P=0.018). In patients with DAT deficits, reduced facial expression was associated with DAT deficiency specifically in the caudate nucleus, and increased upper extremity rigidity was associated with DAT loss in the dorsal putamen (FWE-corrected PPeer reviewe

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

A triplet repeat expansion leading to transcriptional silencing of the FMR1 gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele. The largest increase was found in miR-125a in the FXS sample, and the miR-125a levels were increased in two independent sets of urine samples from a total of 19 FXS children. Urine miR-125a levels appeared to increase with age in control subjects, but varied widely in FXS subjects. Should the results be generalized, it could suggest that two FXS subgroups existed. Predicted gene targets of the differentially regulated miRNAs are involved in molecular pathways that regulate developmental processes, homeostasis, and neuronal function. Regulation of miR-125a has been associated with type I metabotropic glutamate receptor signaling (mGluR), which has been explored as a treatment target for FXS, reinforcing the possibility that urine miR-125a may provide a novel biomarker for FXS

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

A triplet repeat expansion leading to transcriptional silencing of the FMR1 gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele. The largest increase was found in miR-125a in the FXS sample, and the miR-125a levels were increased in two independent sets of urine samples from a total of 19 FXS children. Urine miR-125a levels appeared to increase with age in control subjects, but varied widely in FXS subjects. Should the results be generalized, it could suggest that two FXS subgroups existed. Predicted gene targets of the differentially regulated miRNAs are involved in molecular pathways that regulate developmental processes, homeostasis, and neuronal function. Regulation of miR-125a has been associated with type I metabotropic glutamate receptor signaling (mGluR), which has been explored as a treatment target for FXS, reinforcing the possibility that urine miR-125a may provide a novel biomarker for FXS

Individual parkinsonian motor signs and striatal dopamine transporter deficiency: a study with [I-123]FP-CIT SPECT

IntroductionTotal parkinsonian motor symptom severity correlates with presynaptic striatal dopamine function in patients with Parkinson’s disease. There is a lack of studies that have investigated the associations between parkinsonian motor signs and striatal dopaminergic deficiency in patients with parkinsonism of an unknown origin. Identification of specific motor signs associated with the highest likelihood of striatal dopamine deficiency could aid the differential diagnostics of parkinsonian and tremor syndromes.MethodsIn this cross-sectional clinical and imaging study, detailed motor examinations were performed for 221 patients with parkinsonism or tremor of an unknown origin immediately before dopamine transporter (DAT) [I-123]FP-CIT SPECT imaging. Region-of-interest and voxel-based methods were used to investigate striatal DAT deficiency in relation to individual motor signs.ResultsUpper extremity rigidity and facial expression were the only motor signs that differentiated patients with normal and abnormal striatal DAT function. The presence of any upper extremity rigidity showed the highest likelihood of DAT deficiency (OR 4.79, 95% CI 1.56–14.75, P = 0.006) followed by reduced facial expression (OR 2.14, 95% CI 1.14–4.00, P = 0.018). In patients with DAT deficits, reduced facial expression was associated with DAT deficiency specifically in the caudate nucleus, and increased upper extremity rigidity was associated with DAT loss in the dorsal putamen (FWE-corrected P ConclusionsIncreased upper extremity muscle tone and hypomimia are independently associated with a higher likelihood of striatal hypodopaminergic imaging finding. This information can be used as a factor when the clinical need of auxiliary investigations, such as DAT SPECT, is considered for patients with parkinsonism.</div

Burden of non-motor symptoms in unclear parkinsonism and tremor: A study with [I-123]FP-CIT SPECT

Background: Non-motor symptoms (NMSs) are clearly more prevalent in Parkinson's disease (PD) patients compared to healthy individuals. However, NMSs are also common in the elderly and other neurological conditions, and thus, it is not known whether NMSs could be used to differentiate PD from parkinsonism/tremor without dopamine deficiency.Methods: We prospectively evaluated NMSs immediately before brain dopamine transporter (DAT) [I-123]FP-CIT SPECT scanning in 193 patients with unclear parkinsonism/tremor. According to the clinical follow-up and imaging results, 84 patients had PD. NMSs and their correlations with striatal DAT binding were investigated in PD patients and in parkinsonism/tremor patients with normal dopamine function.Results: Total NMS burden, anxiety or depression did not differ between PD patients and patients with normal DAT binding. DAT-normal patients reported more perception-related (p = 0.045) and attention/memory-related NMSs than PD patients (p < 0.001). Total NMS score did not correlate with striatal DAT binding in either group.Conclusions: In clinically uncertain cases, the total NMS burden cannot be used as a tool in distinguishing PD patients from patients with non-dopaminergic parkinsonism/tremor. Clinical screening of NMSs appears equally important in all patients with parkinsonism

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Astrocyte function intertwines with the extracellular matrix, whose glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities are found in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We generated human induced pluripotent stem cell-derived FXS and control astrocytes and we found that several pathways associated with urokinase plasminogen activator (uPA) that modulates degradation of extracellular matrix were activated in FXS astrocytes compared with controls. Expression of uPA was increased in FXS astrocytes and levels of uPA were also increased in conditioned medium collected from FXS astrocyte cultures. Levels of uPA correlated inversely with intracellular Ca2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB, indicating effects of uPA on neuronal plasticity. FXS-specific changes of gene expression during neuronal differentiation preceding astrogenesis likely contributed to altered properties of FXS astrocytes. Our results identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.Peer reviewe

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

A triplet repeat expansion leading to transcriptional silencing of the FMR1 gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele. The largest increase was found in miR-125a in the FXS sample, and the miR-125a levels were increased in two independent sets of urine samples from a total of 19 FXS children. Urine miR-125a levels appeared to increase with age in control subjects, but varied widely in FXS subjects. Should the results be generalized, it could suggest that two FXS subgroups existed. Predicted gene targets of the differentially regulated miRNAs are involved in molecular pathways that regulate developmental processes, homeostasis, and neuronal function. Regulation of miR-125a has been associated with type I metabotropic glutamate receptor signaling (mGluR), which has been explored as a treatment target for FXS, reinforcing the possibility that urine miR-125a may provide a novel biomarker for FXS