Genetic analysis of transcription factors in dopaminergic neuronal development in Parkinson's disease.

BACKGROUND: Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson's disease (PD) risk factors; however, no comprehensive analyses of these genes in patients with PD have been undertaken. Therefore, we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD. METHODS: Whole-exome sequencing (WES) was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls. Additionally, whole-genome sequencing (WGS) was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls. RESULTS: We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts, respectively. Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD. However, the significance did not pass the Bonferroni correction. Meanwhile, 72 and 1730 common variants were found in the WES and WGS cohorts, respectively. Unfortunately, single-variant logistic association analyses did not identify significant associations between common variants and PD. CONCLUSIONS: Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients. However, we highlight the complexity of PD and the need for extensive research elucidating its etiology.

The growth and developmental of the myodural bridge and its associated structures in the human fetus.

Myodural bridge (MDB) is a dense connective tissue between suboccipital muscle and dura mater. However, there are few reports on the development and maturation of the human MDB. This study aims to explore the developmental relationship between suboccipital muscle and MDB. 30 head and neck specimens from human fetuses (F) ranging from the 12th to 41st week (W) were made into histological sections. The F12W sections showed evidence that the dura mater dominated by fibroblasts, attached to the posterior atlanto-axial membrane (PAAM) which completely sealed the atlanto-axial space. In the F13W stage, myofibrils of the suboccipital muscle fibers increased significantly in number. At the F14W stage, a gap was observed at the caudal end of the PAAM. Numerous myodural bridge-like structures were observed blending into the dura mater through the gap. At the F19W stage, muscle cells mature. Starting at the F21W stage, the MDB were observed as fibroblasts that cross the atlanto-axial interspace and attach to the dura mater. Therefore, the traction generated by the suboccipital muscles seems to promote the maturity of MDB. This study will provide new morphological knowledge to support future research on the function of the human MDB and regulating the development mechanism of MDB.

R-LOOPs on Short Tandem Repeat Expansion Disorders in Neurodegenerative Diseases.

Expansions of short tandem repeats (STRs) have been found to be present in more than 50 diseases and have a close connection with neurodegenerative diseases. Transcriptional silencing and R-LOOP formation, RNA-mediated sequestration of RNA-binding proteins (RBPs), gain-of-function (GOF) proteins containing expanded repeats, and repeat-associated non-AUG (RAN) translation of toxic repeat peptides are some potential molecular mechanisms underlying STR expansion disorders. R-LOOP, a byproduct of transcription, is a three-stranded nucleic acid structure with abnormal accumulation that participates in the pathogenesis of STR expansion disorders by inducing DNA damage and genome instability. R-LOOPs can engender a series of DNA damage, such as DNA double-strand breaks (DSBs), single-strand breaks (SSBs), DNA recombination, or mutations in the DNA replication, transcription, or repair processes. In this review, we provide an in-depth discussion of recent advancements in R-LOOP and systematically elaborate on its genetic destabilizing effects in several neurodegenerative diseases. These molecular mechanisms will provide novel targets for drug design and therapeutic upgrading of these devastating diseases.

Internal Structural Connections in the Popliteus Tendon Complex with Posterior Cruciate Ligament and Clinical Implications / Conexiones Estructurales Internas en el Complejo Tendón Poplíteo con Ligamento Cruzado Posterior e Implicaciones Clínicas

SUMMARY: At present, the anatomical relationship the mid-portion of popliteus tendon complex (PTC) and the surrounding tissues is still unclear, especially its relationship to the posterior cruciate ligament (PCL). It affected the anatomical reconstruction of the posterolateral complex (PLC) injury. A total of 30 cases of the adult human knee joint fixed with formalin were used. Sagittal sections were made in 14 knee joints by the P45 plastination technique and dissection of 16 cases of knee joints. The P45 section revealed that the popliteus muscle fascia ran superiorly over the posterior edge of the tibial intercondylar eminence, and turned forward to be integrated into the PCL. Laterally, near the posterior edge of the lateral tibial plateau, the popliteus tendon penetrates through the articular capsule (AC), where two dense fibrous bundles were given off upwards by the popliteus tendon: one was the ventral fiber bundle, which ran superiorly over the posterior edge of the tibial plateau and then moved forwards to connect with the lateral meniscus; the dorsal fibers bundle ascended directly and participated in the AC. Meanwhile, the popliteus muscle dissection showed that at the posterior edge of the platform of the lateral condyle of the tibia, at the tendon-muscle transition, the PTC and AC were anchored to PCL.

En la actualidad, la relación anatómica entre la porción media del complejo tendinoso poplíteo (CTP) y los tejidos circundantes aún no está clara, especialmente su relación con el ligamento cruzado posterior (LCP). Esto afecta la reconstrucción anatómica de la lesión del complejo posterolateral (LCP). Se utilizaron un total de 30 casos de articulaciones de rodillas humanas de individuos adultos fijadas con formalina. Se realizaron cortes sagitales en 14 articulaciones de rodilla mediante la técnica de plastinación P45 y disección de 16 casos de articulaciones de rodilla. La sección P45 reveló que la fascia del músculo poplíteo discurría superiormente sobre el margen posterior de la eminencia intercondílea tibial y giraba hacia delante para integrarse en el LCP. Lateralmente, cerca del margen posterior de la platillo tibial lateral, el tendón poplíteo penetra a través de la cápsula articular (CA), donde el tendón poplíteo desprendió hacia arriba dos haces fibrosos densos: uno era el haz de fibras ventral, que corría superiormente sobre el margen posterior de la meseta tibial y luego se movió hacia adelante para conectar con el menisco lateral; el haz de fibras dorsales ascendía directamente y participaba en la CA. Por su parte, la disección del músculo poplíteo mostró que en el margen posterior del platillo del cóndilo lateral de la tibia, en la transición tendón-músculo, el CTP y el AC estaban anclados al LCP.

Characteristics of fatigue in Parkinson's disease: A longitudinal cohort study.

Objective: To assess the prevalence, evolution, clinical characteristics, correlates and predictors of fatigue as well as to investigate the influence of comorbid fatigue on the longitudinal changes in motor and non-motor symptoms over a 2-year longitudinal follow-up period in a large cohort of patients with Parkinson's disease (PD). Materials and methods: A total of 2,100 PD patients were enrolled from the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC), and their motor and non-motor symptoms were assessed biennially using comprehensive scales, including the 16-item Parkinson Fatigue Scale (PFS-16). Each PD patient was categorized as PD with or without fatigue on the basis of a cut-off mean PFS-16 score of 3.3. Results: The prevalence of fatigue in our cohort was 36.8%. Compared to PD patients without fatigue, PD patients with fatigue were more likely to be older, have a longer disease duration, and higher baseline levodopa equivalent daily dose (all p < 0.05). Moreover, PD patients with fatigue showed more severe motor and non-motor phenotypes than those without fatigue. Overall, high total Unified Parkinson's Disease Rating Scale (UPDRS) score (odds ratio [OR] = 1.016, 95% confidence interval [CI]: 1.009-1.024), Non-Motor Symptoms Scale score (OR = 1.022, 95% CI: 1.015-1.029), postural instability and gait difficulty (PIGD) subtype (OR = 1.586, 95% CI: 1.211-2.079), presence of excessive daytime sleepiness (EDS; OR = 1.343, 95% CI: 1.083-1.666), and wearing-off (OR = 1.282, 95% CI: 1.023-1.607) were significantly associated with fatigue in PD patients (all p < 0.05). High total UPDRS score at baseline (OR = 1.014, 95% CI: 1.002-1.027, p = 0.028) increased the risk of developing fatigue during follow-up. Although significant, the odds ratios were low and confidence intervals were narrow. Analysis of disease progression showed significant group differences in motor and non-motor symptoms. In comparison with the never-fatigue group, the persistent-fatigue group showed significantly greater progression in motor, autonomic dysfunction, sleep, depression and cognitive symptoms (all p < 0.05). Conclusion: Increased disease severity, presence of the PIGD subtype, EDS, and wearing-off were associated with fatigue in PD patients. Significant subgroup-level differences were observed in the progression of motor and non-motor symptoms across different fatigue subgroups of PD patients.

A novel MYORG mutation causes primary familial brain calcification with migraine: Case report and literature review.

Primary familial brain calcification (PFBC) is a disorder in which pathologic calcification of the basal ganglia, cerebellum, or other brain regions with bilateral symmetry occurs. Common clinical symptoms include dysarthria, cerebellar symptoms, motor deficits, and cognitive impairment. Genetic factors are an important cause of the disease; however autosomal recessive (AR) inheritance is rare. In 2018, the myogenesis-regulated glycosidase (MYORG) gene was the first to be associated with AR-PFBC. The present case is a 24-year-old woman with AR-PFBC that presented with migraine at the age of 16 years. Symmetrical patchy calcifications were seen in the bilateral cerebellopontine nuclei, thalamus, basal ganglia, and radiocoronal area on computed tomography and magnetic resonance imaging. AR-PFBC with migraine as the main clinical symptom is rare. Whole-exome sequencing revealed a compound heterozygous mutation in the MYORG gene, one of which has not been previously reported. Our case highlights the pathogenic profile of the MYORG gene, and demonstrates the need for exclusion of calcium deposits in the brain for migraine patients with AR inheritance.

Bony structures at the attachment areas of the cruciate ligaments in human knee joints and their clinical significance-studied using the P45 plastination technique / Estructuras óseas en las áreas de inserción de los ligamentos cruzados en las articulaciones de la rodilla humana y su importancia clínica, estudiadas mediante la técnica de plastinación P45

SUMMARY: For treating cruciate ligament injuries, especially for characterizing the mechanics of the tunnel in cruciate ligament reconstruction, correctly understanding the bony information of the attachment area of the cruciate ligaments is significant. We studied 31 knee joints of middle-aged Chinese adults using the P45 sheet plastination technique, focusing on the attachment areas of the cruciate ligaments, especially the bony structures. The trabeculae at the attachment area were distributed radially and extended deep into the medial wall of the lateral condyle of the femur. However, in the anterior part of the intercondylar eminence, the trabeculae of the anterior group were parallelly arranged along the tendinous fibers of the anterior cruciate ligament, while the trabeculae of the posterior group were parallelly arranged along the perpendicular direction of the anterior cruciate ligament fibers. Similarly, at the attachment area of the lateral wall of the medial condyle of the posterior cruciate ligament, the trabeculae extended radially toward the deep medial condyle. Deep in the posterior part of the intercondylar eminence, the trabeculae were arranged longitudinally. In the anterior part of the intercondylar eminence, the trabeculae were parallelly arranged along the perpendicular directions of ligament fibers. The distribution patterns of the trabecular at the attachment areas of the cruciate ligaments at the ends of the femur and tibia were different. This difference should be considered when orthopedic surgeons reconstruct anterior cruciate ligaments.

Para el tratamiento de lesiones de los ligamentos cruzados, especialmente para caracterizar la mecánica del túnel en su reconstrucción, es importante comprender correctamente la información ósea del área de inserción de estos ligamentos. Estudiamos 31 articulaciones de rodilla de individuos chinos, adultos, de mediana edad, utilizando la técnica de plastinación de láminas P45, centrándonos en las áreas de unión de los ligamentos cruzados, especialmente en las estructuras óseas. Las trabéculas en el área de inserción se distribuyeron radialmente y se extendieron profundamente en la pared medial del cóndilo lateral del fémur. Sin embargo, en la parte anterior de la eminencia intercondílea, las trabéculas del grupo anterior estaban dispuestas paralelamente a lo largo de las fibras tendinosas del ligamento cruzado anterior, mientras que las trabéculas del grupo posterior estaban dispuestas paralelamente a lo largo de la dirección perpendicular de las fibras del ligamento cruzado anterior. De manera similar, en el área de inserción en la cara lateral del cóndilo medial del ligamento cruzado posterior, las trabéculas se extendían radialmente y profundas hacia el cóndilo medial. Profundamente en la parte posterior de la eminencia intercondílea, las trabéculas estaban dispuestas longitudinalmente. En la parte anterior de la eminencia intercondílea, las trabéculas estaban dispuestas paralelamente a lo largo de las direcciones perpendiculares de las fibras del ligamento. Los patrones de distribución del tejido óseo trabecular en las áreas de unión de los ligamentos cruzados en los extremos del fémur y la tibia eran diferentes. Estas diferencias deben tenerse en consideración cuando los cirujanos ortopédicos reconstruyen los ligamentos cruzados anteriores.

Congenital atlanto-occipital fusion and its effect on the myodural bridge: a case report utilizing the P45 plastination technique / Fusión atlanto-occipital congénita y su efecto sobre el puente miodural: reporte de un caso utilizando la técnica de plastinación P45

SUMMARY: The atlanto-occipital joint is composed of the superior fossa of the lateral masses of the atlas (C1) and the occipital condyles. Congenital Atlanto-occipital fusion (AOF) involves the osseous union of the base of the occiput (C0) and the atlas (C1). AOF or atlas occipitalization/assimilation represents a craniovertebral junction malformation (CVJM) which can be accompanied by other cranial or spinal malformations. AOF may be asymptomatic or patients may experience symptoms from neural compression as well as limited neck movement. The myodural bridge (MDB) complex is a dense fibrous structure that connects the suboccipital muscular and its related facia to the cervical spinal dura mater, passing through both the posterior atlanto-occipital and atlanto-axial interspaces. It is not known if atlas occipitilization can induce structural changes in the MDB complex and its associated suboccipital musculature. The suboccipital region of a cadaveric head and neck specimen from an 87-year-old Chinese male having a congenital AOF malformation with resultant changes to the MDB complex was observed. After being treated with the P45 plastination method, multiple slices obtained from the cadaveric head and neck specimen were examined with special attention paid to the suboccipital region and the CVJM. Congenital atlanto-occipital fusion malformations are defined as partial or complete fusion of the base of the occiput (C0) with the atlas (C1). In the present case of CVJM, unilateral fusion of the left occipital condyle with the left lateral mass of C1 was observed, as well as posterior central fusion of the posterior margin of the foramen magnum with the posterior arch of C1. Also noted was a unilateral variation of the course of the vertebral artery due to the narrowed posterior atlanto-occipital interspace. Surprisingly, complete agenesis of the rectus capitis posterior minor (RCPmi) and the obliques capitis superior (OCS) muscles was also observed in the plastinated slices. Interestingly, the MDB, which normally originates in part from the RCPmi muscle, was observed to originate from a superior bifurcation within an aspect of the nuchal ligament. Therefore, the observed changes involving the MDB complex appear to be an effective compensation to the suboccipital malformations.

RESUMEN: La articulación atlanto-occipital está compuesta por las caras articulares superiores de las masas laterales del atlas (C1) y los cóndilos occipitales. La fusión atlanto-occipital congénita (FAO) implica la unión ósea de la base del occipucio (C0) y el atlas (C1). La FAO u occipitalización/asimilación del atlas representa una malformación de la unión craneovertebral (MUCV) que puede presentar otras malformaciones craneales o espinales. La FAO puede ser asintomática o los pacientes pueden experimentar síntomas de compresión neural así como movimiento limitado del cuello. El complejo del puente miodural (PMD) es una estructura fibrosa densa que conecta el músculo suboccipital y su fascia relacionada con la duramadre espinal cervical, pasando a través de los espacios intermedios atlanto-occipital posterior y atlanto-axial. No se sabe si la occipitilización del atlas puede inducir cambios estructurales en el complejo PMD y en la musculatura suboccipital. Se observó en la región suboccipital de un espécimen cadavérico, cabeza y cuello de un varón chino de 87 años con una malformación congénita de FAO con los cambios resultantes en el complejo PMD. Se examinaron múltiples cortes obtenidos de la muestra de cabeza y cuello después de ser tratados con el método de plastinación P45, con especial atención a la región suboccipital y la MUCV. Las malformaciones congénitas por fusión atlanto-occipital se definen como la fusión parcial o completa de la base del occipucio (C0) con el atlas (C1). En el presente caso de MUCV se observó la fusión unilateral del cóndilo occipital izquierdo con la masa lateral izquierda de C1, así como fusión posterior central del margen posterior del foramen magnum con el arco posterior de C1. También se observó una variación unilateral del curso de la arteria vertebral por el estrechamiento del espacio interatlanto-occipital posterior. Se observó además agenesia completa de los músculos Rectus capitis posterior minor (RCPmi) y oblicuos capitis superior (OCS) en los cortes plastinados. Curiosamente, se observó que el MDB, que normalmente se origina en parte del músculo RCPmi, se origina en una bifurcación superior dentro de un aspecto del ligamento nucal. Por lo tanto, los cambios observados en el complejo PMD parecen ser una compensación de las malformaciones suboccipitales.

Development, maturation, and growth of the myodural bridge within the posterior atlanto-axial interspace in the rat.

The myodural bridge (MDB) complex are fibrous bridges that functionally connect the spinal dura mater to the suboccipital musculature. Previously, we described the maturational sequence of the MDB within the posterior atlanto-occipital interspace of the rat. The present paper describes the morphology and developmental maturation of the MDB within the posterior atlanto-axial interspace of the rat. In the present study, E18 embryonic rats, newborn rats, and adult rats were selected to evaluate the development and growth of the MDB. Within the posterior atlanto-axial interspace of the rat, the fibers of the MDB and its associated muscles, in the embryonic rat, were observed to be scarce and lightly stained. In contrast, these same structures observed in the postnatal rat were quite apparent and robustly stained. After birth, it was observed that MDB originated from the rectus capitis dorsal major muscle, extended forward and downward, and finally merged with the posterior atlanto-axial membrane. As the rats developed and matured, the observed MDB fibers passing through the posterior atlanto-axial interspace appeared denser and more organized. This study evidenced that the MDB fibers within the posterior atlanto-axial interspace were primarily composed of type I collagen fibers in the postnatal rat. By observing the suboccipital region, we are able to hypothesize that the MDB complex plays a key role in maintaining the subdural space located within the upper cervical segment during growth and development. This study provides a morphological basis for future research on the function of the MDB complex.

The Adverse Effect of Anxiety on Dynamic Anticipation Performance.

Anticipation is a crucial perceptual-cognitive skill in fast-ball sports, and the effect of high anxiety on performance has attracted more attention from sports psychologists. Related studies mainly focus on the effect of anxiety on influencing processing efficiency and attentional control (top-down vs. bottom-up) during information processing in sport. Attentional Control Theory (ACT) has been supported by several studies. However, these studies have been criticized by the low ecological validity of task design, such as neglecting the dynamic process of anticipation, and inadequate performance analysis, such as analyzing response accuracy and time separately. Using temporal occlusion paradigm, we tested ACT in a dynamic anticipation process. Eighteen skilled and eighteen less-skilled table tennis players were required to anticipate the serves of opponents under dynamic task constraints (early vs. late occlusion) and anxiety conditions (high vs. low anxiety). High cognitive state anxiety decreased processing efficiency (response time/response accuracy) for both groups whereas performance effectiveness (response accuracy) did not differ. In addition, it negatively affected processing efficiency in early anticipation compared with late anticipation tasks, suggesting that high cognitive state anxiety may have a greater impact on top-down attentional control. Our findings provide support for ACT and show that anxiety impairs anticipation efficiency and performance, possibly due to an ineffectively attentional shift from external kinematic cues to internal long-term working memory. Findings also have implications for the adaptation of attentional strategies and anxiolytic training.

Architecture of the cancellous bone in human proximal tibia based on P45 sectional plastinated specimens.

PURPOSE: To reveal differences in the pattern of trabecular architecture in the epiphysis and metaphysis of the proximal tibia. METHODS: The trabecular architecture of the proximal tibia was observed in 27 P45 plastinated knee specimens. RESULTS: In the medial and lateral condyles, under the articular cartilage surrounded by the medial or lateral meniscus, the cancellous bone is formed by thick and dense trabecular bands, which run longitudinally in the epiphysis and then pass through the epiphyseal line to terminate on the slanted cortex of the metaphysis. In the intercondylar eminence, the trabeculae are arranged basically in a network. In the central portion of the tibial metaphysis, cancellous bone consists of fine arcuate trabeculae, which extend to the anterior and posterior cortices, respectively. These trabeculae are intersected sparsely and form trusses over the medullary cavity. Near the areas of attachment of the iliotibial tract, tibial collateral ligament, anterior and posterior cruciate ligaments, and patellar ligament, the cancellous bone is locally reinforced with patchy trabeculae, dense radiating trabeculae, or two orthotropic trabecular bands. CONCLUSION: This study provides further accurate anatomical information on the trabeculae of the proximal tibia. The soft structures of knee joint, including the articular cartilage, menisci, and ligaments, and the slanted cortices of the metaphysis are important landmarks for the location of different arrangements of the cancellous architecture. The present results are beneficial for clinical diagnosis and treatment of pathologies of the knee joint, or the establishment of a finite element analysis model of the knee joint.

Development of myodural bridge located within the atlanto-occipital interspace of rats.

The myodural bridge (MDB) is a dense connective tissue structure that connects the subocciptal musculature to the spinal dura mater. The purpose of this study was to clarify morphological evolution characteristics and compositional changes in the fibrous structures of MDB during its growth and development in the atlanto-occipital interspace. For this, histological sections from Sprague-Dawley (SD) rats (age, E17 to adulthood) were stained with Masson's Trichrome and Picrosirius Red. The results demonstrated that at age E18, the posterior arch of the atlas was completely closed and MDB fibers had already begun to form. In rat embryos (E18-E21), only few fibers and muscles were present in the suboccipital region, and these were lightly stained. In postnatal rats, an obvious increase in the amount of fibers and muscle tissues was noted. At age P1, MDB fibers originated from the rectus capitis posterior minor muscle and merged into the atlanto-occipital membrane, which was closely attached to the spinal dura mater. As rats matured, MDB fibers gradually became denser and more organized. This study also showed that in postnatal rats, MDB was mainly composed of type I collagen fibers. By observing the development of MDB in SD rats, the function of MDB can be further understood. This study provides a morphological basis for future functional studies involving the MDB.