Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Changes in cerebrospinal fluid proteome of patients with tick-borne encephalitis.

Tick-borne encephalitis (TBE) is one of the main diseases transmitted by ticks, the incidence of which is increasing. Moreover, its diagnosis and therapy are often long and difficult according to nonspecific symptoms and complex etiology. This study aimed to observe changes in the proteome of cerebrospinal fluid from TBE patients. Cerebrospinal fluid (CSF) of TBE patients (n = 20) and healthy individuals (n = 10) was analyzed using a proteomic approach (QExactiveHF-Orbitrap mass spectrometer) and zymography. Obtained results show that in CSF of TBE patients, the top-upregulated proteins are involved in pro-inflammatory reaction (interleukins), as well as antioxidant/protective response (peroxiredoxins, heat shock proteins). Moreover, changes in the proteome of CSF are not only the result of this disease development, but they can also be an indicator of its course. This mainly applies to proteins involved in proteolysis including serpins and metalloproteinases, whose activity is proportional to the length of patients' convalescence. The obtained proteomic data strongly direct attention to the changes caused by the development of TBE to antioxidant, pro-inflammatory, and proteolytic proteins, knowledge about which can significantly contribute to faster and more accurate diagnosis of various clinical forms of TBE.

CSF formation rate-a potential glymphatic flow parameter in hydrocephalus?

BACKGROUND: Studies indicate that brain clearance via the glymphatic system is impaired in idiopathic normal pressure hydrocephalus (INPH). This has been suggested to result from reduced cerebrospinal fluid (CSF) turnover, which could be caused by a reduced CSF formation rate. The aim of this study was to determine the formation rate of CSF in a cohort of patients investigated for INPH and compare this to a historical control cohort. METHODS: CSF formation rate was estimated in 135 (75 ± 6 years old, 64/71 men/women) patients undergoing investigation for INPH. A semiautomatic CSF infusion investigation (via lumbar puncture) was performed. CSF formation rate was assessed by downregulating and steadily maintaining CSF pressure at a zero level. During the last 10 min, the required outflow to maintain zero pressure, i.e., CSF formation rate, was continuously measured. The values were compared to those of a historical reference cohort from a study by Ekstedt in 1978. RESULTS: Mean CSF formation rate was 0.45 ± 0.15 ml/min (N = 135), equivalent to 27 ± 9 ml/hour. There was no difference in the mean (p = 0.362) or variance (p = 0.498) of CSF formation rate between the subjects that were diagnosed as INPH (N = 86) and those who were not (N = 43). The CSF formation rate in INPH was statistically higher than in the reference cohort (0.46 ± 0.15 vs. 0.40 ± 0.08 ml/min, p = 0.005), but the small difference was probably not physiologically relevant. There was no correlation between CSF formation rate and baseline CSF pressure (r = 0.136, p = 0.115, N = 135) or age (-0.02, p = 0.803, N = 135). CONCLUSIONS: The average CSF formation rate in INPH was not decreased compared to the healthy reference cohort, which does not support reduced CSF turnover. This emphasizes the need to further investigate the source and routes of the flow in the glymphatic system and the cause of the suggested impaired glymphatic clearance in INPH.

Evaluation of core Biomarkers of Alzheimer's disease in saliva and plasma measured by chemiluminescent enzyme immunoassays on a fully automated platform.

Cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), including amyloid peptide beta-42 (Aß42), Aß42/40 ratio, and phosphorylated tau (pTau), are precious tools for supporting AD diagnosis. However, their use in clinical practice is limited due to the invasiveness of CSF collection. Thus, there is intensive research to find alternative, noninvasive, and widely accessible biological matrices to measure AD core biomarkers. In this study, we measured AD core biomarkers in saliva and plasma by a fully automated platform. We enrolled all consecutive patients with cognitive decline. For each patient, we measured Aß42, Aß40, and pTau levels in CSF, saliva, and plasma by Lumipulse G1200 (Fujirebio). We included forty-two patients, of whom 27 had AD. Levels of all biomarkers significantly differed in the three biofluids, with saliva having the lowest and CSF the highest levels of Aß42, Aß40, and pTau. A positive correlation of pTau, Aß42/40 ratio, and pTau/Aß42 ratio levels in CSF and plasma was detected, while no correlation between any biomarker in CSF and saliva was found. Our findings suggest that plasma but not saliva could represent a surrogate biofluid for measuring core AD biomarkers. Specifically, plasma Aß42/40 ratio, pTau/Aß42 ratio, and pTau could serve as surrogates of the corresponding CSF biomarkers.

Choroid plexus volume as a novel candidate neuroimaging marker of the Alzheimer's continuum.

BACKGROUND: Enlarged choroid plexus (ChP) volume has been reported in patients with Alzheimer's disease (AD) and inversely correlated with cognitive performance. However, its clinical diagnostic and predictive value, and mechanisms by which ChP impacts the AD continuum remain unclear. METHODS: This prospective cohort study enrolled 607 participants [healthy control (HC): 110, mild cognitive impairment (MCI): 269, AD dementia: 228] from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1, 2021, and December 31, 2022. Of the 497 patients on the AD continuum, 138 underwent lumbar puncture for cerebrospinal fluid (CSF) hallmark testing. The relationships between ChP volume and CSF pathological hallmarks (Aß42, Aß40, Aß42/40, tTau, and pTau181), neuropsychological tests [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Activities of Daily Living (ADL) scores], and multimodal neuroimaging measures [gray matter volume, cortical thickness, and corrected cerebral blood flow (cCBF)] were analyzed using partial Spearman's correlation. The mediating effects of four neuroimaging measures [ChP volume, hippocampal volume, lateral ventricular volume (LVV), and entorhinal cortical thickness (ECT)] on the relationship between CSF hallmarks and neuropsychological tests were examined. The ability of the four neuroimaging measures to identify cerebral Aß42 changes or differentiate among patients with AD dementia, MCI and HCs was determined using receiver operating characteristic analysis, and their associations with neuropsychological test scores at baseline were evaluated by linear regression. Longitudinal associations between the rate of change in the four neuroimaging measures and neuropsychological tests scores were evaluated on the AD continuum using generalized linear mixed-effects models. RESULTS: The participants' mean age was 65.99 ± 8.79 years. Patients with AD dementia exhibited the largest baseline ChP volume than the other groups (P < 0.05). ChP volume enlargement correlated with decreased Aß42 and Aß40 levels; lower MMSE and MoCA and higher NPI and ADL scores; and lower volume, cortical thickness, and cCBF in other cognition-related regions (all P < 0.05). ChP volume mediated the association of Aß42 and Aß40 levels with MMSE scores (19.08% and 36.57%), and Aß42 levels mediated the association of ChP volume and MMSE or MoCA scores (39.49% and 34.36%). ChP volume alone better identified cerebral Aß42 changes than LVV alone (AUC = 0.81 vs. 0.67, P = 0.04) and EC thickness alone (AUC = 0.81 vs.0.63, P = 0.01) and better differentiated patients with MCI from HCs than hippocampal volume alone (AUC = 0.85 vs. 0.81, P = 0.01), and LVV alone (AUC = 0.85 vs.0.82, P = 0.03). Combined ChP and hippocampal volumes significantly increased the ability to differentiate cerebral Aß42 changes and patients among AD dementia, MCI, and HCs groups compared with hippocampal volume alone (all P < 0.05). After correcting for age, sex, years of education, APOE ε4 status, eTIV, and hippocampal volume, ChP volume was associated with MMSE, MoCA, NPI, and ADL score at baseline, and rapid ChP volume enlargement was associated with faster deterioration in NPI scores with an average follow-up of 10.03 ± 4.45 months (all P < 0.05). CONCLUSIONS: ChP volume may be a novel neuroimaging marker associated with neurodegenerative changes and clinical AD manifestations. It could better detect the early stages of the AD and predict prognosis, and significantly enhance the differential diagnostic ability of hippocampus on the AD continuum.

Plasma biomarkers of amyloid, tau, axonal, and neuroinflammation pathologies in dementia with Lewy bodies.

BACKGROUND: Increasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain. METHODS: We conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB (n = 104), Alzheimer's disease (AD, n = 76), and neurological controls (NC, n = 27). Measured biomarkers included plasma Aß40/Aß42 ratio, p-tau181, NfL, and GFAP using SIMOA and plasma YKL-40 and sTREM2 using ELISA. DLB patients with available CSF analysis (n = 90) were stratified according to their CSF Aß profile. RESULTS: DLB patients displayed modified plasma Aß ratio, p-tau181, and GFAP levels compared with NC and modified plasma Aß ratio, p-tau181, GFAP, NfL, and sTREM2 levels compared with AD patients. Plasma p-tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC] = 0.80) and NC (AUC = 0.78), and combining biomarkers did not improve diagnosis performance. Plasma p-tau181 was the best standalone biomarker to differentiate amyloid-positive from amyloid-negative DLB cases (AUC = 0.75) and was associated with cognitive status in the DLB group. Combining plasma Aß ratio, p-tau181 and NfL increased performance to identify amyloid copathology (AUC = 0.79). Principal component analysis identified different segregation patterns of biomarkers in the DLB and AD groups. CONCLUSIONS: Amyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p-tau181 can contribute to identify Aß copathology in DLB.

Cytokine Profiling in Cerebrospinal Fluid of Patients with Newly Diagnosed Relapsing-Remitting Multiple Sclerosis (RRMS): Associations between Inflammatory Biomarkers and Disease Activity.

Cytokines regulate immune responses and are crucial to MS pathogenesis. This study evaluated pro-inflammatory and anti-inflammatory cytokine concentrations in the CSF of de novo diagnosed RRMS patients compared to healthy controls. We assessed cytokine levels in the CSF of 118 de novo diagnosed RRMS patients and 112 controls, analyzing relationships with time from symptom onset to diagnosis, MRI lesions, and serum vitamin D levels. Elevated levels of IL-2, IL-4, IL-6, IL-13, FGF-basic, and GM-CSF, and lower levels of IL-1ß, IL-1RA, IL-5, IL-7, IL-9, IL-10, IL-12p70, IL-15, G-CSF, PDGF-bb, and VEGF were observed in RRMS patients compared to controls. IL-2, IL-4, IL-12p70, PDGF, G-CSF, GM-CSF, and FGF-basic levels increased over time, while IL-10 decreased. IL-1ß, IL-1RA, IL-6, TNF-α, and PDGF-bb levels negatively correlated with serum vitamin D. TNF-α levels positively correlated with post-contrast-enhancing brain lesions. IL-15 levels negatively correlated with T2 and Gd(+) lesions in C-spine MRI, while TNF-α, PDGF-bb, and FGF-basic correlated positively with T2 lesions in C-spine MRI. IL-6 levels positively correlated with post-contrast-enhancing lesions in Th-spine MRI. Distinct cytokine profiles in the CSF of de novo diagnosed MS patients provide insights into MS pathogenesis and guide immunomodulatory therapy strategies.

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

BACKGROUND: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-ß (Aß) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). METHODS: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aß-PET/CSF testing as the standard of truth. RESULTS: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aß-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aß positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. CONCLUSIONS: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aß-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

Involvement of the choroid plexus in Alzheimer's disease pathophysiology: findings from mouse and human proteomic studies.

BACKGROUND: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. METHODS: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. RESULTS: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. CONCLUSIONS: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

Elevated cytokine levels in the central nervous system of cluster headache patients in bout and in remission.

BACKGROUND: Cluster headache is characterized by activation of the trigeminovascular pathway with subsequent pain signalling in the meningeal vessels, and inflammation has been suggested to play a role in the pathophysiology. To further investigate inflammation in cluster headache, inflammatory markers were analysed in patients with cluster headache and controls. METHODS: We performed a case-control study, collecting cerebrospinal fluid and serum samples from healthy controls, cluster headache patients in remission, active bout, and during an attack to cover the dynamic range of the cluster headache phenotype. Inflammatory markers were quantified using Target 48 OLINK cytokine panels. RESULTS: Altered levels of several cytokines were found in patients with cluster headache compared to controls. CCL8, CCL13, CCL11, CXCL10, CXCL11, HGF, MMP1, TNFSF10 and TNFSF12 levels in cerebrospinal fluid were comparable in active bout and remission, though significantly higher than in controls. In serum samples, CCL11 and CXCL11 displayed decreased levels in patients. Only one cytokine, IL-13 was differentially expressed in serum during attacks. CONCLUSION AND INTERPRETATION: Our data shows signs of possible neuroinflammation occurring in biological samples from cluster headache patients. Increased cerebrospinal fluid cytokine levels are detectable in active bout and during remission, indicating neuroinflammation could be considered a marker for cluster headache and is unrelated to the different phases of the disorder.

Predicting Cognitive Decline for Non-Demented Adults with High Burden of Tau Pathology, Independent of Amyloid Status.

BACKGROUND: Abnormal tau proteins are independent contributors to cognitive impairment. Nevertheless, not all individuals exposed to high-level tau pathology will develop cognitive dysfunction. We aimed to construct a model to predict cognitive trajectory for this high-risk population. METHOD: Longitudinal data of 181 non-demented adults (mean age= 73.1; female= 45%), who were determined to have high cerebral burden of abnormal tau by cerebrospinal fluid (CSF) measurements of phosphorylated tau (ptau181) or total tau, were derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Cognitive decline was defined as Mini-Mental State Examination scores decline ≥ 3 over three years. A predictive nomogram was constructed using stepwise backward regression method. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated. The model was validated in another 189 non-demented adults via a cross-sectional set (n=149, mean age = 73.9, female = 51%) and a longitudinal set (n= 40, mean age = 75, female = 48%). Finally, the relationships of the calculated risk scores with cognitive decline and risk of Alzheimer's disease were examined during an extended 8-year follow-up. RESULT: Lower volume of hippocampus (odds ratio [OR] = 0.37, p< 0.001), lower levels of CSF sTREM2 (OR = 0.76, p = 0.003), higher scores of Alzheimer's Disease Assessment Scale-Cognitive (OR = 1.15, p = 0.001) and Functional Activities Questionnaire (OR = 1.16, p = 0.016), and number of APOE ε4 (OR = 1.88, p = 0.039) were associated with higher risk of cognitive decline independent of the amyloid status and were included in the final model. The nomogram had an area of under curve (AUC) value of 0.91 for training set, 0.93 for cross-sectional validation set, and 0.91 for longitudinal validation set. Over the 8-year follow-up, the high-risk group exhibited faster cognitive decline (p< 0.001) and a higher risk of developing Alzheimer's dementia (HR= 6.21, 95% CI= 3.61-10.66, p< 0.001 ). CONCLUSION: APOE ε4 status, brain reserve capability, neuroinflammatory marker, and neuropsychological scores can help predict cognitive decline in non-demented adults with high burden of tau pathology, independent of the presence of amyloid pathology.

Predicting Brain Amyloid Status Using the National Institute of Health Toolbox (NIHTB) for Assessment of Neurological and Behavioral Function.

BACKGROUND: Amyloid-beta (Aß) plaque is a neuropathological hallmark of Alzheimer's disease (AD). As anti-amyloid monoclonal antibodies enter the market, predicting brain amyloid status is critical to determine treatment eligibility. OBJECTIVE: To predict brain amyloid status utilizing machine learning approaches in the Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA) study. DESIGN: ARMADA is a multisite study that implemented the National Institute of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in older adults with different cognitive ability levels (normal, mild cognitive impairment, early-stage dementia of the AD type). SETTING: Participants across various sites were involved in the ARMADA study for validating the NIHTB. PARTICIPANTS: 199 ARMADA participants had either PET or CSF information (mean age 76.3 ± 7.7, 51.3% women, 42.3% some or complete college education, 50.3% graduate education, 88.9% White, 33.2% with positive AD biomarkers). MEASUREMENTS: We used cognition, emotion, motor, sensation scores from NIHTB, and demographics to predict amyloid status measured by PET or CSF. We applied LASSO and random forest models and used the area under the receiver operating curve (AUROC) to evaluate the ability to identify amyloid positivity. RESULTS: The random forest model reached AUROC of 0.74 with higher specificity than sensitivity (AUROC 95% CI:0.73 - 0.76, Sensitivity 0.50, Specificity 0.88) on the held-out test set; higher than the LASSO model (0.68 (95% CI:0.68 - 0.69)). The 10 features with the highest importance from the random forest model are: picture sequence memory, cognition total composite, cognition fluid composite, list sorting working memory, words-in-noise test (hearing), pattern comparison processing speed, odor identification, 2-minutes-walk endurance, 4-meter walk gait speed, and picture vocabulary. Overall, our model revealed the validity of measurements in cognition, motor, and sensation domains, in associating with AD biomarkers. CONCLUSION: Our results support the utilization of the NIH toolbox as an efficient and standardizable AD biomarker measurement that is better at identifying amyloid negative (i.e., high specificity) than positive cases (i.e., low sensitivity).

Novel Blood-Based Biomarkers and Disease Modifying Therapies for Alzheimer's Disease. Are We Ready for the New Era?

Recent positive trials for novel disease modifying therapies of anti-amyloid monoclonal antibodies represent a paradigm shift in the prevention and management of Alzheimer's disease, a relentlessly progressive and debilitating disease of old age. The reported efficacy of these new agents when given early in the disease trajectory is dependent on an early and accurate disease diagnosis, which is currently based on cerebrospinal fluid tests or/and neuro-imaging studies such as positron emission tomography. These confirmatory tests provide in vivo evidence of the pathological signature of Alzheimer's disease, of increased cerebral amyloid and tau burden and neurodegeneration. The emergence of blood-based biomarkers represents another breakthrough, offering a less invasive and scalable diagnostic tool that could be applied in both primary and specialist care settings, potentially revolutionizing Alzheimer's disease clinical pathways. However, healthcare systems face challenges in the adoption of these new technologies and therapies due to diagnostic and treatment capacity constraints, as well as financial and infrastructure requirements.

Performance of Fully-Automated High-Throughput Plasma Biomarker Assays for Alzheimer's Disease in Amnestic Mild Cognitive Impairment Subjects.

INTRODUCTION: Novel plasma biomarkers are promising for identifying Alzheimer's disease (AD) pathological processes in vivo, but most currently employed assays have limitations precluding widespread use. METHODS: CSF and plasma samples were collected from seventy amnestic mild cognitive impairment (aMCI) subjects, stratified as A+ and A-. CSF Aß40, Aß42, p-tau181 and t-tau and plasma Aß40, Aß42 and p-tau181 quantification were conducted using the Lumipulse G assays (Fujirebio), to evaluate the diagnostic performance of plasma biomarkers and assess their associations with CSF biomarkers. RESULTS: All plasma biomarkers except Aß40 showed a very good accuracy in distinguishing A+ aMCI from A- aMCI, Aß42/p-tau181 ratio being the most accurate (AUC 0.895, sensitivity 95.1%, specificity 82.8%). Plasma biomarkers levels were significantly associated with CSF biomarkers concentration. DISCUSSION: High-throughput and fully-automated plasma assays could be helpful in discriminating with high accuracy between aMCI in the AD continuum and aMCI unlikely due to AD in clinical settings.

Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-ß42 over Amyloid Positron Emission Tomography.

BACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-ß42 (Aß42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. RESULTS: NP with CAA had significantly lower CSF Aß42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aß42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CONCLUSIONS: CSF Aß42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

Association between Cerebrospinal Fluid sTREM2 Levels and Depression: The Alzheimer's Disease Neuroimaging Initiative Study.

OBJECTIVE: Previous studies demonstrated a significant protective effect of elevated cerebrospinal fluid (CSF) sTREM2 levels on brain structure and cognitive decline. Nonetheless, the role of sTREM2 in the depression progression remains unclear. This study aimed to investigate the association between CSF sTREM2 levels and longitudinal trajectories of depression. METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study were used. CSF sTREM2 levels and depression were measured using an ELISA-based assay and the Geriatric Depression Scale (GDS-15), respectively. Linear mixed-effect models were employed to assess the relationships between CSF sTREM2 levels and GDS scores. RESULTS: A total of 1,017 participants were enrolled at baseline, with a mean follow-up time of 4.65 years. Baseline CSF sTREM2 levels were negatively correlated with GDS scores (ß=-0.21, P=0.022) after adjustment for age, gender, race/ethnicity, education, APOE ε4 carrier status, TREM2 rare variant carrier status, marital status, smoking, and clinical cognitive status. CONCLUSION: Our findings suggested that a higher level of CSF sTREM2 was associated with a lower risk of depression.

[Evaluation of the Bio-Speedy Meningitis/Encephalitis Panel in the Diagnosis of Central Nervous System Infections]. / Merkezi Sinir Sistemi Enfeksiyonlarinin Tanisinda Bio-Speedy Menenjit/Ensefalit Panelinin Degerlendirilmesi.

Infections of the central nervous system (CNS) can lead to severe outcomes if not accurately diagnosed and treated. The broad spectrum of pathogens involved in CNS infections can make diagnosis challenging. Polymerase chain reaction (PCR) -based multiplex molecular diagnostic panels can rapidly and simultaneously detect multiple neuropathogens in cerebrospinal fluid (CSF). This study was aimed to assess the Bio-Speedy Meningitis/Encephalitis RT-PCR MX-17 panel (Bioeksen, Istanbul, Türkiye), a novel multiplex PCR test, in diagnosing CNS infections. The panel can detect a range of pathogens, including Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus pneumoniae, Streptococcus agalactiae, enterovirus (EV), herpes simplex virus (HSV) 1 and 2, HHV-6, HHV-7, HHV-8, human parechovirus (HPeV), varicella zoster virus (VZV), cytomegalovirus (CMV) and Cryptococcus gatti/neoformans in CSF samples. This retrospective study included 128 CSF samples from 128 patients sent to Bursa Uludag University Health Application and Research Center Microbiology Laboratory between June 2022 and July 2023 to search for CNS infectious agents. Patient clinical, radiological and laboratory data were collected from the Hospital Information Record System (HIRS). Bacterial pathogens were identified through culture, while viral pathogens were detected in CSF samples using the Fast Track Diagnostics (FTD) multiplex RT-PCR panel (Fast Track Diagnostics Ltd., Luxembourg) for HSV-1, HSV-2, VZV, EV, mumps virus and HPeV. The stored CSF samples were then tested using the BioSpeedy panel and the results were compared with those of the culture and the FTD panel. Pathogens that were detected were considered positive if they were consistent with the patient's symptoms and CSF characteristics according to infectious disease and pediatric infectious disease specialists. Pathogens detected but not supported by the patient's symptoms and CSF characteristics were classified as uncertain clinical relevance (UCR). Out of the 128 patients tested for CNS infectious agents, 44 (34.4%) were diagnosed with a CNS infection. The overall pathogen detection rate with all methods was 43.2% (19/44). The Bio-Speedy panel identified pathogens in 29.5% (13/44) of the patients, followed by the FTD panel (20.5%, 9/44) and culture (9.1%, 4/44). Four bacteria were identified with culture, three of which were also detected by the Bio-Speedy panel. Additionally, six bacteria were identified with Bio-Speedy panel, that were not identified by culture. The FTD panel identified nine viruses, four of which were also identified by Bio-Speedy. In total, the Bio-Speedy panel detected 13 of the 19 positive pathogens (nine bacteria and four viruses: [S.pneumoniae (n= 3), VZV (n= 3), N.meningitidis (n= 2), H.influenzae (n= 2), L.monocytogenes (n= 1), E.coli (n= 1) ve EV (n= 1)]. However, the Bio-Speedy panel identified 15 pathogens [S.pneumoniae (n= 1), E.coli (n= 1), C.gatti/neoformans (n= 1), CMV (n= 8), HHV-6 (n= 3) ve HHV-7 (n= 1)] considered as UCR. The Bio-Speedy identified the causative pathogens in the highest percentage (29.5%) of patients with confirmed CNS infections. Nevertheless, test results should be interpreted based on patient characteristics to ensure appropriate patient management. Using multiple methods and multiplex tests may improve diagnostic accuracy for CNS infections.

Primary diffuse large B-cell lymphoma of the central nervous system identified with CSF biomarkers.

BACKGROUND: Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy. CASE PRESENTATIONS: The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3. CONCLUSIONS: Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment.

Headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome with reversible cytotoxic lesion of the corpus callosum (CLOCC) on MRI of the brain.

Headache and neurological deficits with cerebrospinal fluid (CSF) lymphocytosis (HaNDL) is a rare condition characterised by recurrent episodes of headache and transient neurological deficits. This case report presents a young patient initially diagnosed with hemiplegic migraine, having a normal brain CT, with focal cerebral perfusion mismatch not restricted to a single vascular territory on CT angiography. Brain MRI revealed a cytotoxic lesion of the splenium in the corpus callosum (CLOCC), a feature also reported in migraine. However, recurrent headaches with neurological deficits prompted further investigations with CSF analysis and brain MRI, confirming HaNDL and demonstrating reversibility of CLOCC. Recognising HaNDL as a differential diagnosis is essential in patients with recurrent headaches with focal neurological deficits, given the differences in therapeutic approach. The relationship between migraine and HaNDL is not fully understood, but they may share a pathophysiological link. Awareness of this is crucial for accurate diagnosis.

Predictive role of PAR and LAR in refractory suppurative meningitis in infants.

BACKGROUND: Meningitis can be caused by a variety of pathogenic microorganisms, which can lead to higher mortality and disability rates. However, the clinical manifestations of suppurative meningitis are often atypical in infants and young children, which makes early clinical diagnosis difficult.PAR and LAR are considered as a novel inflammatory biomarker and have been applied in tumors, IgA nephropathy, sepsis. OBJECTIVE: To investigate the application of platelet/albumin (PAR) and lactate dehydrogenase/albumin (LAR) in refractory suppurative meningitis in infants. METHODS: The relevant clinical data of 107 children with suppurative meningitis were retrospectively analyzed, and were divided into common group (82 cases) and refractory group (25 cases) according to the severity of the disease according to the relevant clinical consensus. The relevant clinical data and laboratory examination of the children in the two groups were compared. The diagnostic value of PAR and LAR in children with refractory suppurative meningitis was analyzed and multivariate Logistic regression analysis was performed. RESULT: The PAR of children with suppurative meningitis in refractory group was lower than that in common group (P < 0.05), while LAR was higher than that in common group (P < 0.05). Meanwhile, multivariate Logistic regression analysis showed that LAR and cerebrospinal fluid glucose ≤ 1.5mmo/L were risk factors for poor prognosis (OR > 1, P < 0.05). PAR was a protective factor (OR < 1, P < 0.05). CONCLUSION: PAR and LAR can be used for early diagnosis of refractory suppurative meningitis in children as protective and risk factors, respectively.