Associations of apolipoprotein E ε4 allele, regional cerebral blood flow, and serum liver function markers in patients with cognitive impairment.

Introduction: The ε4 allele of the apolipoprotein E gene (APOE4) is expressed abundantly in both the brain and peripheral circulation as a genetic risk factor for Alzheimer's disease (AD). Cerebral blood flow (CBF) dysfunction is an essential feature of AD, and the liver plays an important role in the pathogenesis of dementia. However, the associations of APOE4 with CBF and liver function markers in patients with cognitive impairment remains unclear. We aimed to evaluate the associations of APOE4 with CBF measured by arterial spin labeling (ASL) magnetic resonance imaging (MRI) and serum liver function markers in participants who were diagnosed with cognitive impairment. Methods: Fourteen participants with AD and sixteen with amnestic mild cognitive impairment (MCI) were recruited. In addition to providing comprehensive clinical information, all patients underwent laboratory tests and MRI. All participants were divided into carriers and noncarriers of the ε4 allele, and T-tests and Mann-Whitney U tests were used to observe the differences between APOE4 carriers and noncarriers in CBF and liver function markers. Results: Regarding regional cerebral blood flow (rCBF), APOE4 carriers showed hyperperfusion in the bilateral occipital cortex, bilateral thalamus, and left precuneus and hypoperfusion in the right lateral temporal cortex when compared with noncarriers. Regarding serum liver function markers, bilirubin levels (including total, direct, and indirect) were lower in APOE4 carriers than in noncarriers. Conclusion: APOE4 exerts a strong effect on CBF dysfunction by inheritance, representing a risk factor for AD. APOE4 may be related to bilirubin metabolism, potentially providing specific neural targets for the diagnosis and treatment of AD.

Associations of Serum Liver Function with Cerebral Blood Flow in Patients with Alzheimer's Disease.

Background: Increasing evidence suggests that both amyloid-ß metabolism disorders in the liver and cerebral hypoperfusion play an important role in the pathogenesis of Alzheimer's disease (AD). However, the relevance of liver function alterations to cerebral blood flow (CBF) of patients with AD remains unclear. Objective: We aimed to investigate the associations between liver function changes and CBF of patients with AD. Methods: We recruited 17 patients with sporadic AD. In addition to physical and neurological examinations, detection of AD biomarkers in cerebrospinal fluid by enzyme-linked immunosorbent assay and CBF assessment by arterial spin labeling sequence of magnetic resonance image scans as well as measure of liver function markers in serum by routine laboratory testing were conducted. Neuropsychological tests were evaluated, including Mini-Mental State Examination and Montreal Cognitive Assessment. Linear and rank correlations were performed to test the associations of liver function alterations with regional CBF of AD. Results: We found that liver function markers, especially total protein, the ratio of albumin to globin, globin, alkaline phosphatase, and aspartate aminotransferase were significantly associated with regional CBF of AD patients. Conclusions: These findings demonstrated significant associations between perfusion in certain brain regions of AD and alterations of liver function markers, particularly proteins and liver enzymes, which might provide implications to the pathogenesis and treatment of AD.

Association of lower liver function with cognitive impairment in the Shenzhen ageing-related disorder cohort in China.

Background: Accumulating evidence suggests that alterations in liver function may play an important role in the pathogenesis of Alzheimer's disease (AD). However, it remains unclear whether there is any relationship between lower liver function and cognitive impairment among the elderly. Methods: From 2017 to 2018, we recruited 7,201 older people (over 60 years old) from 51 community health centers in the Luohu District of Shenzhen City. According to the Mini-Mental State Examination (MMSE) score and education level, participants were divided into a cognitive impairment group (n = 372) and a normal cognitive function group (n = 6,829). Nonparametric test, chi-square tests, and binary logistic regression were used to analyze the data. Results: Cognitive impairment group exhibits older age, more female sex, lower education level, and lower levels of albumin and triglyceride. Additionally, the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio was mainly distributed in the range of 1.17 to 1.3 in the cognitive impairment group, and 0.85 to 1.00 in the normal cognitive function group (χ2 = 10.02, p = 0.04). Binary logistic regression showed that cognitive impairment was significantly associated with age (OR = 0.934, 95%CI: 0.886-0.985, p = 0.017), female sex (OR = 2.255, 95%CI: 1.761-2.888, p < 0.001), lower education level (less than senior high school) (OR = 11.509, 95%CI: 9.064-14.613, p < 0.001), and lower albumin (OR = 1.023, 95%CI: 1.004-1.043, p = 0.011). Conclusion: Except for age, female sex, and lower education level, lower level of albumin and elevated AST to ALT ratio correlate with cognitive impairment. Whether lower liver function plays a role in AD needs to be further studied.

Novel heterozygous mutation in alpha-2-macroglobulin (A2M) suppressing the binding of amyloid-ß (Aß).

Introduction: Many studies have suggested that the alpha-2-macroglobulin (A2M) gene may be involved in the pathogenesis of Alzheimer's disease (AD). A2M encoded by the A2M gene can specifically bind to the ß-amyloid peptide and prevent fiber formation. Methods: The patient in this study had progressive memory loss at the age of 60 years and underwent a series of neuropsychological tests, cranial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarker analysis, and whole-exome sequencing (WES) to evaluate possible mutations. We used in silico tools and three-dimensional (3D) protein structure prediction to analyze the pathogenicity of the mutation and used a co-immunoprecipitation experiment to study the effect of mutations on amyloid-ß (Aß) binding. Results: Based on neuropsychological tests, cranial MRI, and CSF biomarker analysis, the patient was diagnosed with AD. WES showed that there was a missense mutation in A2M (c.1229A>C, p.N410T). Bioinformatics analysis showed that this mutation was pathogenic. Moreover, 3D protein structure analysis showed that the A2M Asn410 residue was an N-glycosylation site, which was necessary for A2M activation to bind to Aß. Missense mutations led to the loss of glycosylation at this site, which suppressed the binding of Aß. The functional experiment also confirmed the prediction: the interaction between A2M and Aß from the patient's plasma was weakened. Conclusions: Our results demonstrate that this novel A2M p.N410T mutation may have a pathogenic role in AD, by altering the binding interactions between A2M and Aß.

Identification of two pathogenic mutations in SORL1 in early-onset Alzheimer's disease.

The sortilin-related receptor 1 (SORL1) gene has been the subject of many studies focusing on frequent polymorphisms, which is associated with increased risk for Alzheimer's Disease (AD). By whole-exome sequencing (WES), we identified two pathogenic missense mutations c.579C > G (p.F193L) and c.1397A > G (p.N466S) in SORL1. The two mutations were located in the same protein domain, and the two unrelated probands both had an onset of memory problems at less than 65 years of age, but their clinical manifestations and cranial imaging are different. The protein structure and function affected by these mutations were predicted using bioinformatics analysis, which suggested they were pathogenic. 3D protein structural analysis revealed that these amino acid substitutions might result in instability of protein structure and adverse intramolecular interactions. These findings suggest that both F193L and N466S should be thought as potential causative mutations in early-onset Alzheimer's disease (EOAD) patients. Further functional studies are warranted to evaluate their roles in the pathogenesis of AD.

SORL1 mutations are associated with parkinsonian and psychiatric features in Alzheimer disease: Case reports.

RATIONALE: The sortilin-related receptor 1 gene (SORL1) encodes a key protein (SORLA) involved in the pathophysiology of Alzheimer disease (AD). SORLA also mediates a trophic pathway that acts through glial cell line-derived neurotrophic factor (GDNF), a critical survival factor for the midbrain dopaminergic (DA) neurons. PATIENT CONCERNS: Four patients presented to our hospital with complaints of progressive memory decline, who developed extrapyramidal signs (EPS) and psychiatric symptoms. DIAGNOSES: All 4 patients were diagnosed with AD based on their symptoms, findings from cranial magnetic resonance imaging, and cerebrospinal fluid analysis. INTERVENTIONS: We also performed whole-exome sequencing (WES) and found 4 novel mutations in SORL1. Donepezil, rivastigmine, memantine, madopar, quetiapine, and risperidone were administrated as therapy. OUTCOMES: The four mutations would change the thermal stability of SORLA domain. This could be associated with parkinsonian and psychiatric features in AD. These patients showed improvements in parkinsonian and psychiatric features. LESSONS: These cases suggest that SORL1 mutations might result in aggregation of a-synuclein through altered function of GDNF and further lead to appearance of core dementia with Lewy bodies features.

Long-term recurrence and brain metastasis of nasopharyngeal carcinoma mimicking cystic radiation encephalopathy relapse: a case report.

BACKGROUND: During medical imaging, cystic radiation encephalopathy and brain metastasis are difficult to differentiate, and hence they are easily misdiagnosed. To our knowledge, a nasopharyngeal carcinoma recurrence after more than seven years with cerebral metastasis that mimicked cystic radiation encephalopathy has not been reported. CASE PRESENTATION: A 52-year-old man was admitted to the hospital owing to weakness of the right limb for one month, which increased in intensity for three days. He had been diagnosed with nasopharyngeal carcinoma in 2011, which was treated by radiotherapy. The patient successively developed cystic radiation encephalopathy and brain metastasis from the nasopharyngeal carcinoma, which mimicked cystic radiation encephalopathy relapse. Left frontotemporal craniotomy, surgical resection of brain metastasis, and repair of the skull base and dura were performed. Postoperative computed tomography showed that midline deviation recovered, and brain edema was reduced. CONCLUSIONS: This report is significant because brain metastasis from nasopharyngeal carcinoma can masquerade as a benign entity and cause fatal consequences. In patients presenting with cystic radiation encephalopathy, brain metastasis should be considered as a differential diagnosis.

Early-onset Alzheimer's disease may be associated with sortilin-related receptor 1 gene mutation: A family report and review.

Background: Early-onset Alzheimer's disease is a rare condition that differs from the usual memory-disordered presentation of typical Alzheimer's disease. Early-onset Alzheimer's disease is believed to have a genetic basis, and sporadic Alzheimer's disease has been associated with sortilin-related receptor 1 polymorphism. Case presentation: This report describes and discusses the family report of a 59-year-old patient with early-onset Alzheimer's disease that may have been associated with a sortilin-related receptor 1 gene mutation. The patient was hospitalized in August 2008 for gradually progressive amnesia. Brain magnetic resonance imaging showed that the patient presented with whole-brain atrophy (especially in the bilateral medial temporal lobe and hippocampus). He had an initial Mini-Mental State Examination score of 15 (time orientation: 4/5; place orientation: 4/5; language immediate memory: 2/3; attention and calculation: 1/5; delayed memory: 0/3; naming: 1/2; language retelling, understanding, and expression: 3/6; visuospatial ability: 0/1). Whole-exome sequencing showed a sortilin-related receptor 1 gene mutation, c.3575G>A (chr11:121448104), which was detected in the patient and his children. Discussion: Patients with early-onset Alzheimer's disease present with obvious deficits in language, visuospatial abilities, praxis, or other nonmemory cognitive functions. In this case, the speech, memory, and visuospatial impairment of the patient may be associated with the sortilin-related receptor 1 gene mutation. Atrophy of the bilateral medial temporal lobe/hippocampus on magnetic resonance imaging may be an important marker of early-onset Alzheimer's disease. A sortilin-related receptor 1 gene mutation, c.3575G>A (chr11:121448104), may increase the risk of Alzheimer's disease.

Berberine Protects Secondary Injury in Mice with Traumatic Brain Injury Through Anti-oxidative and Anti-inflammatory Modulation.

Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide. Novel and effective therapy is needed to prevent the secondary spread of damage beyond the initial injury. The aim of this study was to investigate whether berberine has a neuroprotective effect on secondary injury post-TBI, and to explore its potential mechanism in this protection. The mice were randomly divided into Sham-saline, TBI-saline and TBI-Berberine (50 mg/kg). TBI was induced by Feeney's weight-drop technique. Saline or berberine was administered via oral gavage starting 1 h post-TBI and continuously for 21 days. Motor coordination, spatial learning and memory were assessed using beam-walking test and Morris water maze test, respectively. Brain sections were processed for lesion volume assessment, and expression of neuronal nuclei (NeuN), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) were detected via immunohistochemistry and immunofluorescence. There were statistically significant improvement in motor coordination, spatial learning and memory in the TBI-Berberine group, compared to the TBI-saline group. Treatment with berberine significantly reduced cortical lesion volume, neuronal loss, COX-2, iNOS and 8-OHdG expression in both the cortical lesion border zone (LBZ) and ipsilateral hippocampal CA1 region (CA1), compared to TBI-saline. Berberine treatment also significantly decreased Iba1- and GFAP-positive cell number in both the cortical LBZ and ipsilateral CA1, relative to saline controls. These results indicated that berberine exerted neuroprotective effects on secondary injury in mice with TBI probably through anti-oxidative and anti-inflammatory properties.

Alpha-asarone improves striatal cholinergic function and locomotor hyperactivity in Fmr1 knockout mice.

Hyperactivity is a symptom found in several neurological and psychiatric disorders, including Fragile X syndrome (FXS). The animal model of FXS, fragile X mental retardation gene (Fmr1) knockout (KO) mouse, exhibits robust locomotor hyperactivity. Alpha (α)-asarone, a major bioactive component isolated from Acorus gramineus, has been shown in previous studies to improve various disease conditions including central nervous system disorders. In this study, we show that treatment with α-asarone alleviates locomotor hyperactivity in Fmr1 KO mice. To elucidate the mechanism underlying this improvement, we evaluated the expressions of various cholinergic markers, as well as acetylcholinesterase (AChE) activity and acetylcholine (ACh) levels, in the striatum of Fmr1 KO mice. We also analyzed the AChE-inhibitory activity of α-asarone. Striatal samples from Fmr1 KO mice showed decreased m1 muscarinic acetylcholine receptor (m1 mAChR) expression, increased AChE activity, and reduced ACh levels. Treatment with α-asarone improved m1 mAChR expression and ACh levels, and attenuated the increased AChE activity. In addition, α-asarone dose-dependently inhibited AChE activity in vitro. These results indicate that direct inhibition of AChE activity and up-regulation of m1 mAChR expression in the striatum might contribute to the beneficial effects of α-asarone on locomotor hyperactivity in Fmr1 KO mice. These findings might improve understanding of the neurobiological mechanisms responsible for locomotor hyperactivity.

ABCB1 G2677T/A polymorphism is associated with the risk of drug-resistant epilepsy in Asians.

Pharmacogenetic factors may play an important role in drug-resistant epilepsy. The association between the non-synonymous polymorphism G2677T/A in the coding region of the ABCB1 gene, and the risk of resistance to anti-epileptic drugs (AEDs) in epilepsy remains controversial. The present study used a meta-analysis approach to assess the pooled association between this polymorphism and the risk of resistance to AEDs. We used several online libraries to identify suitable studies published before September 2014, and 15 studies (n=1773 drug-resistant, and n=2250 drug-responsive epilepsy cases) were selected for our analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Subgroup analysis was performed taking into account different ethnic groups. Our results suggest that ethnicity plays a role in the association between ABCB1 G2677T/A polymorphism and drug-resistant epilepsy. We found a significant association for Asians both under the codominant model TT vs. GG (OR=1.33, 95% CI: 1.05-1.69; P=0.019), and the allele model T vs. G (OR=1.13, 95% CI: 1.01-1.27; P=0.032). However, no association was observed for Caucasians in either the TT vs. GG (OR=0.85, 95% CI: 0.61-1.18; P=0.335), or the T vs. G (OR=0.93, 95% CI: 0.78-1.09; P=0.362) models. A cumulative meta-analysis showed that these results were robust. In conclusion, our analysis indicates that ABCB1 G2677T/A polymorphism may increase the risk of drug-resistant epilepsy in Asians.

The influence of ESR1 rs9340799 and ESR2 rs1256049 polymorphisms on prostate cancer risk.

Estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) may play a role in the development of prostate cancer. Many studies focused on ESR1 rs9340799 and ESR2 rs1256049 polymorphisms to explore associations with prostate cancer risk. These studies showed inconsistent and conflicting results. The aim of this meta-analysis was to investigate the pooled association of ESR1 rs9340799 and ESR2 rs1256049 polymorphisms with prostate cancer risk. A systematic literature search was conducted to identify related studies (up to February 2014) in several online databases including PubMed, Google Scholar, CNKI and Wanfang online libraries. A total of 16 eligible articles were enrolled in this updated meta-analysis. The result suggested that ESR1 rs9340799 polymorphism was significantly associated with prostate cancer in overall populations (GG+GA vs. AA: P = 0.002; G vs. A: P = 0.004), Caucasians (GG+GA vs. AA: P = 0.008; G vs. A: P = 0.016) and Africans (GG+GA vs. AA: P = 0.005; G vs. A: P = 0.006), but not in Asians (GG+GA vs. AA: P = 0.462; G vs. A: P = 0.665). The result also showed that there was a significant association between ESR2 rs1256049 polymorphism and prostate cancer in Caucasians (AA+AG vs. GG: P = 0.016; A vs. G: P = 0.005), but no association in overall populations (AA+AG vs. GG: P = 0.826; A vs. G: P = 0.478), Asians (AA+AG vs. GG: P = 0.177; A vs. G: P = 0.703) and Africans (AA+AG vs. GG: P = 0.847; A vs. G: P = 0.707). The cumulative meta-analysis and sensitivity analysis showed the results were robust. In conclusion, this meta-analysis indicated that ESR1 rs9340799 polymorphism was associated with prostate cancer risk in overall populations, Caucasians and Africans, while ESR2 rs1256049 polymorphism was associated with prostate cancer risk in Caucasians. However, the biological mechanisms need to be further investigated.

Association between PITX3 promoter polymorphism and risk of Parkinson's disease: the impact of ethnicity and onset age.

The association between the functional SNP (rs3758549) in the promoter region of PITX3 gene and risk of Parkinson's disease (PD) remains controversial. The present study aimed at investigating the pooled association using a meta-analysis on the published studies. A total of nine studies (comprising 4054 cases and 3949 controls) which were in English before September 2013 were involved in this updated and refined meta-analysis. Subgroup analysis was performed in different ethnicity and onset age-matched groups. The results of meta-analysis suggested that the PITX3 SNP rs3758549 was significantly associated with risk of PD in the Asian population (genotype TT+TC vs. CC, P=0.014; allele T vs. C, P=0.019) but not in the Caucasian population (genotype TT+TC vs. CC, P=0.053; allele T vs. C, P=0.251). Analysis of early-onset PD (EOPD) and late-onset PD (LOPD) in the Asian population revealed that rs3758549 was more common in EOPD populations (TT+TC vs. CC, P=0.040; T vs. C, P=0.004). In conclusion, our results indicated that the SNP rs3758549 might contribute to the occurrence of PD in the Asian population, especially EOPD in the Asian population.

Serotonin hyperinnervation and upregulated 5-HT2A receptor expression and motor-stimulating function in nigrostriatal dopamine-deficient Pitx3 mutant mice.

The striatum receives serotonin (5-hydroxytryptamine, 5-HT) innervation and expresses 5-HT2A receptors (5-HT2ARs) and other 5-HT receptors, raising the possibility that the striatal 5-HT system may undergo adaptive changes after chronic severe dopamine (DA) loss and contribute to the function and dysfunction of the striatum. Here we show that in transcription factor Pitx3 gene mutant mice with a selective, severe DA loss in the dorsal striatum mimicking the DA denervation in late Parkinson's disease (PD), both the 5-HT innervation and the 5-HT2AR mRNA expression were increased in the dorsal striatum. Functionally, while having no detectable motor effect in wild type mice, the 5-HT2R agonist 2,5-dimethoxy-4-iodoamphetamine increased both the baseline and l-dopa-induced normal ambulatory and dyskinetic movements in Pitx3 mutant mice, whereas the selective 5-HT2AR blocker volinanserin had the opposite effects. These results demonstrate that Pitx3 mutant mice are a convenient and valid mouse model to study the compensatory 5-HT upregulation following the loss of the nigrostriatal DA projection and that the upregulated 5-HT2AR function in the DA deficient dorsal striatum may enhance both normal and dyskinetic movements.