Magnesium is an essential nutrient involved in a wide range of physiological activities to maintain normal brain functions. So far, magnesium has been recognized as a cofactor for over 600 enzymatic reactions within the body. Importantly, magnesium deficiency has been implicated in the pathogenesis of various dementia-related diseases containing cardiovascular diseases and Alzheimer’s disease (AD). With increased aging, the incidence and prevalence of dementia are expected to rise dramatically double every 20 years worldwide. Accumulating evidence indicates that dementia-related diseases are associated with low magnesium levels, and dietary magnesium intake can improve cognitive function. Many studies have revealed that magnesium ions act as a natural Ca2+ blocker to inhibit calcium overload and halt the course of AD by blocking N-methyl-D-aspartate receptors and thus inhibiting neuronal overactivation. In addition, magnesium ions can inhibit glial cell-mediated neuroinflammation by down-regulating pro-inflammatory cytokines and oxidative stress, which have been implicated in the development of chronic age-related diseases. Thus, magnesium may be a target for the prevention and treatment of neurological diseases. Taken together, maintaining an optimal magnesium balance may help in the prevention of cognitive decline and dementia. In this review, we summarize our current understanding of the role of magnesium in dementia, highlighting recent progresses in the field.

Dementia causes a substantial global economic burden, but effective treatment is lacking. Recently, studies have revealed that gamma-band waves of electrical brain activity, particularly 40 Hz oscillations, are closely associated with high-order cognitive functions and can activate microglia to clear amyloid-β deposition. Here, we found that compared with sham stimulation, applying 40-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) over the bilateral angular gyrus in patients with probable Alzheimer's disease (AD; n = 37) resulted in up to 8 weeks of significantly improved cognitive function. Power spectral density analysis of the resting-state electroencephalography (EEG) demonstrated that 40-Hz rTMS modulated gamma-band oscillations in the left posterior temporoparietal region. Further testing with magnetic resonance imaging and TMS-EEG revealed the following: 40-Hz rTMS 1) prevented gray matter volume loss, 2) enhanced local functional integration within bilateral angular gyrus, as well as global functional integration in bilateral angular gyrus and the left middle frontal gyrus, 3) strengthened information flow from the left posterior temporoparietal region to the frontal areas and strengthened the dynamic connectivity between anterior and posterior brain regions. These findings demonstrate that modulating gamma-band oscillations effectively improves cognitive function in patients with probable AD by promoting local, long-range, and dynamic connectivity within the brain.

During duration spaceflight, or after their return to earth, astronauts have often suffered from gait instability and cerebellar ataxia. Here, we use a mouse model of hindlimb unloading (HU) to explore a mechanism of how reduced hindlimb burden may contribute to motor deficits. The results showed that these mice which have experienced HU for 2 weeks exhibit a rapid accumulation of formaldehyde in the gastrocnemius muscle and fastigial nucleus of cerebellum. The activation of semicarbazide-sensitive amine oxidase and sarcosine dehydrogenase induced by HU-stress contributed to formaldehyde generation and loss of the abilities to maintain balance and coordinate motor activities. Further, knockout of formaldehyde dehydrogenase (FDH-/-) in mice caused formaldehyde accumulation in the muscle and cerebellum that was associated with motor deficits. Remarkably, formaldehyde injection into the gastrocnemius muscle led to gait instability; especially, microinfusion of formaldehyde into the fastigial nucleus directly induced the same symptoms as HU-induced acute ataxia. Hence, excessive formaldehyde damages motor functions of the muscle and cerebellum.

The primordial small gaseous molecules, such as: NO, CO, H2S and formaldehyde (FA) are present in the brains. Whether FA as well as the other molecules participates in brain functions is unclear. Recently, its pathophysiological functions have been investigated. Notably, under physiological conditions, learning activity induces a transient generation of hippocampal FA, which promotes memory formation by enhancing N-methyl-D-aspartate (NMDA)-currents. However, ageing leads to FA accumulation in brain for the dysregulation of FA metabolism; and excessive FA directly impairs memory by inhibiting NMDA-receptor. Especially, in Alzheimer's disease (AD), amyloid-beta (Aβ) accelerates FA accumulation by inactivating alcohol dehydrogenase-5; in turn, FA promotes Aβ oligomerization, fibrillation and tau hyperphosphorylation. Hence, there is a vicious circle encompassing Aβ assembly and FA generation. Even worse, FA induces Aβ deposition in the extracellular space (ECS), which blocks the medicines (dissolved in the interstitial fluid) flowing into the damaged neurons in the deep cortex. However, phototherapy destroys Aβ deposits in the ECS and restores ISF flow. Coenzyme Q10, which scavenges FA, was shown to ameliorate Aβ-induced AD pathological phenotypes, thus suggesting a causative relation between FA toxicity and AD. These findings suggest that the combination of these two methods is a promising strategy for treating AD.

The integrity of myelination is crucial for maintaining brain interstitial fluid (ISF) drainage in adults; however, the mechanism of ISF drainage with immature myelin in the developing brain remains unknown. In the present study, the ISF drainage from the caudate nucleus (Cn) to the ipsilateral cortex was studied at different developmental stages of the rat brain (P 10, 20, 30, 40, 60, 80, 10-80). The results show that the traced ISF drained to the cortex from Cn and to the thalamus in an opposite direction before P30. From P40, we found impeded drainage to the thalamus due to myelin maturation. This altered drainage was accompanied by enhanced cognitive and social functions, which were consistent with those in the adult rats. A significant difference in diffusion parameters was also demonstrated between the extracellular space (ECS) before and after P30. The present study revealed the alteration of ISF drainage regulated by myelin at different stages during development, indicating that a regional ISF homeostasis may be essential for mature psychological and cognitive functions.

Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown. Herein, effects of the inhalational isoflurane, intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters' interstitial fluid drainage and extracellular space and underlying mechanisms were investigated. When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium, inhalational isoflurane induced a restricted diffusion of extracellular space, a decreased extracellular space volume fraction, and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage. A local administration of norepinephrine receptor antagonists, propranolol, atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage. These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage, which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.

This review summarizes recent progress of the anti-inflammatory effect of traditional Chinese medicine on neurocognitive disorders caused by Alzheimer's disease (AD) and Parkinson's disease (PD), and discusses some novel molecular mechanisms of traditional Chinese medicine (such as Xylocoside G, Formononetin, Honokiol, Sodium oligomannate and safflower flavonoid extract), including the regulation on A beta generation and aggregation, tau phosphorylation, gut-brain axis and gut microbiota, autophagy, microglia polarization, extracellular space, neurogenesis and neurotransmission, for the treatment of AD and PD related neurocognitive disorders.

The drainage of brain interstitial fluid (ISF) has been observed to slow down following neuronal excitation, although the mechanism underlying this phenomenon is yet to be elucidated. In searching for the changes in the brain extracellular space (ECS) induced by electrical pain stimuli in the rat thalamus, significantly decreased effective diffusion coefficient (DECS) and volume fraction (α) of the brain ECS were shown, accompanied by the slowdown of ISF drainage. The morphological basis for structural changes in the brain ECS was local spatial deformation of astrocyte foot processes following neuronal excitation. We further studied aquaporin-4 gene (APQ4) knockout rats in which the changes of the brain ECS structure were reversed and found that the slowed DECS and ISF drainage persisted, confirming that the down-regulation of ISF drainage following neuronal excitation was mainly attributable to the release of neurotransmitters rather than to structural changes of the brain ECS. Meanwhile, the dynamic changes in the DECS were synchronized with the release and elimination processes of neurotransmitters following neuronal excitation. In conclusion, the downregulation of ISF drainage following neuronal excitation was found to be caused by the restricted diffusion in the brain ECS, and DECS mapping may be used to track the neuronal activity in the deep brain.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

AbstractIntroductionPharmacological therapies to treat Alzheimer's disease (AD) targeting “Aβ” have failed for over 100 years. Low levels of laser light can disassemble Aβ. In this study, we investigated the mechanisms that Aβ‐blocked extracellular space (ECS) induces memory disorders in APP/PS1 transgenic mice and addressed whether red light (RL) at 630 nm rescues cognitive decline by reducing Aβ‐disturbed flow of interstitial fluid (ISF).MethodsWe compared the heating effects on the brains of rats illuminated with laser light at 630, 680, and 810 nm for 40 minutes, respectively. Then, a light‐emitting diode with red light at 630 nm (LED‐RL) was selected to illuminate AD mice. The changes in the structure of ECS in the cortex were examined by fluorescent double labeling. The volumes of ECS and flow speed of ISF were quantified by magnetic resonance imaging. Spatial memory behaviors in mice were evaluated by the Morris water maze. Then, the brains were sampled for biochemical analysis.ResultsRL at 630 nm had the least heating effects than other wavelengths associated with ~49% penetration ratio into the brains. For the molecular mechanisms, Aβ could induce formaldehyde (FA) accumulation by inactivating FA dehydrogenase. Unexpectedly, in turn, FA accelerated Aβ deposition in the ECS. However, LED‐RL treatment not only directly destroyed Aβ assembly in vitro and in vivo but also activated FA dehydrogenase to degrade FA and attenuated FA‐facilitated Aβ aggregation. Subsequently, LED‐RL markedly smashed Aβ deposition in the ECS, recovered the flow of ISF, and rescued cognitive functions in AD mice.DiscussionAβ‐obstructed ISF flow is the direct reason for the failure of the developed medicine delivery from superficial into the deep brain in the treatment of AD. The phototherapy of LED‐RL improves memory by reducing Aβ‐blocked ECS and suggests that it is a promising noninvasive approach to treat AD.

In searching for the drainage route of the interstitial fluid (ISF) in the deep brain, we discovered a regionalized ISF drainage system as well as a new function of myelin in regulating the drainage. The traced ISF from the caudate nucleus drained to the ipsilateral cortex along myelin fiber tracts, while in the opposite direction, its movement to the adjacent thalamus was completely impeded by a barrier structure, which was identified as the converged, compact myelin fascicle. The regulating and the barrier effects of myelin were unchanged in AQP4-knockout rats but were impaired as the integrity of boundary structure of drainage system was destroyed in a demyelinated rat model. We thus proposed that the brain homeostasis was maintained within each ISF drainage division locally, rather than across the brain as a whole. A new brain division system and a new pathogenic mechanism of demyelination are therefore proposed.

Gaseous formaldehyde is an organic small molecule formed in the early stages of earth’s evolution. Although toxic in high concentrations, formaldehyde plays an important role in cellular metabolism and, unexpectedly, is found even in the healthy brain. However, its pathophysiological functions in the brain are unknown. Here, we report that under physiological conditions, spatial learning activity elicits rapid formaldehyde generation from mitochondrial sarcosine dehydrogenase (SARDH). We find that elevated formaldehyde levels facilitate spatial memory formation by enhancing N-methyl-D-aspartate (NMDA) currents via the C232 residue of the NMDA receptor, but that high formaldehyde concentrations gradually inactivate the receptor by cross-linking NR1 subunits to NR2B. We also report that in mice with aldehyde dehydrogenase-2 ( ALDH2 ) knockout, formaldehyde accumulation due to hypofunctional ALDH2 impairs memory, consistent with observations of Alzheimerʼs disease patients. We also find that formaldehyde deficiency caused by mutation of the mitochondrial SARDH gene in children with sarcosinemia or in mice with Sardh deletion leads to cognitive deficits. Hence, we conclude that endogenous formaldehyde regulates learning and memory via the NMDA receptor.

帕金森病(PD)是一种常见的神经系统变性疾病,其致病因素除细胞功能紊乱及有毒物质作用外,细胞外微环境异常也逐渐受到关注,与此相关的前沿治疗方法主要包括对流增强给药和简单扩散给药,尤其后者的高效性及安全性已在多项研究中得到证实.现以脑间质治疗手段为基础,重点介绍国内学者研发的简单扩散给药在PD治疗领域的全新应用.

Substances transportation in the brain extracellular space (ECS) is crucial to maintain brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substances transportation in the ECS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized by magnetic resonance imaging (MRI). We first observed the ISF flow in the thalamus and caudate nucleus of rats. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the ISF flow slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion in the ECS. This observation suggests that the substances transportation in the ECS can be regulated by a selective external stimulation.

Prolonged exposure to inhaled anesthetics may lead to postoperative cognitive dysfunction (POCD). Nevertheless, the underlying mechanisms are not known. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) and its target gene vascular endothelial growth factor (VEGF) were shown to be activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1 alpha in isoflurane-induced blood brain barrier (BBB) disruption and resultant cognitive impairment. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in vascular permeability, and disrupted BBB ultrastructure were accompanied by the degradation of tight junction proteins occludin and collagen type IV in brain blood vessels. Increases in HIF-1 alpha and VEGF proteins and activation of MMP-2 in the hippocampus were also observed in the hippocamp of isoflurane-exposed rats compared with control rats. Pharmacological inhibition of HIF-1 alpha activation by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) markedly suppressed the expression of HIF-1 alpha, VEGF and MMP-2, and mitigated the severity of BBB disruption.YC-1 pretreatment also significantly attenuated isoflurane-induced cognitive deficits in the Morris water maze task. Overall, our results demonstrate that hippocampal HIF-1 alpha/VEGF signaling seems to be the upstream mechanism of isoflurane-induced cognitive impairment, and provides apotential preventive and therapeutic target for POCD.

Alzheimer's disease(AD) is a progressive neurodegenerative disorder that affects the elderly. Clinical studies have found that the amyloid deposits in the brain are aggravated along with the deterioration of the AD pathology. Indeed,Aβ peptides change particularly significantly early in the preclinical stage,and then detection of Aβ is of great importance in early diagnosis. Therefore,it is critical to diagnose and treat AD at the preclinical stage,and Aβ becomes the key target of international research. We also focus on risk factors for preclinical Alzheimer's disease,especially imbalance in lipid metabolism. Our current study presented a novel model with early onset of cognitive dysfunction by phospholipid transfer protein(PLTP) deficiency in APP/PS1ΔE9 mice without appearance of amyloid deposition. Dysfunction of PLTP might be a risk factor for the elevated Aβ in the preclinical stage of AD. We first found several potential functions of PLTP deficiency in the AD model mice:impairing cognitive performance;involvement in APP trafficking/processing and intracellular Aβ generation;inducing Aβ42 related alteration of BDNF. These established PLTP deficient AD mouse models could provide insights to early stages in AD like mild cognitive impairment(MCI) or preclinical AD(PCAD). Lipoprotein lipase(LPL) is expressed at high levels in hippocampal neurons,although its function is unclear. Lipoprotein lipase(LPL) is expressed at high levels in hippocampal neurons, although its function is unclear. We previously reported that LPL-deficient mice have learning and memory impairment and fewer synaptic vesicles in hippocampal neurons,but properties of synaptic activity in LPL-deficient neurons remain unexplored. In this study,we found reduced frequency of miniature excitatory postsynaptic currents(mEPSCs) and readily releasable pool(RRP) size in LPL-deficient neurons,which led to presynaptic dysfunction and plasticity impairment without altering postsynaptic activity. We demonstrated that synaptic vesicle recycling,which is known to play an important role in maintaining the RRP size in active synapses,is impaired in LPL-deficient neurons. Moreover,lipid assay revealed deficient docosahexaenoic acid(DHA) and arachidonic acid(AA) in the hippocampus of LPL-deficient mice;exogenous DHA or AA supplement partially restored synaptic vesicle recycling capability. These results suggest that impaired synaptic vesicle recycling results from defi cient DHA and AA and contributes to the presynaptic dysfunction and plasticity impairment in LPL-defi cient neurons. Accumulating evidence supported thatα-synuclein(α-syn) and ubiquitin C-terminal hydrolase L1(UCHL1) are required for normal synaptic and cognitive function. In this study,we found thatα-syn aggregated and the expression of UCHL1 decreased in the brain of LPL defi cient mice. Reduction of UCHL1 was resulted from nuclear retention of DNA cytosine-5-methyltransferase 1 in LPL knockout mice. Reverse changes were found in cultured cells overexpressing LPL. Furthermore,defi ciency of LPL increased ubiquitination ofα-syn. These results indicated that aggregation ofα-syn and reduction of UCHL1 expression in LPL-defi cient mice may affect synaptic function.

BACKGROUND AND PURPOSE:We aimed to evaluate the efficacy of remote ischemic conditioning (RIC) in patients with cerebral small-vessel disease. METHODS:Thirty patients with cerebral small-vessel disease-related mild cognitive impairment were enrolled in this prospective, randomized controlled study for 1 year. Besides routine medical treatment, participants were randomized into the experimental group (n=14) undergoing 5 cycles consisting of ischemia followed by reperfusion for 5 minutes on both upper limbs twice daily for 1 year or the control group (n=16) who were treated with sham ischemia-reperfusion cycles. The primary outcome was the change of brain lesions, and secondary outcomes were changes of cognitive function, plasma biomarkers, and cerebral hemodynamic parameters both at baseline and at the end of 1-year follow-up. RESULTS:Compared with pretreatment, the post-treatment white matter hyperintensities volume in the RIC group was significantly reduced (9.10±7.42 versus 6.46±6.05 cm3; P=0.020), whereas no significant difference was observed in the sham-RIC group (8.99±6.81 versus 8.07±6.56 cm3; P=0.085). The reduction of white matter hyperintensities volume in the RIC group was more substantial than that in sham group (-2.632 versus -0.935 cm3; P=0.049). No significant difference was found in the change of the number of lacunes between 2 groups (0 versus 0; P=0.694). A significant treatment difference at 1 year on visuospatial and executive ability was found between the 2 groups (0.639 versus 0.191; P=0.048). RIC showed greater effects compared with sham-RIC on plasma triglyceride (-0.433 versus 0.236 mmol/L; P=0.005), total cholesterol (-0.975 versus 0.134 mmol/L; P<0.001), low-density lipoprotein (-0.645 versus -0.029 mmol/L; P=0.034), and homocysteine (-4.737 versus -1.679 µmol/L; P=0.044). Changes of the pulsation indices of middle cerebral arteries from the baseline to 1 year were different between the 2 groups (right: -0.075 versus 0.043; P=0.030; left: -0.085 versus 0.043; P=0.010). CONCLUSIONS:RIC seems to be potentially effective in patients with cerebral small-vessel disease in slowing cognition decline and reducing white matter hyperintensities. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01658306.

动力蛋白激活蛋白 dynactin 参与调控神经元内大分子、囊泡、细胞器的定位和转运，以及逆向轴突运输，对维持神经元的功能和存活至关重要。 p150glued 是 dynactin 最大的亚基，介导dynactin 与动力蛋白 dynein 、微管以及微管正端结合蛋白等的相互作用。 p150glued 的 G59S 错意突变导致家族性运动神经元病。现对近年来研究中发现的 p150glued 与运动神经元病的关系及相关分子机制进行综述。

佩里综合征是一类特殊的常染色体显性遗传的帕金森综合征,伴发抑郁、体质量减轻和肺换气不足等症状.近年来研究发现,该病的致病原因是DCTN1基因的错义突变,病理基础是黑质和蓝斑神经元的变性死亡,但发病机制和干预靶点仍然未知,临床上缺乏有效的治疗措施.现针对佩里综合征的研究进展作一综述,以期对该病有进一步认识.

Background Postoperative cognitive dysfunctiond (POCD) is a common geriatric complication that may be associated with not only increased morbidity and mortality,but also rising health care costs and reduced patients' quality of life.Objective To provide basis for establishing the preventative or therapeutic strategy for POCD by reviewing reported pharmacological interventions in POCD.Content The risk factors of POCD were summarize,and recently published original reports of clinical and basic research relevant to pharmacological interventions in POCD were also introduced.Trend POCD is a multi-factorial disorder with poorly understood pathophysiology.Many studies suggest that an inflammatory response is a key contributor to POCD.This is confirmed by a series of reported pharmacological interventions in the prevention and treatment of POCD,indicating the pharmacological interventions of POCD have wide prospects for investigation and values for clinical application.