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European Stroke Journal Jun 2024There are limited data regarding cerebrospinal fluid (CSF) and plasma biomarkers among patients with Cerebral Amyloid Angiopathy (CAA). We sought to investigate the...
INTRODUCTION
There are limited data regarding cerebrospinal fluid (CSF) and plasma biomarkers among patients with Cerebral Amyloid Angiopathy (CAA). We sought to investigate the levels of four biomarkers [β-amyloids (Aβ42 and Aβ40), total tau (tau) and phosphorylated tau (p-tau)] in CAA patients compared to healthy controls (HC) and patients with Alzheimer Disease (AD).
PATIENTS AND METHODS
A systematic review and meta-analysis of published studies, including also a 5 year single-center cohort study, with available data on CSF and plasma biomarkers in symptomatic sporadic CAA versus HC and AD was conducted. Biomarkers' comparisons were investigated using random-effects models based on the ratio of mean (RoM) biomarker concentrations. RoM < 1 and RoM > 1 indicate lower and higher biomarker concentration in CAA compared to another population, respectively.
RESULTS
We identified nine cohorts, comprising 327 CAA patients (mean age: 71 ± 5 years; women: 45%) versus 336 HC (mean age: 65 ± 5 years; women: 45%) and 384 AD patients (mean age: 68 ± 3 years; women: 53%) with available data on CSF biomarkers. CSF Aβ42 levels [RoM: 0.47; 95% CI: 0.36-0.62; < 0.0001], Aβ40 levels [RoM: 0.70; 95% CI: 0.63-0.79; < 0.0001] and the ratio Aβ42/Aβ40 [RoM: 0.62; 95% CI: 0.39-0.98; = 0.0438] differentiated CAA from HC. CSF Aβ40 levels [RoM: 0.73; 95% CI: 0.64-0.83; = 0.0003] differentiated CAA from AD. CSF tau and p-tau levels differentiated CAA from HC [RoM: 1.71; 95% CI: 1.41-2.09; = 0.0002 and RoM: 1.44; 95% CI: 1.20-1.73; = 0.0014, respectively] and from AD [RoM: 0.65; 95% CI: 0.58-0.72; < 0.0001 and RoM: 0.64; 95% CI: 0.57-0.71; < 0.0001, respectively]. Plasma Aβ42 [RoM: 1.14; 95% CI: 0.89-1.45; = 0.2079] and Aβ40 [RoM: 1.07; 95% CI: 0.91-1.25; = 0.3306] levels were comparable between CAA and HC.
CONCLUSIONS
CAA is characterized by a distinct CSF biomarker pattern compared to HC and AD. CSF Aβ40 levels are lower in CAA compared to HC and AD, while tau and p-tau levels are higher in CAA compared to HC, but lower in comparison to AD patients.
PubMed: 38869035
DOI: 10.1177/23969873241260538 -
BMJ Mental Health May 2024Does neurodegenerative disease underlie the increased rate of dementia observed in older people with schizophrenia? Several studies have reported a higher prevalence of... (Meta-Analysis)
Meta-Analysis Review
QUESTION
Does neurodegenerative disease underlie the increased rate of dementia observed in older people with schizophrenia? Several studies have reported a higher prevalence of dementia in people with schizophrenia compared with the general population. This may reflect a higher risk of developing neurodegenerative diseases such as vascular dementia or Alzheimer's disease (AD). Alternatively, this may reflect non-pathological, age-related cognitive decline in a population with low cognitive reserve.
STUDY SELECTION AND ANALYSIS
We reviewed papers that compared postmortem findings, hippocampal MRI volume or cerebrospinal fluid (CSF) markers of AD, between patients with schizophrenia with evidence of cognitive impairment (age ≥45 years) with controls. We subsequently performed a meta-analysis of postmortem studies that compared amyloid-β plaques (APs) or neurofibrillary tangles (NFTs) in cognitively impaired patients with schizophrenia to normal controls or an AD group.
FINDINGS
No studies found a significant increase of APs or NFTs in cognitively impaired patients with schizophrenia compared with controls. All postmortem studies that compared APs or NFTs in patients with schizophrenia to an AD group found significantly more APs or NFTs in AD. No studies found a significant differences in CSF total tau or phosphorylated tau between patients with schizophrenia and controls. The two studies which compared CSF Aβ42 between patients with schizophrenia and controls found significantly decreased CSF Aβ42 in schizophrenia compared with controls. Hippocampal volume findings were mixed.
CONCLUSIONS
Studies have not found higher rates of AD-related pathology in cognitively impaired individuals with schizophrenia compared with controls. Higher rates of dementia identified in population studies may reflect a lack of specificity in clinical diagnostic tools used to diagnose dementia.
Topics: Humans; Schizophrenia; Biomarkers; Neurodegenerative Diseases; Alzheimer Disease; Amyloid beta-Peptides; Neurofibrillary Tangles; Plaque, Amyloid
PubMed: 38796179
DOI: 10.1136/bmjment-2024-301017 -
Journal of Cachexia, Sarcopenia and... Jun 2024Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for...
BACKGROUND
Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.
METHODS
We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-C]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.
RESULTS
The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-C]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8).
CONCLUSIONS
Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
Topics: Glucose; Muscle, Skeletal; Animals; Mice; Humans; Hypertrophy; Muscle Fibers, Skeletal; Insulin-Like Growth Factor I; Metabolomics
PubMed: 38742477
DOI: 10.1002/jcsm.13468 -
Cell Journal May 2024The relationship between oxidative stress (OS), insulin resistance (IR), and polycystic ovary syndrome (PCOS) is an important medical issue in human reproduction. Some...
OBJECTIVE
The relationship between oxidative stress (OS), insulin resistance (IR), and polycystic ovary syndrome (PCOS) is an important medical issue in human reproduction. Some of the oxidative phosphorylation (OXPHOS) genes have been previously studied in granulosa and muscle cells of PCOS patients. Cumulus cells (CCs) remain close to the oocyte even after ovulation. This research has been designed to compare the expression of OXPHOS genes in CCs of PCOS, with or without insulin resistance.
MATERIALS AND METHODS
In this experimental study, patients were included in PCOS insulin-resistant, PCOS insulinsensitive (IS), and control (fertile women with male infertility history) groups. The expression of and was studied by real-time polymerase chain reaction (PCR), and normalization was performed considering and as reference genes. One-way ANOVA and Tukey test were used for data analysis.
RESULTS
The results showed that the expression of and was significantly higher in the IR group than IS and control groups (P<0.01). showed the highest expression in the IS group, which was significantly different from other groups (P<0.01). The other genes of interest, except , were observed with the most transcriptional levels in the IS group, although there was no significant difference for those genes.
CONCLUSION
Altered expression of genes involved in mitochondrial function compared to the control group in CCs of both IR and IS categories of the PCOS patients suggests that alteration in OXPHOS genes can contribute to the pathophysiology of PCOS.
PubMed: 38736407
DOI: 10.22074/cellj.2024.2006763.1357 -
Clinical Neurology and Neurosurgery Jul 2024Severe traumatic brain injury (TBI) presentation and late clinical outcomes are usually evaluated by the Glasgow Outcome Scale-Extended (GOS-E), which lacks strong... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Severe traumatic brain injury (TBI) presentation and late clinical outcomes are usually evaluated by the Glasgow Outcome Scale-Extended (GOS-E), which lacks strong prognostic predictability. Several blood biomarkers have been linked to TBI, such as Tau, GFAP, UCH-L1, S-100B, and NSE. Clinical values of TBI biomarkers have yet to be evaluated in a focused multi-study meta-analysis. We reviewed relevant articles evaluating potential relationships between TBI biomarkers and both early and 6-month outcomes.
METHODS
All PubMed article publications from January 2000 to November 2023 with the search criteria "Protein Biomarker" AND "Traumatic Brain Injury" were included. Amongst all comparative studies, the sensitivity means and range values of biomarkers in predicting CT Rotterdam scores, ICU admission in the early period, or predicting GOS-E < 4 at the 6-month period were calculated from confusion matrices. Sensitivity values were modeled for each biomarker across studies and compared statistically for heterogeneity and differences.
RESULTS
From the 65 articles that met the criteria, 13 were included in this study. Six articles involved early-period TBI outcomes and seven involved 6-month outcomes. In the early period TBI outcomes, GFAP had a superior sensitivity to UCH-L1 and S-100B, and similar sensitivity to the CT Rotterdam score. In the 6-month period TBI outcomes, total Tau and NSE both had significant interstudy heterogeneity, making them inferior to GFAP, phosphorylated Tau, UCH-L1, and S-100B, all four of which had similar sensitivities at 75 %. This sensitivity range at 6-month outcomes was still relatively inferior to the CT Rotterdam score. Total Tau did not show any prognostic advantage at six months with GOS-E < 4, and phosphorylated Tau was similar in its sensitivity to other biomarkers such as GFAP and UCH-L1 and still inferior to the CT Rotterdam score.
CONCLUSION
This data suggests that TBI protein biomarkers do not possess better prognostic value with regards to outcomes.
Topics: Brain Injuries, Traumatic; Humans; Biomarkers; Prognosis; Glasgow Outcome Scale; Blood Proteins; tau Proteins; Predictive Value of Tests
PubMed: 38733758
DOI: 10.1016/j.clineuro.2024.108312 -
Genes Apr 2024Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS.
METHODS
Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939.
RESULTS
Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival.
DISCUSSION
Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.
Topics: Amyotrophic Lateral Sclerosis; Humans; Neurofilament Proteins; Biomarkers; Intermediate Filaments; Prognosis
PubMed: 38674431
DOI: 10.3390/genes15040496 -
Antioxidants (Basel, Switzerland) Mar 2024The aging of the global population has increased the prevalence of neurodegenerative conditions. (BM), an herb with active compounds, such as bacosides A and B,... (Review)
Review
Investigating the Neuroprotective and Cognitive-Enhancing Effects of : A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis.
The aging of the global population has increased the prevalence of neurodegenerative conditions. (BM), an herb with active compounds, such as bacosides A and B, betulinic acid, loliolide, asiatic acid, and quercetin, demonstrates the potential for brain health. Limited research has been conducted on the therapeutic applications of BM in neurodegenerative conditions. This systematic review aims to project BM's beneficial role in brain disorders. BM has anti-apoptotic and antioxidant actions and can repair damaged neurons, stimulate kinase activity, restore synaptic function, improve nerve transmission, and increase neuroprotection. The included twenty-two clinical trials demonstrated that BM can reduce Nuclear Factor-κB phosphorylation, improve emotional function, cognitive functions, anhedonia, hyperactivity, sleep routine, depression, attention deficit, learning problems, memory retention, impulsivity, and psychiatric problems. Moreover, BM can reduce the levels of pro-inflammatory biomarkers and oxidative stress. Here, we highlight that BM provides notable therapeutic benefits and can serve as a complementary approach for the care of patients with neurodegenerative conditions associated with brain disorders. This review adds to the growing interest in natural products and their potential therapeutic applications by improving our understanding of the mechanisms underlying cognitive function and neurodegeneration and informing the development of new therapeutic strategies for neurodegenerative diseases.
PubMed: 38671841
DOI: 10.3390/antiox13040393 -
Journal of Alzheimer's Disease : JAD 2024Cognitive deficits observed in Alzheimer's disease (AD) patients have been correlated with altered hippocampal activity. Although the mechanism remains under extensive... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cognitive deficits observed in Alzheimer's disease (AD) patients have been correlated with altered hippocampal activity. Although the mechanism remains under extensive study, neurofibrillary tangles and amyloid plaques have been proposed as responsible for brain activity alterations. Aiming to unveil the mechanism, researchers have developed several transgenic models of AD. Nevertheless, the variability in hippocampal oscillatory alterations found in different genetic backgrounds and ages remains unclear.
OBJECTIVE
To assess the oscillatory alterations in relation to animal developmental age and protein inclusion, amyloid-β (Aβ) load, and abnormally phosphorylated tau (pTau), we reviewed and analyzed the published data on peak power, frequency, and quantification of theta-gamma cross-frequency coupling (modulation index values).
METHODS
To ensure that the search was as current as possible, a systematic review was conducted to locate and abstract all studies published from January 2000 to February 2023 that involved in vivo hippocampal local field potential recording in transgenic mouse models of AD.
RESULTS
The presence of Aβ was associated with electrophysiological alterations that are mainly reflected in power increases, frequency decreases, and lower modulation index values. Concomitantly, pTau accumulation was associated with electrophysiological alterations that are mainly reflected in power decreases, frequency decreases, and no significant alterations in modulation index values.
CONCLUSIONS
In this study, we showed that electrophysiological parameters are altered from prodromal stages to the late stages of pathology. Thus, we found that Aβ deposition is associated with brain network hyperexcitability, whereas pTau deposition mainly leads to brain network hypoexcitability in transgenic models.
Topics: Alzheimer Disease; Animals; tau Proteins; Mice, Transgenic; Amyloid beta-Peptides; Disease Models, Animal; Mice; Phosphorylation; Brain; Humans; Hippocampus
PubMed: 38669540
DOI: 10.3233/JAD-231365 -
Genome Research Apr 2024Mitochondrial DNA (mtDNA) variants cause a range of diseases from severe pediatric syndromes to aging-related conditions. The percentage of mtDNA copies carrying a...
Mitochondrial DNA (mtDNA) variants cause a range of diseases from severe pediatric syndromes to aging-related conditions. The percentage of mtDNA copies carrying a pathogenic variant, variant allele frequency (VAF), must reach a threshold before a biochemical defect occurs, termed the biochemical threshold. Whether the often-cited biochemical threshold of >60% VAF is similar across mtDNA variants and cell types is unclear. In our systematic review, we sought to identify the biochemical threshold of mtDNA variants in relation to VAF by human tissue/cell type. We used controlled vocabulary terms to identify articles measuring oxidative phosphorylation (OXPHOS) complex activities in relation to VAF. We identified 76 eligible publications, describing 69, 12, 16, and 49 cases for complexes I, III, IV, and V, respectively. Few studies evaluated OXPHOS activities in diverse tissue types, likely reflective of clinical access. A number of cases with similar VAFs for the same pathogenic variant had varying degrees of residual activity of the affected complex, alluding to the presence of modifying variants. Tissues and cells with VAFs <60% associated with low complex activities were described, suggesting the possibility of a biochemical threshold of <60%. Using Kendall rank correlation tests, the VAF of the m.8993T > G variant correlated with complex V activity in skeletal muscle (τ = -0.58, = 0.01, n = 13); however, no correlation was observed in fibroblasts ( = 0.7, n = 9). Our systematic review highlights the need to investigate the biochemical threshold over a wider range of VAFs in disease-relevant cell types to better define the biochemical threshold for specific mtDNA variants.
Topics: Humans; DNA, Mitochondrial; Gene Frequency; Genetic Variation; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation
PubMed: 38627095
DOI: 10.1101/gr.278200.123 -
Alzheimer's Research & Therapy Apr 2024Measurement of beta-amyloid (Aβ) and phosphorylated tau (p-tau) levels offers the potential for early detection of neurocognitive impairment. Still, the probability of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Measurement of beta-amyloid (Aβ) and phosphorylated tau (p-tau) levels offers the potential for early detection of neurocognitive impairment. Still, the probability of developing a clinical syndrome in the presence of these protein changes (A+ and T+) remains unclear. By performing a systematic review and meta-analysis, we investigated the risk of mild cognitive impairment (MCI) or dementia in the non-demented population with A+ and A- alone and in combination with T+ and T- as confirmed by PET or cerebrospinal fluid examination.
METHODS
A systematic search of prospective and retrospective studies investigating the association of Aβ and p-tau with cognitive decline was performed in three databases (MEDLINE via PubMed, EMBASE, and CENTRAL) on January 9, 2024. The risk of bias was assessed using the Cochrane QUIPS tool. Odds ratios (OR) and Hazard Ratios (HR) were pooled using a random-effects model. The effect of neurodegeneration was not studied due to its non-specific nature.
RESULTS
A total of 18,162 records were found, and at the end of the selection process, data from 36 cohorts were pooled (n= 7,793). Compared to the unexposed group, the odds ratio (OR) for conversion to dementia in A+ MCI patients was 5.18 [95% CI 3.93; 6.81]. In A+ CU subjects, the OR for conversion to MCI or dementia was 5.79 [95% CI 2.88; 11.64]. Cerebrospinal fluid Aβ42 or Aβ42/40 analysis and amyloid PET imaging showed consistent results. The OR for conversion in A+T+ MCI subjects (11.60 [95% CI 7.96; 16.91]) was significantly higher than in A+T- subjects (2.73 [95% CI 1.65; 4.52]). The OR for A-T+ MCI subjects was non-significant (1.47 [95% CI 0.55; 3.92]). CU subjects with A+T+ status had a significantly higher OR for conversion (13.46 [95% CI 3.69; 49.11]) than A+T- subjects (2.04 [95% CI 0.70; 5.97]). Meta-regression showed that the ORs for Aβ exposure decreased with age in MCI. (beta = -0.04 [95% CI -0.03 to -0.083]).
CONCLUSIONS
Identifying Aβ-positive individuals, irrespective of the measurement technique employed (CSF or PET), enables the detection of the most at-risk population before disease onset, or at least at a mild stage. The inclusion of tau status in addition to Aβ, especially in A+T+ cases, further refines the risk assessment. Notably, the higher odds ratio associated with Aβ decreases with age.
TRIAL REGISTRATION
The study was registered in PROSPERO (ID: CRD42021288100).
Topics: Humans; Prospective Studies; Retrospective Studies; Amyloidogenic Proteins; Cognitive Dysfunction; Dementia
PubMed: 38610055
DOI: 10.1186/s13195-024-01455-2