Case report: Recurrent pontine stroke and leukoencephalopathy in a patient with de novo mutation in COL4A1.

This report presents a case of pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) in a 35 year-old male patient. The patient exhibited a consistent history of recurrent ischemic strokes, concentrated primarily in the pons region, accompanied by concurrent manifestations of leukoencephalopathy and microbleeds. Genetic evaluation revealed a heterozygous missense mutation consistent with c.3431C>G, p. Thr1144Arg substitution within exon 40 of the COL4A1 gene. This mutation was also identified in the patient's mother, affirming an autosomal dominant inheritance model. Our findings serve as testament to the potential role of mutation in the exon 40 of COL4A1 in the pathogenesis and progression of PADMAL, contributing to ongoing efforts aimed at better understanding the genetic basis of this debilitating disorder.

Stiffness changes in internal rotation muscles of the shoulder and its influence on hemiplegic shoulder pain.

Background: Hemiplegic shoulder pain (HSP) is a common complication in patients with stroke. The pathogenesis of HSP is complex, and muscle hypertonia, especially the hypertonia of internal rotation muscles of the shoulder, may be one of the important causes of shoulder pain. However, the relationship between muscle stiffness and HSP has not been well studied. The purpose of this study is to explore the correlations between the stiffness of internal rotation muscles and clinical symptoms in patients with HSP. Methods: A total of 20 HSP patients and 20 healthy controls were recruited for this study. The stiffness of internal rotation muscles was quantified using shear wave elastography, and Young's modulus (YM) of the pectoralis major (PM), anterior deltoid (AD), teres major ™, and latissimus dorsi (LD) were measured. Muscle hypertonia and pain intensity were evaluated using the Modified Ashworth Scale (MAS) and Visual Analog Scale (VAS), respectively. The mobility of the shoulder was evaluated using the Neer score. The correlations between muscle stiffness and the clinical scales were analyzed. Results: YM of internal rotation muscles on the paretic side was higher than that of the control group in the resting and passive stretching positions (P < 0.05). YM of internal rotation muscles on the paretic side during passive stretching was significantly higher than that at rest (P < 0.05). YM of PM, TM, and LD during passive stretching were correlated with MAS (P < 0.05). In addition, the YM of TM during passive stretching was positively correlated with VAS and negatively correlated with the Neer score (P < 0.05). Conclusion: Increased stiffness of PM, TM, and LD was observed in patients with HSP. The stiffness of TM was associated with pain intensity of the shoulder and shoulder mobility.

An Update on Nondopaminergic Treatments for Motor and Non-motor Symptoms of Parkinson's Disease.

Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

Free water imaging as a novel biomarker in Wilson's disease: A cross-sectional study.

BACKGROUND: The bi-tensor free water imaging may provide more specific information in detecting microstructural brain tissue alterations than conventional single tensor diffusion tensor imaging. The study aimed to investigate microstructural changes in deep gray matter (DGM) nuclei of Wilson's disease (WD) using a bi-tensor free water imaging and whether the findings correlate with the neurological impairment in WD patients. METHODS: The study included 29 WD patients and 25 controls. Free water and free water corrected fractional anisotropy (FAT) in DGM nuclei of WD patients were calculated. The correlations of free water and FAT with the Unified WD Rating Scale (UWDRS) neurological subscale of WD patients were performed. RESULTS: Free water and FAT values were significantly increased in multiple DGM nuclei of neurological WD patients compared to controls. WD patients with normal appearing on conventional MRI also had significantly higher free water and FAT values in multiple DGM nuclei than controls. Positive correlations were noted between the UWDRS neurological subscores and free water values of the putamen and pontine tegmentum as well as FAT values of the dentate nucleus, red nucleus, and globus pallidus. In addition, the measured free water and FAT values of specific structures also showed a positive correlation with specific clinical symptoms in neurological WD patients, such as dysarthria, parkinsonian signs, tremor, dystonia, and ataxia. CONCLUSIONS: Free water imaging detects microstructural changes in both normal and abnormal appearing DGM nuclei of WD patients. Free water imaging indices were correlated with the severity of neurological impairment in WD patients.

A 16S rDNA sequencing-based analysis of airway microecology in patients with an acute exacerbation of chronic obstructive pulmonary disease: A cross-sectional study in Inner Mongolia, China.

Aim: To study the microecological characteristics of the airway and similarities and differences between healthy people and patients with the acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Inner Mongolia, and analyze the correlation between the characteristics of the airway microecological structure and clinical indicators of AECOPD patients. Methods: Sputum samples from 36 healthy volunteers and 34 patients with AECOPD were detected by 16S rDNA high-throughput sequencing, and the airway microecological characteristics of healthy people and AECOPD patients were revealed by an alpha diversity analysis, beta diversity analysis, and LefSe difference analysis. Results: There were differences in the airway microecological structure between healthy people and AECOPD patients in Inner Mongolia. The airway microbiota composition of AECOPD patients showed an increase in the abundance of common pathogens and a decrease in the abundance of commensal bacteria, and the airway microbial diversity in AECOPD patients was lower than that in healthy people. Long-term use of inhaled glucocorticoid + long-acting ß2 agonist mixture (ICS + LABA), procalcitonin (PCT), blood monocyte count (MONO), hemoglobin (HGB), D-dimer (D-D), and body temperature were negatively correlated with the alpha diversity of the airway micro-ecosystem. Conclusion: The airway microecological composition of the AECOPD population in Inner Mongolia was different from that of the healthy population, and the airway microecological diversity was lower than that of the healthy population. The long-term use of ICS + LABA preparation by patients with AECOPD leads to lower alpha diversity. Alpha diversity was negatively correlated with inflammatory markers (PCT, MONO, D-dimer, body temperature) and HGB in AECOPD patients.

Increased Stiffness of the Superficial Cervical Extensor Muscles in Patients With Cervicogenic Headache: A Study Using Shear Wave Elastography.

Background: Cervicogenic headache (CEH) is a secondary headache caused by lesions of the cervical spine and surrounding soft tissues. Cervical muscle dysfunction may be related to the onset of CEH. However, whether cervical muscle stiffness changes in patients with CEH has not been well studied. The purpose of this study was to explore changes in superficial cervical extensor muscle stiffness in patients with CEH using shear wave elastography (SWE). Methods: In this study, 19 patients with CEH and 20 healthy controls were recruited. Superficial cervical extensor muscle stiffness was obtained from SWE, and the SuperLinear SL10-2 MHz linear array probe in the musculoskeletal muscle mode was chosen as the transducer. Regions of interest in the trapezius (TRAP), splenius capitis (SPL), semispinalis capitis (SCap), and semispinalis cervicis (SCer) were manually segmented. Correlations between superficial cervical extensor muscle stiffness and visual analog scale (VAS) scores, age, and body mass index (BMI) were analyzed using Pearson's correlation. Receiver operating characteristic (ROC) curve was used to investigate the diagnostic ability of superficial cervical extensor stiffness for CEH. Results: Superficial cervical extensor muscle stiffness on the headache side of patients with CEH was higher than that on the non-headache side and in healthy controls (p < 0.05). Increased stiffness was also observed in SCer on the non-headache side of patients with CEH compared to healthy controls (p < 0.01). In patients with CEH, SCer stiffness was positively correlated with VAS scores (r = 0.481, p = 0.037), but no correlation was found between other muscles and VAS scores (p > 0.05). The areas under the curve of TRAP, SPL, SCap, and SCer in diagnosing CEH were 0.766, 0.759, 0.964, and 1.000, respectively. Conclusions: Increased stiffness was observed in the superficial cervical extensor muscles on the headache side of patients with CEH. SCer stiffness was correlated with headache intensity in patients with CEH and may provide clues for the diagnosis of CEH.

Increased Magnetic Susceptibility in the Deep Gray Matter Nuclei of Wilson's Disease: Have We Been Ignoring Atrophy?

Background: Histopathological studies in Wilson's disease (WD) have revealed increased copper and iron concentrations in the deep gray matter nuclei. However, the commonly used mean bulk susceptibility only reflects the regional metal concentration rather than the total metal content, and regional atrophy may affect the assessment of mean bulk susceptibility. Our study aimed to quantitatively assess the changes of metal concentration and total metal content in deep gray matter nuclei by quantitative susceptibility mapping to distinguish patients with neurological and hepatic WD from healthy controls. Methods: Quantitative susceptibility maps were obtained from 20 patients with neurological WD, 10 patients with hepatic WD, and 25 healthy controls on a 3T magnetic resonance imaging system. Mean bulk susceptibility, volumes, and total susceptibility of deep gray matter nuclei in different groups were compared using a linear regression model. The area under the curve (AUC) was calculated by receiver characteristic curve to analyze the diagnostic capability of mean bulk susceptibility and total susceptibility. Results: Mean bulk susceptibility and total susceptibility of multiple deep gray matter nuclei in patients with WD were higher than those in healthy controls. Compared with patients with hepatic WD, patients with neurological WD had higher mean bulk susceptibility but similar total susceptibility in the head of the caudate nuclei, globus pallidus, and putamen. Mean bulk susceptibility of putamen demonstrated the best diagnostic capability for patients with neurological WD, the AUC was 1, and the sensitivity and specificity were all equal to 1. Total susceptibility of pontine tegmentum was most significant for the diagnosis of patients with hepatic WD, the AUC was 0.848, and the sensitivity and specificity were 0.7 and 0.96, respectively. Conclusion: Brain atrophy may affect the assessment of mean bulk susceptibility in the deep gray matter nuclei of patients with WD, and total susceptibility should be an additional metric for total metal content assessment. Mean bulk susceptibility and total susceptibility of deep gray matter nuclei may be helpful for the early diagnosis of WD.

Management Perspective of Wilson's Disease: Early Diagnosis and Individualized Therapy.

Wilson's disease (WD) is an inherited disease caused by mutations in ATP7B and is characterized by the pathological accumulation of copper in the liver and brain. Common clinical manifestations of WD include a wide range of liver disease and neurological symptoms. In some patients, psychiatric symptoms may be the only manifestation at the time of diagnosis. The clinical features of WD are highly variable and can mimic any disease of internal medicine. Therefore, for unexplained medical diseases, the possibility of WD should not be ignored. Early diagnosis and treatment can improve the prognosis of WD patients and reduce disability and early death. Gene sequencing is becoming a valuable method to diagnose WD, and if possible, all WD patients and their siblings should be genetically sequenced. Copper chelators including D-penicillamine, trientine, and dimercaptosuccinic acid can significantly improve the liver injury and symptoms of WD patients but may have a limited effect on neurological symptoms. Zinc salts may be more appropriate for the treatment of asymptomatic patients or for the maintenance treatment of symptomatic patients. High-quality clinical trials for the drug treatment of WD are still lacking, therefore, individualized treatment options for patients are recommended. Individualized treatment can be determined based on the clinical features of the WD patients, efficacy and adverse effects of the drugs, and the experience of the physician. Liver transplantation is the only effective method to save patients with acute liver failure or with severe liver disease who fail drug treatment.

Paramagnetic Metal Accumulation in the Deep Gray Matter Nuclei Is Associated With Neurodegeneration in Wilson's Disease.

BACKGROUND: Neuropathological studies have revealed copper and iron accumulation in the deep gray matter (DGM) nuclei of patients with Wilson's disease (WD). However, the association between metal accumulation and neurodegeneration in WD has not been well studied in vivo. The study was aimed to investigate whether metal accumulation in the DGM was associated with the structural and functional changes of DGM in neurological WD patients. METHODS: Seventeen neurological WD patients and 20 healthy controls were recruited for the study. Mean bulk susceptibility values and volumes of DGM were obtained from quantitative susceptibility mapping (QSM). Regions of interest including the head of the caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, red nucleus, and dentate nucleus were manually segmented. The susceptibility values and volumes of DGM in different groups were compared using a linear regression model. Correlations between susceptibility values and volumes of DGM and Unified Wilson's Disease Rating Scale (UWDRS) neurological subscores were investigated. RESULTS: The susceptibility values of all examined DGM in WD patients were higher than those in healthy controls (P < 0.05). Volume reductions were observed in the head of the caudate nucleus, globus pallidus, putamen, thalamus, and substantia nigra of WD patients (P < 0.001). Susceptibility values were negatively correlated with the volumes of the head of the caudate nucleus (r p = -0.657, P = 0.037), putamen (r p = -0.667, P = 0.037), and thalamus (r p = -0.613, P = 0.046) in WD patients. UWDRS neurological subscores were positively correlated with the susceptibility values of all examined DGM. The susceptibility values of putamen, head of the caudate nucleus, and dentate nucleus could well predict UWDRS neurological subscores. CONCLUSION: Our study provided in vivo evidence that paramagnetic metal accumulation in the DGM was associated with DGM atrophy and neurological impairment. The susceptibility of DGM could be used as a biomarker to assess the severity of neurodegeneration in WD.

Transverse Strips Instead of Wearable Laser Lights Alleviate the Sequence Effect Toward a Destination in Parkinson's Disease Patients With Freezing of Gait.

Background: The sequence effect (SE), referring to step-to-step reduction in amplitude, is considered to lead to freezing of gait (FOG) in Parkinson's disease (PD). Visual cues may alleviate SE and help reduce freezing episodes. FOG patients show significant SE prior to turning or toward a doorway, but the SE toward a destination has not been clearly studied. Objectives: To examine the SE when approaching a destination in PD patients with FOG, and to further explore the effects of different types of visual cues on destination SE. Methods: Thirty-five PD patients were divided into a freezing (PD+FOG, n = 15) group and a non-freezing (PD-FOG, n = 20) group. Walking trials were tested under three conditions, including without cues (no-cue condition), with wearable laser lights (laser condition), and with transverse strips placed on the floor (strip condition). Kinematic data was recorded by a portable Inertial Measurement Unit (IMU) system. The destination SE and some key gait parameters were evaluated. Results: The PD+FOG group showed greater destination SE in the no-cue and laser conditions when compared to the PD-FOG group. There were no significant differences in the strip condition when comparing destination SE of the two groups. The destination SE was alleviated only by using the transverse strips on the floor. In contrast, transverse strips and wearable laser lights could increase the step length. Conclusions: The significant destination SE may explain why FOG patients are prone to freezing when heading toward their destination. Visual cues using transverse strips on the floor may be a more effective strategy for FOG rehabilitation in PD patients.

[Mobilization of Bone Marrow Mesenchymal Stem Cells Inhibits TGF-ß Non-classical Pathway Against Myocardial Fibrosis in Rats].

OBJECTIVE: To observe the relationship between the mechanism of bone marrow stem cell mobilization mediated the myocardial fibrosis inhibition in rats and the non-classical pathway mediated by transforming growth factor-ß (TGF-ß). METHODS: Twenty two Wistar rats were subcutaneously injected with isoproterenol (Iso) to establish the model of myocardial fibrosis, and then were randomly divided into control group and granulocyte colony-stimulating factor (G-CSF)-treat group (GT group). The rats in GT group were subcutaneously injected with recombinant human granulocyte stimulating factor for 5 days, and the control group was injected with normal saline. After 4 weeks, the myocardial structure was observed by pathological staining, the content of serum B type natriuretic peptide (BNP) was detected by ELISA , the expression of type Ⅲ collagen was detected by immunohistochemistry staining and the protein expression level of typeⅠcollagen, TGF-ß, transforming growth factor kinase 1 (TAK1), mitogen-activated protein kinase kinase (MKK) and p38 mitogen-activated protein kinase (p38MAPK) was determined by Western blot. RESULTS: Compared with the control group, the serum BNP level, Masson staining collagen deposition, collagen area ratio and the expression of typeⅠcollagen, TGF- ß, TAK1, MKK3 and p38MAPK in the GT group were lower than those in the control group. CONCLUSION: Bone marrow stem cell mobilization can alleviate the degree of myocardial fibrosis in rats, which is related to the inhibition of TGF- ß/TAK1/MKK/p38MAPK pathway.

Genome-wide association study identifies two loci influencing plasma neurofilament light levels.

BACKGROUND: Plasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD. METHODS: This study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model. RESULTS: The minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10- 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10- 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018-2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234). CONCLUSION: GWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus.

The Role of ADAM10 in Alzheimer's Disease.

As a member of the A Disintegrin And Metalloproteinase (ADAM) family, ADAM10 has been identified as the constitutive α-secretase in the process of amyloid-ß protein precursor (AßPP) cleavage and plays a critical role in reducing the generation of the amyloid-ß (Aß) peptides. Recent studies have demonstrated its beneficial role in alleviating the pathologic impairment in Alzheimer's disease (AD) both in vitro and in vivo. However, the role of ADAM10 in AD and the underlying molecular mechanisms are still not well established. Increasing evidence indicates that ADAM10 not only reduces the generation of Aß but may also affect the pathology of AD through potential mechanisms including reducing tau pathology, maintaining normal synaptic functions, and promoting hippocampal neurogenesis and the homeostasis of neuronal networks. Mechanistically, ADAM10 regulates these functions by interacting with postsynaptic substrates in brain, especially synaptic cell receptors and adhesion molecules. Furthermore, ADAM10 protein in platelets seems to be a promising biomarker for AD diagnosis. This review will summarize the role of ADAM10 in AD and highlight its functions besides its role as the α-secretase in AßPP cleavage. Meanwhile, we will discuss the therapeutic potential of ADAM10 in treating AD.