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The Journal of Head Trauma... Jun 2024The purpose of this review is to systematically assess primary research publications on known genetic variants, which modify the risk for symptoms or dysfunction...
OBJECTIVE
The purpose of this review is to systematically assess primary research publications on known genetic variants, which modify the risk for symptoms or dysfunction persisting 30 days or more following mild traumatic brain injury (mTBI).
SUMMARY OF REVIEW
A search of PubMed and Embase from inception through June 2022 identified 42 studies that associated genetic variants with the presence of symptoms or cognitive dysfunction 30 days or more following mTBI. Risk of bias was assessed for each publication using the Newcastle Ottawa Scale (NOS). Fifteen of the 22 studies evaluating apolipoprotein E ( APOE ) ɛ4 concluded that it was associated with worse outcomes and 4 of the 8 studies investigating the brain-derived neurotrophic factor ( BDNF ) reported the Val66Met allele was associated with poorer outcomes. The review also identified 12 studies associating 28 additional variants with mTBI outcomes. Of these, 8 references associated specific variants with poorer outcomes. Aside from analyses comparing carriers and noncarriers of APOE ɛ4 and BDNF Val66Met, most of the reviewed studies were too dissimilar, particularly in terms of specific outcome measures but also in genes examined, to allow for direct comparisons of their findings. Moreover, these investigations were observational and subject to varying degrees of bias.
CONCLUSIONS
The most consistent finding across articles was that APOE ɛ4 is associated with persistent post-mTBI impairment (symptoms or cognitive dysfunction) more than 30 days after mTBI. The sparsity of other well-established and consistent findings in the mTBI literature should motivate larger, prospective studies, which characterize the risk for persistent impairment with standardized outcomes in mTBI posed by other genetic variants influencing mTBI recovery.
PubMed: 38668678
DOI: 10.1097/HTR.0000000000000907 -
Current Pain and Headache Reports Apr 2024Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide... (Review)
Review
PURPOSE OF REVIEW
Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide significant biological information for the pathophysiology of the disease but may also reveal biomarkers for diagnosis or therapeutic targets. The present systematic review aims to synthesize the evidence regarding the proteome of adult patients with FMS using data from observational studies.
RECENT FINDINGS
An extensive literature search was conducted in MEDLINE/PubMed, CENTRAL, and clinicaltrials.gov from inception until November 2022. The study protocol was published in OSF. Two independent reviewers evaluated the studies and extracted data. The quality of studies was assessed using the modified Newcastle-Ottawa scale adjusted for proteomic research. Ten studies fulfilled the protocol criteria, identifying 3328 proteins, 145 of which were differentially expressed among patients with FMS against controls. The proteins were identified in plasma, serum, cerebrospinal fluid, and saliva samples. The control groups included healthy individuals and patients with pain (inflammatory and non-inflammatory). The most important proteins identified involved transferrin, α-, β-, and γ-fibrinogen chains, profilin-1, transaldolase, PGAM1, apolipoprotein-C3, complement C4A and C1QC, immunoglobin parts, and acute phase reactants. Weak correlations were observed between proteins and pain sensation, or quality of life scales, apart from the association of transferrin and a2-macroglobulin with moderate-to-severe pain sensation. The quality of included studies was moderate-to-good. FMS appears to be related to protein dysregulation in the complement and coagulation cascades and the metabolism of iron. Several proteins may be dysregulated due to the excessive oxidative stress response.
PubMed: 38652420
DOI: 10.1007/s11916-024-01244-4 -
CNS Neuroscience & Therapeutics Apr 2024Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as... (Review)
Review
BACKGROUND
Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.
AIMS
Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.
METHODS
A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.
RESULTS
Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).
DISCUSSION
The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).
CONCLUSION
The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.
Topics: Humans; Alzheimer Disease; CCAAT-Enhancer-Binding Protein-beta; Disease Progression; Animals; Amyloid beta-Peptides
PubMed: 38644578
DOI: 10.1111/cns.14721 -
Medicine Apr 2024Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial.
OBJECTIVE
The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis.
METHODS
We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results.
RESULTS
All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs.
CONCLUSION
ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.
Topics: Humans; Alzheimer Disease; Donepezil; Galantamine; Memantine; Molecular Docking Simulation; Cholinesterase Inhibitors; Rivastigmine
PubMed: 38640313
DOI: 10.1097/MD.0000000000037799 -
Dementia and Geriatric Cognitive... Apr 2024Vascular dementia (VaD), a neurocognitive impairment directly related to vascular injury, is the second most common cause of age-related dementia. Although numerous...
INTRODUCTION
Vascular dementia (VaD), a neurocognitive impairment directly related to vascular injury, is the second most common cause of age-related dementia. Although numerous studies have investigated candidate genetic polymorphisms associated with VaD in Asia, the genetics of VaD remains unclear.
METHODS
This review provides an updated meta-analysis of genetic polymorphisms associated with VaD in Asians, using the PRISMA guidelines. Published literature up to May 2021 was extracted from the PubMed, Scopus, Ovid, and EBSCOhost databases. Meta-analysis was conducted using the Open Meta analyst, Review Manager, and MedCalc® Statistical Software. Trial sequential analysis (TSA) was performed using TSA viewer software.
RESULTS
A total of 46 eligible studies, comprising 23 genes and 35 single nucleotide polymorphisms, were retrieved. The meta-analysis was conducted on the following genetic polymorphisms, APOE ε2/3/4, MTHFR rs1801131, ACE rs4340 (I/D) gene polymorphism, and a PSEN1 intron 8 variant. The pooled odds ratio (ORs) revealed a significant increase in the risk of VaD in the apolipoprotein E (APOE) ε4 allelic model (OR, 1.79, p < 0.001), and the methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism T allele in the allelic model (OR, 1.23, p = 0.013).
CONCLUSION
Our findings provide evidence that genetic polymorphisms of the APOE ε4 allele and MTHFR rs1801133 T allele increase the risk of developing VaD in Asians. However, future large-scale investigations examining particularly on South-Eastern and West-Asian populations are highly recommended.
PubMed: 38636474
DOI: 10.1159/000538864 -
Current Issues in Molecular Biology Mar 2024Subjective cognitive decline (SCD) has been described as a probable early stage of dementia, as it has consistently appeared to precede the onset of objective cognitive... (Review)
Review
Subjective cognitive decline (SCD) has been described as a probable early stage of dementia, as it has consistently appeared to precede the onset of objective cognitive impairment. SCD is related to many risk factors, including genetic predisposition for dementia. The Apolipoprotein (APOE) ε4 allele, which has been thoroughly studied, seems to explain genetic risk for SCD only partially. Therefore, we aimed to summarize existing data regarding genetic factors related to SCD, beyond APOE ε4, in order to improve our current understanding of SCD. We conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keywords "subjective cognitive decline" and "genetic predisposition" with specific inclusion and exclusion criteria. From the 270 articles identified, 16 were finally included for the qualitative analysis. Family history of Alzheimer's disease (AD) in regard to SCD was explored in eight studies, with conflicting results. Other genes implicated in SCD, beyond APOE ε4, were investigated in six studies, which were not strong enough to provide clear conclusions. Very few data have been published regarding the association of polygenic risk for AD and SCD. Thus, many more genes related to AD must be studied, with polygenic risk scores appearing to be really promising for future investigation.
PubMed: 38534745
DOI: 10.3390/cimb46030129 -
Multiple Sclerosis and Related Disorders May 2024Cognitive impairment is highly prevalent in multiple sclerosis (MS) with poorly understood underlying mechanisms. Lipids are considered to be associated with MS... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cognitive impairment is highly prevalent in multiple sclerosis (MS) with poorly understood underlying mechanisms. Lipids are considered to be associated with MS progression through the inflammatory and oxidative stress pathways, brain atrophy, cellular signaling, and tissue physiology. In addition, serum lipids are proposed as a modifiable factor affecting the neuropsychiatric condition; therefore, this study aims to assess the association between serum lipid levels and cognitive outcomes in MS.
METHODS
This study was carried out following the PRISMA 2020 statement. A systematic search was conducted in PubMed, Scopus, Web of Science, and Embase in March 2023, and the Joanna Briggs Institute (JBI)'s critical appraisal tools were utilized for risk of bias (RoB) assessments in the included studies. The quantitative synthesis was performed with the comprehensive meta-analysis (CMA3) software.
RESULTS
Out of 508 screened records, 7 studies were eventually found to meet our inclusion criteria. In two studies, the course of MS in the sample of the study was only Relapsing-Remitting MS (RRMS), whereas the other five studies' sample was a combination of different phenotypes. Studies utilized different scales such as Minimal Assessment of Cognitive Function in MS (MACFIMS), Brief International Cognitive Assessment for MS (BICAMS), Montreal Cognitive Assessment (MoCA), Brief Repeatable Battery of Neuropsychological Tests (BRB-N) for cognitive evaluations. Dealing with possible confounders such as age, disease duration and level of disability was the most common possible source of bias in the included studies. One study revealed an inverse relationship between serum levels of apolipoproteins (including ApoA-I, ApoB, and ApoB/ApoA-I) and Symbol Digit Modalities Test (SDMT) scores. Also, a correlation between 24S-hydroxycholesterol (24OHC) serum concentrations and SDMT score was reported in one study. The association between serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) and different aspects of cognitive function was reported in the studies; however, serum levels of high-density lipoprotein cholesterol (HDL) were not found to be associated. The quantitative synthesis revealed a significant correlation between TC and the MoCA scores (r =-0.238; 95 %CI: -0.366 to -0.100; p-value = 0.001); however, the correlation between TG levels and MoCA were not statistically significant (r:-0.070; 95 %CI: -0.209 to 0.072; p-value: 0.334). In addition, the mata-analyses were not associated with significant findings regarding the correlation between lipid profiles (including HDL, LDL, TG, and TC) and other cognitive assessment scales including SDMT, Brief Visuospatial Memory Test (BVMT), and California Verbal Learning Test (CVLT) (p-values>0.05).
DISCUSSION
Available evidence suggested a link between TC and LDL with cognitive outcomes of MS patients which was not evident in our quantitative synthesis. The limited number of studies, high RoB, different cognitive assessment scales and reporting methods, and the cross-sectional design of the included studies, were the main limitations that alleviate the clinical significance of the findings of this study and suggested further investigations on this topic.
FUNDING AND REGISTRATION
The research protocol was approved and supported by the Student Research Committee, Tabriz University of Medical Sciences (grant number: 71,909). This study is registered in the international prospective register of systematic reviews (PROSPERO ID: CRD42023441625).
Topics: Humans; Cognitive Dysfunction; Multiple Sclerosis; Lipids
PubMed: 38522226
DOI: 10.1016/j.msard.2024.105530 -
Medicine Mar 2024Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to be effective and safe in patients with stable angina and previous myocardial... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to be effective and safe in patients with stable angina and previous myocardial infarction. However, evidence for initiating their use in patients hospitalized with acute coronary syndrome (ACS) is limited. This systematic review and meta-analysis was performed to provide more clinical evidence.
METHODS
PubMed, Embase, OVID, Cochrane Library and ClinicalTrials.gov were systematically searched for eligible randomized controlled trials up to March 20, 2023. The risk ratios, standardized mean differences and 95% confidence intervals were calculated for primary and secondary outcomes. The bias risk of the included studies was assessed using the Cochrane RoB 2 criteria.
RESULTS
About 8 randomized controlled trials involving 1255 inpatients with ACS were included. PCSK9 inhibitor treatment significantly reduced low-density lipoprotein cholesterol (LDL-C) (SMD -1.28, 95% CI -1.76 to -0.8, P = .001), triglycerides (TG) (SMD -0.93, 95% CI -1.82 to -0.05, P = .03), total cholesterol (SMD -1.36, 95% CI -2.01 to -0.71, P = .001), and apolipoprotein B (Apo B) (SMD -0.81, 95% CI -1.09 to -0.52, P = .001) within approximately 1 month. PCSK9 inhibitor treatment significantly reduced the total atheroma volume (TAV) (SMD -0.33, 95% CI -0.59 to -0.07, P = .012). It also significantly increased minimum fibrous cap thickness (FCT) (SMD 0.41, 95% CI 0.22-0.59, P = .001) in long-term follow-up (>6 months). PCSK9 inhibitor treatment significantly reduced the risk of readmission for unstable angina (RR 0.32, 95% CI 0.12-0.91, P = .032) in short-term follow-up (<6 months). There were no significant differences in all-cause mortality, cardiovascular death, myocardial infarction, ischemic stroke, coronary revascularization or heart failure. Only nasopharyngitis (RR 1.71, 95% CI 1.01-2.91, P = .047) adverse events were significantly observed in the PCSK9 inhibitor group.
CONCLUSION
Application of a PCSK9 inhibitor in hospitalized patients with ACS reduced lipid profiles and plaque burdens and was well tolerated with few adverse events.
Topics: Humans; Anticholesteremic Agents; Proprotein Convertase 9; PCSK9 Inhibitors; Acute Coronary Syndrome; Antibodies, Monoclonal; Randomized Controlled Trials as Topic; Cholesterol, LDL; Myocardial Infarction; Hospitals; Cardiovascular Diseases
PubMed: 38457555
DOI: 10.1097/MD.0000000000037416 -
Critical Pathways in Cardiology Jun 2024To find out whether inclisiran sodium has different efficacy in heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH)... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To find out whether inclisiran sodium has different efficacy in heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH) patient groups.
METHODS
We conducted the systematic review and meta-analysis of ORION clinical trials. PubMed, Embase, and Clinicaltrials.gov databases were searched for the relevant studies. Atheroscalerotic parameters considered for our objective were low-density lipoprotein cholesterol, total cholesterol, proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B, and nonhigh-density lipoprotein cholesterol. Primary outcomes were the percentage difference in atheroscalerotic parameters at follow-up relative to baseline values. Our study examined these primary outcomes to determine whether there is a statistically significant difference between the HeFH and HoFH groups. Risk of bias was assessed by the Cochrane risk of bias tool. Meta-analysis was performed when at least 2 studies reported on the same variable.
RESULTS
Four ORION clinical trials provided the data related to the mean difference in the atheroscalerotic parameters at follow-up relative to baseline, of HeFH and HoFH patient populations, after administration of 300 mg inclisiran subcutaneously. We pooled together these mean differences for each group and applied a statistical test to analyze if the values were significantly different between the groups. The results of our study unveiled the significant difference in pooled mean differences in low-density lipoprotein cholesterol (HeFH: -48.62%; HoFH: -9.12%; P < 0.05), total cholesterol (HeFH: -30.31%; HoFH: -11.50%; P < 0.05), apolipoprotein (HeFH: -39.97%; HoFH: -14.68%; P < 0.05), and nonhigh-density lipoprotein (HeFH: -44.51%; HoFH: -12.22%; P < 0.05) between HeFH and HoFH groups. However, the difference in pooled mean difference in PCSK9 values (HeFH: -68.41%; HoFH: -56.25%; P = 0.2) between HeFH and HoFH groups was statistically insignificant. Studies were of high quality.
CONCLUSIONS
There was a significant difference in the reductions in atherosclerotic lipid parameters in heterozygous and homozygous populations after the administration of inclisiran except for PCSK9 parameter. Further studies are needed to support this conclusion.
Topics: Humans; Hyperlipoproteinemia Type II; Heterozygote; Homozygote; Cholesterol, LDL; Treatment Outcome; Anticholesteremic Agents; RNA, Small Interfering
PubMed: 38446086
DOI: 10.1097/HPC.0000000000000353 -
Phytotherapy Research : PTR May 2024Proanthocyanidins (PCs) are natural antioxidant polyphenols and their effect on the regulation of blood lipids is still controversial. This study was conducted to... (Meta-Analysis)
Meta-Analysis Review
Proanthocyanidins (PCs) are natural antioxidant polyphenols and their effect on the regulation of blood lipids is still controversial. This study was conducted to evaluate the effect of PCs on lipid metabolism. We searched PubMed, Embase, Web of Science, Chinese biomedical literature service system, China National Knowledge Internet, and Wanfang Data with no time restriction until March 18, 2022, using various forms of "proanthocyanidins" and "blood lipid" search terms. Randomized controlled trials investigating the relationship between PCs and lipid metabolism were included. The standard system of Cochrane Collaboration was used to assess the quality of studies. We standardized mean differences (SMDs) with 95% confidence interval (CI) using the random-effects model, Cohen approach. Seventeen studies (17 trials, N = 1138) fulfilled the eligibility criteria. PCs significantly reduced triglyceride, and increased recombinant apolipoprotein A1. Subgroup analysis showed a significant reduction in triglycerides in older adults (≥60 years) and total cholesterol for participants who were not overweight or obese (body mass index <24). An intervention duration of greater than 8 weeks reduced triglyceride and low-density lipoprotein cholesterol levels but increased high-density lipoprotein cholesterol. Different doses of PCs could regulate triglycerides, high-density lipoprotein cholesterol and total cholesterol. PCs have beneficial effects on circulating lipids and may represent a new approach for treating or preventing lipid metabolism disorders. However, more high-quality studies are needed to confirm these results.
Topics: Proanthocyanidins; Humans; Triglycerides; Lipids; Randomized Controlled Trials as Topic; Lipid Metabolism; Cholesterol, LDL; Cholesterol, HDL; Apolipoprotein A-I; Cholesterol; Antioxidants
PubMed: 38391003
DOI: 10.1002/ptr.8162