Amyloid-ß mediates intestinal dysfunction and enteric neurons loss in Alzheimer's disease transgenic mouse.

Alzheimer's disease (AD) is traditionally considered as a brain disorder featured by amyloid-ß (Aß) deposition. The current study on whether pathological changes of AD extend to the enteric nervous system (ENS) is still in its infancy. In this study, we found enteric Aß deposition, intestinal dysfunction, and colonic inflammation in the young APP/PS1 mice. Moreover, these mice exhibited cholinergic and nitrergic signaling pathways damages and enteric neuronal loss. Our data show that Aß42 treatment remarkably affected the gene expression of cultured myenteric neurons and the spontaneous contraction of intestinal smooth muscles. The intra-colon administration of Aß42 induced ENS dysfunction, brain gliosis, and ß-amyloidosis-like changes in the wild-type mice. Our results suggest that ENS mirrors the neuropathology observed in AD brains, and intestinal pathological changes may represent the prodromal events, which contribute to brain pathology in AD. In summary, our findings provide new opportunities for AD early diagnosis and prevention.

Characteristics of MRI­based vertebral bone quality scores in elderly patients with vertebral fragility fractures.

OBJECTIVE: To explore the characteristics of vertebral bone quality (VBQ) scores in patients with vertebral fragility fractures, including VBQ score and single-level VBQ score, and evaluate their effectiveness as predictors. METHODS: The VBQ scores were measured using T1-weighted MRI images. VBQ scores were compared in patients with different times of previous fragility fractures. In addition, patients with fractures were matched for age and sex with patients without fractures, and VBQ scores were compared between the two groups. Finally, the predictive efficiency of VBQ scores for vertebral fragility fractures was analyzed by the receiver-operator curve (ROC). RESULTS: The average VBQ score and single-level VBQ score in patients with fractures were 3.48 ± 0.56 and 3.60 ± 0.60 and no difference among patients with different times of previous fractures. As for the age- and sex-matched patients, fracture patients had higher VBQ scores (VBQ score: 3.48 ± 0.56 vs. 2.88 ± 0.40, p < 0.001; single-level VBQ score: 3.60 ± 0.60 vs. 2.95 ± 0.44, p < 0.001). The AUCs using the VBQ score and single-level VBQ score to predict fragility fractures were 0.815 and 0.817, respectively. The optimal thresholds of the VBQ score and single-level VBQ score for predicting fragility fractures were 3.22 and 3.16, respectively. CONCLUSION: MRI­based VBQ scores are important predictors of vertebral fragility fracture but have no predictive value for the recurrence of fractures in patients with a history of fragility fractures. The VBQ score of 3.22 and single-level VBQ score of 3.16 are optimal thresholds that can be used when using lumbar MRI scans to identify individuals at high risk for fragility fractures.

Combinations of two imaging parameters to improve bone mineral density (BMD) assessment in patients with lumbar degenerative diseases.

PURPOSE: To explore whether combining the Hounsfield unit (HU) values and vertebral bone quality (VBQ) scores can improve the BMD assessment in patients with lumbar degenerative diseases. METHODS: The HU values were measured by CT image, and VBQ scores were calculated by lumbar MRI image. The correlations of the opportunistic imaging parameters to the lowest T-scores were analyzed. Receiver-operating characteristic curve (ROC) analysis was used to evaluate the accuracy in detecting osteoporosis. Finally, the specificity and sensitivity of different combined methods of the HU values and VBQ scores in the diagnosis of osteoporosis were compared. RESULTS: Patients with osteoporosis had the lowest HU values and the highest VBQ scores. The correlation coefficients between the VBQ scores and the T-scores were smaller than HU values (L1 HU value: 0.702; average HU value:0.700; L1 VBQ score: -0.413; VBQ score: -0.386). The areas under the curve (AUCs) of the HU values were greater than those of the VBQ scores, and the AUCs of the L1 VBQ score were similar to the VBQ score (L1 HU value: 0.850; average HU value:0.857; L1 VBQ score: 0.704; VBQ score: 0.673). When combining the two imaging parameters in series, the specificity of the detection of osteoporosis was improved (L1 HU value and L1 VBQ score: 87.3%; Average HU value and VBQ score: 85.9%). When combining the two imaging parameters in parallel, the sensitivity of the detection of osteoporosis was improved (L1 HU value or L1 VBQ score: 88.1%; Average HU value or VBQ score: 91.5%). CONCLUSIONS: Combinations of the HU values and VBQ scores could improve the diagnostic performance of osteoporosis. In addition, considering the same diagnostic performance but easier measurement, parameters at the single-segment level were recommended to assist in the diagnosis of osteoporosis.

Selective Degeneration of Entorhinal-CA1 Synapses in Alzheimer's Disease via Activation of DAPK1.

Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1PV) and undergo selective degeneration in the early stages of Alzheimer's disease (AD). Here, we show that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PV synaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECIIPN contributes to a memory loss in AD and hence warrants a promising target for the treatment of AD. SIGNIFICANCE STATEMENT: Our recent study reported that excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) target to CA1 parvalbumin-type inhibitory neurons (CA1PV) at a direct pathway and are one of the most vulnerable brain cells that are selectively degenerated in the early stage of Alzheimer's disease (AD). Our present study shows that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PV synaptic loss and improves spatial learning and memory in the early stage of AD. These data not only demonstrate a crucial molecular event for synaptic degeneration but also provide a therapeutic target for the treatment of AD.

MRI­based vertebral bone quality score is a comprehensive index reflecting the quality of bone and paravertebral muscle.

BACKGROUND: Recently, vertebral bone quality (VBQ) score has been shown to predict bone mineral density (BMD) and spine-related postoperative complications. However, in clinical work, we found that patients with higher VBQ scores also had more severe paravertebral muscle degeneration. PURPOSE: To explore the ability of the VBQ score to evaluate BMD and paravertebral muscle quality. STUDY DESIGN/SETTING: Retrospective single-center cohort. PATIENT SAMPLE: Patients in the spinal surgery department of our hospital. OUTCOME MEASURES: Bone mineral density and T-score were measured by dual-energy X-ray absorptiometry (DXA). The Picture Archiving and Communication Systems (PACS) measured the cross-sectional area (CSA) of the paravertebral muscles. Image J software was used to measure the degree of fat infiltration (DFF) of the paraspinal muscle. METHODS: Patients who underwent lumbar MRI and DXA simultaneously within two weeks were enrolled. The VBQ score was calculated using T1-weighted lumbar MRI images. Firstly, BMD-related and muscle-related parameters of patients with different VBQ scores were compared. Then, the correlation coefficients between the VBQ score and the parameters of BMD and paravertebral muscle were calculated. Finally, multivariate linear analysis was used to compare the contribution of each variable to the VBQ score. RESULTS: A total of 101 patients were eventually included in this study for analysis. When the VBQ score was greater than 3.0, the patients were mostly female, older, less likely to smoke, and had lower BMD. Interestingly, we found that patients with VBQ scores greater than 3.0 had smaller CSA of the paravertebral muscles (ES: 17.53±3.36 vs 19.13±3.97, p=.032; total: 29.59±5.27 vs 34.12±7.02, p<.001) and higher DFF (MF: 22.47±5.93 vs 19.64±5.28, p=.015; ES: 17.71±4.67 vs 15.74±4.62, p=.038; PM: 13.70±3.32 vs 11.33±3.02, p<.001; average: 17.96±3.78 vs 15.57±3.42, p=.001). The VBQ score was negatively correlated with the CSA (MF: r=-0.316, p=.001; ES: r =-0.388, p=.001; PM: r=0.388, p=.001) and positively correlated with the DFF (MF: r=0.344, p<.001; ES: r=0.439, p<.001; PM: =0.416, p<.001). In multivariate linear analysis, BMD, total CSA, and average DFF determined the value of the VBQ score, and the contribution of paravertebral muscle was higher than that of BMD (BMD: r=-0.203, p=.024; total CSA: r=-0.294, p=.003; average DFF: r=0.261, p=.011). CONCLUSIONS: This study is the first to find a positive association between the VBQ score and paravertebral muscle degeneration, and this association may be independent of BMD. VBQ can reflect the quality of bone and paravertebral muscle, which is its special advantage in clinical application.

Sex differences in the accuracy of vertebral bone quality score assessing bone density in patients undergoing lumbar spinal fusion.

OBJECTIVE: Low bone mineral density (BMD) significantly increases the risk of complications in patients undergoing spinal fusion. Existing evidence indicates that traditional dual-energy x-ray absorptiometry (DEXA) and quantitative CT (QCT) screening are underutilized in spine surgery. The MRI-based vertebral bone quality (VBQ) score provides a tool for primary screening of bone density. The validity of this score as a predictor across sexes has not been investigated. This study aimed to explore the effect of sex on the diagnostic efficacy of the VBQ in predicting osteopenia/osteoporosis and whether a sex-specific threshold exists. METHODS: In this retrospective cohort study, patients who underwent lumbar fusion at a tertiary care center were reviewed. VBQ was obtained by noncontrast T1-weighted MRI. Patients were stratified according to sex and bone density. Data were analyzed between the groups. Pearson correlation analysis and linear regression were used to analyze the correlation between the VBQ and DEXA T values. Receiver operating characteristic (ROC) curve analysis, including area under the curve (AUC) calculation, was used to evaluate the predictive performance of VBQ for low BMD in both sexes. RESULTS: A total of 271 patients (92 male, 179 female patients) were analyzed. The correlation coefficient between VBQ and the lowest T value was -0.40 for male and -0.554 for female patients. In comparing the bone density subgroups, among male patients a significant difference in the VBQ scores was observed only between the normal and osteoporosis subgroups (p = 0.012). VBQ demonstrated statistically significant differences among female patients across all three subgroups (p < 0.001). The ROC analysis revealed that the predictive performance of VBQ in detecting low BMD was more consistent with the gold-standard DEXA results in female than in male patients (AUC 0.647 vs AUC 0.823, p = 0.02). The optimal thresholds were similar in both sexes. CONCLUSIONS: Compared with male patients, VBQ has better discrimination between female patients with low BMD and those with normal bone density. Although the correlation between VBQ and bone density is weaker in male than in female patients, the optimal thresholds are similar in both sexes.

Predictive value of different site-specific MRI-based assessments of bone quality for cage subsidence among patients undergoing oblique lumbar interbody fusion.

OBJECTIVE: The aim of this study was to investigate the predictive value of different site-specific MRI-based assessments of bone quality for cage subsidence among patients undergoing oblique lumbar interbody fusion (OLIF) with or without posterior internal fixation. METHODS: The authors retrospectively reviewed the records of patients who underwent OLIF between 2017 and 2022. Endplate bone quality (EBQ), mean vertebral bone quality (MVBQ), and vertebral bone quality (VBQ) scores were measured using preoperative non-contrast-enhanced T1-weighted MRI of the lumbar spine. Logistic regression analysis was used to identify factors associated with cage subsidence. Receiver operating characteristic curve analysis was used to evaluate the value of different site-specific MRI-based assessments of bone quality in predicting cage subsidence. RESULTS: Of the 124 patients who underwent OLIF, subsidence was found in 42 (33.9%). The VBQ, MVBQ, and EBQ scores were higher in the subsidence group than in the no-subsidence group. In the stand-alone OLIF (SA-OLIF) group, logistic regression analysis showed that the EBQ score was significantly associated with subsidence (OR 13.656, 95% CI 2.561-72.806; p = 0.002). Furthermore, the areas under the curve (AUCs) for using the VBQ, MVBQ, and EBQ scores and T-score to predict cage subsidence were 0.684, 0.683, 0.745, and 0.685, respectively. In the OLIF with posterior internal fixation (OLIF-PF) group, logistic regression analysis showed that the MVBQ score was significantly associated with subsidence (OR 8.301, 95% CI 2.064-33.385; p = 0.003). The AUCs for using the VBQ score, MVBQ score, and T-score to predict cage subsidence were 0.757, 0.774, and 0.685, respectively. CONCLUSIONS: There are significant differences in the predictive value of different site-specific bone quality assessments for cage subsidence among patients undergoing OLIF. For SA-OLIF, the EBQ score is recommended, while for OLIF-PF, the VBQ score is preferable.

Vertebral Bone Quality Score as a Predictor of Pedicle Screw Loosening Following Surgery for Degenerative Lumbar Disease.

STUDY DESIGN: Retrospective study. OBJECTIVE: To investigate whether magnetic resonance imaging-based vertebral bone quality (VBQ) score can predict pedicle screw loosening in patients who underwent pedicle screw fixation, and to compare, which measurement, the VBQ score or the Hounsfield unit (HU) value, is more predictive of pedicle screw loosening. SUMMARY OF BACKGROUND DATA: In clinical work, we found that patients with screw loosening had higher VBQ scores. In addition, some studies have found a correlation between VBQ scores and osteoporosis. PATIENTS AND METHODS: Patients who were treated with lumbar pedicle screw fixation were reviewed. The VBQ score was measured using magnetic resonance imaging scans. The HU value for L1 to L4 lumbar bone mineral density was measured with computed tomography scans. Logistic regression analysis was used to identify factors associated with pedicle screw loosening. Receiver-operating characteristic curve analysis was used to evaluate the value of VBQ scores in predicting pedicle screw loosening. RESULTS: A total of 156 patients were included in the final analysis. The pedicle screw loosening rate was 35% (55 of 156 patients). The postoperative low-back pain visual analog scale score was higher in the loosening group (3.0 ± 2.0 vs . 2.4 ± 1.8; P < 0.05). The VBQ score was higher in the loosening group than in the nonloosening group (3.28 ± 0.58 vs . 2.82 ± 0.50; P < 0.01). In multivariable analysis, nonsingle segment fixation [odds ratio (OR): 3.992; 95% CI: 1.643-9.701; P = 0.002], lowest instrumented vertebrae at S1 (OR: 3.378; 95% CI: 1.387-8.226; P = 0.007), HU value (OR: 0.988; 95% CI: 0.976-1.000; P = 0.047), and VBQ score (OR: 3.908; 95% CI: 1.624-9.405; P = 0.002) were factors associated with screw loosening. The areas under the curve for using the VBQ score and HU value to predict pedicle screw loosening were 0.720 and 0.702, respectively. The optimal VBQ score threshold was 3.05 for predicting pedicle screw loosening (sensitivity: 0.655; specificity: 0.713). CONCLUSIONS: The VBQ score was an influential factor associated with lumbar pedicle screw loosening, and a higher VBQ score was significantly correlated with a higher risk of screw loosening. The VBQ score was a better predictor of pedicle screw loosening than the HU value in patients who underwent pedicle screw fixation for degenerative lumbar disease.

Genetic Mutation of GluN2B Protects Brain Cells Against Stroke Damages.

Immediately following ischemia, glutamate accumulates in the extracellular space and results in extensive stimulation of its receptors including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. A large amount of Ca2+ influx directly through the receptor-gated ion channels which leads to Ca2+ overload and triggers several downstream lethal reactions. As a result, cell dies via apoptosis or necrosis, or both. Death-associated protein kinase 1 (DAPK1) physically and functionally interacts with the NMDA receptor GluN2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. The goal of this study is to explore an effective strategy in the treatment of stroke with a molecular genetic manipulation to interrupt DAPK1-GluN2B interaction. We generated a mutant strain of mice with the conditional deletion of GluN2B C-terminal tail consisting of amino acids 886-1269 in the forebrain excitatory neurons (the GluN2B mutant mice) and tested the protective effects of this mutation in stroke damages. GluN2B mutation effectively disrupted the DAPK1-GluN2B interaction and inhibited extra-synaptic NMDA receptor currents without affecting synaptic NMDA receptor channel activity in the central neurons. GluN2B mutation protected against stroke damages both in vitro and in vivo and hence improved behavioral performance. Disruption of the DAPK1-GluN2B interaction is therapeutically effective against stroke damages.

The Lesion Analysis of Cholinergic Neurons in 5XFAD Mouse Model in the Three-Dimensional Level of Whole Brain.

Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer's disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole-brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9 months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15 months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain.

Expression of BC1 Impairs Spatial Learning and Memory in Alzheimer's Disease Via APP Translation.

Aggregation of amyloid-ß (Aß) peptides, which are the cleavage products of amyloid precursor protein (APP), is a major pathological hallmark in the brain of Alzheimer's disease (AD). Now, we know little about the roles of APP translation in the disease progression of AD. Here, we show that BC1, a long noncoding RNA (lncRNA), is expressed in the brain of AD mice. BC1 induces APP mRNA translation via association with a fragile X syndrome protein (FMRP). Inhibition of BC1 or BC1-FMRP association in AD mice blocks aggregation of Aß in the brain and protects against the spatial learning and memory deficits. Expression of exogenous BC1 in excitatory pyramidal neurons of mice induces Aß peptides accumulation and the spatial learning and memory impairments. This study provides a novel mechanism underlying aggregation of Aß peptides via BC1 induction of APP mRNA translation and hence warrants a promising target for AD therapy.

Impairments of spatial memory in an Alzheimer's disease model via degeneration of hippocampal cholinergic synapses.

Choline acetyltransferase neurons in the vertical diagonal band of Broca (vChATs) degenerate in the early stage of Alzheimer's disease (AD). Here, we report that vChATs directly innervate newly generated immature neurons (NGIs) in the dorsal hippocampus (dNGIs) of adult mice and regulate both the dNGIs survival and spatial pattern separation. In a mouse model that exhibits amyloid-ß plaques similar to AD patients, cholinergic synaptic transmission, dNGI survival and spatial pattern separation are impaired. Activation of vChATs with theta burst stimulation (TBS) that alleviates the decay in cholinergic synaptic transmission effectively protects against spatial pattern separation impairments in the AD mice and this protection was completely abolished by inhibiting the dNGIs survival. Thus, the impairments of pattern separation-associated spatial memory in AD mice are in part caused by degeneration of cholinergic synaptic transmission that modulates the dNGIs survival.

Infralimbic Endothelin1 Is Critical for the Modulation of Anxiety-Like Behaviors.

Endothelin1 (ET1) is a potent vasoconstrictor that is also known to be a neuropeptide that is involved in neural circuits. We examined the role of ET1 that has been implicated in the anxiogenic process. We found that infusing ET1 into the IL cortex increased anxiety-like behaviors. The ET(A) receptor (ET(A)R) antagonist (BQ123) but not the ET(B) receptor (ET(B)R) antagonist (BQ788) alleviated ET1-induced anxiety. ET1 had no effect on GABAergic neurotransmission or NMDA receptor (NMDAR)-mediated neurotransmission, but increased AMPA receptor (AMPAR)-mediated excitatory synaptic transmission. The changes in AMPAR-mediated excitatory postsynaptic currents were due to presynaptic mechanisms. Finally, we found that the AMPAR antagonists (CNQX) and BQ123 reversed ET1's anxiogenic effect, with parallel and corresponding electrophysiological changes. Moreover, infusing CNQX + BQ123 into the IL had no additional anxiolytic effect compared to CNQX treatment alone. Altogether, our findings establish a previously unknown anxiogenic action of ET1 in the IL cortex. AMPAR-mediated glutamatergic neurotransmission may underlie the mechanism of ET1-ET(A)R signaling pathway in the regulation of anxiety.

Post-stroke depression and lesion location: a systematic review.

Post-stroke depression (PSD) is a frequent problem in stroke rehabilitation. Several studies have evaluated association between the lesion location and the risk of depression. Different conclusions and contradictory findings have been published. The aim of the present study was to perform a systematic meta-analysis to evaluate the relationship between PSD and lesion location. We researched PubMed, ISI Web of Science, EMBASE, and systematically reviewed available publications reporting investigations on stroke location and risk of PSD. Subgroup analyses were performed according to the time since stroke onset to assessment for PSD or the source of patients. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used for pooled analyses. Heterogeneity was assessed with Cochran's Q test and I (2) test. Begg's funnel plot and Egger's test were used to examine the publication bias. A total of 43 studies involving 5,507 patients suffering from stroke were included in this meta-analysis. The pooled OR with 95 % CI for the overall association of stroke location and depression risk was 0.99 (0.88-1.11). Subgroups analyses highlighted that only studies with subacute post-stroke group (1-6 months) showed a statistical association between right hemisphere stroke and risk of depression (OR = 0.79, 95 % CI 0.66-0.93). This systematic review offered no support for the hypothesis that lesion of the left hemisphere was associated with an increased risk of depression after stroke. We only find significant association between right hemisphere stroke and incidence of depression for studies within subacute post-stroke phase.

Improved isolation of good-quality total RNA from the optic stalk of mud crab, scylla paramamosain

An improved and efficient protocol was developed based on the TaKaRa RNAiso Plus Kit (Code: D9108A) for isolating good-quality total RNA from the optic stalk of mud crab, Scylla paramamosain. The protocol was based on the Trizol method with modifications. The carapace overlapping the optic stalk was retained with RNA in regular protocol. In order to remove the abundant deposition correlative with the carapace which makes the isolation of RNA particularly difficult, 5M potassium acetate solution (pH = 6.0) was added before the precipitation of RNA, and the temperature of RNA deposition was also decreased to -70ºC to ensure the stabilization of RNA. Good-quality total RNA from the optic stalk of S. paramamosain could be easily isolated with this modified protocol and three conventional methods were also employed to confirm the quality of RNA. This improved method would be helpful in facilitating molecular research of crabs involving RNA from the optic stalk.