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.

[Asthenic disorders correction with Recognan]. / Korrektsiya astenicheskikh sostoyanii preparatom Rekognan.

Asthenia, asthenic syndrome, asthenic condition, asthenic reaction, asthenic disorders are terms that describe the state of «impotence¼. Fatigue that occurs against the background of habitual physical or intellectual stress for a person, and persists after rest, is asthenia. For people of the older age group, the term senile asthenia syndrome is used. Asthenia manifests itself with increased fatigue and exhaustion, mood instability, increased irritability, sleep disorders. Asthenic conditions manifest themselves along with a decrease in physical activity, increased cognitive and mental fatigue. Asthenic syndrome (AS) are considered as an integral part of cardiovascular diseases (CVD), as one of the manifestations of cerebrovascular pathology. Senile asthenia syndrome (SAS) is a geriatric syndrome characterized by an age-associated decrease in the physiological reserve and functions of many body systems, including cognitive functions. One of the drugs that has a positive effect on the severity of AS and improves the state of cognitive functions is the domestic drug Recognan (citicoline). The effectiveness of Recognan in the treatment of AS in patients with CVD, SAS, and post-COVID asthenia has been shown. It is recommended to prescribe Recognan orally at 500 mg / day for 30 days. Recognan has a nootropic and antiasthenic effect.

[Neurometabolic therapy of mild cognitive impairment in patients with chronic cerebral ischemia]. / Neirometabolicheskaya terapiya umerennykh kognitivnykh rasstroistv u patsientov s khronicheskoi ishemiei golovnogo mozga.

OBJECTIVE: To evaluate the effect of a sequential therapy regimen with Mexidol (500 mg injections intravenously for 14 days) and Mexidol FORTE 250 (250 mg tablets 3 times a day for 60 days) on higher cortical functions in patients with moderate cognitive disorders in chronic cerebral ischemia. MATERIAL AND METHODS: A comparative, prospective study included 63 patients with chronic cerebral ischemia with moderate cognitive impairment. All patients received basic therapy aimed at reducing risk factors (antihypertensive, antithrombotic drugs as indicated). Patients of the main group (30 people: 12 men, 18 women) received Mexidol intravenously 500 mg in 100 ml of 0.9% NaCl solution once a day for 14 days, then Mexidol FORTE 250 (film-coated tablets) 250 mg 3 times a day for the next 60 days. The comparison group consisted of 33 patients (14 men, 19 women) who received only basic therapy. The groups were comparable in terms of age, sex characteristics and severity of cognitive deficit. We examined cognitive status (MoCA scale, Frontal Dysfunction Battery, 10 Word Memorization tests), severity of asthenia (MFI-20 scale), anxiety and depression (HADS scale), patient's subjective assessment of the dynamics of the condition (CGI-improvement scale) in 1st, 14th and 74th±5 days of observation. On days 1 and 74±5 of observation, patients were examined using transcranial magnetic stimulation to study the neuronal activity of the cerebral cortex. RESULTS: In the main group, at the time of completion of taking Mexidol and Mexidol FORTE 250, a pronounced cognitive regression was noted (MoCA scale +3 points, difference with the comparison group 1 point (p<0.0001); Frontal Dysfunction Battery test +4 points, difference with comparison group 2 points (p<0.001); memory test «10 words¼ +2 points, difference with the comparison group 1 point (p<0.05), emotional (HADS anxiety scale -8 points, difference with the comparison group 3 points (p<0.001), depression -3.5 points, difference with the comparison group 1.5 points (p<0.01), asthenic disorders (MFI-20 scale -30 points, difference with the comparison group 15.5 points (p<0.01), improvement in the well-being of patients (CGI-improvement scale -2 points, difference with the comparison group 1 point (p<0.0001). According to the transcranial magnetic stimulation performed, a statistically significant decrease in the central motor conduction time at the level of 1 and 2 motor neurons of the pyramidal tract bilaterally from the start to the end of therapy with Mexidol and Mexidol FORTE 250 was determined (p<0.01). An inverse correlation was found between the time of central motor conduction and the results of the Frontal Dysfunction Battery test at the same time points with left-sided localization of 1 motor neuron (p<0.01). The results of a study of the use of sequential therapy with Mexidol 500 mg IV drip 1 time per day for 14 days followed by oral administration of Mexidol FORTE 250 1 tablet 3 times a day for 60 days indicate its clinical effectiveness and safety in patients with chronic cerebral ischemia with mild cognitive impairment, and also confirm its importance for preventing the progression of cognitive disorders.

Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings.

BACKGROUND: Numerous studies have implicated abnormal insulin-like growth factor 1 (IGF-1) in the pathophysiology of schizophrenia, but findings have been inconsistent. METHODS: We conducted a meta-analysis to compare IGF-1 levels in schizophrenia patients with healthy controls and explored factors contributing to variability between estimates. In an independent sample (58 chronic schizophrenia patients and 30 healthy controls), we investigated differences in IGF-1 levels among schizophrenia subgroups with distinct cognitive profiles, identified using k-means clustering based on five cognitive domains from The Repeatable Battery for the Assessment of Neuropsychological Status. Associations between serum IGF-1 levels and clinical and neurocognitive improvements were also examined. RESULTS: The meta-analysis revealed significantly lower serum IGF-1 levels in schizophrenia patients compared to healthy controls, albeit with high heterogeneity. Medication status, BMI, and severity of negative symptoms were identified as potential contributors to this heterogeneity. In our independent study, antipsychotic treatment led to a significant increase in IGF-1 levels, and lower pre-treatment serum IGF-1 levels correlated with greater improvement in cognitive deficits, particularly in a subgroup with more severe cognitive symptoms. CONCLUSIONS: Our findings support the "IGF-1 deficiency hypothesis" in the pathogenesis of schizophrenia. Further research is crucial to elucidate the role of IGF-1 in the cognitive impairments associated with schizophrenia.

Coconut oil ameliorates behavioral and biochemical alterations induced by D-GAL/AlCl3 in rats.

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative condition marked by cognitive impairment. Although coconut oil has been shown to be potentially beneficial in reducing AD-related cognitive deficits, information on its mechanism of action is limited. Thus, we investigated the effects of coconut oil on spatial cognitive ability and non-cognitive functions in a rat model of AD induced by G-galactose (D-GAL) and aluminum chloride (AlCl3), and examined the changes in synaptic transmission, cholinergic activity, neurotrophic factors and oxidative stress in this process. The AD model was established by administering D-GAL and AlCl3 for 90 days, while also supplementing with coconut oil during this time. Cognitive and non-cognitive abilities of the rats were evaluated at the end of the 90-day supplementation period. In addition, biochemical markers related to the pathogenesis of the AD were measures in the hippocampus tissue. Exposure to D-GAL/AlCl3 resulted in a reduction in locomotor activity, an elevation in anxiety-like behavior, and an impairment of spatial learning and memory (P < 0.05). The aforementioned behavioral disturbances were observed to coincide with increased oxidative stress and cholinergic impairment, as well as reduced synaptic transmission and levels of neurotrophins in the hippocampus (P < 0.05). Interestingly, treatment with coconut oil attenuated all the neuropathological changes mentioned above (P < 0.05). These findings suggest that coconut oil shows protective effects against cognitive and non-cognitive impairment, AD pathology markers, oxidative stress, synaptic transmission, and cholinergic function in a D-GAL/AlCl3-induced AD rat model.

Mechanisms of multi-omics and network pharmacology to explain traditional chinese medicine for vascular cognitive impairment: A narrative review.

BACKGROUND: The term "vascular cognitive impairment" (VCI) describes various cognitive conditions that include vascular elements. It increases the risk of morbidity and mortality in the elderly population and is the most common cognitive impairment associated with cerebrovascular disease. Understanding the etiology of VCI may aid in identifying approaches to target its possible therapy for the condition. Treatment of VCI has focused on vascular risk factors. There are no authorized conventional therapies available right now. The medications used to treat VCI are solely approved for symptomatic relief and are not intended to prevent or slow the development of VCI. PURPOSE: The function of Chinese medicine in treating VCI has not yet been thoroughly examined. This review evaluates the preclinical and limited clinical evidence to comprehend the "multi-component, multi-target, multi-pathway" mechanism of Traditional Chinese medicine (TCM). It investigates the various multi-omics approaches in the search for the pathological mechanisms of VCI, as well as the new research strategies, in the hopes of supplying supportive evidence for the clinical treatment of VCI. METHODS: This review used the Preferred Reporting Items for Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. Using integrated bioinformatics and network pharmacology approaches, a thorough evaluation and analysis of 25 preclinical studies published up to July 1, 2023, were conducted to shed light on the mechanisms of TCM for vascular cognitive impairment. The studies for the systematic review were located using the following databases: PubMed, Web of Science, Scopus, Cochrane, and ScienceDirect. RESULTS: We discovered that the multi-omics analysis approach would hasten the discovery of the role of TCM in the treatment of VCI. It will explore components, compounds, targets, and pathways, slowing the progression of VCI from the perspective of inhibiting oxidative stress, stifling neuroinflammation, increasing cerebral blood flow, and inhibiting iron deposition by a variety of molecular mechanisms, which have significant implications for the treatment of VCI. CONCLUSION: TCM is a valuable tool for developing dementia therapies, and further research is needed to determine how TCM components may affect the operation of the neurovascular unit. There are still some limitations, although several research have offered invaluable resources for searching for possible anti-dementia medicines and treatments. To gain new insights into the molecular mechanisms that precisely modulate the key molecules at different levels during pharmacological interventions-a prerequisite for comprehending the mechanism of action and determining the potential therapeutic value of the drugs-further research should employ more standardized experimental methods as well as more sophisticated science and technology. Given the results of this review, we advocate integrating chemical and biological component analysis approaches in future research on VCI to provide a more full and objective assessment of the standard of TCM. With the help of bioinformatics, a multi-omics analysis approach will hasten the discovery of the role of TCM in the treatment of VCI, which has significant implications for the treatment of VCI.

Cognitive impairment after recovery from COVID-19: Frequency, profile, and relationships with clinical and laboratory indices.

Cognitive impairment (CI) is regarded as a remarkable burden in COVID-19 survivors. Its prevalence and profile, and relationships with the disease clinical and laboratory indices, remain unclear. The present study investigated, in a large sample of patients recovered from COVID-19, the frequency of CI with both a face-to-face screening tool and comprehensive test battery (MCCB). The study also evaluated the profile of CI and its relationships with COVID-19 clinical and laboratory indices and with psychopathological features. Out of 1344 subjects assessed for eligibility, 736 completed the screening phase 11 months after the COVID-19 infection; 402 participated in the baseline phase and completed an in depth cognitive, clinical and laboratory assessment about one month later. More than one third of the screened subjects presented a CI (COG+); it was associated to age, education, male gender, COVID-19 severity, and presence of anosmia, dyspnea at rest and exertional dyspnea during the acute phase. COG+ subjects showed a higher severity of depression, anxiety and post-traumatic distress, and worse global functioning, than subjects without CI. The MCCB showed that 45% of the subjects had a CI involving attention, working memory, verbal learning, visual learning, and reasoning and problem solving. Finally, neurocognitive functioning was inversely correlated with LDH blood levels, a potential biomarker of disease severity. According to our findings, cognitive functioning should be routinely and periodically assessed in COVID-19 patients, especially in older subjects, who experienced more severe COVID-19 symptoms. In case of persisting dysfunctions cognitive training programs should be considered as treatment strategies.

NeuroEPO plus (NeuralCIM®) in mild-to-moderate Alzheimer's clinical syndrome: the ATHENEA randomized clinical trial.

BACKGROUND: NeuroEPO plus is a recombinant human erythropoietin without erythropoietic activity and shorter plasma half-life due to its low sialic acid content. NeuroEPO plus prevents oxidative damage, neuroinflammation, apoptosis and cognitive deficit in an Alzheimer's disease (AD) models. The aim of this study was to assess efficacy and safety of neuroEPO plus. METHODS: This was a double-blind, randomized, placebo-controlled, phase 2-3 trial involving participants ≥ 50 years of age with mild-to-moderate AD clinical syndrome. Participants were randomized in a 1:1:1 ratio to receive 0.5 or 1.0 mg of neuroEPO plus or placebo intranasally 3 times/week for 48 weeks. The primary outcome was change in the 11-item cognitive subscale of the AD Assessment Scale (ADAS-Cog11) score from baseline to 48 weeks (range, 0 to 70; higher scores indicate greater impairment). Secondary outcomes included CIBIC+, GDS, MoCA, NPI, Activities of Daily Living Scales, cerebral perfusion, and hippocampal volume. RESULTS: A total of 174 participants were enrolled and 170 were treated (57 in neuroEPO plus 0.5 mg, 56 in neuroEPO plus 1.0 mg and 57 in placebo group). Mean age, 74.0 years; 121 (71.2%) women and 85% completed the trial. The median change in ADAS-Cog11 score at 48 weeks was -3.0 (95% CI, -4.3 to -1.7) in the 0.5 mg neuroEPO plus group, -4.0 (95% CI, -5.9 to -2.1) in the 1.0 mg neuroEPO plus group and 4.0 (95% CI, 1.9 to 6.1) in the placebo group. The difference of neuroEPO plus 0.5 mg vs. placebo was 7.0 points (95% CI, 4.5-9.5) P = 0.000 and between the neuroEPO plus 1.0 mg vs. placebo was 8.0 points (95% CI, 5.2-10.8) P = 0.000. NeuroEPO plus treatment induced a statistically significant improvement in some of clinical secondary outcomes vs. placebo including CIBIC+, GDS, MoCA, NPI, and the brain perfusion. CONCLUSIONS: Among participants with mild-moderate Alzheimer's disease clinical syndrome, neuroEPO plus improved the cognitive evaluation at 48 weeks, with a very good safety profile. Larger trials are warranted to determine the efficacy and safety of neuroEPO plus in Alzheimer's disease. TRIAL REGISTRATION: https://rpcec.sld.cu Identifier: RPCEC00000232.

Receptor-Independent Therapies for Forensic Detainees with Schizophrenia-Dementia Comorbidity.

Forensic institutions throughout the world house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, psychiatric treatment, and nutrition led to an unmatched longevity in this population, which previously lived, on average, 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management, increasing healthcare expenditures. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who have aged on dopamine-blocking agents. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss may contribute to the development of early dementia. Taken together, increased lifespan and the subsequent cognitive deficit observed in long-term forensic institutions raise questions and dilemmas unencountered by the previous generations of clinicians. These include: does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? Can patients with schizophrenia and dementia meet the Dusky standard to stand trial? Should neurocognitive disorders in the elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we hypothesize that gray matter loss is the core symptom of schizophrenia which leads to dementia. We hypothesize further that strategies to delay or stop gray matter depletion would not only improve the schizophrenia sustained recovery, but also avert the development of major neurocognitive disorders in people living with schizophrenia. Based on this hypothesis, we suggest utilization of both receptor-dependent and independent therapeutics for chronic psychosis.

[Cognitive impairment in children with organic asthenic disorder]. / Kognitivnye narusheniya u detei s organicheskim astenicheskim rasstroistvom.

OBJECTIVE: To study cognitive impairment and neurophysiological characteristics in children with organic asthenia, as well as the effectiveness of the drug Cogitum in the treatment of this pathology. MATERIAL AND METHODS: The main study group included 40 children aged 8 to 10 years with a diagnosis of «Organic asthenic disorder¼ (F06.6). The control group consisted of 30 children aged 8 to 10 years without manifestations of asthenia. The following research methods were used in the work: the asthenic state scale (ASS) by L.D. Malkova to assess the severity of asthenic syndrome, the S. Lee «SCT¼ (sluggish cognitive tempo) scale to assess manifestations of low cognitive tempo, the «Random Access Memory¼ method to quantify working memory, the TOVA (The Test of Variables of Attention) computer test to quantify assessment of attention disorders and impulsivity level, electroencephalogram (routine and spectral analysis) (p<0.05). For the treatment of patients from the study group, the drug Cogitum was used at a dose of 10 ml of a drinking solution per day for 30 days. RESULTS: In was shown that children from the study group were characterized by a decrease in working memory (7.8±2.9 vs 14.9±5.4), a statistically significant increase in SCT scores (p<0.05), a significantly greater degree of inattention and impulsivity with a tendency to an increase in the number of errors in the second half of the TOVA test (p<0.05). Comparative analysis of EEG relative power data showed a statistically significant increase in the power of waves in the alpha and theta ranges in the fronto-central leads of both hemispheres in the group of children with organic asthenic disorder (p<0.05). When re-evaluating the condition of children after treatment, a statistically significant decrease in the manifestations of asthenia on the ASS scale was recorded in 77.5% of cases. At the same time, there was a significant improvement in attention, memory, and indicators characterizing a low cognitive pace. The results of an electroencephalographic study after a course of treatment showed a decrease in the relative power of the EEG in the theta and alpha ranges in the anterior sections of the cerebral cortex (p<0.05), which indicates an increase in the level of activation of neocortical structures. CONCLUSION: Thus, the use of the drug Cogitum for the treatment of organic asthenic disorder leads not only to a decrease in asthenia and cognitive impairment, but also to an improvement in the functional state of the brain.

[Recognan (citicoline) efficacy and safety in cognitive impairment correction of various nosological forms]. / Effektivnost' i bezopasnost' Rekognana (tsitikolin) pri korrektsii kognitivnykh narushenii razlichnoi etiologii.

Insufficiency of a choline derivative (acetylcholine) can lead to the development of cognitive impairment (CI). One of the most well-known and well-studied medical drugs (MD) containing choline and having neuroprotective properties is citicoline (Recognan). A number of studies have demonstrated the effectiveness of Recognan in relation to mild CI, chronic cerebrovascular diseases (CVD), acute vascular disorders (including post-traumatic genesis). Recognan improves memory and other cognitive functions in healthy young people against the background of asthenia due to stress or increased cognitive and emotional stress or infection, and also has a preventive effect on fading cognitive functions in the process of age-related changes. The duration of neuroprotection can reach 6 months or more - up to 12 months, depending on the patient's condition. Therapy regimens include two-stage Recognan prescribing: with CVD intramuscularly (i/m) at 1000 mg /d for 30 days, in the acute period of ischemic stroke, i/m or intravenously (i/v) at 1000 mg every 12 hours from the first day after diagnosis, 3-5 days after the start of therapy, with preservation functions of swallowing, it is possible to switch to per oral (p/o) drug administration.

Roles of Omega-3 Polyunsaturated Fatty Acids in Managing Cognitive Impairment in Chronic Obstructive Pulmonary Disease: A Review.

Chronic obstructive pulmonary disease (COPD) contributes significantly to the death of people worldwide, especially the elderly. An essential feature of COPD is pulmonary inflammation, which results from long-term exposure to noxious substances from cigarette smoking and other environmental pollutants. Pulmonary inflammatory mediators spill over to the blood, leading to systemic inflammation, which is believed to play a significant role in the onset of a host of comorbidities associated with COPD. A substantial comorbidity of concern in COPD patients that is often overlooked in COPD management is cognitive impairment. The exact pathophysiology of cognitive impairment in COPD patients remains a mystery; however, hypoxia, oxidative stress, systemic inflammation, and cerebral manifestations of these conditions are believed to play crucial roles. Furthermore, the use of medications to treat cognitive impairment symptomatology in COPD patients has been reported to be associated with life-threatening adverse effects, hence the need for alternative medications with reduced side effects. In this Review, we aim to discuss the impact of cognitive impairment in COPD management and the potential mechanisms associated with increased risk of cognitive impairment in COPD patients. The promising roles of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in improving cognitive deficits in COPD patients are also discussed. Interestingly, ω-3 PUFAs can potentially enhance the cognitive impairment symptomatology associated with COPD because they can modulate inflammatory processes, activate the antioxidant defence system, and promote amyloid-beta clearance from the brain. Thus, clinical studies are crucial to assess the efficacy of ω-3 PUFAs in managing cognitive impairment in COPD patients.

[Cognitive impairment and tactics of using the drug Cerebrolysin. Resolution of the International Council of Experts (May 12, 2023)]. / Kognitivnye narusheniya i taktika primeneniya preparata Tserebrolizin. Rezolyutsiya mezhdunarodnogo soveta ekspertov (12 maya 2023 g.).

The aging of the population and the associated increase in the share of cognitive impairments in the structure of a wide range of diseases are a serious challenge for modern healthcare. Difficulties in the treatment of cognitive disorders are determined by many factors, including the age of patients, comorbidity, forced polypragmasia and the adequacy of the dosage of drugs that restore cognitive activity. The experts discussed information about the therapeutic potential of the drug Cerebrolysin in the treatment of cognitive disorders of various origins, stated significant experience of its effective and safe use in many clinical studies in mild and moderate forms of dementia. At the same time, there was a lack of consistent and systematic data on the dosage regimen, frequency, and duration of use of the drug in different forms of cognitive impairment and the degree of their severity. The aim of the international council of experts was to determine the optimal dosage regimens of the drug Cerebrolysin in patients with various etiologies and severity of cognitive impairment. The result of the work was the approval of a unified scheme for the use of the drug Cerebrolysin, considering the severity of the disease and its duration.

Selective serotonin reuptake inhibitor use, age-related neuropathology and cognition in late-life.

The objective of this study was to evaluate an association of selective serotonin reuptake inhibitor (SSRI) use with late life cognitive decline and further investigate the association with brain pathology. Using the data are from two harmonized clinical-pathologic cohort studies with annual cognitive testing we found that SSRI use was associated with significantly faster global cognitive decline and this association was present in those with and without pre-existing cognitive impairment at the time of SSRI initiation. In separate analyses of persons who died during the study and underwent neuropathologic examination, SSRI use was related to higher level of paired helical filament tau tangles and faster rate of global cognitive decline. However, when SSRI use and tangles were included in the same model, the association of SSRI use with rate of global cognitive decline was reduced by more than 50% and no longer statistically significant. SSRI use was associated with higher postmortem level of tau tangles, possibly because SSRI are being used to treat neurobehavioral symptoms associated with dementia, and this relationship appears to partly account for the association of SSRI use with more rapid cognitive decline.

Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial.

BACKGROUND: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. OBJECTIVE: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. METHODS: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. RESULTS: With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit. CONCLUSIONS: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients' decline of -12.8 SIB points.

Folate deprivation induced neuroinflammation impairs cognition.

Nutritional status is associated with many neurocognitive diseases. Folate is one of the micronutrients, and its deficiency is associated with clinical outcomes of neurological diseases. Nevertheless, molecular mechanism behind the folate deficiency induced neurological disorders are not well-known. We have hypothesized that folate-deficiency is a cardinal determinant responsible for manifestation of cognitive impairment through inflammation mediated neurodegenerative pathologies. Objective of the current study was to assess whether folate deficiency is associated with cognitive dysfunction or is merely an epiphenomenon and to identify the underlying mechanisms. We developed folate insufficient zebrafish model through intra-peritoneal treatment of methotrexate. T-maze test was carried to assess the spatial learning and memory of the fish. Higher latency of the folate-deprived zebrafishes in the T-maze test is a reflection of altered cognition. This result is supported by declined levels of dopamine and serotonin, neurotransmitters linked with learning and memory. Elevated IL-6 and CRP in peripheral blood, along with increased expression of NF-ĸB in brain indicates manifestation of neuroinflammation. Indeed, together with upregulation of maptb gene it can be implied that folate deficiency acts as a risk factor for neurodegeneration in the form of tauopathies. Furthermore, diminished localisation of synaptopodin, a protein linked to neural plasticity, suggests that neuroinflammation caused by folate deprivation hampers the plasticity of brain. Histological analysis of brain revealed the development of histopathological features including spongiform degeneration and neuronal loss in folate deprived condition. We thus conclude that folate deficiency results in NF-ĸB activation, which through multiple processes mediated by neuroinflammation could lead to cognitive decline.

Effectiveness of vitamin-B supplements on cognition in older adults: A meta-analysis.

OBJECTIVES: We aimed to investigate the efficacy of B-vitamin and folic acid supplementation in slowing down cognitive function decline among older adults. METHODS: We searched databases for trials comparing B-vitamin and folate supplementation versus placebo in older adults identified with or without impaired cognition. RESULTS: 23 articles were eligible and included in this meta-analysis. The mean difference (MD) in homocysteine levels was significant between the compared groups (MD:-4.52; 95%CI:-5.41 to 3.63, P < 0.001). However, the difference in the Mini-Mental State Examination (MMSE) was non-significant between the compared groups with or without cognitive impairment (MD:0.19; 95%CI: -0.148 to 0.531, P = 0.27), and (MD:0.04; 95%CI:-0.1 to 0.18, P = 0.59), respectively. The difference in Clinical Dementia Rating-sum of box (CDR-SOB) scores was non-significant (MD:-0.16; 95%CI:-0.49 to 0.18; P = 0.36). CONCLUSIONS: B-vitamin and folate supplementations significantly reduced homocysteine levels. However, it failed to provide significant benefits over placebo in preventing or slowing the decline in cognitive function.

Yuanzhi Powder inhibits tau pathology in SAMP8 mice: Mechanism research of a traditional Chinese formula against Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Yuanzhi Powder (YZP), a classical Chinese medicine formula, is good at tonifying heart-Qi and improving cognitive ability. YZP has been reported to show therapeutic effect on alleviating the symptoms of Alzheimer's disease (AD). AIM OF THE STUDY: This study was conducted to observe the effects of YZP on improving the cognitive abilities of SAMP8 mice, and explore the involved mechanisms on inhibiting the excessive accumulation of phosphorylated tau. MATERIAL AND METHODS: Thirty SAMP8 mice were randomly divided into five groups: AD group, AD + DO group, AD + YZP group, AD + LAC group and AD + LAC + YZP group. Age-matched SAMR1 mice were served as CTL group. AD + LAC group and AD + LAC + YZP group received 1 µg Lactacystin solution via intra-cerebroventricular injection. All mice (except the CTL group and AD + LAC group) were intragastrically administrated for 8 consecutive weeks. Then, the Morris Water Maze (MWM) test was conducted for evaluation of learning and memory abilities. The pathological changes of hippocampal CA1 were observed by Hematoxylin & eosin (H&E) staining. The expression of 26S proteasome in the hippocampus was measured by Western Blot (WB) and immunohistochemistry (IHC). The expressions of total tau (Tau5) and hyperphosphorylated tau (pS199, pT231 and pS396) were detected by WB. The aggregation of hyperphosphorylated tau and the binding ability of tau protein to microtubules were evaluated respectively by immunostaining and Thioflavin-S staining and double-label immunofluorescence. RESULTS: SAMP8 mice showed serious cognitive impairment in behavioral tests. However, treatment of YZP significantly ameliorated the cognitive deficits of SAMP8 mice. The H&E staining suggested that YZP could protect against neuronal loss in SAMP8 mice. The IHC and WB results showed that YZP increases 26S proteasome expression in SAMP8 mice and 26S proteasome expression was effectively inhibited by Lactacystin. Meanwhile, The WB results demonstrated that YZP can inhibit the expression of hyperphosphorylated tau (pT231, pS396 and pS199). Furthermore, the immunostaining and Thioflavin-S staining and double-label immunofluorescence results indicated that YZP attenuates the excessive aggregation of hyperphosphorylated tau and enhances the binding ability of tau to stabilize microtubules in SAMP8 mice. CONCLUSIONS: YZP could enhance cognitive performance and learning of AD, ameliorate tau pathology and significantly improve the binding ability of tau to microtubules, based potentially on inhibiting the excessive aggregation of hyperphosphorylated tau via the 26Sproteasome pathway but not necessarily the only one.