Patient-reported cognitive impairments and objective neuropsychological deficits in young sarcoma patients undergoing chemotherapy and its comparison to healthy controls: A tertiary health care study from India.

The study aims to investigate the patient-reported cognitive deficits and objective neuropsychological functions in younger adult (YA) sarcoma patients (16-40 years of age). Ninety patients and 30 age-matched healthy controls from a single tertiary healthcare hospital, were recruited into four groups: Pre-chemotherapy (Pre Cx), During chemotherapy (During Cx), Post-chemotherapy (Post Cx) and Controls. Neurocognitive functions were assessed subjectively using FACT-Cog v3 questionnaire; objectively using ACE-III and neuropsychological tests (NPT). FACT-Cog scores of During Cx (P = .041) and Post Cx (P = .008) groups were significantly lower than Pre Cx group. ACE-III scores of During Cx (P = .048) and Post Cx (P = .043) groups were lower as compared to Pre Cx group. In addition, reaction times and accuracies of the NPT (Flanker's, Sternberg's and Emotional Stroop tests) were worse (P < .05) in During Cx and Post Cx groups as compared to either Pre Cx or control groups. In the Post Cx group, the dose of chemotherapy showed significant negative correlation with the Sternberg reaction time (P = .040) as well as the scores of language (P = .047), and attention (P = .044) domains of ACE-III. Observations demonstrate that cancer/chemotherapy-related neurocognitive deficits fail to improve even after cessation of treatment, and high dosage of chemotherapy used, could be an underlying factor. This emphasizes the need for developing 'model of care' in these patients for monitoring the side effects, and possible titration in the therapeutic regimen for sarcoma in YA.

Hippocampal acetylcholinesterase activation induced by streptozotocin in mice is protected by an organotellurium compound without evidence of toxicity.

The cognitive deficit, which is like Alzheimer's disease and is associated with oxidative damage, may be induced by exposure to streptozotocin. This study aimed to evaluate if the tellurium-containing organocompound, 3j, 5'-arylchalcogeno-3-aminothymidine derivative, interferes with the effects of streptozotocin, as well as to investigate its toxicity in adult mice. Cognitive deficit was induced by two doses of streptozotocin (2.25 mg/kg/day, 48 h interval) intracerebroventricularly. After, the mice were subcutaneously treated with 3j (8.62 mg/kg/day) for 25 days. The effects were assessed by evaluating hippocampal and cortical acetylcholinesterase and behavioral tasks. 3j toxicity was investigated for 10 (0, 21.55, or 43.10 mg/kg/day) and 37 (0, 4.31, or 8.62 mg/kg/day) days by assessing biometric parameters and glucose and urea levels, and alanine aminotransferase activity in blood plasma. 3j exposure did not alter the behavioral alterations induced by streptozotocin exposure. On the other hand, 3j exposure normalized hippocampus acetylcholinesterase activity, which is enhanced by streptozotocin exposure. Toxicity evaluation showed that the administration of 3j for either 10 or 37 days did not cause harmful effects on the biometric and biochemical parameters analyzed. Therefore, 3j does not present any apparent toxicity and reverts acetylcholinesterase activity increase induced by streptozotocin in young adult mice.

Repeated sevoflurane exposures inhibit neurogenesis by inducing the upregulation of glutamate transporter 1 in astrocytes.

Sevoflurane is a widely used general anaesthetic in paediatric patients. Although repeated sevoflurane exposure is known to cause neurodevelopmental disorders in children, the mechanism of this neurotoxicity remains largely unknown. Herein, we investigated the role of glutamate transporter 1 (GLT1) in sevoflurane-induced decreased neurogenesis. Neonatal rat pups (postnatal Day 7, PN7) were exposed to 3% sevoflurane for 2 h for three consecutive days. Neuron loss and decreased neurogenesis have been observed in the neonatal rat brain, along with decreased number of astrocytes. Apoptotic astrocytes were observed after repeated sevoflurane exposure in vitro, resulting in decreased levels of brain-derived neurotrophic factor (BDNF). Calcium overload was observed in astrocytes after repeated sevoflurane exposure, in addition to upregulation of GLT1. Inhibition of GLT1 activity ameliorates repeated sevoflurane exposure-induced cognitive deficits in adult rats. Mechanically, the upregulation of GLT1 was caused by the activation of mRNA translation. RNA-sequencing analysis further confirmed that translation-related genes were activated by repeated sevoflurane exposure. These results indicate that cognitive deficits caused by repeated sevoflurane exposure during PN7-9 are triggered decreased neurogenesis. The proposed underlying mechanism involves upregulation of apoptosis in astrocytes induced by GLT1; therefore, we propose GLT1 as a potential pharmacological target for brain injury in paediatric practice.

Cognitive deficits after general anaesthesia in animal models: a scoping review.

BACKGROUND: It remains controversial whether general anaesthetic drugs contribute to perioperative neurocognitive disorders in adult patients. Preclinical studies have generated conflicting results, likely because of differing animal models, study protocols, and measured outcomes. This scoping review of preclinical studies addressed the question: 'Do general anaesthetic drugs cause cognitive deficits in adult animals that persist after the drugs have been eliminated from the brain?' METHODS: Reports of preclinical studies in the MEDLINE database published from 1953 to 2021 were examined. A structured review process was used to assess original studies of cognitive behaviours, which were measured after treatment (≥24 h) with commonly used general anaesthetic drugs in adult animals. RESULTS: The initial search yielded 380 articles, of which 106 were fully analysed. The most frequently studied animal model was male (81%; n=86/106) rodents (n=106/106) between 2-3 months or 18-20 months of age. Volatile anaesthetic drugs were more frequently studied than injected drugs, and common outcomes were memory behaviours assessed using the Morris water maze and fear conditioning assays. Cognitive deficits were detected in 77% of studies (n=82/106) and were more frequent in studies of older animals (89%), after inhaled anaesthetics, and longer drug treatments. Limitations of the studies included a lack of physiological monitoring, mortality data, and risk of bias attributable to the absence of randomisation and blinding. CONCLUSIONS: Most studies reported cognitive deficits after general anaesthesia, with age, use of volatile anaesthetic drugs, and duration of anaesthesia as risk factors. Recommendations to improve study design and guide future research are presented.

Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment.

Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca2+ signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain.

Flexible versus Fixed Spatial Self-Ordered Response Sequencing: Effects of Inactivation and Neurochemical Modulation of Ventrolateral Prefrontal Cortex.

Previously, studies using human neuroimaging and excitotoxic lesions in non-human primate have demonstrated an important role of ventrolateral prefrontal cortex (vlPFC) in higher order cognitive functions such as cognitive flexibility and the planning of behavioral sequences. In the present experiments, we tested effects on performance of temporary inactivation (using GABA receptor agonists) and dopamine (DA) D2 and 5-HT2A-receptor (R) blockade of vlPFC via local intracerebral infusions in the marmoset. We trained common marmosets to perform spatial self-ordered sequencing tasks in which one cohort of animals performed two and three response sequences on a continuously varying spatial array of response options on a touch-sensitive screen. Inactivation of vlPFC produced a marked disruption of accuracy of sequencing which also exhibited significant error perseveration. There were somewhat contrasting effects of D2 and 5-HT2A-R blockade, with the former producing error perseveration on incorrect trials, though not significantly impairing accuracy overall, and the latter significantly impairing accuracy but not error perseveration. A second cohort of marmosets were directly compared on performance of fixed versus variable spatial arrays. Inactivation of vlPFC again impaired self-ordered sequencing, but only with varying, and not fixed spatial arrays, the latter leading to the consistent use of fewer, preferred sequences. These findings add to evidence that vlPFC is implicated in goal-directed behavior that requires higher-order response heuristics that can be applied flexibly over different (variable), as compared with fixed stimulus exemplars. They also show that dopaminergic and serotonergic chemomodulation has distinctive effects on such performance.SIGNIFICANCE STATEMENT This investigation employing local intracerebral infusions to inactivate the lateral prefrontal cortex (PFC) of the New World marmoset reveals the important role of this region in self-ordered response sequencing in variable but not fixed spatial arrays. These novel findings emphasize the higher order functions of this region, contributing to cognitive flexibility and planning of goal directed behavior. The investigation also reports for the first time somewhat contrasting neuromodulatory deficits produced by infusions of dopamine (DA) D2 and 5-HT2A receptor (R) antagonists into the same region, of possible significance for understanding cognitive deficits produced by anti-psychotic drugs.

l-Theanine Prevents Long-Term Affective and Cognitive Side Effects of Adolescent Δ-9-Tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry.

Chronic adolescent exposure to Δ-9-tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioral abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathologic alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations. l-Theanine is an amino acid analog of l-glutamate and l-glutamine derived from various plant sources, including green tea leaves. l-Theanine has previously been shown to modulate levels of GABA, DA, and glutamate in various neural regions and to possess neuroprotective properties. Using a preclinical model of adolescent THC exposure in male rats, we report that l-theanine pretreatment before adolescent THC exposure is capable of preventing long-term, THC-induced dysregulation of both PFC and VTA DAergic activity states, a neuroprotective effect that persists into adulthood. In addition, pretreatment with l-theanine blocked THC-induced downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways directly in the PFC, two biomarkers previously associated with cannabis-related psychiatric risk and subcortical DAergic dysregulation. Finally, l-theanine powerfully blocked the development of both affective and cognitive abnormalities commonly associated with adolescent THC exposure, further demonstrating functional and long-term neuroprotective effects of l-theanine in the mesocorticolimbic system.SIGNIFICANCE STATEMENT With the increasing trend of cannabis legalization and consumption during adolescence, it is essential to expand knowledge on the potential effects of adolescent cannabis exposure on brain development and identify potential pharmacological strategies to minimize Δ-9-tetrahydrocannabinol (THC)-induced neuropathology. Previous evidence demonstrates that adolescent THC exposure induces long-lasting affective and cognitive abnormalities, mesocorticolimbic dysregulation, and schizophrenia-like molecular biomarkers that persist into adulthood. We demonstrate for the first time that l-theanine, an amino acid analog of l-glutamate and l-glutamine, is capable of preventing long-term THC side effects. l-Theanine prevented the development of THC-induced behavioral aberrations, blocked cortical downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways, and normalized dysregulation of both PFC and VTA DAergic activity, demonstrating powerful and functional neuroprotective effects against THC-induced developmental neuropathology.

Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events.

Cognitive dysfunction has been one of the most reported and studied adverse effects of cancer treatment, but, for many years, it was overlooked by the medical community. Nevertheless, the medical and scientific communities have now recognized that the cognitive deficits caused by chemotherapy have a strong impact on the morbidity of cancer treated patients. In fact, chemotherapy-induced cognitive dysfunction or 'chemobrain'  (also named also chemofog) is at present a well-recognized effect of chemotherapy that could affect up to 78% of treated patients. Nonetheless, its underlying neurotoxic mechanism is still not fully elucidated. Therefore, this work aimed to provide a comprehensive review using PubMed as a database to assess the studies published on the field and, therefore, highlight the clinical manifestations of chemobrain and the putative neurotoxicity mechanisms.In the last two decades, a great number of papers was published on the topic, mainly with clinical observations. Chemotherapy-treated patients showed that the cognitive domains most often impaired were verbal memory, psychomotor function, visual memory, visuospatial and verbal learning, memory function and attention. Chemotherapy alters the brain's metabolism, white and grey matter and functional connectivity of brain areas. Several mechanisms have been proposed to cause chemobrain but increase of proinflammatory cytokines with oxidative stress seem more relevant, not excluding the action on neurotransmission and cellular death or impaired hippocampal neurogenesis. The interplay between these mechanisms and susceptible factors makes the clinical management of chemobrain even more difficult. New studies, mainly referring to the underlying mechanisms of chemobrain and protective measures, are important in the future, as it is expected that chemobrain will have more clinical impact in the coming years, since the number of cancer survivors is steadily increasing.

Modafinil rescues repeated morphine-induced synaptic and behavioural impairments via activation of D1R-ERK-CREB pathway in medial prefrontal cortex.

Long-term opioid abuse causes a variety of long-lasting cognitive impairments such as attention, impulsivity and working memory. These cognitive impairments undermine behavioural treatment for drug abuse and lead to poor treatment retention and outcomes. Modafinil is a wake-promoting drug that shows potential in improving attention and memory in humans and animals. However, modafinil's effect on opioid-induced cognitive impairments remains unclear, and the underlying mechanism is poorly understood. This study showed that repeated morphine administration significantly impairs attention, increases impulsivity and reduces motivation to natural rewards in mice. Systemic modafinil treatment at low dose efficiently ameliorates morphine-induced attention dysfunction and improves motivation and working memory in mice. High dose of modafinil has adverse effects on impulsive action and attention. Local infusion of D1R antagonist SCH-23390 reverses the morphine-induced synaptic abnormalities and activation of the D1R-ERK-CREB pathway in medial prefrontal cortex (mPFC). This study demonstrated a protective effect of modafinil in mPFC neurons and offered a therapeutic potential for cognitive deficits in opioid abuse.

Post-operative behavioural disorders in paediatric anaesthesia caused by anaesthetics and sedatives.

Neurotoxicity of anaesthetics have become one of the most discussed problems in paediatric anaesthesiology. The experimental studies on animal models have shown that the anaesthetics used in general anaesthesia should have an influence on neurodegenerative processes, neuroapoptosis and irregulated death of the neuronal cells.Because of this fact, scientists are trying to discover the possibilities of how to minimize the adverse effects of anaesthesia and revise the other alternatives of prevention of anaesthesia-induced maladaptive behavioural disorders (Tab. 1, Fig. 1, Ref. 21). Keywords: neurotoxicity of anaesthetics, maladaptive behavioural disorders, mechanism of neurotoxicity, post-anaesthetic behavioural changes in children, future of paediatric anaesthesiology.

[Chemobrain - cognitive disorders after chemotherapy]. / Chemobrain ­ zaburzenia poznawcze po chemioterapii.

In recent years, more and more attention has been paid to the deterioration of cognitive functioning after the use of chemotherapy. The article presents the problems of cognitive disorders caused by chemotherapy in cancer patients. These deficits in scientific terminology are called chemobrain. Patients in particular indicate disorders of: longterm verbal memory and executive functions (planning, verbal fluency and working memory). This is confirmed by the results of neuroimaging studies. It has been observed that higher doses of cytostatics may contribute to the development of cognitive deficits. This article is a general introduction to the problems of chemobrain - the definition of the phenomenon and a discussion of neuroanatomical issues related to the influence of chemotherapy on the central nervous system. Moreover, the article tries to draw attention to the application of neuropsychological rehabilitation after chemotherapy.

Effects of combination antiretroviral drugs (cART) on hippocampal neuroplasticity in female mice.

The incidence of HIV-associated neurocognitive disorder (HAND) continues despite the introduction of combination antiretroviral drugs (cART). Several studies have reported the neurotoxicity of individual antiretroviral drugs (monotherapy), while the common approach for HIV treatment is through cART. Hence, the current study investigated the effects of long-term exposure to cART on cognitive function, oxidative damage, autophagy, and neuroplasticity in the hippocampus of mice. Female Balb/c mice received a once-a-day oral dose of cART composed of emtricitabine + tenofovir disoproxil fumarate or vehicle for 8 weeks. On week 7 of drug administration, all mice were assessed for spatial learning in the Morris water maze (MWM), and then on week 8, mice were sacrificed, and hippocampal tissue dissected from the brain. For biochemical analyses, we measured the concentration of 4-hydroxynonenal, and the expression of autophagic marker LC3B, synaptophysin, and brain-derived neurotrophic factor (BDNF) in the hippocampus. Our results showed that cART exposure increased escape latency in the MWM test. The cART-treated mice also showed increased 4-hydroxynonenal concentration and expression of LC3B. Furthermore, cART treatment decreased the expression of synaptophysin and BDNF. These findings further support the evidence that cART may be neurotoxic and therefore may play a role in the neuropathogenesis of HAND.

Lasting impact of general anaesthesia on the brain: mechanisms and relevance.

General anaesthesia is usually considered to safely induce a reversible brain state allowing the performance of surgery under optimal conditions. An increasing number of clinical and experimental observations, however, suggest that anaesthetic drugs, especially when they are administered at the extremes of age, can trigger long-term morphological and functional alterations in the brain. Here, we review available mechanistic data linking general-anaesthesia exposure to impaired cognitive performance in both young and mature nervous systems. We also provide a critical appraisal of the translational value of animal models and highlight the important challenges that need to be addressed to strengthen the link between laboratory work and clinical investigations in the field of anaesthesia-neurotoxicity research.

Neuroimmune reactivity marker expression in rodent models of chemotherapy-induced cognitive impairment: A systematic scoping review.

BACKGROUND: Chemotherapy-induced cognitive impairment (CICI) is a debilitating side effect arising from chemotherapy treatments. The condition is characterised by a range of cognitive deficits including impairment to memory, attention, and concentration. Whilst the underlying mechanisms that contribute to CICI remain unclear, neuroinflammation has been suggested as one key contributor. METHOD: A comprehensive systematic search of EMBASE and Medline via PubMed was conducted to identify studies on neuroimmune reactivity marker expression changes and resulting cognitive changes in preclinical rodent models of CICI. RESULTS: A total of twenty studies met the eligibility criteria and were included in the scoping review. There was significant heterogeneity in the methodology employed in the included studies. Our findings demonstrate that widespread changes in cytokines, chemokines, microglia reactivity, and astrocyte reactivity are observed in CICI in the brain regions expected to be affected, given the nature of the cognitive impairment observed in CICI. CONCLUSIONS: Although there was considerable heterogeneity in study design that made comparisons between studies difficult, our findings suggest that neuroinflammation commonly occurs in CICI preclinical rodent models and shows an association with cognitive impairment.

Quality of anticholinergic burden scales and their impact on clinical outcomes: a systematic review.

PURPOSE: Older people are at risk of anticholinergic side effects due to changes affecting drug elimination and higher sensitivity to drug's side effects. Anticholinergic burden scales (ABS) were developed to quantify the anticholinergic drug burden (ADB). We aim to identify all published ABS, to compare them systematically and to evaluate their associations with clinical outcomes. METHODS: We conducted a literature search in MEDLINE and EMBASE to identify all published ABS and a Web of Science citation (WoS) analysis to track validation studies implying clinical outcomes. Quality of the ABS was assessed using an adapted AGREE II tool. For the validation studies, we used the Newcastle-Ottawa Scale and the Cochrane tool Rob2.0. The validation studies were categorized into six evidence levels based on the propositions of the Oxford Center for Evidence-Based Medicine with respect to their quality. At least two researchers independently performed screening and quality assessments. RESULTS: Out of 1297 records, we identified 19 ABS and 104 validations studies. Despite differences in quality, all ABS were recommended for use. The anticholinergic cognitive burden (ACB) scale and the German anticholinergic burden scale (GABS) achieved the highest percentage in quality. Most ABS are validated, yet validation studies for newer scales are lacking. Only two studies compared eight ABS simultaneously. The four most investigated clinical outcomes delirium, cognition, mortality and falls showed contradicting results. CONCLUSION: There is need for good quality validation studies comparing multiple scales to define the best scale and to conduct a meta-analysis for the assessment of their clinical impact.

Lavender and coriander essential oils and their main component linalool exert a protective effect against amyloid-ß neurotoxicity.

Alzheimer's disease (AD) is a neurodegenerative disorder leading to cognitive deficits and cognitive decline. Since no cure or preventing therapy is currently available to counteract AD, natural-derived compounds are investigated to find new potential neuroprotective agents for its treatment. In the present study, we tested the neuroprotective effect of lavender and coriander essential oils (EOs) and their main active constituent linalool, against the neurotoxicity elicited by Aß1-42 oligomers, a key molecular factor in the neurodegeneration of AD. Importantly, our findings on neuronally differentiated PC12 cells exposed to Aß1-42 oligomers are in accordance with previous in vivo studies reporting the neuroprotective potential of lavender and coriander EOs and linalool. We found that lavender and coriander EOs at the concentration of 10 µg/mL as well as linalool at the same concentration were able to improve viability and to reduce nuclear morphological abnormalities in cells treated with Aß1-42 oligomers for 24 hours. Lavender and coriander EOs and linalool also showed to counteract the increase of intracellular reactive oxygen species production and the activation of the pro-apoptotic enzyme caspase-3 induced by Aß1-42 oligomers. Our findings provide further evidence that these EOs and their main constituent linalool could be natural agents of therapeutic interest against Aß1-42 -induced neurotoxicity.

Olive oil and oleic acid-based self nano-emulsifying formulation of omega-3-fatty acids with improved strength, stability, and therapeutics.

AIM: To develop, characterise, and optimise SNEDDS formulation to enhance organoleptics, bioavailability, physical & oxidative-stability, and extend shelf-life of pure Ω-3-fatty acids oil for use in the food fortification industry as nutraceuticals. METHODS: SNEDDS formulations were prepared using a simple stirring technique and optimised based on in-vitro characterisation. RESULTS: The optimised SNEDDS formulation (F3) had a mean diameter of 52.9 ± 0.4 nm, PDI of 0.229 ± 0.02, zeta potential of -17.3 ± 0.1 mV, cloud temperature of 92 ± 0.2 °C, self-emulsification time of 50 ± 0.2 sec, and stable under accelerated stability conditions. Intestinal permeability study on rat ileum depicted absorption of 88.5 ± 0.2% DHA at 5 h for F3 formulation in comparison to 61.5 ± 0.2% for commercial counterpart. F3 formulation exhibited better therapeutics for melamine-induced cognitive dysfunction. CONCLUSIONS: The developed Ω-3-loaded SNEDDS heralds the future for an efficacious, safer, and higher strength formulation intended as a better substitute for currently available formulations.

Silver Nanoparticles Impair Cognitive Functions and Modify the Hippocampal Level of Neurotransmitters in a Coating-Dependent Manner.

Due to their potent antibacterial properties, silver nanoparticles (AgNPs) are widely used in industry and medicine. However, they can cross the brain-blood barrier, posing a risk to the brain and its functions. In our previous study, we demonstrated that oral administration of bovine serum albumin (BSA)-coated AgNPs caused an impairment in spatial memory in a dose-independent manner. In this study, we evaluated the effects of AgNPs coating material on cognition, spatial memory functioning, and neurotransmitter levels in rat hippocampus. AgNPs coated with BSA (AgNPs(BSA)), polyethylene glycol (AgNPs(PEG)), or citrate (AgNPs(Cit)) or silver ions (Ag+) were orally administered at a dose of 0.5 mg/kg b.w. to male Wistar rats for a period of 28 days, while the control (Ctrl) rats received 0.2 mL of water. The acquisition and maintenance of spatial memory related to place avoidance were assessed using the active allothetic place avoidance task, in which rats from AgNPs(BSA), AgNPs(PEG), and Ag+ groups performed worse than the Ctrl rats. In the retrieval test assessing long-term memory, only rats from AgNPs(Cit) and Ctrl groups showed memory maintenance. The analysis of neurotransmitter levels indicated that the ratio between serotonin and dopamine concentration was disturbed in the AgNPs(BSA) rats. Furthermore, treatment with AgNPs or Ag+ resulted in the induction of peripheral inflammation, which was reflected by the alterations in the levels of serum inflammatory mediators. In conclusion, depending on the coating material used for their stabilization, AgNPs induced changes in memory functioning and concentration of neurotransmitters.

Antidopaminergic treatment is associated with reduced chorea and irritability but impaired cognition in Huntington's disease (Enroll-HD).

OBJECTIVES: Alterations in dopamine neurotransmission underlie some of the clinical features of Huntington's disease (HD) and as such are a target for therapeutic intervention, especially for the treatment of chorea and some behavioural problems. However, justification for such an intervention is mainly based on case reports and small open label studies and the effects these drugs have on cognition in HD remain unclear. METHODS: In this study, we used the Enroll-HD observational database to assess the effects of antidopaminergic medication on motor, psychiatric and cognitive decline, over a 3-year period. We first looked at the annual rate of decline of a group of HD patients taking antidopaminergic medication (n=466) compared with an untreated matched group (n=466). The groups were matched on specified clinical variables using propensity score matching. Next, we studied a separate group of HD patients who were prescribed such medications part way through the study (n=90) and compared their rate of change before and after the drugs were introduced and compared this to a matched control group. RESULTS: We found that HD patients taking antidopaminergic medication had a slower progression in chorea and irritability compared with those not taking such medications. However, this same group of patients also displayed significantly greater rate of decline in a range of cognitive tasks. CONCLUSION: In conclusion we found that antidopaminergic treatment is associated with improvements in the choreic movements and irritability of HD but worsens cognition. However, further research is required to prospectively investigate this and whether these are causally linked, ideally in a double-blind placebo-controlled trial.

Chemoradiotherapy with temozolomide after high-dose methotrexate for primary CNS lymphoma: a multicenter phase I study of a response-adapted strategy.

This study aimed to define the maximum tolerated dose (MTD) of temozolomide (TMZ) concurrent with radiotherapy (RT) after high-dose methotrexate (HD-MTX) for newly diagnosed primary central nervous system lymphoma (PCNSL). Adult patients with PCNSL were treated according to a response-adapted strategy. HD-MTX (3.5 g/m2) was followed by concomitant RT and escalating TMZ (50-60-75 mg/m2/day, 5 days/week). The total radiation dose was modulated according to the patient's response to HD-MTX. All patients received 30 Gy to the whole brain plus leptomeninges to C2, including the third posterior of the orbital cavity (clinical target volume 2; CTV2), plus 6, 10, or 16 Gy to the primary site, including the residual mass (CTV1), if a complete response (CR), partial response (PR)/stable disease (SD), or progressive disease (PD) was observed, respectively. Acute toxicities were graded according to the RTOG-EORTC criteria. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity or grade 3-4 hepatic toxicity, although 75 mg/m2/day was the maximum dose regardless of DLT. Neurocognitive function was evaluated using the Mini-Mental State Examination. Three patients were enrolled at each TMZ dose level (total = 9 patients). Twelve lesions were treated. Six patients received 2 cycles of HD-MTX, while 3 received only 1 cycle because of hepatic or renal toxicity. All patients completed chemoradiotherapy without interruptions. No DLT events were recorded. TMZ appears to be tolerable at a dose of 75 mg/m2/day when administered concomitantly with radiotherapy and after HD-MTX.