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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. The pathological accumulation of tau in neurons is one of the hallmarks of AD and has been connected to the loss of dendritic spines of pyramidal cells, which are the major targets of cortical excitatory synapses and key elements in memory storage. However, the detailed mechanisms underlying the loss of dendritic spines in individuals with AD are still unclear. Here, we used graph-theory approaches to compare the distribution of dendritic spines from neurons with and without tau pathology of AD individuals. We found that the presence of tau pathology determines the loss of dendritic spines in clusters, ruling out alternative models where spine loss occurs at random locations. Since memory storage has been associated with synaptic clusters, the present results provide a new insight into the mechanisms by which tau drives synaptic damage in AD, paving the way to memory deficits through alterations of spine organization., This work was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (Grant IJCI-2016-27658 to PMS, Grant PGC2018-094307-B-I00), the Cajal Blue Brain Project (the Spanish partner of the Blue Brain Project initiative from EPFL, Switzerland) and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, CB06/05/0066, Spain). JBP is currently supported by Grants from the Swedish Research Council (#2018-02201), Hjärnfonden (#FO2019-0289), Alzheimerfonden (#AF-930827) and the Strategic Research Programme in Neuroscience at Karolinska Institutet (Stratneuro Startup Grant).

A major complication with spinal cord injury (SCI) is the development of spasticity, a clinical symptom of hyperexcitability within the spinal H-reflex pathway. We have previously demonstrated a common structural motif of dendritic spine dysgenesis associated with hyperexcitability disorders after injury or disease insults to the CNS. Here, we used an adeno-associated viral (AAV)-mediated Cre-Lox system to knockout Rac1 protein expression in motor neurons after SCI. Three weeks after AAV9-Cre delivery into the soleus/gastrocnemius of Rac1-“floxed” adult mice to retrogradely infect spinal alpha-motor neurons, we observed significant restoration of RDD and reduced H-reflex excitability in SCI animals. Additionally, viral-mediated Rac1 knockdown reduced presence of dendritic spine dysgenesis on motor neurons. In control SCI animals without Rac1 knockout, we continued to observe abnormal dendritic spine morphology associated with hyperexcitability disorder, including an increase in mature, mushroom dendritic spines, and an increase in overall spine length and spine head size. Taken together, our results demonstrate that viral-mediated disruption of Rac1 expression in ventral horn motor neurons can mitigate dendritic spine morphological correlates of neuronal hyperexcitability, and reverse hyperreflexia associated with spasticity after SCI. Finally, our findings provide evidence of a putative mechanistic relationship between motor neuron dendritic spine dysgenesis and SCI-induced spasticity.

Radiotherapy has played an important role in the treatment of spinal metastases. One of the major complications of radiotherapy is vertebral compression fracture (VCF). Although the spinal instability neoplastic score (SINS) was developed for evaluating spinal instability in patients with spinal metastases, it is also commonly used to predict VCF after radiotherapy in patients with spinal metastases. However, its accuracy for predicting radiotherapy-induced VCF and precision remain controversial. The aim of this study was to clarify the diagnostic value of the SINS to predict radiotherapy-induced VCF and to make recommendations for improving its diagnostic power. We searched core databases and identified 246 studies. Fourteen studies were analyzed, including 7 studies (with 1269 segments) for accuracy and 7 studies (with 280 patients) for precision. For accuracy, the area under the summary receiver operating characteristic curve was 0.776. When a SINS cut-off value of 7 was used, as was done in the included studies, the pooled sensitivity was 0.790 and the pooled specificity was 0.546. For precision, the summary estimate of interobserver agreement was the highest dividing 2 categories based on a cut-off value of 7, and the value was 0.788. The body collapse showed moderate relationship and precision with the VCF. The lytic tumor of bone lesion showed high accuracy and fair reliability, while location had excellent reliability, but low accuracy. The SINS system can be used to predict the occurrence of VCF after radiotherapy in spinal metastases with moderate accuracy and substantial reliability. Increasing the cut-off value and revising the domains may improve the diagnostic performance to predict the VCF of the SINS.

The central nervous system is involved in regulation of defaecation. It is generally considered that supraspinal regions control the spinal defaecation centre. However, signal transmission from supraspinal regions to the spinal defaecation centre is still unclear. In this study, we investigated the regulatory role of an anorexigenic neuropeptide, α-MSH, in the spinal defaecation centre in rats. Intrathecal administration of α-MSH to the L6-S1 spinal cord enhanced colorectal motility. The prokinetic effect of α-MSH was abolished by severing the pelvic nerves. In contrast, severing the colonic nerves or thoracic cord transection at the T4 level had no impact on the effect of α-MSH. RT-PCR analysis revealed MC1R mRNA and MC4R mRNA expression in the L6-S1 spinal cord. Intrathecally administered MC1R agonists, BMS470539 and SHU9119, mimicked the α-MSH effect, but a MC4R agonist, THIQ, had no effect. These results demonstrate that α-MSH binds to MC1R in the spinal defaecation centre and activates pelvic nerves, leading to enhancement of colorectal motility. This is, to our knowledge, the first report showing the functional role of α-MSH in the spinal cord. In conclusion, our findings suggest that α-MSH is a candidate for a neurotransmitter from supraspinal regions to the spinal defaecation centre.