Effectiveness and safety of monoclonal antibodies against amyloid-beta vis-à-vis placebo in mild or moderate Alzheimer's disease.

Backgrounds and objectives: Currently, no consensus has been reached on the therapeutic implications of monoclonal antibodies against amyloid-beta (Aß) in Alzheimer's disease (AD). This study aimed to examine the effectiveness and safety of monoclonal antibodies against Aß as a whole and also to determine the superiority of individual antibodies vis-à-vis placebo in mild or moderate AD. Methods: Literature retrieval, article selection, and data abstraction were performed independently and in duplicate. Cognition and function were appraised by the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Disability Assessment for Dementia (DAD), and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). Effect sizes are expressed as standardized mean difference (SMD) with a 95% confidence interval (CI). Results: Twenty-nine articles involving 108 drug-specific trials and 21,383 participants were eligible for synthesis. Of the four assessment scales, only CDR-SB was significantly reduced after using monoclonal antibodies against Aß relative to placebo (SMD: -0.12; 95% CI: -0.2 to -0.03; p = 0.008). Egger's tests indicated a low likelihood of publication bias. At individual levels, bapineuzumab was associated with a significant increase in MMSE (SMD: 0.588; 95% CI: 0.226-0.95) and DAD (SMD: 0.919; 95% CI: 0.105-1.943), and a significant decrease in CDR-SB (SMD: -0.15; 95% CI: -0.282-0.018). Bapineuzumab can increase the significant risk of serious adverse events (OR: 1.281; 95% CI: 1.075-1.525). Conclusion: Our findings indicate that monoclonal antibodies against Aß can effectively improve instrumental activities of daily life in mild or moderate AD. In particular, bapineuzumab can improve cognition and function, as well as activities of daily life, and meanwhile, it triggers serious adverse events.

SPECT findings on neuropsychiatric symptoms caused by nitrous oxide abuse.

Objective: The aim of the study was to investigate the clinical, neuropsychological, and regional cerebral blood flow (rCBF) perfusion changes in patients with neuropsychiatric symptoms caused by nitrous oxide (N2O) abuse. Methods: A total of 16 patients with neuropsychiatric symptoms caused by nitrous oxide abuse were recruited for this study. The study was carried out in the withdrawal phase of N2O abuse. A 925-1110 MBq 99mTc-ECD was administered intravenously. SPECT/CT images were collected with a low-energy and high-resolution collimator. The region uptake statistics of different brain regions of interest between patients with N2O abuse and normal people of the databases for younger subjects from the Scenium DB Comparison software were calculated automatically. Results: The clinical manifestations of the 16 patients with neuropsychiatric symptoms were mood lability, anxiety, hallucination, delusion, agitation, confusion, and other psychiatric symptoms. In addition, 15 of the patients also complained of memory decline; 14 patients manifested numbness or paresthesia; 14 patients developed limb weakness, and their motor impairments were more severe in the lower limbs than in the upper limbs; and eight patients had urinary and defecation disturbances. In the neuropsychological examination, the BPRS score was 54.69 ± 11.48, the HAMD score was 30.00 ± 11.06, the HAMA score was 18.06 ± 5.77, the MMSE score was 28.06 ± 2.29, and the MoCA score was 25.06 ± 3.40. SPECT showed hypoperfusion in the frontal and temporal lobes, which is consistent with the clinical findings. Conclusion: This was the first study to demonstrate the obvious effect of N2O abuse on CBF in patients with neuropsychiatric symptoms. CBF perfusion imaging is helpful to detect the changes in the local brain functional activity in patients with N2O abuse.

Clinical feature and sural biopsy study in nitrous oxide-induced peripheral neuropathy.

OBJECTIVE: The objective was to analyze the clinical characteristics and pathological characteristics of sural biopsy in nitrous oxide (N2O) -induced peripheral neuropathy. METHODS: We recruited 18 patients with N2O abuse-induced neurological disorders and reported their demographic data, clinical manifestations, laboratory examinations, and nerve conduction studies. Seven patients underwent sural nerve biopsy pathologic examination. RESULTS: All 18 patients had polyneuropathy, the nerve conduction results showed significant reductions in motor and sensory amplitudes, slowing of conduction velocities, and prolongation of latencies in most tested nerves compared to the controls. Toluidine blue staining of semi-thin sections of sural nerve biopsy showed decreased myelinated nerve fiber density, increased thin myelinated nerve fiber density, and axonal regeneration. Electron microscopy showed axonal degeneration and nerve regeneration. CONCLUSION: The main manifestations of peripheral nerve damage caused by the abuse of N2O are lower limb weakness and distal sensory disorder. The nerve conduction study results demonstrated that mixed axonal and demyelinating neuropathy was the most common type of neuropathy. Sural biopsy showed the main pathological change was chronic axonal degeneration.

Characterization of genotype-phenotype correlation with MORC2 mutated Axonal Charcot-Marie-Tooth disease in a cohort of Chinese patients.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum. The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of CMT2Z in 2016. We aimed to describe the phenotypic-genetic spectrum of MORC2-related diseases in the Chinese population. METHODS: With the use of Sanger sequencing and Next Generation Sequencing (NGS) technologies, we screened a cohort of 284 unrelated Chinese CMT2 families. Pathogenicity assessments of MORC2 variants were interpreted according to the ACMG guidelines. Potential pathogenic variants were confirmed by Sanger sequencing. RESULTS: We identified 4 different heterozygous MORC2 mutations in four unrelated families, accounting for 1.4% (4/284). A novel mutation c.1397A>G p. D466G was detected in family 1 and all affected patients presented with later onset axonal CMT with hyperCKemia. The patient in family 2 showed a spinal muscular atrophy (SMA)-like disease with cerebellar hypoplasia and mental retardation, with a hot spot de novo mutation c.260C>T p. S87L. The twin sisters in family 3 were identified as having the most common mutation c.754C>T p. R252W and suffered from axonal motor neuropathy with high variability in disease severity and duration. The patient in family 4 developed an early onset axonal motor and sensory neuropathy, with a reported mutation c.1220G>A p.C407Y. All identified mutations associated with MORC2-related neuropathies are localized in the N-terminal ATPase module. CONCLUSIONS: Our study confirmed that MORC2-related neuropathies exist in the Chinese population at a relatively high mutation rate. We revealed a complex genotype-phenotype correlation with MORC2 mutations. This report adds a new piece to the puzzle of the genetics of CMT and contributes to a better understanding of the disease mechanisms.

Area Postrema Syndrome: A Rare Feature of Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids.

Background: The area postrema syndrome (APS) is a unique diagnostic criterion for neuromyelitis optica spectrum disorders (NMOSD). However, APS has rarely been reported in cases of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Case presentation: A 36-year-old woman presented with APS and clinical features of diffuse central nervous system involvement during the early stage of the disease. Owing to the absence of serum aquaporin 4 antibodies, she was initially misdiagnosed as a case of seronegative NMOSD. However, the distinct neuroimaging characteristics [symmetrical small punctuate gadolinium enhancing lesions (pepper-like)], typical clinical/radiological relapse, and intense steroid-dependence in this case, prompted us to correct the diagnosis as probable CLIPPERS. To prevent relapse, long-term oral steroids and an immunosuppressive agent were administered. Conclusions: CLIPPERS may present as APS, and should be considered in the differential diagnosis of NMOSD.

Reduced sarcolemmal aquaporin 4 expression can support the differential diagnosis of neuromyelitis optica spectrum disorders.

This study aimed to investigate the underlying pathological muscle damage in neuromyelitis optica spectrum disorder (NMOSD) patients without muscular symptoms. We prospectively enrolled 15 patients with aquaporin 4 (AQP4) antibody seropositive NMOSD and 16 patients with non-NMOSD diseases as a control group. Biceps biopsy samples from 18 patients were examined. Six NMOSD patients exhibited inflammatory lesions/edema in lower muscles on muscle MRI. On histopathological examination, NMOSD samples showed significantly decreased IgG-targeting AQP4 expression on sarcolemma compared with non-NMOSD samples in terms of the area of positive staining and integrated optical density. Muscle biopsy can support the differential diagnosis of NMOSD.

[Clinical and genetic analysis of a patient with Perrault syndrome and additional neurological features].

OBJECTIVE: To explore the clinical, neuropathological and genetic characteristics of a patient with Perrault syndrome caused by TWNK mutation. METHODS: Potential variation of the TWNK gene was detected by next-generation sequencing (NGS) and verified by Sanger sequencing. RESULTS: The patient has featured primary amenorrhoea and progressive sensorineural hearing loss since childhood. She also had gait anormaly, distal limb atrophy and weakness, and nystagmus. Further study confirmed sensory neuronopathy accompanied with upper and lower motor neuron involvement as well as cerebellum atrophy. NGS has identified two heterozygous variants of the TWNK gene, namely c.794G>A (p.Arg265His) and c.1181G>A (p.Arg394His). Sanger sequencing confirmed that c.1181G>A (p.Arg394His), a known pathogenic variant, was derived from her farther, while c.794G>A(p.Arg265His), a novel variant, was derived from her mother and likely pathogenic according to the ACMG guidelines. CONCLUSION: Perrault syndrome is a group of disorders with a high phenotypic heterogeneity. The compound heterozygous variation of c.794G>A (p.Arg265His) and c.1181G>A(p.Arg394His) of the TWNK gene may underlie Perrault syndrome in the patient.

Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease.

Neuroinflammation is known to have a pivotal role in the pathogenesis of Alzheimer's disease (AD), and curcumin has been reported to have therapeutical effects on AD because of its anti-inflammatory effects. Curcumin is not only a potent PPARγ agonist, but also has neuroprotective effects on cerebral ischemic injury. However, whether PPARγ activated by curcumin is responsible for the anti-neuroinflammation and neuroprotection on AD remains unclear, and needs to be further investigated. Here, using both APP/PS1 transgenic mice and beta-amyloid-induced neuroinflammation in mixed neuronal/glial cultures, we showed that curcumin significantly alleviated spatial memory deficits in APP/PS1 mice and promoted cholinergic neuronal function in vivo and in vitro. Curcumin also reduced the activation of microglia and astrocytes, as well as cytokine production and inhibited nuclear factor kappa B (NF-κB) signaling pathway, suggesting the beneficial effects of curcumin on AD are attributable to the suppression of neuroinflammation. Attenuation of these beneficial effects occurred when co-administrated with PPARγ antagonist GW9662 or silence of PPARγ gene expression, indicating that PPARγ might be involved in anti-inflammatory effects. Circular dichroism and co-immunoprecipitation analysis showed that curcumin directly bound to PPARγ and increased the transcriptional activity and protein levels of PPARγ. Taking together, these data suggested that PPARγ might be a potential target of curcumin, acting to alleviate neuroinflammation and improve neuronal function in AD.

Milder forms of muscular dystrophy associated with POMGNT2 mutations.

OBJECTIVE: To determine the genetic variants in patients with dystroglycanopathy (DGP) and assess the pathogenicity of these variants. METHODS: A total of 20 patients with DGP were identified by immunohistochemistry or Western blot analysis. Whole-exome sequencing (WES) was performed using patient samples. The pathogenicity of the variants identified was evaluated on the basis of the phenotypic recovery in a knockout (KO) haploid human cell line by transfection with mutated POMGNT2 cDNA and on the basis of the in vitro enzymatic activity of mutated proteins. RESULTS: WES identified homozygous and compound heterozygous missense variants in POMGNT2 in 3 patients with the milder limb-girdle muscular dystrophy (LGMD) and intellectual disability without brain malformation. The 2 identified variants were located in the putative glycosyltransferase domain of POMGNT2, which affected its enzymatic activity. Mutated POMGNT2 cDNAs failed to rescue the phenotype of POMGNT2-KO cells. CONCLUSIONS: Novel variants in POMGNT2 are associated with milder forms of LGMD. The findings of this study expand the clinical and pathologic spectrum of DGP associated with POMGNT2 variants from the severest Walker-Warburg syndrome to the mildest LGMD phenotypes. The simple method to verify pathogenesis of variants may allow researchers to evaluate any variants present in all of the known causative genes and the variants in novel candidate genes to detect DGPs, particularly without using patients' specimens.

[Carpal tunnel syndrome with cervical spondylotic radiculopathy: a clinical and electrophysiological study].

OBJECTIVE: To study the clinical and electrophysiological characteristics of carpal tunnel syndrome (CTS) with cervical spondylotic radiculopathy (CSR) and simple-CTS, and compare the effect of double crush with that of simple entrapment on a nerve and investigate the association between CTS and CSR. METHOD: From January 2011 to August 2014, clinical data from 96 patients with double crush syndrome (DCS, CTS with CSR) and 165 patients with simple-CTS were examined, and the electrophysiologic parameters of median nerve in patients with DCS were compared with that in patients with simple-CTS. RESULTS: In 96 patients with DCS, most of them were female; neck and shoulder pain or simultaneously accompanied by numbness and pain of upper limb was observed in 34 patients, upper limb symptoms and hand weakness and muscle atrophy were observed in the other 62 patients, 124 median nerves with abnormal conduction were found in these DCS patients, including 68 cases with unilateral abnormalities and 28 cases with bilateral abnormalities. Cervical radiculopathies of the C5-7 mainly involved in patients with DCS.223 median nerves with abnormal conduction found in the 165 patients with simple-CTS, including 107 cases with unilateral abnormalities and 58 cases with bilateral abnormalities. The average sensory nerve conduction velocity (SCV), motor nerve conduction velocity (MCV) and distal motor latency (DML) of median nerve for DCS and simple-CTS were (32±7) m/s vs (35±5) m/s, (55±7) m/s vs (57±5) m/s and (4.6±1.6) ms vs (4.0±0.8) ms, respectively, and their corresponding amplitudes were 6.4 µV vs 9.5 µV, 10.9 mV vs 13.1 mV and 11.3 mV vs 14.1 mV, respectively. The SCV, MCV and DML and their corresponding amplitude of DCS were significantly greater decreased than that of simple-CTS (P<0.01). CONCLUSION: DCS is a common clinical syndrome, and patients with DCS may have neck and shoulder symptoms in addition to the common manifestations of simple-CTS. Abnormal conduction of median nerve of CTS with CSR is more severe than that of simple-CTS, which neurophysiologically proves the association between CTS and CSR and supports double crush hypothesis.

DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of α-dystroglycan.

OBJECTIVES: To identify gene mutations in patients with dystroglycanopathy and prove pathogenicity of those mutations using an in vitro cell assay. METHODS: We performed whole-exome sequencing on 20 patients, who were previously diagnosed with dystroglycanopathy by immunohistochemistry and/or Western blot analysis. We also evaluated pathogenicity of identified mutations for phenotypic recovery in a DAG1-knockout haploid human cell line transfected with mutated DAG1 complementary DNA. RESULTS: Using exome sequencing, we identified compound heterozygous missense mutations in DAG1 in a patient with asymptomatic hyperCKemia and pathologically mild muscular dystrophy. Both mutations were in the N-terminal region of α-dystroglycan and affected its glycosylation. Mutated DAG1 complementary DNAs failed to rescue the phenotype in DAG1-knockout cells, suggesting that these are pathogenic mutations. CONCLUSION: Novel mutations in DAG1 are associated with asymptomatic hyperCKemia with hypoglycosylation of α-dystroglycan. The combination of exome sequencing and a phenotype-rescue experiment on a gene-knockout haploid cell line represents a powerful tool for evaluation of these pathogenic mutations.

The clinical and myopathological features of oculopharyngodistal myopathy in a Chinese family.

Oculopharyngodistal myopathy is a rare type of hereditary myopathy characterised pathologically by the changes of muscular dystrophy with rimmed vacuoles and intra-muscular tubulofilamentous inclusions. Here we report the clinical and myopathological changes in a Chinese family with oculopharyngodistal myopathy. The proband showed external ophthalmoplegia, dysphagia, distal weakness and atrophy in all extremities. Serum creatine kinase level was mildly elevated and a myopathic pattern with myotonic discharge was demonstrated by electromyography (EMG). Molecular genetic analysis showed that the number of trinucleotide repeat expansions in the polyadenylate-binding protein nuclear 1 gene was within the normal limit. No mutations were indentified in the GNE gene. Five other persons with similar symptoms were found in the same generation. Muscle biopsy was performed on the tibialis anterior muscle in the proband. Muscular dystrophy changes with rimmed vacuoles were the main histopathological changes. Ultrastructural examination revealed numerous tubulofilamentous inclusions in both sarcoplasm and nucleus. EMG showed myotonic discharges in oculopharyngodistal myopathy. In addition to the sarcoplasm inclusions, we confirmed that tubulofilamentous inclusions appeared also in the nucleus.

Hereditary sensory and autonomic neuropathy type I in a Chinese family: British C133W mutation exists in the Chinese.

Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disorder of the peripheral nervous system characterized by marked progressive sensory loss, with variable autonomic and motor involvement. The HSAN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long chain base subunit 1 (SPTLC1). Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. Here we report the clinical, electrophysiological and pathological findings of a proband in a Chinese family with HSAN I. The affected members showed almost typical clinical features. Electrophysiological findings showed an axonal, predominantly sensory, neuropathy with motor and autonomic involvement. Sural nerve biopsy showed loss of myelinated and unmyelinated fibers. SPTLC1 mutational analysis revealed the C133W mutation, a mutation common in British HSAN I families.