Endocan may predict the presence of coronary slow flow and coronary artery disease.

OBJECTIVE: Coronary artery disease (CAD) is frequent, but coronary slow flow (CSF) is a less common cardiovascular disease with a significant risk of mortality and morbidity. Endocan is a proinflammatory glycopeptide that has been investigated in cardiovascular diseases as well as some inflammatory diseases in recent years. We planned to compare the levels of endocan in both CAD and CSF in a similar population and examine the relationship of endocan with additional clinical variables. MATERIALS AND METHODS: In the trial, we included 169 consecutive subjects having a coronary angiography indication. According to the results of coronary angiography, 58 people were included in the CAD group, 52 were in the CSF group, and 59 people were in the control group. The control group includes those who did not have any lesions in their epicardial coronary arteries. Thrombolysis in myocardial infarction (TIMI)-frame counts (TFC) were calculated for all patients. RESULTS: Notably, 2.6% of the population in our study had CSF. Both the CAD (555±223 pg/mL) and CSF (559±234 pg/mL) groups had higher endocan levels than the control group (331±252 pg/mL) (p<0.001). There were similar endocan levels between the CAD and CSF groups. Endocan levels were shown to be favorably associated with mean TFC (r=0.267; p0.001). Serum endocan levels (particularly those above 450 pg/mL) and the presence of hyperlipidemia were the most important predictors of both CAD and CSF. CONCLUSION: Endocan levels are higher in CAD and CSF patients than in those with normal coronary arteries.

Challenges in the Diagnosis of SARS-CoV-2 Infection in the Nervous System.

Neurological involvement has been widely reported in SARS-CoV-2 infection. However, viral identification in the cerebrospinal fluid (CSF) is rarely found. The aim of this study is to evaluate the accuracy of virological and immunological biomarkers in CSF for the diagnosis of neuroCOVID-19. We analyzed 69 CSF samples from patients with neurological manifestations: 14 with suspected/confirmed COVID-19, with 5 additional serial CSF samples (group A), and as a control, 50 non-COVID-19 cases (group B-26 with other neuroinflammatory diseases; group C-24 with non-inflammatory diseases). Real-time reverse-transcription polymerase chain reaction (real-time RT-PCR) was used to determine SARS-CoV-2, and specific IgG, IgM, neopterin, and protein 10 induced by gamma interferon (CXCL-10) were evaluated in the CSF samples. No samples were amplified for SARS-CoV-2 by real-time RT-PCR. The sensitivity levels of anti-SARS-CoV-2 IgG and IgM were 50% and 14.28%, respectively, with 100% specificity for both tests. CXCL-10 showed high sensitivity (95.83%) and specificity (95.83%) for detection of neuroinflammation. Serial CSF analysis showed an association between the neuroinflammatory biomarkers and outcome (death and hospital discharge) in two cases (meningoencephalitis and rhombencephalitis). The detection of SARS-CoV-2 RNA and specific immunoglobulins in the CSF can be used for neuroCOVID-19 confirmation. Additionally, CXCL-10 in the CSF may contribute to the diagnosis and monitoring of neuroCOVID-19.

Prospects and challenges in using neuronal extracellular vesicles in biomarker research.

Extracellular vesicles (EVs) hold promise as a source of disease biomarkers. The diverse molecular cargo of EVs can potentially indicate the status of their tissue of origin, even against the complex background of whole plasma. The main tools currently available for assessing biomarkers of brain health include brain imaging and analysis of the cerebrospinal fluid of patients. Given the costs and difficulties associated with these methods, isolation of EVs of neuronal origin (NEVs) from the blood is an attractive approach to identify brain-specific biomarkers. This perspective describes current key challenges in EV- and NEV-based biomarker research. These include the relative low abundance of EVs, the lack of validated isolation methods, and the difficult search for an adequate target for immunocapturing NEVs. We discuss that these challenges must be addressed before NEVs can fulfill their potential for biomarker research. HIGHLIGHTS: NEVs are promising sources of biomarkers for brain disorders. Immunocapturing NEVs from complex biofluids presents several challenges. The choice of surface target for capture will determine NEV yield. Contamination by non-EV sources is relevant for biomarkers at low concentrations.

CSF dynamics of orexin and ß-amyloid42 levels in narcolepsy and Alzheimer's disease patients: a controlled study.

ß-amyloid42 (Aß42) in Alzheimer's disease (AD) and orexin in narcolepsy are considered crucial biomarkers for diagnosis and therapeutic targets. Recently, orexin and Aß cerebral dynamics have been studied in both pathologies, but how they interact with each other remains further to be known. In this study, we investigated the reliability of using the correlation between orexin-A and Aß42 CSF levels as a candidate marker to explain the chain of events leading to narcolepsy or AD pathology. In order to test the correlation between these biomarkers, patients diagnosed with AD (n = 76), narcolepsy type 1 (NT1, n = 17), narcolepsy type 2 (NT2, n = 23) and healthy subjects (n = 91) were examined. Patients and healthy subjects underwent lumbar puncture between 8:00 and 10:00 am at the Neurology Unit of the University Hospital of Rome "Tor Vergata". CSF levels of Aß42, total-tau, phosphorylated-tau, and orexin-A were assessed. The results showed that CSF levels of Aß42 were significantly lower (p < 0.001) in AD (332.28 ± 237.36 pg/mL) compared to NT1 (569.88 ± 187.00 pg/mL), NT2 (691.00 ± 292.63 pg/mL) and healthy subjects (943.68 ± 198.12 pg/mL). CSF orexin-A levels were statistically different (p < 0.001) between AD (148.01 ± 29.49 pg/mL), NT1 (45.94 ± 13.63 pg/mL), NT2 (104.92 ± 25.55 pg/mL) and healthy subjects (145.18 ± 27.01 pg/mL). Moderate-severe AD patients (mini mental state examination < 21) showed the highest CSF orexin-A levels, whereas NT1 patients showed the lowest CSF orexin-A levels. Correlation between CSF levels of Aß42 and orexin-A was found only in healthy subjects (r = 0.26; p = 0.01), and not in narcolepsy or AD patients. This lack of correlation in both diseases may be explained by the pathology itself since the correlation between these two biomarkers is evident only in the healthy subjects. This study adds to the present literature by further documenting the interplay between orexinergic neurotransmission and cerebral Aß dynamics, possibly sustained by sleep.

Cerebrospinal Fluid Biomarkers of Symptomatic Neurosyphilis in People With HIV Compared with Uninfected Individuals.

We evaluated the diagnostic clinical performance characteristics (DCPC) of cerebrospinal fluid (CSF) total protein (TP), white blood cell count (WBC), and lactate (LA) with different cutoff points as adjunct biomarkers of confirmed or presumptive symptomatic neurosyphilis (NS) and the impact of HIV infection. From 5,640 participants who underwent lumbar punctures, 236 participants were included, and classified as either people with HIV (PWH) or people without HIV (PWoH) according to the CDC criteria for confirmed NS (n = 42), presumptive NS (n = 74), systemic syphilis (SS) (n = 38), serological diagnosis of syphilis (n = 18), PWH without SS and NS (n = 10), and negative control (n = 72). In PWoH, for presumptive NS, the combination of CSF TP > 45 mg/dL and/or WBC > 5.0 cells/mm3 is valuable for screening, whereas in PWH, it is not recommended for either screening or case-finding NS, however the DCPC were better in the suppressed group. In PWoH, the value of CSF TP > 45 mg/dL is adequate for both screening and confirmation of presumptive NS, subject to prevalence. For WBC count > 20 cell/mm3, the positive predictive value (PPV) of the test is almost perfect, suggesting a confirmatory test. In PWH, CSF TP is an inadequate marker of NS. The WBC count, with cutoffs of > 10 or > 20 cells/mm3, was moderately applicable for screening.As conclusions: CSF WBC count and TP showed distinct DCPC in confirmed or presumptive NS, better in the former. These biomarkers could be included for presumptive NS diagnosis. DCPC of these biomarkers for the diagnosis of NS is greatly affected by HIV co-infection.

miRNAs in cerebrospinal fluid associated with Alzheimer's disease: A systematic review and pathway analysis using a data mining and machine learning approach.

Alzheimer's disease (AD) is the most common type and accounts for 60%-70% of the reported cases of dementia. MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in gene expression regulation. Although the diagnosis of AD is primarily clinical, several miRNAs have been associated with AD and considered as potential markers for diagnosis and progression of AD. We sought to match AD-related miRNAs in cerebrospinal fluid (CSF) found in the GeoDataSets, evaluated by machine learning, with miRNAs listed in a systematic review, and a pathway analysis. Using machine learning approaches, we identified most differentially expressed miRNAs in Gene Expression Omnibus (GEO), which were validated by the systematic review, using the acronym PECO-Population (P): Patients with AD, Exposure (E): expression of miRNAs, Comparison (C): Healthy individuals, and Objective (O): miRNAs differentially expressed in CSF. Additionally, pathway enrichment analysis was performed to identify the main pathways involving at least four miRNAs selected. Four miRNAs were identified for differentiating between patients with and without AD in machine learning combined to systematic review, and followed the pathways analysis: miRNA-30a-3p, miRNA-193a-5p, miRNA-143-3p, miRNA-145-5p. The pathways epidermal growth factor, MAPK, TGF-beta and ATM-dependent DNA damage response, were regulated by these miRNAs, but only the MAPK pathway presented higher relevance after a randomic pathway analysis. These findings have the potential to assist in the development of diagnostic tests for AD using miRNAs as biomarkers, as well as provide understanding of the relationship between different pathophysiological mechanisms of AD.

Cortical folding correlates to aging and Alzheimer's Disease's cognitive and CSF biomarkers.

This manuscript presents the quantification and correlation of three aspects of Alzheimer's Disease evolution, including structural, biochemical, and cognitive assessments. We aimed to test a novel structural biomarker for neurodegeneration based on a cortical folding model for mammals. Our central hypothesis is that the cortical folding variable, representative of axonal tension in white matter, is an optimal discriminator of pathological aging and correlates with altered loadings in Cerebrospinal Fluid samples and a decline in cognition and memory. We extracted morphological features from T1w 3T MRI acquisitions using FreeSurfer from 77 Healthy Controls (age = 66 ± 8.4, 69% females), 31 Mild Cognitive Impairment (age = 72 ± 4.8, 61% females), and 13 Alzheimer's Disease patients (age = 77 ± 6.1, 62% females) of recruited volunteers in Brazil to test its discriminative power using optimal cut-point analysis. Cortical folding distinguishes the groups with reasonable accuracy (Healthy Control-Alzheimer's Disease, accuracy = 0.82; Healthy Control-Mild Cognitive Impairment, accuracy = 0.56). Moreover, Cerebrospinal Fluid biomarkers (total Tau, A[Formula: see text]1-40, A[Formula: see text]1-42, and Lipoxin) and cognitive scores (Cognitive Index, Rey's Auditory Verbal Learning Test, Trail Making Test, Digit Span Backward) were correlated with the global neurodegeneration in MRI aiming to describe health, disease, and the transition between the two states using morphology.

The Memory Alteration Test Is Correlated with Clinical, Cerebrospinal Fluid, and Brain Imaging Markers of Alzheimer Disease in Lima, Peru.

INTRODUCTION: As disease-modifying therapies become available for Alzheimer's disease (AD), detection of AD in early stages of illness (mild cognitive impairment [MCI], early dementia) becomes increasingly important. Biomarkers for AD in low- and middle-income countries (LMICs) are costly and not widely available; hence, it is important to identify cognitive tests that correlate well with AD biomarker status. In this study, we evaluated the memory alteration test (M@T) to detect biomarker-proven AD and quantify its correlation with neurodegeneration and cerebrospinal fluid (CSF) AD biomarkers in a cohort of participants from Lima, Peru. METHODS: This is a secondary analysis of a cohort of 185 participants: 63 controls, 53 with amnestic MCI (aMCI), and 69 with dementia due to AD. Participants underwent testing with M@T and a gold standard neuropsychological battery. We measured total tau (t-tau), phosphorylated tau (p-tau), and beta-amyloid (ß-amyloid) in CSF, and evaluated neurodegeneration via medial temporal atrophy score in MRI. We used receiver-operator curves to determine the discriminative capacity of the total M@T score and its subdomains. We used the Pearson coefficient to correlate M@T score and CSF biomarkers. RESULTS: The M@T had an area under the curve (AUC) of 0.994 to discriminate between controls and cognitively impaired (aMCI or AD) patients, and an AUC of 0.98 to differentiate between aMCI and AD patients. Free-recall and cued recall had the highest AUCs of all subdomains. Total score was strongly correlated with t-tau (-0.77) and p-tau (-0.72), and moderately correlated with ß-amyloid (0.66). The AUC for discrimination of neurodegeneration was 0.87. CONCLUSION: The M@T had excellent discrimination of aMCI and dementia due to AD. It was strongly correlated with CSF biomarkers and had good discrimination of neurodegeneration. In LMICs, the M@T may be a cost-effective screening tool for aMCI and dementia caused by AD.

Systematic review: fluid biomarkers and machine learning methods to improve the diagnosis from mild cognitive impairment to Alzheimer's disease.

Mild cognitive impairment (MCI) is often considered an early stage of dementia, with estimated rates of progression to dementia up to 80-90% after approximately 6 years from the initial diagnosis. Diagnosis of cognitive impairment in dementia is typically based on clinical evaluation, neuropsychological assessments, cerebrospinal fluid (CSF) biomarkers, and neuroimaging. The main goal of diagnosing MCI is to determine its cause, particularly whether it is due to Alzheimer's disease (AD). However, only a limited percentage of the population has access to etiological confirmation, which has led to the emergence of peripheral fluid biomarkers as a diagnostic tool for dementias, including MCI due to AD. Recent advances in biofluid assays have enabled the use of sophisticated statistical models and multimodal machine learning (ML) algorithms for the diagnosis of MCI based on fluid biomarkers from CSF, peripheral blood, and saliva, among others. This approach has shown promise for identifying specific causes of MCI, including AD. After a PRISMA analysis, 29 articles revealed a trend towards using multimodal algorithms that incorporate additional biomarkers such as neuroimaging, neuropsychological tests, and genetic information. Particularly, neuroimaging is commonly used in conjunction with fluid biomarkers for both cross-sectional and longitudinal studies. Our systematic review suggests that cost-effective longitudinal multimodal monitoring data, representative of diverse cultural populations and utilizing white-box ML algorithms, could be a valuable contribution to the development of diagnostic models for AD due to MCI. Clinical assessment and biomarkers, together with ML techniques, could prove pivotal in improving diagnostic tools for MCI due to AD.

Differential associations of clinical features with cerebrospinal fluid biomarkers in dementia with Lewy bodies and Alzheimer's disease.

AIM: To explore associations of cerebrospinal fluid biomarkers of neurodegeneration and amyloidosis with caregiver burden, cognition and functionality in dementia with Lewy bodies (DLB) paired with late-onset Alzheimer's disease (AD) and healthy older people. METHODS: Consecutive outpatients with DLB were matched with outpatients with AD according to sex, cognitive scores and dementia stage, and with cognitively healthy controls according to age and sex to investigate associations of cerebrospinal fluid amyloid-ß (Aß42,Aß40,Aß38), tau, phospho-tau Thr181, ubiquitin, α-synuclein and neurofilament light with caregiver burden, functionality, reverse digit span, a clock drawing test, Mini-Mental State Examination (MMSE) and Severe MMSE, adjusted for sex, age, education, dementia duration and APOE-ε4 alleles. RESULTS: Overall, 27 patients with DLB (78.98 ± 9.0 years-old; eleven APOE-ε4 +) were paired with 27 patients with AD (81.50 ± 5.8 years-old; twelve APOE-ε4 +) and 27 controls (78.98 ± 8.7 years-old; four APOE-ε4 +); two-thirds were women. In AD, Aß42/Aß38 and Aß42 were lower, while tau/Aß42 and phospho-tau Thr181/Aß42 were higher; α-synuclein/Aß42 was lower in DLB and higher in AD. The following corrected associations remained significant: in DLB, instrumental functionality was inversely associated with tau/phospho-tau Thr181 and tau/Aß42, and reverse digit span associated with α-synuclein; in AD, instrumental functionality was inversely associated with neurofilament light, clock drawing test scores inversely associated with phospho-tau Thr181/Aß42 and α-synuclein/Aß42, and Severe MMSE inversely associated with tau/Aß42 and tau/phospho-tau Thr181. CONCLUSIONS: Cerebrospinal fluid phospho-tau Thr181 in DLB was similar to AD, but not Aß42. In associations with test scores, biomarker ratios were superior to isolated biomarkers, while worse functionality was associated with axonal degeneration only in AD.

Advances in sample preparation and HPLC-MS/MS methods for determining amyloid-ß peptide in biological samples: a review.

Alzheimer's disease (AD), a neurological disorder, is a major public health concern and the most common form of dementia. Its typical symptoms include memory loss, confusion, changes in personality, and cognitive impairment, which result in patients gradually losing independence. Over the last decades, some studies have focused on searching for effective biomarkers as early diagnostic indicators of AD. Amyloid-ß (Aß) peptides have been consolidated as reliable AD biomarkers and have been incorporated into modern diagnostic research criteria. However, quantitative analysis of Aß peptides in biological samples remains a challenge because both the sample and the physical-chemical properties of these peptides are complex. During clinical routine, Aß peptides are measured in the cerebrospinal fluid by immunoassays, but the availability of a specific antibody is critical-in some cases, an antibody may not exist, or its specificity may be inadequate, leading to low sensitivity and false results. HPLC-MS/MS has been reported as a sensitive and selective method for determining different fragments of Aß peptides in biological samples simultaneously. Developments in sample preparation techniques (preconcentration platforms) such as immunoprecipitation, 96-well plate SPME, online SPME, and fiber-in-tube SPME have enabled not only effective enrichment of Aß peptides present at trace levels in biological samples, but also efficient exclusion of interferents from the sample matrix (sample cleanup). This high extraction efficiency has provided MS platforms with higher sensitivity. Recently, methods affording LLOQ values as low as 5 pg mL-1 have been reported. Such low LLOQ values are adequate for quantifying Aß peptides in complex matrixes including cerebrospinal fluid (CSF) and plasma samples. This review summarizes the advances in mass spectrometry (MS)-based methods for quantifying Aß peptides and covers the period 1992-2022. Important considerations regarding the development of the HPLC-MS/MS method such as the sample preparation step, optimization of the HPLC-MS/MS parameters, and matrix effects are described. Clinical applications, difficulties related to analysis of plasma samples, and future trends of these MS/MS-based methods are also discussed.

Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults.

Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-ß (Aß) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau181), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain Aß deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau181 levels and frontoparietal atrophy in CU Aß-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in Aß-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of Aß pathology.

Cerebrospinal fluid levels of sortilin-1, lipocalin-2, autotaxin, decorin and interleukin-33 in patients with idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is characterized by increased cerebrospinal fluid (CSF) pressure of unknown cause. It has been suggested that the inflammatory process plays a role in the pathophysiology of the disease. Sortilin-1, lipocalin-2, autotaxin, decorin, and interleukin-33 (IL-33) are among the factors involved in inflammatory processes. OBJECTIVE: To investigate the CSF levels of sortilin-1, lipocalin-2, autotaxin, decorin, and IL-33 in patients with IIH. METHODS: A total of 24 IIH patients and 21 healthy controls were included in the study. Demographic characteristics of the patients and of the control group as well as CSF pressures were evaluated. Sortilin-1, lipocalin-2, autotaxin, decorin and IL-33 levels in the CSF were measured. RESULTS: The CSF levels lipocalin-2, sortilin-1, autotaxin, IL-33 and CSF pressure were significantly higher in the patients group compared with the control group (p < 0.001). Decorin levels were reduced in patients (p < 0.05). There was no correlation between the autotaxin and IL-33 levels and age, gender, CSF pressure, and body mass index. The results of our study showed that inflammatory activation plays an important role in the development of the pathophysiology of IIH. In addition, the fact that the markers used in our study have never been studied in the etiopathogenesis of IIH is important in explaining the molecular mechanism of this disease. CONCLUSION: Studies are needed to evaluate the role of these cytokines in the pathophysiology of the disease. It is necessary to evaluate the effects of these molecules on this process.

ANTECEDENTES: A hipertensão intracraniana idiopática (HII) é caracterizada pelo aumento da pressão do líquido cefalorraquidiano (LCR) de causa desconhecida. Tem sido sugerido que o processo inflamatório desempenha um papel na fisiopatologia da doença. Sortilina-1, lipocalina-2, autotaxina, decorina e interleucina-33 (IL-33) estão entre os fatores envolvidos nos processos inflamatórios. OBJETIVO: Investigar os níveis de sortilina-1, lipocalina-2, autotaxina, decorina e IL-33 no LCR de pacientes com HII. MéTODOS: Um total de 24 pacientes com HII e 21 controles saudáveis foram incluídos no estudo. Foram avaliadas as características demográficas dos pacientes e do grupo controle, bem como as pressões liquóricas. Os níveis de sortilina-1, lipocalina-2, autotaxina, decorina e IL-33 no LCR foram medidos. RESULTADOS: Os níveis no líquido cefalorraquidiano lipocalina-2, sortilina-1, autotaxina, IL-33 e pressão liquórica foram significativamente maiores no grupo de pacientes em comparação com o grupo controle (p < 0,001). Os níveis de decorina foram reduzidos nos pacientes (p < 0,05). Não houve correlação entre os níveis de autotaxina e IL-33 e idade, sexo, pressão liquórica e índice de massa corporal. Os resultados do nosso estudo mostraram que a ativação inflamatória desempenha um papel importante no desenvolvimento da fisiopatologia da HII. Além disso, o fato de os marcadores utilizados em nosso estudo nunca terem sido estudados na etiopatogenia da HII é importante para explicar o mecanismo molecular dessa doença. CONCLUSãO: Estudos são necessários para avaliar o papel dessas citocinas na fisiopatologia da doença. É necessário avaliar os efeitos dessas moléculas nesse processo.

Decision tree-based classification as a support to diagnosis in the Alzheimer's disease continuum using cerebrospinal fluid biomarkers: insights from automated analysis.

OBJECTIVE: Cerebrospinal fluid (CSF) biomarkers add accuracy to the diagnostic workup of cognitive impairment by illustrating Alzheimer's disease (AD) pathology. However, there are no universally accepted cutoff values for the interpretation of AD biomarkers. The aim of this study is to determine the viability of a decision-tree method to analyse CSF biomarkers of AD as a support for clinical diagnosis. METHODS: A decision-tree method (automated classification analysis) was applied to concentrations of AD biomarkers in CSF as a support for clinical diagnosis in older adults with or without cognitive impairment in a Brazilian cohort. In brief, 272 older adults (68 with AD, 122 with mild cognitive impairment [MCI], and 82 healthy controls) were assessed for CSF concentrations of Aß1-42, total-tau, and phosphorylated-tau using multiplexed Luminex assays; biomarker values were used to generate decision-tree algorithms (classification and regression tree) in the R statistical software environment. RESULTS: The best decision tree model had an accuracy of 74.65% to differentiate the three groups. Cluster analysis supported the combination of CSF biomarkers to differentiate AD and MCI vs. controls, suggesting the best cutoff values for each clinical condition. CONCLUSION: Automated analyses of AD biomarkers provide valuable information to support the clinical diagnosis of MCI and AD in research settings.

Brain ventricles, CSF and cognition: a narrative review.

The brain ventricles are structures that have been related to cognition since antiquity. They are essential components in the development and maintenance of brain functions. The aging process runs with the enlargement of ventricles and is related to a less selective blood-cerebrospinal fluid barrier and then a more toxic cerebrospinal fluid environment. The study of brain ventricles as a biological marker of aging is promissing because they are structures easily identified in neuroimaging studies, present good inter-rater reliability, and measures of them can identify brain atrophy earlier than cortical structures. The ventricular system also plays roles in the development of dementia, since dysfunction in the clearance of beta-amyloid protein is a key mechanism in sporadic Alzheimer's disease. The morphometric and volumetric studies of the brain ventricles can help to distinguish between healthy elderly and persons with mild cognitive impairment (MCI) and dementia. Brain ventricle data may contribute to the appropriate allocation of individuals in groups at higher risk for MCI-dementia progression in clinical trials and to measuring therapeutic responses in these studies, as well as providing differential diagnosis, such as normal pressure hydrocephalus. Here, we reviewed the pathophysiology of healthy aging and cognitive decline, focusing on the role of the choroid plexus and brain ventricles in this process.

Cerebrospinal fluid analysis in patients with COVID-19-associated central nervous system manifestations: a systematic review.

BACKGROUND: Central nervous system (CNS) symptoms may occur in patients with acute COVID-19. The role of CSF examination in these patients remains to be established. OBJECTIVE: A systematic review of CSF findings relating to COVID-19 was carried out. METHODS: CSF parameters, including cytological and biochemical analyses, SARS-CoV-2 RT-PCR and other CSF markers, were recorded and analyzed among patients with acute COVID-19 and one of the following CNS syndromes: stroke, encephalopathy, encephalitis, inflammatory syndromes, seizure, headache and meningitis. RESULTS: Increased white blood cells and/or increased protein concentration were found in 52.7% of the patients with encephalitis, 29.4% of the patients with encephalopathy and 46.7% of the patients with inflammatory syndromes (P < 0.05). CSF RT-PCR for SARS-CoV-2 was positive in 17.35% of the patients with encephalitis and less than 3.5% of the patients with encephalopathy or inflammatory syndromes (P < 0.05). Intrathecal production of immunoglobulins was found in only 8% of the cases. More than 85% of the patients had increased CSF cytokines and chemokines. Increased CSF neurofilament light chain (NfL) and CSF Tau were found in 71% and 36% of the cases, respectively. CONCLUSION: Non-specific inflammatory CSF abnormalities were frequently found in patients with COVID-19 CNS syndromes. The increase in neurodegeneration biomarkers suggests that neuronal damage occurs, with long-term consequences that are still unknown.

Cerebrospinal fluid purinomics as a biomarker approach to predict outcome after severe traumatic brain injury.

Severe traumatic brain injury (TBI) is associated with high rates of mortality and long-term disability linked to neurochemical abnormalities. Although purine derivatives play important roles in TBI pathogenesis in preclinical models, little is known about potential changes in purine levels and their implications in human TBI. We assessed cerebrospinal fluid (CSF) levels of purines in severe TBI patients as potential biomarkers that predict mortality and long-term dysfunction. This was a cross-sectional study performed in 17 severe TBI patients (Glasgow Coma Scale <8) and 51 controls. Two to 4 h after admission to ICU, patients were submitted to ventricular drainage and CSF collection for quantification of adenine and guanine purine derivatives by HPLC. TBI patients' survival was followed up to 3 days from admission. A neurofunctional assessment was performed through the modified Rankin Scale (mRS) 2 years after ICU admission. Purine levels were compared between control and TBI patients, and between surviving and non-surviving patients. Relative to controls, TBI patients presented increased CSF levels of GDP, guanosine, adenosine, inosine, hypoxanthine, and xanthine. Further, GTP, GDP, IMP, and xanthine levels were different between surviving and non-surviving patients. Among the purines, guanosine was associated with improved mRS (p = 0.042; r = -0.506). Remarkably, GTP displayed predictive value (AUC = 0.841, p = 0.024) for discriminating survival versus non-survival patients up to 3 days from admission. These results support TBI-specific purine signatures, suggesting GTP as a promising biomarker of mortality and guanosine as an indicator of long-term functional disability.

Higher Cerebrospinal Fluid Soluble Urokinase-type Plasminogen Activator Receptor, But Not Interferon γ-inducible Protein 10, Correlate With Higher Working Memory Deficits.

BACKGROUND: We hypothesized that the induction of monocyte activation biomarkers, especially soluble urokinase-type plasminogen activator receptor (suPAR) and interferon γ-inducible protein 10 (IP-10), is lower in HIV-1C than HIV-1B, owing to a defective Tat cysteine dimotif (C30S). METHODS: A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH), free of CNS opportunistic infections, from a Southern Brazil outpatient HIV clinic were evaluated such as HIV-1B subtype (n = 27), HIV-1C (n = 26), other (n = 15), and 19 HIV-negative controls. The levels of suPAR, IP-10, neopterin, and ß2 microglobulin (ß2m) in the CSF and serum were quantified using different immunoassays. RESULTS: Overall, in PWH, increases in CSF suPAR, CSF/serum suPAR, and CSF/serum ß2m correlated with worse working memory deficits (r = 0.303, 0.353, and 0.289, respectively, all P < 0.05). The medians of IP-10, suPAR, neopterin, and ß2m in CSF and serum and the CSF/serum ratio and suPAR index were comparable between the HIV-1B and HIV-1C subtypes. CSF IP-10 and neopterin and serum IP-10 and suPAR levels were higher in PWH than the HIV-negative controls (P = 0.015, P = 0.001, P < 0.0001, and P < 0.001, respectively). The serum ß2m level was higher in HIV-associated dementia than neuropsychologically normal or asymptomatic (P = 0.024). DISCUSSION: We observed that higher levels of CSF suPAR and the suPAR quotient correlated with worse working memory deficit. Elevated levels of monocyte activation were similar in both HIV-1 B and C subtypes, providing no evidence of reduced neuropathogenicity of HIV-1 subtype C Tat compared with subtype B.

Accuracy of the brief cognitive screening battery for diagnosing Alzheimer's disease defined by cerebrospinal fluid biomarkers and AT(N) classification: a case-control study / Acurácia da bateria breve de rastreio cognitivo no diagnóstico da doença de Alzheimer definida por biomarcadores no líquido cefalorraquidiano e classificação pelo sistema AT(N): estudo caso-controle

ABSTRACT Background: Validation of cognitive instruments for detection of Alzheimer's disease (AD) based on correlation with diagnostic biomarkers allows more reliable identification of the disease. Objectives: To investigate the accuracy of the Brief Cognitive Screening Battery (BCSB) in the differential diagnosis between AD, non-AD cognitive impairment (both defined by cerebrospinal fluid [CSF] biomarkers) and healthy cognition, and to correlate CSF biomarker results with cognitive performance. Methods: Overall, 117 individuals were evaluated: 45 patients with mild cognitive impairment (MCI) or mild dementia within the AD continuum defined by the AT(N) classification [A+T+/-(N)+/]; 27 non-AD patients with MCI or mild dementia [A-T+/-(N)+/-]; and 45 cognitively healthy individuals without CSF biomarker results. All participants underwent evaluation using the BCSB. Results: The total BCSB and delayed recall (DR) scores of the BCSB memory test showed high diagnostic accuracy, as indicated by areas under the ROC curve (AUC): 0.89 and 0.87, respectively, for discrimination between AD and non-AD versus cognitively healthy controls. Similarly, total BCSB and DR displayed high accuracy (AUC-ROC curves of 0.89 and 0.91, respectively) for differentiation between AD and controls. BCSB tests displayed low accuracy for differentiation between AD and non-AD. The CSF levels of biomarkers correlated significantly, though weakly, with DR. Conclusions: Total BCSB and DR scores presented good accuracy for differentiation between patients with a biological AD diagnosis and cognitively healthy individuals, but low accuracy for differentiating AD from non-AD patients.

RESUMO Antecedentes: A validação de testes cognitivos para identificação da doença de Alzheimer (DA) definida por biomarcadores aumenta a confiabilidade diagnóstica. Objetivos: Investigar a acurácia da Bateria Breve de Rastreio Cognitivo (BBRC) no diagnóstico diferencial entre DA, comprometimento cognitivo não-DA (ambos diagnósticos definidos por biomarcadores no líquido cefalorraquidiano-LCR) e indivíduos cognitivamente saudáveis, e investigar correlações entre desempenho nos testes e concentrações dos biomarcadores no LCR. Métodos: No total, 117 indivíduos foram avaliados. Quarenta e cinco pacientes com comprometimento cognitivo leve (CCL) ou demência leve com diagnóstico do continuum de DA definido pela classificação AT(N) [A+T+/-(N)+/-], 27 pacientes com CCL ou demência leve não-DA [A-T+/-(N)+/-], e 45 controles cognitivamente saudáveis sem estudo de biomarcadores no LCR. Os participantes foram submetidos à BBRC. Resultados: O escore total da BBRC e a evocação tardia (ET) no teste de memória da BBRC apresentaram elevada acurácia diagnóstica na diferenciação entre DA e não-DA versus controles, indicada pelas áreas sob a curva ROC (AUC) de 0,89 e 0,87, respectivamente. De modo semelhante, o escore total da BBRC e a ET mostraram elevadas acurácias (AUC-ROC de 0,89 e 0,91, respectivamente) para o diagnóstico diferencial entre DA e controles. A acurácia da BBRC foi baixa na diferenciação entre DA e não-DA. Os níveis dos biomarcadores no LCR se correlacionaram de forma significativa, embora fraca, com ET. Conclusões: Os escores totais da BCSB e a ET apresentaram boa acurácia na diferenciação entre pacientes com diagnóstico biológico de DA e controles cognitivamente saudáveis, mas baixa acurácia para diferenciar DA de não-DA.

Accuracy of the Brief Cognitive Screening Battery for diagnosing Alzheimer's disease defined by cerebrospinal fluid biomarkers and AT(N) classification: a case-control study.

BACKGROUND: Validation of cognitive instruments for detection of Alzheimer's disease (AD) based on correlation with diagnostic biomarkers allows more reliable identification of the disease. OBJECTIVES: To investigate the accuracy of the Brief Cognitive Screening Battery (BCSB) in the differential diagnosis between AD, non-AD cognitive impairment (both defined by cerebrospinal fluid [CSF] biomarkers) and healthy cognition, and to correlate CSF biomarker results with cognitive performance. METHODS: Overall, 117 individuals were evaluated: 45 patients with mild cognitive impairment (MCI) or mild dementia within the AD continuum defined by the AT(N) classification [A+T+/-(N)+/]; 27 non-AD patients with MCI or mild dementia [A-T+/-(N)+/-]; and 45 cognitively healthy individuals without CSF biomarker results. All participants underwent evaluation using the BCSB. RESULTS: The total BCSB and delayed recall (DR) scores of the BCSB memory test showed high diagnostic accuracy, as indicated by areas under the ROC curve (AUC): 0.89 and 0.87, respectively, for discrimination between AD and non-AD versus cognitively healthy controls. Similarly, total BCSB and DR displayed high accuracy (AUC-ROC curves of 0.89 and 0.91, respectively) for differentiation between AD and controls. BCSB tests displayed low accuracy for differentiation between AD and non-AD. The CSF levels of biomarkers correlated significantly, though weakly, with DR. CONCLUSIONS: Total BCSB and DR scores presented good accuracy for differentiation between patients with a biological AD diagnosis and cognitively healthy individuals, but low accuracy for differentiating AD from non-AD patients.