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Purpose: The development of blood biomarkers that reflect Alzheimer's disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers. Methods: A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Results: Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aβ remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aβ, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria. Conclusions: Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 – with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved. [ABSTRACT FROM AUTHOR]

Osteoporosis and Alzheimer's disease (AD) mainly affect older individuals, and the possibility of an underlying link contributing to their shared epidemiological features has rarely been investigated. In the current study, we investigated the association between levels of plasma sclerostin (SOST), a protein primarily produced by bone, and brain amyloid-beta (Aβ) load, a pathological hallmark of AD. The study enrolled participants meeting a set of screening inclusion and exclusion criteria and were stratified into Aβ- (n = 65) and Aβ+ (n = 35) according to their brain Aβ load assessed using Aβ-PET (positron emission tomography) imaging. Plasma SOST levels, apolipoprotein E gene (APOE) genotype and several putative AD blood-biomarkers including Aβ40, Aβ42, Aβ42/Aβ40, neurofilament light (NFL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and phosphorylated tau (p-tau181 and p-tau231) were detected and compared. It was found that plasma SOST levels were significantly higher in the Aβ+ group (71.49 ± 25.00 pmol/L) compared with the Aβ- group (56.51 ± 22.14 pmol/L) (P < 0.01). Moreover, Spearman's correlation analysis showed that plasma SOST concentrations were positively correlated with brain Aβ load (ρ = 0.321, P = 0.001). Importantly, plasma SOST combined with Aβ42/Aβ40 ratio significantly increased the area under the curve (AUC) when compared with using Aβ42/Aβ40 ratio alone (AUC = 0.768 vs 0.669, P = 0.027). In conclusion, plasma SOST levels are elevated in cognitively unimpaired older adults at high risk of AD and SOST could complement existing plasma biomarkers to assist in the detection of preclinical AD., (© 2023. The Author(s).)

Purpose: In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer's disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers—encompassing the 42 amino-acid isoform of amyloid-β (Aβ42), phosphorylated-tau (P-tau), and Total-tau (T-tau)—with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. Methods: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. Results: By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aβ42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. Conclusions: Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy. [ABSTRACT FROM AUTHOR]

The article discusses the use of cerebrospinal fluid (CSF) in Alzheimer's Disease clinical trials. The article stresses that the possibility of identifying a positive effect on this new treatment is dependent on the factors related to AD. It also explains that CSF biomarkers reflect specific central pathogenic professes in the brain. With this, the article concludes that CSF biomarkers have proven useful as diagnostic markers in large studies and may be implemented in clinical trials for diagnostic purposes and enrichment of AD cases.

Summary. Alzheimer’s disease (AD) is a complex neurodegenerative dementing illness. Over the past few years, however, remarkable advances have taken place in understanding both the genetic and molecular biology with the intracellular processing of amyloid and tau and the changes leading to the pathologic formation of extracellular amyloid plaques and the intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles. This progress in our understanding of the molecular pathology has set the stage for clinically meaningful advances in the development of biomarkers. Emerging diagnostic methods that are based on biochemical and imaging biomarkers of disease specific pathology hold the potential to provide effective measures of natural history (marker of disease that is predictive of outcome), biological activity (such as magnitude and frequency of response correlating with drug potency) and markers of surrogate endpoints (single or composite marker that accounts for clinical benefit of the therapy). Markers of biological activity should be also evaluated regarding their value to reflect disease progression, heterogeneity of the clinical population, for early decision making and characterization of new treatments. We focussed on the current status of core analytes which provide reasonable evidence for association with key mechanisms of pathogenesis or neurodegeneration in AD. In addition, feasibility was important, such as availability of a validated assay for the biological measure in question, with properties that included high precision and reliability of measurement, reagents and standards well described. On this basis we reviewed the body of literature that has examined CSF total tau (t-tau) and β-amyloid 1–42 (Aβ1–42), phosphorylated tau (p-tau) and β-amyloid-antibodies as diagnostic tests for AD versus clinically representative comparison groups. Measurement of t-tau and Aβ1–42 in the CSF seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. First studies showed that measurement of p-tau proteins significantly improves early and differential diagnosis, as well as disease prediction in subjects at risk for AD and comes closest to fulfilling proposed criteria of a biological marker for AD. However, the nature of the majority of reported findings are still preliminary and retrospective. General issues for biomarkers have to be adequately addressed, such as sensitivity of the method, frequency of assessments, stability of the method, standardization of methods and dynamic range. There is still a partial lack of comparison patient populations that must be addressed in future studies. International dementia networks have been recently established to advance the establishment of core biomarker candidates of AD as potential surrogate endpoints for clinical trials and their clinical use for predictive and diagnostic purposes. [ABSTRACT FROM AUTHOR]

Summary. Cerebral dysfunction without corresponding structural pathology has been reported in brain imaging studies of violent offenders. Biochemical markers in the CSF reflect various types of CNS pathology, such as blood-brain barrier dysfunction (CSF/S albumin ratio), infectious or inflammatory processes (IgG and IgM indices), neuronal or axonal degeneration (CSF-tau protein) and synaptic de- or regeneration (CSF-growth associated protein-43 (GAP-43)). We compared these CSF markers in 19 non-psychotic perpetrators of severe violent crimes undergoing pretrial forensic psychiatric investigation and 19 age- and sex-matched controls. Index subjects had significantly higher albumin ratios (p = 0.002), indicating abnormal vascular permeability as part of the complex CNS dysfunction previously reported in violent offenders. Axis I disorders, including substance abuse or current medication, did not explain this finding. Since Ig-indices, CSF-tau protein or CSF-GAP-43 were not increased, there was no support for inflammation or neuronal/synaptic degeneration as etiological factors to CNS dysfunction in this category of subjects. [ABSTRACT FROM AUTHOR]

Summary. Cerebrospinal fluid (CSF) levels of tau, β-amyloid1–42 and growth-associated protein 43 (GAP-43) were studied in patients with frontotemporal dementia (FTD; n = 17), Alzheimer's disease (AD; n = 60), subcortical white-matter dementia (SWD; n = 24), Parkinson's disease (PD; n = 23) and dysthymia (n = 19) and in age-matched controls (n = 32). CSF-tau was significantly increased only in AD, and CSF-β-amyloid1–42 was significantly decreased in AD and SWD as compared to controls, and in AD compared to FTD. CSF-GAP-43 was significantly decreased only in PD. The GAP-43/tau ratio was decreased in all the patient groups except the dysthymia group compared to controls. A positive correlation was found between CSF-GAP-43 and CSF-tau in all groups. The results suggest normal levels of CSF-tau and CSF-β-amyloid1–42 in FTD, which will aid in the clinical separation of FTD from AD. In SWD, decreased levels of CSF-β-amyloid1–42 suggest concomitant involvement of vascular and amyloid protein mechanisms. [ABSTRACT FROM AUTHOR]

Objectives. S100B is an established marker of brain damage. Used in the context as a biochemical marker, S100B denotes a measurement of all S100 proteins, including at least one S100B monomer, i.e. the sum of the two dimers S100A1B and S100BB. Almost all published studies are based on this “sum concentration”. However, the brain specificity of S100B has been questioned and increased serum levels have also been reported after trauma without head injury. Since the S100B monomer dominates in the brain, we hypothesised that the S100BB dimer should be better related to outcome after severe traumatic brain injury than S100A1B or the “sum concentration”. Methods. Daily serum samples were collected from 59 patients with severe traumatic brain injury. Three different ELISA methods were used for measurements of S100B, S100A1B and S100BB respectively. Outcome was assessed after one year and categorised according to the Glasgow Outcome Scale. Results. Serum levels of S100B, S100A1B and S100BB followed the same temporal course, with early maximum and rapidly decreasing values over the first days after the trauma. Maximum serum concentrations of each of the parameters were increased in the patient group with an unfavourable outcome compared with those with a favourable outcome ( p = 0.01, 0.006 and 0.004, respectively). Conclusion. Both S100A1B and S100BB were related to outcome after severe traumatic brain injury. Even though this study is small, it seems unlikely that separate analyses of the dimers are of any advantage compared with measuring S100B alone. [ABSTRACT FROM AUTHOR]

MK-801, a glutamergic, N-methyl-D-aspartate (NMDA)-receptor antagonist that mediates neurotransmission and has psychotomimetic properties, giving schizophrenia-like symptom. The objective of this study was to investigate the effects on the thalamic and cortical proteome of one typical (haloperidol) and one atypical (clozapine) antipsychotic drug in interaction with MK-801 in rats. Rats received subcutaneous injections of MK-801 or vehicle (controls) or MK-801 together with concurrent administration of haloperdol or clozapine for eight days. Protein samples from thalamus and cortex were analyzed with two-dimensional gel electrophoresis in combination with mass spectrometry. MK-801 induced alterations in the levels of three proteins in both cortex and thalamus. Clozapine reversed all the protein changes. Haloperidol reversed two. Both antipsychotics induced new protein changes in both cortex and thalamus not seen after MK-801-treatment by alone. In conclusion, the MK-801 animal model shows potential for investigation of different antipsychotic drugs and biochemical treatment effects in schizophrenia. [ABSTRACT FROM AUTHOR]

Changes in the metabolism of tryptophan, other amino acids, and steroid hormones have been implicated in aggression. We compared tryptophan, competing long amino acids (CAAs), and cortisol in serum (S) and CSF in 22 violent offenders and 15 healthy controls. Offenders had significantly increased S-L-tryptophan, S-free tryptophan, S-CAAs, S-cortisol and CSF-cortisol, indicating abnormal neurophysiological processes. Larger studies on the interplay between violence, serotonin precursors, and stress hormones need to integrate personality traits, life situations, and physiological adaptation. [ABSTRACT FROM AUTHOR]

Summary. Do the CNS monoaminergic (MA) systems regulate thyroid hormone metabolism in humans? In 23 unmedicated, male, violent offenders without signs of thyroid disease, we found positive correlations between the catecholaminergic CSF metabolites HVA and MHPG and the peripheral T3/T4 ratio (rho=0.55, p=0.010 and 0.51, p=0.018), indicating that increased activity in the brain MA systems, especially the dopaminergic, is associated with increased peripheral thyroid hormone activity. [ABSTRACT FROM AUTHOR]

Summary. Low serotonin activity in man has been related to impulsive, self-destructive violence but not to instrumental aggression aimed at dominance. A relationship has also been suggested between aggression and high catecholaminergic activity. Several studies have reported signs of aberrant dopaminergic function in attention deficit hyperactivity disorder, autism, and schizophrenia. In 22 violent offenders undergoing pretrial forensic psychiatric investigation, interpersonal and behavioral features of psychopathy, measured by the Psychopathy Checklist Revised (PCL-R), were significantly predicted by low cerebrospinal fluid (CSF) concentrations of 5-HIAA and high CSF concentrations of HVA in multivariate regression models. CSF concentrations of MHPG did not contribute to the model. This seems to link the outward-directed aggression of psychopathy to serotonergic hypofunctioning and high dopamine turnover, which might account for disinhibition of destructive impulses. [ABSTRACT FROM AUTHOR]

Summary. Today, cognitive impairment can be successfully treated with acetylcholine esterase inhibitors (AChE-I) in many, but not all, patients with Alzheimer's disease (AD). To investigate the relation between tacrine treatment, inheritance of ApoE ε4 alleles, and rate of progression, the differences in MMSE and CIBIC scores (efficacy parameters) after 6 and 12 months of tacrine (an AChE-I) treatment were investigated in 145 AD patients. Of these, 84 were ApoE ε4-positive (ApoE4) and 61 were ApoE ε4-negative (ApoE2-3). No differences were found after 6 months of treatment, but after 12 months the CIBIC scores revealed that the ApoE4 patients had declined more than the ApoE2-3 patients (p < 0.05). No differences were found for the last 6 months of treatment. The results primarily suggest a faster rate of decline in the ApoE4 AD compared to the ApoE2-3, but may also reflect that ApoE ε4 genotype inheritance is a negative predictor of treatment effect of tacrine in AD patients. [ABSTRACT FROM AUTHOR]

Summary. Although the psychotic symptoms in schizophrenia can be alleviated by treatment with dopaminergic receptor antagonists, the etiology and underlying neurochemical pathology remains obscure. Both neuropathological and magnetic resonance imaging studies have found evidence for neuronal loss and atrophy in the thalamus in schizophrenia, implicating this key structure for gating information to cortical areas in the pathophysiology. Recent studies have also found evidence of synaptic loss in the thalamus in schizophrenia. To further examine possible synaptic disturbances, we studied the synaptic related protein rab3a as a marker for synaptic density, using both quantitative Western blotting and immunohistochemistry. The material consisted of brains from 22 schizophrenic patients (mean age 79.3 years), and 24 control subjects (74.8 years). Reduced rab3a protein levels were found in the left thalamus in schizophrenia (0.47 ± 0.17 vs. 1.00 ± 0.18; p < 0.0001), while a less marked decrease was found also in the right thalamus (0.75 ± 0.13 vs. 1.00 ± 0.09; p < 0.0001). Immunohistochemistry, performed on two schizophrenic and two control brains, revealed that rab3a immunoreactivity was most reduced in the left anterior and mediodorsal thalamic nuclei. Therefore, we extended the study to brain regions connected these thalamic nuclei. Reduced rab3a protein levels were found schizophrenia also in the frontal cortex, hippocampus, gyrus cinguli, and parietal cortex, while no significant differences were found in the temporal cortex, or in cerebellum. The reduction in rab3a was not found to be secondary to confounding factors such as age-differences, post-mortem delay time, generalized brain atrophy, or antipsychotic medication. Therefore, the reduction of rab3a probably reflects synaptic disturbances, possibly synaptic loss, in the limbic system and neocortical areas, in schizophrenia. This part of the brain is known to be in-volved in behavioral and emotional control, and thus to be crucial for higher mental functions, suggesting that synaptic disturbances in the limbic system may be of importance in the development of psychotic symptoms in schizophrenia. [ABSTRACT FROM AUTHOR]

Summary. A polymorphism consisting of a deletion near the 5′ splice site of exon 18 on the α2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n = 449) and age-matched controls (n = 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p < 0.0001) in ApoE ε4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE ε4 allele. No change in A2M exon 17–18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD. [ABSTRACT FROM AUTHOR]

Summary. We studied the growth-associated protein, GAP-43 (also called neuromodulin and B-50) in post-mortem brain tissue using immunohistochemistry and quantitative Western blotting, from patients with Alzheimer's disease (AD) and age-matched control subjects. By immunohistochemistry, we found a clear reduction of GAP-43 in the frontal cortex, while in the hippocampus, there was a marked reduction in some areas (dentate molecular layer, stratum moleculare and radiale of CA1 and CA4), while not in other areas (stratum lacunosum, pyramidale and oriens of CA1). Moreover, in the hippocampus, neuritic staining was prominent, and was often associated with senile plaques. Quantitative analysis showed that GAP-43 was significantly reduced in AD, both in the frontal cortex (70% of the control value, p < 0.01) and in the hippocampus (81% of the control value, p < 0.05). In the frontal cortex, there was a significant negative correlation between GAP-43 and duration of dementia (r = -0.58; p < 0.02) and a positive correlation between GAP-43 and the synaptic vesicle-specific protein rab3a (r = 0.62; p < 0.05), while no such correlation were found in the hippocampus. In contrast, a significant positive correlation was found between GAP-43 and the number of senile plaques in the hippocampus (r = 0.64; p < 0.05), but not in the frontal cortex. GAP-43 is known to be involved in maintenance of synapses and in neuritic regeneration. Our findings may suggest that in the frontal cortex, GAP-43 levels decline as a consequence of the synaptic degeneration, while in the hippocampus, sprouting processes, involving GAP-43, are active. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, yet the dearth of readily accessible diagnostic biomarkers is a substantial hindrance towards progressing to effective preventive and therapeutic approaches. Due to a long delay between cerebral amyloid-β (Aβ) accumulation and the onset of cognitive impairments, biomarkers that reflect Aβ pathology and enable routine screening for disease progression are of urgent need for application in the clinical diagnosis of AD. According to accumulating evidences, cerebrospinal fluid (CSF) and plasma offer windows to the brain as they allow monitoring of biochemical changes in the brain. Considering the high availability and accuracy in depicting Aβ deposition in the brain, Aβ levels in CSF and plasma are regarded as promising fluid biomarkers for the diagnosis of AD patients at an early stage. However, clinical data with intra- and interindividual variations in the concentrations of CSF and plasma Aβ implicate the need to reevaluate current Aβ detection methods and establish a standardized operating procedure. Therefore, this review introduces three bias-generating factors in biofluid Aβ measurement that may hamper the accurate Aβ quantification and how such complications can be overcome for the widespread implementation of fluid Aβ detection in clinical practice. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common disease causing dementia. Today the clinical diagnosis of AD is made by way of exclusion, and no biochemical markers are available to assist the clinical diagnosis. We examined the potential of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF) as a diagnostic marker for AD. NSE was determined with a monoclonal antibody two-site immunoradiometric assay (IRMA) in serum (S) and cerebrospinal fluid (CSF) samples from 45 patients with 'probable Alzheimer's disease (AD)', 19 patients with vascular dementia (VAD) and 33 age-matched healthy individuals. There was no significant correlation between S-NSE and CSF-NSE, or between CSF/S albumin ratio and CSF-NSE, findings suggesting that the major portion of CSF-NSE is intrathecally produced and that analysis of CSF-NSE alone (without accompanying analysis of serum) is sufficient. CSF-NSE was significantly higher in the AD group (4.7±2.7 ng/mL; p<0.0001) and in VAD group (4.5±2.5 ng/mL; p<0.001) as compared with the control group (2.2±1.0 ng/mL), while it did not differ significantly between the AD and the VAD group. These findings suggest that CSF-NSE have a potential as a non-disease specific marker for the neuronal degeneration in dementia disorders. [ABSTRACT FROM AUTHOR]

Background: Previous studies showed conflicting results regarding soluble triggering receptor expressed on myeloid cells 2 (sTREM2) level alteration in body fluid in Alzheimer's disease (AD) and Parkinson's disease (PD). Methods: We applied the STATA 12.0 software to compute standard mean difference (SMD) and 95% confidence interval (CI). Results: The study showed elevated sTREM2 level in cerebrospinal fluid (CSF) in AD, mild cognitive impairment (MCI), and preclinical AD (pre-AD) patients, compared to healthy controls (HCs) with random effects models (AD: SMD 0.28, 95% CI 0.12 to 0.44, I2 = 77.6%, p < 0.001; MCI: SMD 0.29, 95% CI 0.09 to 0.48, I2 = 89.7%, p < 0.001; pre-AD: SMD 0.24, 95% CI 0.00 to 0.48, I2 = 80.8%, p < 0.001). The study showed no significant difference in sTREM2 level in plasma between AD patients and HCs with a random effects model (SMD 0.06, 95% CI − 0.16 to 0.28, I2 = 65.6%, p = 0.008). The study showed no significant difference in sTREM2 level in CSF or plasma between PD patients and HCs with random effects models (CSF: SMD 0.33, 95% CI − 0.02 to 0.67, I2 = 85.6%, p < 0.001; plasma: SMD 0.37, 95% CI − 0.17 to 0.92, I2 = 77.8%, p = 0.011). Conclusions: In conclusion, the study highlighted the CSF sTREM2 as a promising biomarker in the different clinical stages of AD. More studies were essential to explore the CSF and plasmatic concentrations of sTREM2 alteration in PD. [ABSTRACT FROM AUTHOR]

There is a paucity of studies assessing changes in measures of human neurotransmission during stressful events, such as surgery. Thirty-five patients without any neurological disorders undergoing knee replacements with spinal bupivacaine anaesthesia and propofol sedation had cerebrospinal fluid (CSF) drawn from a spinal catheter before, three hours after and the morning after surgery. The CSF concentrations of the dopamine metabolite homovanillinic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which are related to the activity of the dopaminergic and serotonergic systems of the brain, increased sharply during surgery and reached 188% and 166% of their initial concentrations on the morning after the intervention ( p < 0.0001). The CSF concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglucol (MHPG) increased modestly (non-significantly) during and after surgery. The HVA/5-HIAA ratios initially increased but returned to the initial level during the night after surgery. We conclude that non-neurological surgery, in this case to the lower limb, is accompanied by a marked central nervous stress response in spite of a spinal blockade. [ABSTRACT FROM AUTHOR]

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a severe and long-lasting side effect of anticancer therapy, which can severely impair patients' quality of life. It is a sensory and length-dependent neuropathy, which predominantly affects large myelinated fibers. Easy and reliable monitoring of CIPN in patients is still an unmet clinical need. Since increasing clinical evidence supports the potential use of neurofilament light chain (NfL) as a biomarker of axonal injury, in this study we measured serum NfL levels in animals chronically treated with cisplatin (CDDP) and paclitaxel (PTX), two antineoplastic drugs with different neuronal targets. Wistar rats were treated with CDDP (2 mg/kg i.p. twice/week for 4 weeks) or PTX (10 mg/kg i.v. once/week for 4 weeks). Repeated serum NfL quantification was obtained using the Single Molecule Array (Simoa) technology. The onset and progression of peripheral neurotoxicity were evaluated through neurophysiology, morphological assessments and intraepidermal nerve fibers density quantification. Our results showed that serum NfL measurements correlated with the severity of axonal damage. In fact, both treatments induced serum NfL increase, but higher levels were evidenced in PTX-treated animals, compared with CDDP-treated rats, affected by a milder neurotoxicity. Notably, also the timing of the NfL level increase was associated with the severity of morphological and functional alterations of axonal structure. Therefore, NfL could be a useful biomarker for axonal damage in order to follow the onset and severity of axonal degeneration and possibly limit the occurrence of serious PNS disease. [ABSTRACT FROM AUTHOR]

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) ß-amyloid1-42 (Aß1-42) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Aß1-42 and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Aß1-42 and CSF tau. The levels of CSF tau were increased, whereas levels of Aß1-42 were decreased in MCI subjects. Aß1-42 predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Aß1-42, but not other predictor variables (tau protein, gender, age, apolipoprotein E ?4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Aß1-42 may be useful biomarkers in the early identification of AD in MCI subjects.Molecular Psychiatry (2004) 9, 705-710. doi:10.1038/sj.mp.4001473 Published online 30 December 2003 [ABSTRACT FROM AUTHOR]

Summary. Cerebrospinal fluid levels of methionine (MET), homocysteine (HCY) and cystathionine were studied in patients with psychotic disorders (n=36) and in healthy controls (n=25). Patients had significantly higher MET than controls (p<0.00001), and ten of the patients had MET levels above anyone of the controls. Moreover, three young male patients had HCY levels highly above any of the controls. There were no significant gender differences in any of the parameters. Neither ageing nor neuroleptic treatment offered an explanation for the increase of MET, because also young and drug-naive patients had significantly higher MET than the controls. We conclude that patients with psychotic disorders, at least in a phase of acute exacerbation, are often in a state of disturbed one-carbon metabolism. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) encompasses a long continuum from a preclinical phase, characterized by neuropathological alterations albeit normal cognition, to a symptomatic phase, marked by its clinical manifestations. Yet, the neural mechanisms responsible for cognitive decline in AD patients remain poorly understood. Here, we posit that anosognosia, emerging from an error-monitoring failure due to early amyloid-β deposits in the posterior cingulate cortex, plays a causal role in the clinical progression of AD by preventing patients from being aware of their deficits and implementing strategies to cope with their difficulties, thus fostering a vicious circle of cognitive decline. This article advances the view of anosognosia as a driver of cognitive decline in Alzheimer's disease, due to early amyloid-β deposits in the posterior cingulate cortex, with error-monitoring failure and patients' inability to counter their deficits. [ABSTRACT FROM AUTHOR]

The Bio-Hermes Study was a cross-sectional observational study designed to develop a database of blood-based and digital biomarkers to improve detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI). We examined the ability of Cognivue Clarity to (a) detect MCI and AD in clinical diagnostics groups, (b) determine the presence of amyloid, and (c) distinguish between biomarker-confirmed groups. Bio-Hermes enrolled 887 participants who completed both Cognivue Clarity and amyloid PET scans (388 Cognitively Normal, 282 MCI, 217 Probable AD). Cognivue Clarity differentiated between Cognitively Normal, MCI, and probable AD in clinical cohorts, amyloid positive from amyloid negative individuals, and True Controls from MCI due to AD and AD in biomarker-confirmed cohorts (all p < 0.001) with large effect sizes. Cognivue Clarity correlated with amyloid PET and plasma amyloid and pTau (all p < 0.001). In biomarker confirmed groups, Cognivue Clarity had a positive likelihood ratio of 2.17, a negative likelihood ratio of 0.29, and a diagnostic odds ratio of 7.48. Cognivue Clarity detected cognitive impairment and differentiated between both clinically and biomarker defined MCI and AD groups. The use of Cognivue Clarity could assist with identification of MCI-AD or AD for inclusion into current treatment protocols or for enriching recruitment into clinical trials. Trial registration ClinicalTrials.gov (NCT04733989). [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with regulatory RNAs playing significant roles in its etiology. Circular RNAs (CircRNA) are enriched in human brains and contribute to AD progression. Many circRNA isoforms derived from same gene loci share common back splicing sites, thus often form clusters and work as a group to additively regulate their downstream targets. Unfortunately, the coordinated role of clustered circRNAs is often overlooked in individual circRNA differential expression (DE) analysis. To address these challenges, we develop circMeta2, a computational tool designed to perform DE analysis focused on circRNA clusters, equipped with modules tailored for both a small sample of biological replicates and a large-scale population study. Using circMeta2, we identify brain region-specific circRNA clusters from six distinct brain regions in the ENCODE datasets, as well as brain region-specific alteration of circRNA clusters signatures associated with AD from Mount Sinai brain bank (MSBB) AD study. We also illustrate how AD-associated circRNA clusters within and across different brain regions work coordinately to contribute to AD etiology by impacting miRNA-mediated gene expression and identified key circRNA clusters that associated with AD progression and severity. Our study demonstrates circMeta2 as a highly accuracy and robust tool for analyzing circRNA clusters, offering valuable molecular insights into AD pathology. circMeta2 performs differential expression analysis for clustered circRNAs. Using this tool, the authors identify brain region-specific circRNA clusters in healthy controls, as well as their key dysregulations associated with Alzheimer's Disease progression. [ABSTRACT FROM AUTHOR]

The cerebral biomarkers, neurofilament light chain (NfL), amyloid-β, tau, and neuron specific enolase (NSE) reflect a wide spectrum of neurological damage in the brain and spinal cord. With this study, we aimed to assess whether these biomarkers hold any potential diagnostic value for the three most common canine neurological diseases. Canines suffering from meningoencephalitis of unknown origin (MUO), brain tumors, and selected non-infectious myelopathies were included. For each diagnosis, we analyzed these biomarkers in the cerebrospinal fluid collected via cranial puncture from the cisterna magna. Elevated levels of CSF tau, NfL, and NSE were observed in MUO, with all three biomarkers being intercorrelated. Tau and NSE were increased while amyloid-β was decreased in dogs suffering from tumors. In contrast, no biomarker changes were observed in dogs with myelopathies. Covariates such as age, sex, or castration had minimal impact. CSF biomarkers may reflect molecular changes related to MUO and tumors, but not to non-infectious myelopathies. The combination of NfL, tau, and NSE may represent useful biomarkers for MUO as they reflect the same pathology and are not influenced by age. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to assess the impact of Traditional Chinese Medicine (TCM) on dementia patients, utilizing real-world data. Specifically, it seeks to evaluate how TCM influences clinical outcomes by examining changes in the Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE) scores, as well as its effect on medical expenses over a two-year period. Data from a multi-center research database spanning from 2004 to 2021 will be used to achieve these objectives, addressing the current gap in empirical data concerning intuitive outcomes and cognitive function assessments. Methods: Propensity score matching was adopted to improve comparability among the intervention and control groups. Due to repeated dependent variable measurements, the generalized estimating equation was used to control for socio-demographic characteristics, regional characteristics, and Western medicine treatments for dementia. Results: After propensity score matching, a total of 441 research subjects were included: 90 in the TCM intervention group and 351 in the non-TCM intervention group. The results of multivariate regression analysis showed that compared with the non-TCM intervention group, the MMSE scores in the TCM intervention group increased by 0.608 points each year. The annual change in CDR scores in the TCM intervention group was 0.702 times that of the non-TCM utilization group. After TCM intervention, annual outpatient expenses increased by US$492.2, hospitalization expenses increased by US$324.3, and total medical expenses increased by US$815.9, compared with the non-intervention group. Conclusions: TCM interventions significantly decelerate cognitive decline in dementia patients, evidenced by slower reductions in MMSE scores and mitigated increases in CDR scores. However, these benefits are accompanied by increased medical expenses, particularly for outpatient care. Future healthcare strategies should balance the cognitive benefits of TCM with its economic impact, advocating for its inclusion in dementia care protocols. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) as a neurodegenerative dementia is reviewed based on its mechanisms of development, the impact of genetic factors on its aetiology, and epigenetic interaction. The hypotheses proposed on AD mechanisms examined briefly include amyloid-β, protein cascade, tau-protein, cholinergic neurone, vascular, inflammation cascade, and calcium hypotheses. This review provides insight into the potential of antioxidant intervention in the management of AD in retrospect of the pathophysiology. The database search engines PubMed, Scopus, ScienceDirect, and Google Scholar were searched in writing this article; using the keywords pathophysiology, Alzheimer's disease, natural antioxidants, camel milk, and taurine, emphasis is laid on the oxidative stress mechanism underlying AD development and the role of oxidative biomarkers. The promising interventions by antioxidants and their beneficial effects on AD amelioration are highlighted. Natural antioxidants with potential beneficial effects in the management of AD include taurine and active constituents of medicinal plants and food, such as flavonoids, non-flavonoids, and mitochondrial-targeted antioxidants. Others are organo-sulphate compounds, carotenoids, and camel milk. The natural antioxidants exhibit neuroprotective activities by neutralising reactive oxygen species (ROS) and protecting the brain cells from ROS-induced damage. They inhibit the aggregation of amyloid-β and ameliorate inflammatory responses, leading to a reduction in AD-associated neurodegeneration. In conclusion, prophylactic and therapeutic interventions, involving anti-amyloid and/or anti-inflammatory agents, as well as co-administration of antioxidants as an adjunctive therapy, based on consideration of individual variations in oxidative stress levels and genetic factors, may yield substantial benefits. Such interventions may enhance the efficacy of treatment outcomes in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), characterized by cognitive impairment, brain plaques, and tangles, is a global health concern affecting millions. It involves the build-up of amyloid-β (Aβ) and tau proteins, the formation of neuritic plaques and neurofibrillary tangles, cholinergic system dysfunction, genetic variations, and mitochondrial dysfunction. Various signaling pathways and metabolic processes are implicated in AD, along with numerous biomarkers used for diagnosis, risk assessment, and research. Despite these, there is no cure or effective treatment for AD. It is critically important to address this immediately to develop novel drug delivery systems (NDDS) capable of targeting the brain and delivering therapeutic agents to modulate the pathological processes of AD. This review summarizes AD, its pathogenesis, related signaling pathways, biomarkers, conventional treatments, the need for NDDS, and their application in AD treatment. It also covers preclinical, clinical, and ongoing trials, patents, and marketed AD formulations. [ABSTRACT FROM AUTHOR]

(-)-Phenserine ("phenserine") and (+)-phenserine (posiphen; buntanetap) are longer-acting enantiomeric analogs of physostigmine with demonstrated promise in the treatment of Alzheimer's and Parkinson's diseases. Both enantiomers have short plasma half-lives, and their pharmacokinetics might be improved through the use of either once or twice-daily administration of an extended-release dosage form. Phenserine was observed to form a colored degradation product in near-neutral and alkaline pH environments, and at pH 7, the half-life of posiphen was determined to be ~ 9 h (40 °C). To limit luminal degradation which would reduce bioavailability, a gastroretentive tablet composed of a polyethylene oxide-xanthan gum matrix was developed. When placed in simulated gastric fluid (pH 1.2), approximately 70% of the phenserine was released over a 12 h period, and no degradants were detected in the release medium. In comparison, a traditional hydrophilic-matrix, extended-release tablet showed measurable amounts of phenserine degradation in a pH 7.2 medium over an 8 h release interval. These results confirm that a gastroretentive tablet can reduce the luminal degradation of phenserine or posiphen by limiting exposure to neutral pH conditions while providing sustained release of the drug over at least 12 h. Additional advantages of the gastroretentive tablet include reduced gastric and intestinal concentrations of the drug resulting from the slower release from the gastroretentive tablet which may also limit the occurrence of the dose-limiting GI side effects previously observed with immediate-release phenserine capsules. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI), a non-ionizing radiation imaging method, is widely utilized in diagnosing Alzheimer's disease (AD) due to its excellent imaging ability for brain soft tissues and high-resolution slice imaging. However, the enormous size of 3D MRI makes it difficult to process and analyze it. Therefore, a challenge is to accurately mine encephalatrophy patches from 3D MRI and build a patch-based diagnostic model. The existing patch-based methods mainly extract and fuse features of each patch in isolation, ignoring mutual information between patches, which makes the diagnosis performance unsatisfactory. We propose a novel dual-branch AD diagnostic model based on distinguishing atrophic patch localization. (1) We propose a Distinguishing Atrophic Patch Localization (DAPL) algorithm based on Distinguishing Index (DI) and Spatial Contact Ratio (SCR) to extract lesion areas that have significant impacts on diagnosis from 3D MRI. Meanwhile, we proposed a Discontinuity-voxel-based Dynamic Voxel Wrapping algorithm (DV 2 W) to calculate DI for each patch. (2) A dual-branch diagnostic network (DBDN) is constructed to obtain intra-patch and inter-patch features synchronously. The intra-feature extraction branch extracts feature from each patch through a parallel multi-channel network and fuse them. The Inter-feature extraction branch defines the Spatial Context Mixing matrix (SCM) and performs feature extraction on SCM to obtain mutual information. The performance evaluation demonstrates that our DBDN model has adequate diagnostic performance compared to state-of-the-art methods. In addition, the distinguishing pathological locations identified by our DAPL algorithm can effectively guide inexperienced clinical doctors to identify lesion areas and guide doctors in diagnosis quickly. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive and irreversible neurological condition that occurs with age and poses a significant global public health concern, is distinguished by the degeneration of neurons and synapses in various regions of the brain. While the exact processes behind the neurodegeneration in AD are not completely known, it is now acknowledged that inflammation may have a significant impact on the beginning and advancement of AD neurodegeneration. The severity of many neurological illnesses can be influenced by the equilibrium between pro-inflammatory and anti-inflammatory mediators. The IL-1 family of cytokines is linked to innate immune responses, which are present in both acute inflammation and chronic inflammatory diseases. Research on the role of the IL-1 family in chronic neurological disease has been concentrated on AD. In this context, there is indirect evidence suggesting its involvement in the development of the disease. This review aims to provide a summary of the contribution of every IL-1 family member in AD pathogenesis, current immunotherapies in AD disease, and present treatment possibilities for either targeting or boosting these cytokines. [ABSTRACT FROM AUTHOR]

Introduction: This study explores the interaction between cytokines, cell-mediated immunity (T cells, B cells, and NK cells), and prolonged morphine administration in chronic neuropathic pain patients without cancer-related issues. Despite evidence of opioid immunomodulation, few studies have compared these interactions. Methods: In a cross-sectional and comparative study, 50 patients with chronic low back radicular pain ("Failed Back Surgery Syndrome") were categorized into intrathecal morphine infusion (IT group, n = 18), oral morphine (PO group, n = 17), and non-opioid treatment (NO group, n = 15). Various parameters, including plasma and cerebrospinal fluid (CSF) cytokine concentrations, lymphocyte immunophenotyping, opioid escalation indices, cumulative morphine dose, and treatment duration, were assessed. Results: CSF IL-8 and IL-1β concentrations exceeded plasma levels in all patients. No differences in T, B, and NK lymphocyte numbers were observed between morphine-treated and non-treated patients. Higher plasma IL-5 and GM-CSF concentrations were noted in IT and PO groups compared to NO. CSF IFNγ concentrations were higher in PO and NO than IT. Positive correlations included CD4 concentrations with opioid escalation indices, and negative correlations involved NK cell concentrations, CSF TNFα concentrations, and opioid escalation indices. Positive correlations were identified between certain cytokines and pain intensity in IT patients, and between NK cells and cumulative morphine dose. Negative correlations were observed between CSF IL-5 concentrations and pain intensity in IT and PO, and between opioid escalation indices and CSF cytokine concentrations in PO and IT. Conclusion: Associations between cytokines, cellular immunity, and prolonged morphine treatment, administered orally and intrathecally were identified. [ABSTRACT FROM AUTHOR]