Recent developments of neuroprotective agents for degenerative retinal disorders

Retinal degeneration is a debilitating ocular complication characterized by the progressive loss of photoreceptors and other retinal neurons,which are caused by a group of retinal diseases affecting various age groups,and increasingly prevalent in the elderly.Age-related macular degeneration,diabetic retinopathy and glaucoma are among the most common complex degenerative retinal disorders,posing significant public health problems worldwide largely due to the aging society and the lack of effective therapeutics.Whilst pathoetiologies vary,if left untreated,loss of retinal neurons can result in an acquired degeneration and ultimately severe visual impairment.Irrespective of underlined etiology,loss of neurons and supporting cells including retinal pigment epithelium,microvascular endothelium,and glia,converges as the common endpoint of retinal degeneration and therefore discovery or repurposing of therapies to protect retinal neurons directly or indirectly are under intensive investigation.This review overviews recent developments of potential neuroprotectants including neuropeptides,exosomes,mitochondrial-derived peptides,complement inhibitors,senolytics,autophagy enhancers and antioxidants either still experimentally or in clinical trials.Effective treatments that possess direct or indirect neuroprotective properties would significantly lift the burden of visual handicap.

Design, synthesis and pharmacological evaluation of caffeic acid phenethyl ester acylation as multifunctional neuroprotective agents against oxidative stress injury

4-Acylated or 3,4-diacylated caffeic acid phenethyl ester （CAPE） was prepared as prodrug to improve its stability and lipid solubility. Their neuroprotective activities were assessed by H202 model and 6-OHDA model. The results showed that target compounds displayed positive abilities to protect PC 12 nerve cells from oxidative stress injury, superior to that of CAPE. Additionally, target compounds showed high blood-brain barrier permeability.

Research advances on the usage of traditional Chinese medicine for neuroprotection in glaucoma

Progressive loss of retinal ganglion cells （RGCs） and their axons is the main pathogenesis of glaucoma. The cause of glaucoma is not fully understood, but the neurodegeneration of glaucoma involves many mechanisms such as oxidative stress, glutamate toxicity and ischemia/ reperfusion insult. In order to target these mechanisms, multiple neuroprotective interventions have been investigated to prevent the death of RGCs. Of note are some tonic herbs from the traditional Chinese medicine （TCM） pharmacopeia that have shown neuroprotective effects in glaucoma. TCM differs from Western medicine in that TCM exhibits complicated bioactive com- ponents, triggering many signaling pathways and extensive actions on vital organs. Modern scientific approaches have demonstrated some of their underlying mechanisms. In this review, we used Lycium barbarum and Ginkgo biloba as examples to elaborate the characteristics of TCM and their potential applications in neuroprotection in glaucoma.

Effect of Batroxobin on Expression of Neural Cell Adhesion Molecule in Temporal Infarction Rats and Spatial Learning and Memory Disorder

The effect of Batroxobin expression of neural cell adhesion molecule (NCAM) in left temporal ischemic rats with spatial memory disorder was investigated by means of Morri's water maze and immunohistochemical methods. The results showed that the mean reaction time and distance of temporal ischemic rats for searching a goal were significantly longer than those of sham-operated rats and at the same time NCAM expression of left temporal ischemic region was significantly increased. However, the mean reaction time and distance of Batroxobin-treated rats were shorter and they used normal strategies more often and earlier than those of ischemic rats. The number of NCAM immune reactive cells of Batroxobin-treated rats was more than that of ischemic group. In conclusion, Batroxobin can improve spatial memory disorder of temporal ischemic rats and the regulation of the expression of NCAM is probably related to the neuroprotective mechanism.

Effect of Batroxobin on Neuronal Apoptosis During Focal Cerebral Ischemia and Reperfusion in Rats

We have found that Batroxobin plays a protective role in ischemic brain injury, which attracted us to investigate the effect of Batroxobin on apoptosis of neurons during cerebral ischemia and reperfusion. The apoptotic cells in ischemic rat brains at different reperfusion intervals were tested with method of TdT-mediated dUTP-DIG nick end labeling (TUNEL) and the effect of Batroxobin on the apoptosis of neurons was studied in left middle cerebral artery (LMCA) occlusion and reperfusion in rat models (n = 18). The results showed that few scattered apoptosis cells were observed in right cerebral hemispheres after LMCA occlusion and reperfusion, and that a lot of apoptosis cells were found in left ischemic cortex and caudoputamen at 12 h reperfusion, and they reached peak at 24 h-48 h reperfusion. However, in the rats pretreated with Batroxobin, the number of apoptosis cells in left cerebral cortex and caudoputamen reduced significantly and the neuronal damage was much milder at 24 h reperfusion than that of saline-treated rats. The results indicate that administration of Batroxobin may reduce the apoptosis of neurons induced by cerebral ischemia and reperfusion and afford significant cerebroprotection in the model of focal cerebral ischemia and reperfusion.

EFFECTS OF TRANSIENT FOREBRAIN ISCHEMIA AND RADIX SALVIAE MILTIORRHIZAE (RSM) ON EXTRACELLULAR LEVELS OF MONOAMINE NEUROTRANSMITTERS AND METABOLITES IN THE GERBIL STRIATUM-An in vivo Microdialysis Study

The aim of this study was to investigate the effect of 30 min forebrain ischemia, followed by 120 min reperfusion on extracellular fluid (ECF) levels of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of gerbils, so as to obtain further information on the mechanism of Radix Salviae Miltiorrhizae (RSM)-induced neuroprotection. Microdialysis was used to sample the extracellular space. Dialysate was measured by high performance liquid chromatography with electrochemical detector (HPLC-ED). ECF DA, NE levels increased from basal levels by 282, 227 and 221 folds, by 9.14, 8.51 and 8.25 folds, respectively for the three ischemic duration (0-10; 11-20; 21-30 min). ECF DA, NE, 5-HT levels in the RSM-treated group were significantly decreased as compared with those in the control group during ischemia (P

Six psychotropics for pre-symptomatic ＆ early Alzheimer＇s (MCI), Parkinson＇s, and Huntington＇s disease modification

The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases （NDDs）, including Alzheimer＇s disease （AD）, Parkinson＇s disease （PD）, and Huntington＇s disease （HD）, has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious findings follow. Mild cognitive impairment （MCI） phase of AD： salutary human randomized controlled trial findings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD： human epidemiological data indicate that lithium reduc- es AD risk. Animal model studies （AMS） reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD： valproate AMS findings show promise. Pre-symptomatic PD： lithium and valproate AMS findings are encouraging. Early HD： uncontrolled clinical data indicate non-progression with lithium, fluoxetine, donepezil, and memantine. Pre-symptomatic HD： lithium and valproate are auspicious in AMS. Many other promising findings awaiting replication （valproate in MCI; lithium, valproate, fluoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, fluoxetine in pre-symptomatic PD; donepezil in early HD; lithium, fluoxetine, memantine in pre-symptomatic HD） are reviewed. Dose- and stage-dependent effects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage.

Batroxobin Against Anoxic Damage of Rat Hippocampal Neurons in Culture:Morphological Changes and Hsp70 Expression

Batroxobin,the thrombin-like enzyme,is used for therapeutic defibrination. We have found that batroxobin has good therapeutic effect in ischemic reperfusion rats and clinical practices in vivo. But we have not studied the neuroprotective effect of batroxobin on anoxic hippocampal neurons in vitro. The purpose of this study was to obtain further information on the mechanism of the batroxobin-induced neuroprotection and examine the neuroprotective effect on neurons exposed to anoxia. The effect of batroxobin on anoxic damages in cultured hippocampal neurons of neonatal rats was investigated by using morphological changes and heat shock protein 70Kd (Hsp70) immunoreactive expression as indicators. The results indicate that batroxobin, besides its defibrination, may have a direct neuroprotective effect on anoxic damage of hippocampal neurons.

Drug therapy for Parkinson's disease: An update

Parkinson's disease(PD) is the most common neurodegenerative movement disorder, affecting about 1% of the population above the age of 65. PD is characterized by a selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta. This results in a marked loss of striatal dopamine and the development of the characteristic features of the disease, i.e., bradykinesia, rest tremor, rigidity, gait abnormalities and postural instability. Other types of neurons/neurotransmitters are also involved in PD, including cholinergic, serotonergic, glutamatergic, adenosine, and GABAergic neurotransmission which might have relevance to the motor, non-motor, neuro-psychiatric and cognitive disturbances that occur in the course of the disease. The treatment of PD relies on replacement therapy with levodopa(L-dopa), the precursor of dopamine, in combination with a peripheral decarboxylase inhibitor(carbidopa or benserazide). The effect of L-dopa, however, declines over time together with the development of motor complications especially dyskinesia in a significant proportion of patients within 5 years of therapy. Other drugs include dopaminereceptor-agonists, catechol-O-methyltransferase inhibitors, monoamine oxidase type B(MAO-B) inhibitors, anticholinergics and adjuvant therapy with the antiviral drug and the N-methyl-D-aspartate glutamate receptor antagonist amantadine. Although, these medications can result in substantial improvements in parkinsonian symptoms, especially during the early stages of the disease, they are often not successful in advanced disease. Moreover, dopaminergic cell death continues over time, emphasizing the need for neuroprotective or neuroregenerative therapies. In recent years, research has focused on non-dopaminergic approach such as the use of A2 A receptor antagonists: istradefylline and preladenant or the calcium channel antagonist isradipine. Safinamide is a selective and reversible inhibitor of MAO-B, a glutamate receptor inhibitor as well as sodium and calcium channel blocker. Minocycline and pioglitazone are other agents which have been shown to prevent dopaminergic nigral cell loss in animal models of PD. There is also an evidence to suggest a benefit from iron chelation therapy with deferiprone and from the use of antioxidants or mitochondrial function enhancers such as creatine, alpha-lipoic acid, l-carnitine, and coenzyme Q10.

RADIX SALVIAE MILTIORRHIZAE PROTECTS RAT HIPPOCAMPAL NEURON IN CULTURE FROM ANOXIC DAMAGE

Radix Salviae Miltiorrhizae (RSM), a well-known traditional Chinese medicinal herb, has been used to improve blood circulation and resolve blood stasis. We have previously found that RSM has neuroprotective effect on ischemia and/ or ischemia-reperfusion rats. The purpose of this study was to obtain further information on the mechanism of the RSM-in-duced neuroprotection and to examine the neuroprotective effect on neurons exposed to anoxia. The effect of RSM on anoxic damage in cultured hippocampal neurons of neonatal rat was investigated by using morphological changes and heat shock protein 70kD (HSP70) expression as indicators. RSM given 0.5h before 2h-anoxia followed by 48 hours reoxygenation could significantly increase survival rate of hippocampal neurons and number of HSP70 positive cells. The results suggest that RSM has a direct neuroprotective effects on anoxic damage in hippocampal neurons.

Research advances on how metformin improves memory impairment in “chemobrain”

Cognitive impairment caused by chemotherapy,referred to as“chemobrain,”is observed in approximately 70% of cancer survivors.However,it is not completely understood how chemotherapy induces cognitive dysfunction,and clinical treatment strategies for this problem are lacking.Metformin,used as a first-line treatment for type 2 diabetes mellitus,is reported to reduce the effects of chemobrain.Recently,several studies have examined the effect of metformin in rescuing chemobrain.This review discusses recent clinical/preclinical studies that addressed some mechanisms of chemobrain and evaluates the effect of metformin in rescuing chemobrain and its potential mechanisms of action.

Lithium beyond psychiatric indications:the reincarnation of a new old drug

Lithium has been used in the treatment of bipolar disorders for decades,but the exact mechanisms of action remain elusive to this day.Recent evidence suggests that lithium is critically involved in a variety of signaling pathways affecting apoptosis,inflammation,and neurogenesis,all of which contributing to the complex pathophysiology of various neurological diseases.As a matter of fact,preclinical work reports both acute and longterm neuroprotection in distinct neurological disease models such as Parkinson’s disease,traumatic brain injury,Alzheimer’s disease,and ischemic stroke.Lithium treatment reduces cell injury,decreasesα‑synuclein aggregation and Tau protein phosphorylation,modulates inflammation and even stimulates neuroregeneration under experimental conditions of Parkinson’s disease,traumatic brain injury,and Alzheimer’s disease.The therapeutic impact of lithium under conditions of ischemic stroke was also studied in numerous preclinical in vitro and in vivo studies,giving rise to a randomized double-blind clinical stroke trial.The preclinic data revealed a lithium-induced upregulation of anti-apoptotic proteins such as B-cell lymphoma 2,heat shock protein 70,and activated protein 1,resulting in decreased neuronal cell loss.Lithium,however,does not only yield postischemic neuroprotection but also enhances endogenous neuroregeneration by stimulating neural stem cell proliferation and by regulating distinct signaling pathways such as the RE1-silencing transcription factor.In line with this,lithium treatment has been shown to modulate postischemic cytokine secretion patterns,diminishing microglial activation and stabilizing blood-brain barrier integrity yielding reduced levels of neuroinflammation.The aforementioned observations culminated in a first clinical trial,which revealed an improved motor recovery in patients with cortical stroke after lithium treatment.Beside its well-known psychiatric indications,lithium is thus a promising neuroprotective candidate for the aforementioned neurological diseases.A detailed understanding of the lithium-induced mechanisms,however,is important for prospective clinical trials which may pave the way for a successful benchto-bedside translation in the future.In this review,we will give an overview of lithiuminduced neuroprotective mechanisms under various pathological conditions,with special emphasis on ischemic stroke.

Neuroprotective Effect of Fructus broussonetiae on APP/PS1 Mice via Upregulation of AKT/β-Catenin Signaling

Objective:To evaluate the mechanisms underlying the protective effect of Chinese herbal medicine Fructus broussonetiae(FB)in both mouse and cell models of Alzheimer’s disease(AD).Methods:APP/PS1 mice treated with FB for 2 months and vehicle-treated controls were run through the Morris water maze and object recognition test to evaluate learning and memory capacity.RNA-Seq,Western blotting,and immunofluorescence staining were also conducted to evaluate the effects of FB treatment on various signaling pathways altered in APP/PS1 mice.To further explore the mechanisms underlying FB’s protective effect,PC-12 cells were treated with Aβ25–35 in order to establish an in vitro model of AD.Results:FB-treated mice showed improved learning and memory capacity on both the Morris water maze and object recognition tests.RNA-seq of hippocampal tissue from APP/PS1 mice showed that FB had effects on multiple signaling pathways,specifically decreasing cell apoptotic signaling and increasing AKT and β-catenin signaling.Similarly,FB up-regulated both AKT and β-catenin signaling in PC-12 cells pre-treated with Aβ25–35,in which AKT positively regulated β-catenin signaling.Further study showed that AKT promoted β-catenin signaling via enhancing β-catenin(Ser552)phosphorylation.Moreover,AKT and β-catenin signaling inhibition both resulted in the attenuated survival of FB-treated cells,indicating the AKT/β-catenin signaling is a crucial mediator in FB promoted cell survival.Conclusions:FB exerted neuroprotective effects on hippocampal cells of APP/PS1 mice,as well as improved cell viability in an in vitro model of AD.The protective actions of FB occurred via the upregulation of AKT/β-catenin signaling.

Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent

Bibenzyls,a kind of important plant polyphenols,have attracted growing attention for their broad and remarkable pharmacological activities.However,due to the low abundance in nature,uncontrollable and environmentally unfriendly chemical synthesis processes,these compounds are not readily accessible.Herein,one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes.Three types of efficiently postmodifying modular strains were engineered by employing methyltransferases,prenyltransferase,and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules.Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes.Especially,a prenylated bibenzyl derivative(12)was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke.RNA-seq,quantitative RT-PCR,and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor,mitochondria associated 3(Aifm3),suggesting that Aifm3 might be a new target in ischemic stroke therapy.This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.

Protective effects of Ginkgo biloba extract on rats during cerebral ischemia/reperfusion

OBJECTIVE: To study the effect of Ginkgo biloba extract on rats during ischemia/reperfusion and its influence on intracellular calcium in hippocampal neurons. METHODS: Model of intraluminal occlusion of the middle cerebral artery (MCAO) was used to prepare the ischemia/reperfusion cortex tissue. Concentration of MDA was determined by measuring thiobarbituric acid-reactive substance. GSH-PX was quantified using the thiobarbituric acid (TBA) technique. SOD was assayed througha xanthine method. Endogenous amino acids were quantified by high performance liquid chromatographic (HPLC) analysis. Primary culturs of hippocampal neurons were prepared for a free intracellular calcium ([Ca(2+)]I) assay by Fura-2 based single cell microfluoremetric technique. RESULTS: Comparing control and treatment groups, the concentration of SOD and GSH-PX were higher, whereas that of MDA was much lower; the concentration of glutamate and aspartate decreased and that of GABA increased markedly at all time point (P

Effect of glycyrrhizin on traumatic brain injury in rats and its mechanism

Objective： To investigate the neuropro- tective effects of glycyrrhizin （Gly） as well as its effect on expression of high-mobility group box 1 （HMGB1） in rats after traumatic brain injury （TBI）. Methods： Male Sprague-Dawley rats were randomly divided into three groups： sham group, TBI group, and TBI＋Gly group （n=36 per group）. Rat TBI model was made by using the modified Feeney＇s method. In TBI＋Gly group, Gly was administered intravenously at a dosage of l0 mg/kg 30 min after TBI. At 24 h after TBI, motor function and brain water content were evaluated. Meanwhile, HMGB 1/HMGB 1 receptors including toll-like receptor 4 （TLR4） and receptor for advanced glycation end products （RAGE）/nuclear fac- tor-κ B（NF- κ B） signaling pathway and inflammatory cytokines in the injured brain tissues were detected using quantitative real-time polymerase chain reaction, western blot, electrophoretic mobility shift assay and enzyme-linked immunosorbent assay. Furthermore, HMGB l, RAGE and TLR4 immunohistochemistry and apoptosis were analyzed. Results： Beam walking performance impairment and brain edema were significantly reduced in TBI＋Gly group compared with TBI group; meanwhile, the over-expressions of HMGB 1PHMGB 1 receptors （TLR4 and RAGE）/NF- κB DNA-binding activity and inflammatory cytokines were inhibited. The percentages of HMGB 1, RAGE and TLR4- positive cells and apoptotic cells were respectively 58.37%±5.06%, 54.15%±4.65%, 65.50%± 4.83%, 52.02%±4.63% in TBI group and 39.99%±4.99%, 34.87%±5.02%, 43.33%±4.54%, 37.84%±5.16% in TBI＋Gly group （all P〈0.01 compared with TBI group）. Conclusion： Gly can reduce secondary brain injury and improve outcomes in rat following TBI by down-regula- tion of HMGB 1/HMGB 1 receptors （TLR4 and RAGE）/NF- κB - mediated inflammatory responses in the injured rat brain.

Biocompatible custom ceria nanoparticles against reactive oxygen species resolve acute inflammatory reaction after intracerebral hemorrhage

Intracerebral hemorrhage （ICH） is a devastating subtype of stroke with a high mortality rate, for which there currently is no effective treatment. A perihematomal edema caused by an intense inflammatory reaction is more deleterious than the hematoma itself and can result in neurological deterioration and death. Ceria nanoparticles （CeNPs） are potent free radical scavengers with potential for biomedical applications. As oxidative stress plays a major role in post-ICH inflammation, we hypothesized that CeNPs might protect against ICH. To test this hypothesis, core CeNPs were synthesized using a modified reverse micelle method and covered with phospholipid-polyethylene glycol （PEG） to achieve biocompatibility. We investigated whether our custom-made biocompatible CeNPs have protective effects against ICH. The CeNPs reduced oxidative stress, hemin-induced cytotoxicity, and inflammation in vitro. In a rodent ICH model, intravenously administered CeNPs were mainly distributed in the hemorrhagic hemisphere, suggesting that they could diffuse through the damaged blood-brain barrier. Moreover, CeNPs attenuated microglia/macrophage recruitment around the hemorrhagic lesion and inflammatory protein expression. Finally, CeNP treatment reduced the brain edema by 68.4% as compared to the control. These results reveal the great potential of CeNPs as a novel therapeutic agent for patients with ICH.

Intranasal administration of induced pluripotent stem cell-derived cortical neural stem cell-secretome as a treatment option for Alzheimer’s disease

Background Alzheimer’s disease(AD)is the most common neurodegenerative disorder in the elderly,resulting in gradual destruction of cognitive abilities.Research on the development of various AD treatments is underway;however,no definitive treatment has been developed yet.Herein,we present induced pluripotent stem cell(iPSC)-derived cortical neural stem cell secretome(CNSC-SE)as a new treatment candidate for AD and explore its efficacy.Methods We first assessed the effects of CNSC-SE treatment on neural maturation and electromagnetic signal during cortical nerve cell differentiation.Then to confirm the efficacy in vivo,CNSC-SE was administered to the 5×FAD mouse model through the nasal cavity(5μg/g,once a week,4 weeks).The cell-mediated effects on nerve recovery,amyloid beta(Aβ)plaque aggregation,microglial and astrocyte detection in the brain,and neuroinflammatory responses were investigated.Metabolomics analysis of iPSC-derived CNSC-SE revealed that it contained components that could exert neuro-protective effects or amplify cognitive restorative effects.Results Human iPSC-derived CNSC-SE increased neuronal proliferation and dendritic structure formation in vitro.Furthermore,CNSC-SE-treated iPSC-derived cortical neurons acquired electrical network activity and action potential bursts.The 5×FAD mice treated with CNSC-SE showed memory restoration and reduced Aβplaque accumulation.Conclusions Our findings suggest that the iPSC-derived CNSC-SE may serve as a potential,non-invasive therapeutic option for AD in reducing amyloid infiltration and restoring memory.

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995–2015

Stroke is a brain damage caused by a loss of blood supply to a portion of the brain, which requires prompt and effective treatment. The current pharmacotherapy for ischemic stroke primarily relies on thrombolysis using recombinant tissue plasminogen activators(rt-PAs) to breakdown blood clots. Neuroprotective agents that inhibit excitatory neurotransmitters are also used to treat ischemic stroke but have failed to translate into clinical benefits. This poses a major challenge in biomedical research to understand what causes the progressive brain cell death after stroke and how to develop an effective pharmacotherapy for stroke. This brief review analyzes the fate of about 430 potentially useful stroke medications over the period 1995–2015and describes in detail those that successfully reached the market. Hopefully, the information from this analysis will shed light on how future stroke research can improve stroke drug discovery.

Are memantine, methylphenidate and donepezil effective in sparing cognitive functioning after brain irradiation?

One strategy to reduce neurocognitive deterioration in patients after brain irradiation is the use of neuroprotective medication.To generate up-to date knowledge regarding neuroprotective agents we performed a systematic review on the clinical effectiveness of three agents that were reported to have neuroprotective characteristics:memantine,methylphenidate and donepezil.The use of memantine after brain irradiation showed a delay in cognitive deterioration,although at 24 weeks this did not reach significance(P=0.059).Lack of significance is likely to be the result of the limited statistical power of 35%and memantine did show significant differences in secondary outcomes.The study on methylphenidate was not conclusive.Donepezil revealed significant differences in a few cognitive tests however no difference in global cognition was found.In addition,larger effects were observed in individuals with greater cognitive dysfunction prior to treatment.