Cerebrospinal Fluid Biomarker Analysis Research Articles

Difference of Cerebrospinal Fluid Biomarkers and Neuropsychiatric Symptoms Profiles among Normal Cognition, Mild Cognitive Impairment, and Dementia Patient.

The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-β42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer's Coordinating Center's Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-β42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer's disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-β at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aβ-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aβ-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer's patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies.

Plasma melatonin night‐time peak levels and 24‐hour area under the curve profile seem higher in AD patients with epileptiform activity than in those without

AbstractBackgroundPlasma melatonin levels drop in elderly, which might become more pronounced in Alzheimer’s disease (AD) as compared to controls.(1) Melatonin can serve as a potential biomarker for AD, given the inverse correlation between cerebrospinal fluid (CSF) melatonin levels and severity of neuropathology (Braak stages).(2) Due to suggested antiepileptic effects(6), melatonin can potentially slow down disease progression as epileptiform activity may contribute to AD disease progression.(3‐5). We here present a preliminary interim analysis of an ongoing study.Aims1. To evaluate melatonin’s potential as biomarker for AD by comparing blood melatonin levels between patients with mild cognitive impairment (MCI) and dementia due to AD and preclinical AD subjects.2. To study the link between melatonin levels and epileptiform activity in AD.MethodsAll subjects underwent a neuropsychological examination, and lumbar puncture for analysis of core AD CSF biomarkers or amyloid brain PET. Subjects belonging to the AD continuum (dementia [n = 7]; MCI [n = 4]; preclinical AD [n = 1]) were diagnosed according to the NIA‐AA research criteria. A subset of subjects (n = 6) underwent 50‐minute magnetoencephalography to detect epileptiform activity. Blood samples were taken multiple times during a 24‐hour period, in in‐hospital controlled circumstances, and were analysed by use of liquid chromatography‐mass spectrometry.ResultsAD patients with epileptiform activity (n = 2) tended to have a higher melatonin 24‐hour area under the curve (AUC) and peak concentration (AUC 517.9pg/ml.h [+/‐140.1pg/ml.h] versus 204.5pg/ml.h [+/‐115.5pg/ml.h]; peak 65.4pg/ml [+/‐14.6pg/ml] versus 25.8pg/ml [+/‐17.5pg/ml]) than AD patients without (n = 4) (p = 0.064 for both; MWU test). There was no statistical difference regarding the melatonin 24‐hour plasma AUC or peak levels between patients with dementia, MCI, preclinical AD subjects (p = 0.760 for both; Kruskall‐Wallis test). We have to interpret these data with caution since sample sizes are still small and more patients are being recruited.ConclusionOn the basis of very preliminary data, 24‐hour plasma melatonin profile and peak plasma melatonin concentration tended to be higher in AD patients with epileptiform activity than in those without. Whether this could be a potential compensatory mechanism against epileptiform activity in AD or whether melatonin could rather have pro‐epileptic effects, remains to be elucidated in future research.

Cerebrospinal-fluid biomarkers for predicting phenoconversion in patients with isolated rapid-eye movement sleep behavior disorder.

Patients with isolated rapid-eye-movement sleep behavior disorder (iRBD) have an increased risk of developing neurodegenerative diseases. This study assessed cerebrospinal-fluid (CSF) biomarkers of neurodegeneration and blood-brain barrier (BBB) alteration in patients with iRBD compared to controls and ascertain whether these biomarkers may predict phenoconversion to alpha-synucleinopathies (Parkinson's Disease (PD), Dementia with Lewy bodies (DLB), Multiple System Atrophy (MSA)). Patients and controls underwent between 2012 and 2016 a neurological assessment, a lumbar puncture for CSF biomarker analysis (β-amyloid42 - Aβ42; total-tau, and phosphorylated tau), and BBB alteration (CSF/serum albumin ratio). All patients with iRBD were followed until 2021 and then classified into patients who converted to alpha-synucleinopathies (iRBD converters, cRBD) or not (iRBD non-converters, ncRBD). Thirty-four patients with iRBD (mean age 67.12 ± 8.14) and 33 controls (mean age 64.97 ± 8.91) were included. At follow-up (7.63 ± 3.40 years), eight patients were ncRBD and 33 patients were cRBD: eleven converted to PD, 10 to DLB, and two to MSA. Patients with iRBD showed lower CSF Aβ42 levels and higher CSF/serum albumin ratio than controls. Cox regression analysis showed that the phenoconversion rate increases with higher motor impairment (hazard ratio [HR] = 1.23, p = 0.032). CSF Aβ42 levels predicted phenoconversion to DLB (HR = 0.67, p = 0.038) and BBB alteration predicted phenoconversion to PD (HR = 1.20, p = 0.038). This study showed that low CSF Aβ42 levels and high BBB alteration may predict the phenoconversion to DLB and PD in patients with iRBD, respectively. These findings highlight the possibility to discriminate phenoconversion in iRBD patients through CSF biomarkers; however, further studies are needed.

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study.

One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

High ß‐synuclein plasma levels are coupled with amyloid PET positivity in memory clinic patients

AbstractBackgroundSynaptic dysfunction plays a key role in cognitive decline during progression of Alzheimer’s disease (AD). Higher levels of several synaptic proteins including the presynaptic protein ß‐synuclein have been measured in cerebrospinal fluid (CSF) of individuals with AD. Recently a quantitative assay using mass spectrometry allowed detection of ß‐synuclein in plasma. The aim of this study was to investigate the relationship between plasma ß‐synuclein levels and brain amyloid‐β (Aβ) plaque load in a cohort of memory clinic patients who underwent [18F]flutemetamol PET.MethodA clinical cohort of 118 patients (age = 65.6±8.3, 65F/53M), who despite extensive clinical assessment (including neuropsychological testing, CT/MRI, CSF biomarker analysis) at the Karolinska University Hospital, Sweden had an uncertain diagnosis and were referred to [18F]flutemetamol PET, was included in this work. The diagnostic groups were as follows: mild cognitive impairment (MCI, n = 16 Aβ+, and n = 24 Aβ‐), AD (n = 53), non‐AD dementia (n = 20),no dementia (n = 5). Plasma and CSF ß‐synuclein were measured using targeted mass spectrometry and ELISA.ResultWe found a significant correlation between β‐synuclein values in plasma and CSF (p&lt;0.001), with higher plasma β‐synuclein levels in AD (11.53±3.25pg/mL,p&lt;0.001) compared to MCI Aβ‐ (7.74±2.63pg/mL) and non‐AD (8.18±3.00 pg/mL), and also between MCI Aβ+ (10.85±2.75pg/mL,p&lt;0.01) in comparison to MCI Aβ‐. No significant difference was observed in plasma/CSF β‐synuclein levels between AD and MCI Aβ+. 18F‐Flutemetamol uptake positively correlated with plasma ß‐synuclein levels in the whole sample (R2 = 0.29,p&lt;0.001) and in the MCI group (R2 = 0.26,p&lt;0.01) (after controlling for sex and age). Individuals with comparable [18F]flutemetamol uptake values showed great variability in plasma ß‐synuclein levels. No correlation was observed between plasma ß‐synuclein and MMSE, brain atrophy, or white matter changes.ConclusionIn a clinical cohort of patients with [18F]flutemetamol‐PET, significantly elevated ß‐synuclein in plasma mirrored the higher levels of ß‐synuclein in CSF of Aß+ individuals. In the AD continuum, plasma ß‐synuclein seemed to capture pathological processes which were more closely associated with amyloid‐pathology rather than neuronal loss or clinical stage of the disease. The variability in plasma ß‐synuclein levels of Aß+ subjects warrants further exploration of factors that might contribute to increased plasma ß‐synuclein.

Novel heterozygous mutation in alpha-2-macroglobulin (A2M) suppressing the binding of amyloid-β (Aβ).

Many studies have suggested that the alpha-2-macroglobulin (A2M) gene may be involved in the pathogenesis of Alzheimer's disease (AD). A2M encoded by the A2M gene can specifically bind to the β-amyloid peptide and prevent fiber formation. The patient in this study had progressive memory loss at the age of 60 years and underwent a series of neuropsychological tests, cranial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarker analysis, and whole-exome sequencing (WES) to evaluate possible mutations. We used in silico tools and three-dimensional (3D) protein structure prediction to analyze the pathogenicity of the mutation and used a co-immunoprecipitation experiment to study the effect of mutations on amyloid-β (Aβ) binding. Based on neuropsychological tests, cranial MRI, and CSF biomarker analysis, the patient was diagnosed with AD. WES showed that there was a missense mutation in A2M (c.1229A>C, p.N410T). Bioinformatics analysis showed that this mutation was pathogenic. Moreover, 3D protein structure analysis showed that the A2M Asn410 residue was an N-glycosylation site, which was necessary for A2M activation to bind to Aβ. Missense mutations led to the loss of glycosylation at this site, which suppressed the binding of Aβ. The functional experiment also confirmed the prediction: the interaction between A2M and Aβ from the patient's plasma was weakened. Our results demonstrate that this novel A2M p.N410T mutation may have a pathogenic role in AD, by altering the binding interactions between A2M and Aβ.

Decreased Electroencephalography Global Field Synchronization in Slow-Frequency Bands Characterizes Synaptic Dysfunction in Amnestic Subtypes of Mild Cognitive Impairment.

BackgroundMild cognitive impairment (MCI) is highly prevalent in a memory clinic setting and is heterogeneous regarding its clinical presentation, underlying pathophysiology, and prognosis. The most prevalent subtypes are single-domain amnestic MCI (sd-aMCI), considered to be a prodromal phase of Alzheimer’s disease (AD), and multidomain amnestic MCI (md-aMCI), which is associated with multiple etiologies. Since synaptic loss and dysfunction are the closest pathoanatomical correlates of AD-related cognitive impairment, we aimed to characterize it in patients with sd-aMCI and md-aMCI by means of resting-state electroencephalography (EEG) global field power (GFP), global field synchronization (GFS), and novel cerebrospinal fluid (CSF) synaptic biomarkers.MethodsWe included 52 patients with sd-aMCI (66.9 ± 7.3 years, 52% women) and 30 with md-aMCI (63.1 ± 7.1 years, 53% women). All patients underwent a detailed clinical assessment, resting-state EEG recordings and quantitative analysis (GFP and GFS in delta, theta, alpha, and beta bands), and analysis of CSF biomarkers of synaptic dysfunction, neurodegeneration, and AD-related pathology. Cognitive subtyping was based on a comprehensive neuropsychological examination. The Mini-Mental State Examination (MMSE) was used as an estimation of global cognitive performance. EEG and CSF biomarkers were included in a multivariate model together with MMSE and demographic variables, to investigate differences between sd-aMCI and md-aMCI.ResultsPatients with sd-aMCI had higher CSF phosphorylated tau, total tau and neurogranin levels, and lower values in GFS delta and theta. No differences were observed in GFP. The multivariate model showed that the most important synaptic measures for group separation were GFS theta, followed by GFS delta, GFP theta, CSF neurogranin, and GFP beta.ConclusionPatients with sd-aMCI when compared with those with md-aMCI have a neurophysiological and biochemical profile of synaptic damage, neurodegeneration, and amyloid pathology closer to that described in patients with AD. The most prominent signature in sd-aMCI was a decreased global synchronization in slow-frequency bands indicating that functional connectivity in slow frequencies is more specifically related to early effects of AD-specific molecular pathology.

Isolated Amyloid-β Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer's Disease Patients.

Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer's disease (AD) patients. In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer's Association (NIA-AA) classification and APOE genotype. 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of amyloid-β (Aβ) deposition (A) and fibrillar tau (T), in four groups: A+/T-E4 (n = 9), A+/T-E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation protocol over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination (MMSE) scores respect to the baseline. A+/T-E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T-E3 and to A+/T+ patients independently from genotype (p < 0.001). In addition, A+/T-E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (delta MMSE -0.5±2.12 versus -6.05±4.95; post-hocp = 0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p = 0.028). No differences were found for SAI protocol (p > 0.05). Our results suggest that APOE4 in patients with isolated Aβ pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

Biomarkers of Cerebral Glucose Metabolism and Neurodegeneration in Parkinson's Disease: A Cerebrospinal Fluid-Based Study.

Several biomarkers have been evaluated in Parkinson's disease (PD); cerebrospinal fluid (CSF) levels of lactate may reflect cerebral metabolism function and CSF amyloid-β42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) concentrations may detect an underlying neurodegenerative process. CSF levels of lactate, Aβ42, t-tau, and p-tau were measured in patients with mild to moderate PD. CSF levels of dopamine (DA) and its metabolite 3,4-Dihydroxyphenylacetic acid (DOPAC) were also assessed, exploring their relations with the other CSF biomarkers. 101 drug-naive PD patients and 60 controls were included. Participants underwent clinical assessments and CSF biomarker analysis. Patients were divided into subgroups according to their Hoehn & Yahr stage (PD-1, PD-2, PD-3). PD patients showed higher lactate levels (M = 1.91; p = 0.03) and lower Aβ42 (M = 595; p < 0.001) and DA levels (M = 0.32; p = 0.04) than controls (Mlactate = 1.72; MAβ42 = 837; MDA = 0.50), while no significant differences were found in t-tau, p-tau and DOPAC concentrations. Considering the subgroup analysis, PD-3 group had higher lactate (M = 2.12) and t-tau levels (M = 333) than both PD-1 (Mlactate = 1.75, p = 0.006; Mt-tau = 176, p = 0.008) and PD-2 groups (Mlactate = 1.91, p = 0.01; Mt-tau = 176, p = 0.03), as well as the controls (Mlactate = 1.72, p = 0.04; Mt-tau = 205, p = 0.04). PD-2 group showed higher lactate levels than PD-1 group (p = 0.04) and controls (p = 0.03). Finally, CSF lactate levels negatively correlated with DA (r = -0.42) and positively with t-tau CSF levels (r = 0.33). This CSF-based study shows that lactate levels in PD correlated with both clinical disease progression and neurodegeneration biomarkers, such as tau proteins and DA. Further studies should explore the clinical potential of measuring CSF biomarkers for better understanding the role of brain energy metabolism in PD, for research and therapeutic options.

Brain oscillatory patterns in mild cognitive impairment due to Alzheimer’s and Parkinson’s disease: An exploratory high-density EEG study

ObjectiveWe investigated brain cortical activity alterations, using a resting-state 256-channel high-density EEG (hd-EEG), in Alzheimer’s (AD) and Parkinson’s (PD) disease subjects with mild cognitive impairment (MCI) and correlations between quantitative spectral EEG parameters and the global cognitive status assessed by Montreal Cognitive Assessment (MoCA) score. MethodsFifteen AD-MCI, eleven PD-MCI and ten age-matched healthy-controls (HC) underwent hd-EEG recordings and neuropsychological assessment. Cerebrospinal fluid biomarker analysis was performed to obtain well-characterized groups. EEG spectral features were extracted and the differences between the three groups, as well as correlations with MoCA, were investigated. ResultsThe results showed significantly lower alpha2 power and alpha2/alpha1 ratio in both AD-MCI and PD-MCI compared to controls. The significantly higher theta and lower beta power and alpha/theta ratio were observed in PD-MCI compared to AD-MCI and HC. MoCA score correlated inversely with theta power and directly with alpha2 and beta powers, as well as with alpha2/alpha1 and alpha/theta ratios. ConclusionsThis study highlighted significant differences in EEG patterns in AD-MCI and PD-MCI patients and remarked the role of EEG parameters as possible surrogate markers of cognitive status in both neurodegenerative diseases. SignificanceIn addition to well-established biomarkers, our findings could support early detection of cognitive dysfunction in neurodegenerative disorders and could help to monitor disease progression and therapeutic responses.

Four Swedish cases of CSF1R-related leukoencephalopathy: Visualization of clinical phenotypes.

Colony stimulating factor 1 receptor (CSF1R)‐related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances.ObjectiveTo describe four cases of CSF1R‐related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter‐individual diversity of clinical presentations.MethodsThis is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein.ResultsTwo heterozygous missense mutations in the CSF1R gene were identified, c.2344C>T; p.Arg777Trp and c.2329C>T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter‐individual diversity in the loss of cognitive, motor‐neuronal, and extrapyramidal functions.ConclusionsIncluding the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow‐up for this and other leukoencephalopathies.

Robust structural color beads by self-adhesion amorphous colloidal particles for detection of cerebrospinal fluid biomarkers

Analysis of cerebrospinal fluid (CSF) biomarkers plays a crucial role in prediction and diagnosis of physiological function of brain and neurological diseases. However, due to the lack of extraction volume, especially for mice, it is very difficult to realize multiple biomarkers analysis from the CSF extracted only once. Thus, a novel method with the ability to multiplex analyze mice CSF biomarkers are still anticipated. Here, we proposed a kind of amorphous photonic structure (APS) barcodes using for the multiplex analysis of mice CSF biomarkers. These barcodes were fabricated by assembling easy-to-operated partially adherent polydopamine coated SiO2 nanoparticles (SiO2@PDA NPs), which were derived from a droplet-based microfluidic approach. Owing to adhesion, melanin-like and “active” functional groups of PDA, the obtained APS beads present pigment-like color, robust structure and “active” surface. Moreover, the APS beads possessed close to 13 times coding signal area than the previous spectral coded photonic crystal beads. Besides, through Michael reaction, the APS beads could readily graft the needed biomoleculars. Finally, establishing the animal model of sepsis related encephalopathy and extracting trace amount of CSF from rats’ cisterna magna, three inflammatory cytokines (TNF-α, IL-1β, and IL-6) could be relatively accurate analysis simultaneously using three colored APS beads as barcode carries. These results indicated that the APS barcodes are promising for screening and monitoring many inflammatory related neurological diseases on mice models.

State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease.

Recent advances in developing disease‐modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health‐care systems toward biomarker‐guided early detection, diagnosis, and therapeutic decision‐making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs—once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state‐of‐the‐art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP‐associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.

Heterogeneity of Cerebrospinal Fluid Biomarkers Profiles in Individuals with Distinct Levels of Cognitive Decline: A Cross-Sectional Study.

Decreased cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ), along with increased total (T-tau) and phosphorylated tau protein (P-tau), are widely accepted as core biomarkers of Alzheimer's disease (AD) pathology. Nonetheless, there are a few remaining caveats that still preclude the full incorporation of AD biomarkers into clinical practice. To determine the frequency of clinical-biological mismatches in a clinical sample of older adults with varying degrees of cognitive impairment. 204 participants were enrolled for a cross-sectional assessment and allocated into diagnostic groups: probable AD (n = 60, 29.4%); MCI (n = 84, 41.2%); or normal cognition (NC, n = 60, 29.4%). CSF concentrations of Aβ42, T-tau, and 181Thr-P-tau were determined, and Aβ42/P-tau ratio below 9.53 was used as a proxy of AD pathology. The AT(N) classification was further used as a framework to ascertain the biological evidence of AD. The majority (73.7%) of patients in the AD group had the Aβ42/P-tau ratio below the cut-off score for AD, as opposed to a smaller proportion in the MCI (42.9%) and NC (23.3%) groups. In the latter, 21 subjects (35%) were classified as A+, 28 (46.7%) as T+, and 23 (38.3%) as N + . In the AD group, 66.7%of the cases were classified as A+, 78.3%as T+, and 80%as N+. Analysis of CSF biomarkers was able to discriminate between AD, MCI, and NC. However, clinical-biological mismatches were observed in a non-negligible proportion of cases.

Tract-Specific Relationships Between Cerebrospinal Fluid Biomarkers and Periventricular White Matter in Posthemorrhagic Hydrocephalus of Prematurity.

Posthemorrhagic hydrocephalus (PHH) is associated with neurological morbidity and complex neurosurgical care. Improved tools are needed to optimize treatments and to investigate the developmental sequelae of PHH. To examine the relationship between diffusion magnetic resonance imaging (dMRI) and cerebrospinal fluid (CSF) biomarkers of PHH. A total of 14 preterm (PT) infants with PHH and 46 controls were included. PT CSF was collected at temporizing surgery in PHH infants (PHH PT CSF) or lumbar puncture in controls. Term-equivalent age (TEA) CSF was acquired via implanted device or at permanent CSF diversion surgery in PHH (PHH-TEA-CSF) or lumbar puncture in controls. TEA dMRI scans were used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum (gCC), posterior limb of internal capsule (PLIC), and optic radiations (OPRA). Associations between dMRI measures and CSF amyloid precursor protein (APP), neural cell adhesion-1 (NCAM-1), and L1 cell adhesion molecule (L1CAM) were assessed using Pearson correlations. APP, NCAM-1, and L1CAM were elevated over controls in PHH-PT-CSF and PHH-TEA-CSF. dMRI FA and MD differed between control and PHH infants across all tracts. PHH-PT-CSF APP levels correlated with gCC and OPRA FA and PLIC MD, while L1CAM correlated with gCC and OPRA FA. In PHH-TEA-CSF, only L1CAM correlated with OPRA MD. Tract-specific associations were observed between dMRI and CSF biomarkers at the initiation of PHH treatment. dMRI and CSF biomarker analyses provide innovative complementary methods for examining PHH-related white matter injury and associated developmental sequelae.

Characteristics and prognosis of patients with mild cognitive impairment by cerebrospinal fluid biomarker profiles

AbstractBackgroundBiomarkers have an important diagnostic and prognostic value in neurodegenerative diseases, especially in early stages. We analyzed the differences in baseline characteristics and clinical evolution of patients with mild cognitive impairment (MCI) according to their cerebrospinal fluid (CSF) Alzheimer Disease biomarkers profile.MethodWe retrospectively selected all patients evaluated in the Sant Pau Memory Unit that had a neuropsychological evaluation compatible with MCI, analysis of Alzheimer CSF biomarkers and clinical follow‐up for at least 6 months. Patients were classified applying our internal cutoffs for CSF levels of Aβ1‐42 as a marker of amyloidosis (A+/A‐) and CSF levels of pTau as a marker of Tau pathology (T+/T‐).We compared demographic characteristics, cognitive progression, and final clinical diagnoses between groups.ResultWe included 274 participants: 103 A‐/T‐, 43 A+/T‐, 40 A‐/T+ and 88 A+/T+. The mean follow‐up was 3.4 years. Patients in the A‐/T‐ group were younger (67.8 years) compared to those in the A+/T+ group (72.3 years, p=0.002). During follow‐up, the A+/T+ group showed greater global cognitive impairment (‐1.5 MMSE score/year; p &lt;0.001)and higher risk of progression to dementia (OR=3,13, p&lt;0.001). There were no differences in baseline neuropsychological scores between A+/T‐ and A‐/T+ groups. The proportions of patients with a final clinical diagnosis of Alzheimer's dementia (AD), Lewy body Dementia (LBD) and frontotemporal lobar degeneration related syndromes(FTLD) were 37%, 16% and 12% in the A+/T‐ group, and 25%, 10% and 5% in the A‐/T+ group, respectively. Compared to the A+/T‐ group, the A‐/T+ group had a higher proportion of patients whose final clinical diagnosis was non‐neurodegenerative or undetermined (60% vs. 35%, respectively; p=0.022) and a lower risk of progression to dementia (OR=0.37; p=0.032).ConclusionA CSF profile suggestive of AD pathophysiology is associated with greater global cognitive impairment and a higher risk of progression to dementia. Although we did not find differences in baseline neuropsychological scores between patients with positive markers of amyloidosis and those with tau pathology only, patients with amyloidosis showed a higher risk of progression to dementia in follow‐up. The benefit of using additional markers of amyloidosis and/or tau pathology in the assessment of prognosis of these patients needs to be further explored.

Association Analysis of Peripheral and CSF Biomarkers in Late Mild Cognitive Impairment.

Research shows that late mild cognitive impairment (LMCI) has a high risk of turning into Alzheimer’s disease (AD). Due to the invasion of detection methods and physical damage to the patients, it is not a convenient way to diagnose and detect early AD and LMCI by cerebrospinal fluid (CSF) data. So there is an urgent need to find the correlation between peripheral biological data and CSF data in the brain, and to find new diagnostic methods through changes in the peripheral biological data. Studies have shown that during the pathogenesis of LMCI and AD, peripheral immune cells specifically infiltrate into the brain through the blood–brain barrier, causing an imbalance in the brain’s immune response and dysregulating the clearance of Aβ in CSF. Therefore, in this paper, canonical correlation analysis (CCA) algorithm is presented to derive the correlation between peripheral and CSF biomarkers based on LMCI peripheral gene expression data and plasma marker information. Firstly, to explore the influence of the infiltration of peripheral blood immune cells on the brain, the abundance of 28 immune cells were calculated by using the gene set enrichment analysis algorithm of LMCI samples. Then, to identify the correlation between biomarkers inside and outside of the brain, we performed CCA to calculate the relationship between CSF and peripheral biomarkers. Results of CCA showed significant correlations between the variable sets of 8 peripheral biomarkers and the variable sets of CSF biomarkers (at 0.794). Finally, according to Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis, it was found that the obtained peripheral biomarkers are involved in many immune-related pathways and functions which can be activated in peripheral blood of LMCI patients. Most related genes enriched in immune-related pathways and functions were up-regulated. Through receiver operating characteristic curve (ROC) analysis, it was also found that FP40/FP42 and type 1 T helper can accurately predict the pathological changes of LMCI (at 0.747).

Cisternal versus lumbar cerebrospinal fluid lactate concentration in healthy dogs

The analysis of cerebrospinal fluid biomarkers provides a wide range of information about the neurological health of a patient. Lactate is a metabolic precursor necessary for brain gluconeogenesis. When oxidative impairment or mitochondrial damage is present, lactate alteration occurs. The rostro-caudal dynamics of cerebrospinal biomarkers along the craniospinal axis in humans and horses was demonstrated in other studies. To the authors’ knowledge, no clinical study has, so far, investigated the cerebrospinal fluid lactate concentration in dogs in association with the puncture site. The purpose of this study was to compare the cerebellomedullary cistern and lumbar cistern cerebrospinal fluid lactate concentrations in healthy dogs. Cerebellomedullary and lumbar cerebrospinal fluids were collected for the cell count, total protein determination and lactate analysis from ten healthy Beagle dogs. The results revealed a significantly increased lumbar cerebrospinal fluid lactate concentration when compared with the cerebellomedullary cistern level. The results included: the total nucleated cell count &amp;lt; 5 cells/µl, the red blood cell count &amp;lt; 500 cell/µl, the total proteins &amp;lt; 0.3 g/l, as well as the cerebellomedullary lactate values (1.44 ± 0.06 mM/l) and the lumbar cistern lactate values (1.58 ± 0.1 mM/l). The results of this study highlight useful data that help to understand the physiological lactate variations depending on the cerebrospinal fluid puncture site.

Pathological and clinical comparison of Parkinson’s disease dementia and dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are two major neurodegenerative diseases sharing common clinical, pathophysiological and morphologic features. The pathological hallmark of both diseases is the presence of Lewy-bodies (LB). The main constituent of these inclusions is the pathologically aggregated α-synuclein protein. In DLB, LBs are predominantly located in the cortex, whereas in PDD, the subcortical regions are predominantly affected. Furthermore, in DLB, coexisting Alzheimer's disease (AD), pathology with β-amyloid plaques and neurofibrillary tangles are more common. It is still debated whether DLB and PDD are two distinct entities or different phenotypes of the same disease. Clinical diagnosis is based on the temporal sequence of motor and cognitive symptoms. Dementia often precedes parkinsonism in DLB, while in PDD, cognitive decline generally appears after the onset of motor symptoms. Also, fluctuation of cognitive functions and neuroleptic sensitivity is more severe in DLB than PDD. The recent advancements of imaging techniques revealed that cortical damage, cholinergic deficit and concomitant AD pathology are more severe in DLB compared to PDD. The analysis of cerebrospinal fluid biomarkers shows higher oligomeric α-synuclein burden in PDD. Levodopa is less effective in DLB than in PDD and may increase the risk of psychosis. In this review, we comprehensively analyse the pathological, radiological and clinical features of DLB and PDD, highlighting the overlaps and differences. Orv Hetil. 2020; 161(18): 727-737.

Plasma Amyloid Concentration in Alzheimer's Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer's Disease Cases from Controls.

Background:Collection of cerebrospinal fluid (CSF) for measurement of amyloid-β (Aβ) species is a gold standard in Alzheimer’s disease (AD) diagnosis, but has risks. Thus, establishing a low-risk blood Aβ test with high AD sensitivity and specificity is of outmost interest.Objective:We evaluated the ability of a commercially available plasma Aβ assay to distinguish AD patients from biomarker-healthy controls.Method:In a case-control design, we examined plasma samples from 44 AD patients (A + N+) and 49 controls (A–N–) from a memory clinic. AD was diagnosed using a combination of neuropsychological examination, CSF biomarker analysis and brain imaging. Total Aβ40 and total Aβ42 in plasma were measured through enzyme-linked immunosorbent assay (ELISA) technology using ABtest40 and ABtest42 test kits (Araclon Biotech Ltd.). Receiver operating characteristic (ROC) analyses with outcome AD were performed, and sensitivity and specificity were calculated.Results:Plasma Aβ42/40 was weakly positively correlated with CSF Aβ42/40 (Spearman’s rho 0.22; p = 0.037). Plasma Aβ42/40 alone was not able to statistically significantly distinguish between AD patients and controls (AUC 0.58; 95% CI 0.46, 0.70). At a cut-point of 0.076 maximizing sensitivity and specificity, plasma Aβ42/40 had a sensitivity of 61.2% and a specificity of 63.6%.Conclusion:In this sample, the high-throughput blood Aβ assay was not able to distinguish well between AD patients and controls. Whether or not the assay may be useful in large-scale epidemiological settings remains to be seen.