Cerebrospinal Fluid Biomarker Levels Research Articles

Lipocalin-type prostaglandin D synthase: a glymphopathy marker in idiopathic hydrocephalus.

Idiopathic normal pressure hydrocephalus in elderly people is considered a form of glymphopathy caused by malfunction of the waste clearance pathway, called the glymphatic system. Tau is a representative waste material similar to amyloid-β. During neurodegeneration, lipocalin-type prostaglandin D synthase (L-PGDS), a major cerebrospinal fluid (CSF) protein, is reported to act as a chaperone that prevents the neurotoxic aggregation of amyloid-β. L-PGDS is also a CSF biomarker in idiopathic normal pressure hydrocephalus and significantly correlates with tau concentration, age, and age-related brain white matter changes detected by magnetic resonance imaging. To investigate this glymphopathy, we aimed to analyze white matter changes and contributing factors in vivo and their interactions ex vivo. Cerebrospinal tap tests were performed in 60 patients referred for symptomatic ventriculomegaly. Patients were evaluated using an idiopathic normal pressure hydrocephalus grading scale, mini-mental state examination, frontal assessment battery, and timed up-and-go test. The typical morphological features of high convexity tightness and ventriculomegaly were measured using the callosal angle and Evans index, and parenchymal white matter properties were evaluated with diffusion tensor imaging followed by tract-based spatial statistics. Levels of CSF biomarkers, including tau, amyloid-β, and L-PGDS, were determined by ELISA, and their interaction, and localization were determined using immunoprecipitation and immunohistochemical analyses. Tract-based spatial statistics for fractional anisotropy revealed clusters that positively correlated with mini-mental state examination, frontal assessment battery, and callosal angle, and clusters that negatively correlated with age, disease duration, idiopathic normal pressure hydrocephalus grading scale, Evans index, and L-PGDS. Other parameters also indicated clusters that correlated with symptoms, microstructural white matter changes, and L-PGDS. Tau co-precipitated with L-PGDS, and colocalization was confirmed in postmortem specimens of neurodegenerative disease obtained from the human Brain Bank. Our study supports the diagnostic value of L-PGDS as a surrogate marker for white matter integrity in idiopathic normal pressure hydrocephalus. These results increase our understanding of the molecular players in the glymphatic system. Moreover, this study indicates the potential utility of enhancing endogenous protective factors to maintain brain homeostasis.

Alzheimer's disease cerebrospinal fluid biomarkers and kidney function in normal and cognitively impaired older adults.

Recent Alzheimer's disease (AD) clinical trials have used cerebrospinal fluid (CSF) biomarker levels for screening and enrollment. Preliminary evidence suggests that AD risk is related to impaired renal function. The impact of kidney function on commonly used AD biomarkers remains unknown. Participants in studies conducted at the Goizueta Alzheimer's Disease Research Center (N=973) had measurements of serum creatinine and CSF AD biomarkers. General linear models and individual data were used to assess the relationships between biomarkers and eGFR. Lower estimated glomerular filtration rate (eGFR) was associated with lower amyloid beta (Aβ)42/tau ratio (p<0.0001) and Aβ42 (p=0.002) and higher tau (p<0.0001) and p-tau (p=0.0002). The impact of eGFR on AD biomarker levels was more robust in individuals with cognitive impairment (all p-values were<0.005). The association between eGFR and CSF AD biomarkers has a significant impact that varies by cognitive status. Future studies exploring this impact on the pathogenesis of AD and related biomarkers are needed. There is a significant association between Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers and both estimated glomerular filtration rate (eGFR) and mild cognitive impairment (MCI).Kidney function influences CSF biomarker levels in individuals with normal cognitive function and those with MCI.The impact of kidney function on AD biomarker levels is more pronounced in individuals with cognitive impairment.The variation in CSF tau levels is independent of cardiovascular factors and is likely directly related to kidney function.Tau may have a possible role in both kidney and cognitive function.

Lumbar puncture increases Alzheimer’s disease biomarker levels in cerebrospinal fluid of rhesus monkeys

Cerebrospinal fluid (CSF) samples are commonly collected via lumbar puncture (LP) in both clinical and research settings for measurement of biomarkers of Alzheimer's disease (AD). To determine the effects of LP on CSF AD biomarkers, we collected CSF samples at seven different time points after an LP in rhesus monkeys. We find that amyloid-beta (Aβ) and Tau levels increased significantly on day 1, peaked on day 3, and returned to baseline on day 10 after LP. The NFL levels increased significantly on day 5, peaked on day 10, and returned to baseline after day 30. The increased AD biomarker levels were mainly due to CSF outflow and deep intrathecal invasion during LP. Therefore, if LPs are repeated within a short period of time, prior LP can affect Aβ and Tau levels within 10days and NFL levels within 30days, which may lead to clinical misdiagnosis or incorrect scientific conclusions.

Beyond CSF and Neuroimaging Assessment: Evaluating Plasma miR-145-5p as a Potential Biomarker for Mild Cognitive Impairment and Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. New strategies for the early detection of MCI and sporadic AD are crucial for developing effective treatment options. Current techniques used for diagnosis of AD are invasive and/or expensive, so they are not suitable for population screening. Cerebrospinal fluid (CSF) biomarkers such as amyloid β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau181 (P-tau181) levels are core biomarkers for early diagnosis of AD. Several studies have proposed the use of blood-circulating microRNAs (miRNAs) as potential novel early biomarkers for AD. We therefore applied a novel approach to identify blood-circulating miRNAs associated with CSF biomarkers and explored the potential of these miRNAs as biomarkers of AD. In total, 112 subjects consisting of 28 dementia due to AD cases, 63 MCI due to AD cases, and 21 cognitively healthy controls were included. We identified seven Aβ1-42-associated plasma miRNAs, six P-tau181-associated plasma miRNAs, and nine Aβ1-42-associated serum miRNAs. These miRNAs were involved in AD-relevant biological processes, such as PI3K/AKT signaling. Based on this signaling pathway, we constructed an miRNA-gene target network, wherein miR-145-5p has been identified as a hub. Furthermore, we showed that miR-145-5p performs best in the prediction of both AD and MCI. Moreover, miR-145-5p also improved the prediction performance of the mini-mental state examination (MMSE) score. The performance of this miRNA was validated using different datasets including an RT-qPCR dataset from plasma samples of 23 MCI cases and 30 age-matched controls. These findings indicate that blood-circulating miRNAs that are associated with CSF biomarkers levels and specifically plasma miR-145-5p alone or combined with the MMSE score can potentially be used as noninvasive biomarkers for AD or MCI screening in the general population, although studies in other AD cohorts are necessary for further validation.

Biomarker Changes during 20 Years Preceding Alzheimer’s Disease

BackgroundBiomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer’s disease have not been extensively investigated in longitudinal studies.MethodsWe conducted a multicenter, nested case–control study of Alzheimer’s disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year–to–3-year intervals. A total of 648 participants in whom Alzheimer’s disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups.ResultsThe median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer’s disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aβ)42, 18 years; the ratio of Aβ42 to Aβ40, 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer’s disease group initially accelerated and then slowed.ConclusionsIn this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer’s disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. (Funded by the Key Project of the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03653156.)

Polygenic Risk Score Reveals Genetic Heterogeneity of Alzheimer's Disease between the Chinese and European Populations.

The polygenic risk score (PRS) aggregates the effects of numerous genetic variants associated with a condition across the human genome and may help to predict late-onset Alzheimer's disease (LOAD). Most of the current PRS studies on Alzheimer's disease (AD) have been conducted in Caucasian ancestry populations, while it is less studied in Chinese. To establish and examine the validity of Chinese PRS, and explore its racial heterogeneity. We constructed a PRS using both discovery (N = 2012) and independent validation samples (N = 1008) from Chinese population. The associations between PRS and age at onset of LOAD or cerebrospinal fluid (CSF) biomarkers were assessed. We also replicated the PRS in an independent replication cohort with CSF data and constructed an alternative PRS using European weights. Multi-center genetics study. A total of 3020 subjects were included in the study. PRS was calculated using genome-wide association studies data and evaluated the performance alone (PRSnoAPOE) and with other predictors (full model: LOAD ~ PRSnoAPOE + APOE+ sex + age) by measuring the area under the receiver operating curve (AUC). PRS of the full model achieved the highest AUC of 84.0% (95% CI = 81.4-86.5) with pT< 0.5, compared with the model containing APOE alone (61.0%). The AUC of PRS with pT<5e-8 was 77.8% in the PRSnoAPOE model, 81.5% in the full model, and only ranged from 67.5% to 75.1% in the PRS with the European weights model. A higher PRS was significantly associated with an earlier age at onset (P <0.001). The PRS also performed well in the replication cohort of the full model (AUC=83.1%, 95% CI = 74.3-92.0). The CSF biomarkers of Aβ42 and the ratio of Aβ42/Aβ40 were significantly inversely associated with the PRS, while p-Tau181 showed a positive association. This finding suggests that PRS reveal genetic heterogeneity and higher prediction accuracy of the PRS for AD can be achieved using a base dataset and validation within the same ethnicity. The effective PRS model has the clinical potential to predict individuals at risk of developing LOAD at a given age and with abnormal levels of CSF biomarkers in the Chinese population.

Discrimination between dementia with Lewy bodies and Alzheimer’s disease based on biofluid monoamines, biomarker values and cognitive parameters

AbstractBackgroundDespite disease‐specific symptoms, differentiation between Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) remains challenging, especially in early, prodromal stages. This is fueled by overlapping pathology in both diseases (Slaets et al., 2013). Monoamine neurotransmitters are significantly altered between DLB and AD and are capable of distinguishing DLB from AD, when added to the panel of cerebrospinal fluid (CSF) dementia biomarkers (Aβ1‐40, Aβ1‐42, T‐tau, P‐tau) and as standalone biomarkers (Janssens et al., 2018). Additionally, cognitive and behavioral differences linked to monoaminergic changes between DLB, AD patients and non‐demented control individuals, have been previously described (Engelborghs et al., 2006, Vermeiren et al., 2015).This study aimed to further explore these dissimilarities for improving discrimination between prodromal and advanced DLB and AD stages.MethodMonoamine neurotransmitter levels were measured in CSF and plasma of 160 prodromal AD (proAD), prodromal DLB (proDLB), AD and DLB patients and 40 non‐demented individuals, using ultra‐high‐performance liquid chromatography. CSF biomarker levels were determined through ELISA. A battery of cognitive and behavioral tests was performed. Monoaminergic, biomarker, cognitive and demographic data were integrated in stepwise regression models to discriminate between (prodromal) DLB and AD.ResultSignificant serotonergic differences in CSF between DLB and AD, as well as noradrenergic, dopaminergic and serotonergic differences in plasma between DLB and AD and with non‐demented individuals were noted. CSF dementia biomarkers levels differed significantly between proAD, proDLB, DLB and AD stages and with non‐demented individuals. There were no CSF, plasma monoamines or CSF biomarker changes between proDLB versus DLB, and proAD versus AD stages. Cognitive functioning differed significantly between prodromal and advanced DLB and AD stages and with non‐demented individuals. Stepwise regression identified that models including plasma and CSF serotonergic components, as well as cognitive tests were the most accurate at discriminating between proDLB versus DLB, proAD versus AD, proDLB versus proAD and DLB versus AD, with area under the curve (AUC), sensitivity and specificity values &gt; 0.9.ConclusionThese findings support differentially affected monoaminergic, pathological biomarker levels and cognitive abilities between (prodromal) AD and DLB, and with non‐demented individuals. In addition, this study provides robust models for discrimination between (prodromal) DLB and AD.

Sex‐associated differences in plasma and cerebrospinal fluid biomarkers in Early‐onset Alzheimer’s disease

AbstractBackgroundFemale sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐ε4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐ε4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aβ 42/40, and pTau231. CSF markers included: Aβ 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1).MethodWe included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐ε4 genotype. Demographics (age, education, APOE‐ε4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers.ResultCompared to men, EOAD women showed greater levels of plasma NfL (p = .03), and GFAP (p&lt;.001) while Aβ 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05). APOE‐ε4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex.ConclusionAs highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD.This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐ε4 genotype‐based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.

Sex‐associated differences in plasma and cerebrospinal fluid biomarkers in Early‐onset Alzheimer’s disease

AbstractBackgroundFemale sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐e4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐e4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aß 42/40, and pTau231. CSF markers included: Aß 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1).MethodWe included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐e4 genotype. Demographics (age, education, APOE‐e4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers.ResultCompared to men, EOAD women showed greater levels of plasma NfL (p = .03), and GFAP (p&lt;.001) while Aß 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05). APOE‐e4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex.ConclusionAs highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD. This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐e4 genotype‐based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.

96 The Proportion of Patients with Cerebrospinal Fluid Biomarkers Consistent with Alzheimer’s Disease in a Cohort with Suspected Normal Pressure Hydrocephalus

Objective:Normal pressure hydrocephalus (NPH) is characterized by pathologically enlarged ventricles without elevated cerebrospinal fluid (CSF) pressure along with a triad of clinical symptoms including gait disturbances, urinary incontinence, and cognitive impairment. NPH is evaluated with lumbar drain trials (LDTs) where CSF is removed over several days to determine if patients would benefit from ventricular shunting. Candidate selection and success for these surgeries remains challenging because other diseases such as Alzheimer’s disease (AD) share common features with NPH in cognitive impairment and enlarged ventricles. Prior research has found that 20%-40% of presumed NPH cases have AD pathology as determined by brain biopsy or autopsy. CSF biomarkers of AD can be altered in NPH and are not always conclusive, complicating the interpretation of results when formulating diagnoses and prognoses. Studies to refine the analyses of AD CSF biomarkers in NPH are needed. We aimed to examine the frequency of CSF biomarker results among patients presenting for NPH evaluations with LDTs.Participants and Methods:62 patients presented for LDTs upon physician recommendations. CSF specimens were sent to Mayo Clinic Laboratories for Alzheimer Disease Evaluation (ADEVL) that utilizes Elecsys (Lenexa, KS) CSF electrochemiluminescence immunoassays (Roche Diagnostics, Basel, Switzerland) to measure levels of amyloid-beta 42 (Aβ42), total tau (t-tau), and phosphorylatedtau (p-tau), and p-tau:Aβ42 ratio. Results were classified based on interpretation through the Amyloid/Tau/Neurodegeneration (ATN) framework1: 1) AD - biomarker profile consistent with AD pathologic change, 2) non-AD profile - biomarker levels normal or inconsistent with AD pathologic change, or 3) indeterminate - biomarkers were incongruous with only one or two abnormal levels of Aβ42, t-tau, p-tau, or ptau: Aβ42. Indeterminate cases may represent altered protein levels due to CSF dynamics or AD-related pathologic change. In reviewing recent research on CSF dynamics and AD biomarkers in NPH2 a p-tau threshold of 15 pg/mL was derived and implemented such that cases with Aß42 &lt;=1026 pg/mL and p-tau &lt;15 pg/mL were designated as suspected non-AD, and those with Aß42 &lt;=1026 pg/mL and p-tau &gt;15 pg/mL were designated suspected AD.Results:Of the 62 LDT cases, 12 (19.35%) were classified as AD, 31 (50%) were indeterminate and 22 (35.48%) were non-AD. Of the 31 indeterminate cases, 21 (33.87% of the overall sample) were suspected non-AD and 7 (11.29% of the full sample) were categorized as suspected AD.Conclusions:Our findings show that 20%-30% of patients presenting for LDT showed evidence for AD-type pathologic change, consistent with prior reports of AD pathology in cases of possible NPH. Half of all LDT cases had indeterminate AD CSF biomarker results, the interpretations of which were confounded by the potential alterations of CSF biomarkers levels due to NPH independent of AD. Our findings emphasize the need to establish better approaches to interpreting CSF AD biomarkers in evaluating NPH. Future research should examine the discriminative utility of CSF AD biomarkers and the selected p-tau threshold in indeterminate cases for predicting response to LDT and shunting.

The Association of Selected GWAS Reported AD Risk Loci with CSF Biomarker Levels and Cognitive Decline in Slovenian Patients.

Alzheimer's disease (AD) is the most common neurodegenerative disease, with a complex genetic background. Apart from rare, familial cases, a combination of multiple risk loci contributes to the susceptibility of the disease. Genome-wide association studies (GWAS) have identified numerous AD risk loci. Changes in cerebrospinal fluid (CSF) biomarkers and imaging techniques can detect AD-related brain changes before the onset of clinical symptoms, even in the presence of preclinical mild cognitive impairment. In this study, we aimed to assess the associations between SNPs in well-established GWAS AD risk loci and CSF biomarker levels or cognitive test results in Slovenian patients with cognitive decline. The study included 82 AD patients, 28 MCI patients with pathological CSF biomarker levels and 35 MCI patients with normal CSF biomarker levels. Carriers of at least one polymorphic TOMM40 rs157581 C allele had lower Aβ42 (p = 0.033) and higher total tau (p = 0.032) and p-tau181 levels (p = 0.034). Carriers of at least one polymorphic T allele in SORCS1 rs1358030 had lower total tau (p = 0.019), while polymorphic SORCS1 rs1416406 allele was associated with lower total tau (p = 0.013) and p-tau181 (p = 0.036). In addition, carriers of at least one polymorphic T allele in BCHE rs1803274 had lower cognitive test scores (p = 0.029). The study findings may contribute to the identification of genetic markers associated with AD and MCI and provide insights into early disease diagnostics.

Grey matter volume and CSF biomarkers predict neuropsychological subtypes of MCI

There is increasing evidence of different subtypes of individuals with mild cognitive impairment (MCI). An important line of research is whether neuropsychologically-defined subtypes have distinct patterns of neurodegeneration and cerebrospinal fluid (CSF) biomarker composition. In our study, we demonstrated that MCI participants of the ADNI database (N = 640) can be discriminated into 3 coherent neuropsychological subgroups. Our clustering approach revealed amnestic MCI, mixed MCI, and cluster-derived normal subgroups. Furthermore, classification modeling revealed that specific predictive features can be used to differentiate amnestic and mixed MCI from cognitively normal (CN) controls: CSF Aβ142 concentration for the former and CSF Aβ1–42 concentration, tau concentration as well as grey matter atrophy (especially in the temporal and occipital lobes) for the latter. In contrast, participants from the cluster-derived normal subgroup exhibited an identical profile to CN controls in terms of cognitive performance, brain structure, and CSF biomarker levels. Our comprehensive data analytics strategy provides further evidence that multimodal neuropsychological subtyping is both clinically and neurobiologically meaningful.

Lower Cerebrospinal Fluid Amyloid-β42 Predicts Sooner Time to Antipsychotic Use in Alzheimer's Disease.

Cerebrospinal fluid (CSF) biomarkers of amyloid-β42 (Aβ42) and phosphorylated-tau help clinicians accurately diagnose Alzheimer's disease (AD). Whether biomarkers help prognosticate behavioral and psychological symptoms of dementia (BPSD) is unclear. Determine whether CSF biomarker levels aid prognostication of BPSD in AD. This retrospective cohort study included patients over 65 with a diagnosis of AD based on CSF biomarkers. We measured time from CSF testing to the first antipsychotic use in the following months. We then analyzed time to antipsychotic (AP) use with respect to Aβ42, total tau, phosphorylated tau, and amyloid-to-tau index using a survival analysis approach. Of 86 AD patients (average 72±5 years, 46.5% male), 11 patients (12.7%) received APs following CSF testing. Patients with Aβ42 below the median had sooner time-to-AP use. This was significant on a log-rank test (p = 0.04). There was no difference in time-to-AP use if the group was stratified by levels of total tau, phosphorylated tau, or amyloid-to-tau index. These results suggest a relationship between lower CSF Aβ42 levels and sooner AP use. This supports prior reports suggesting a correlation between BPSD and Aβ deposition on PET. These results highlight the need for further prospective studies on Aβ levels and BPSD.

Genome‐Wide Association Study for CSF Aβ42, Tau, and pTau in a Large Multi‐cohort Study to Identify Novel AD Genetic Variants

AbstractBackgroundPrevious studies have identified more than 20 genetic loci to be associated with AD risk. These reported loci do not account for all the estimated heritability nor report enough information on the undelaying biological mechanism. Genome‐wide association studies of endophenotypes have identified new loci associated with Alzheimer’s disease. To better understand AD pathology and identify new variants implicated in AD much larger samples size is needed. We conducted a GWAS of Amyloid‐beta (Aβ42) tau, and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) to detect novel variants associated with AD.MethodsAD CSF biomarkers were measured in 7282 individuals from 24 different cohorts. Samples were genotyped using different array technology with stringent quality control standards to each dataset before combining datasets. Minimum call rate for single nucleotide polymorphism (SNP) and individuals was 99.85%. SNPs not in Hardy–Weinberg equilibrium were excluded. X‐chromosome SNPs were analyzed to verify sex identification. Duplicates and cryptic relatedness among samples were tested by pairwise genome‐wide estimates of proportion identity‐by‐descent. PLINK was used to calculate principal component analysis. CSF biomarker levels were log10‐transformed to approximate a normal distribution with the mean standardized to zero for each dataset to account for the variability on the different platforms used to measure proteins levels. One‐stage joint‐GWAS to maximize the power in our analysis. Post‐GWAS analyses Colocalization, Madelian Randomization, LD Score Regression, were implemented to detect colocalization of two potential related signals to detect common causal variant and to evaluate the overlap in genetic architecture of CSF Biomarkers and risk factor for ADResultsThis study represents one of the largest multi‐cohort GWAS analyses on CSF AD biomarkers. Several genome‐wide significant hits were found including APOE. Additional analyses are underway.ConclusionsCSF Aβ42, tau, and ptau are well established AD endophenotypes with a clear genetic association with APOE genotype and AD risk. Genetic studies on endophenotypes provide enough power to detect association with a smaller sample size than case‐control studies helping us to better understand the biological mechanism of the disease. With this study we aim to identify novel variants implicated in AD.

Associations of cortisol with neuroinflammation biomarkers in a memory clinic cohort

AbstractBackgroundCortisol, one of the most important mediators of stress in humans, is often found increased in Alzheimer’s disease (AD) patients and correlates with disease severity. Stress response and inflammation are two systems that are tightly associated to one another. Several lines of evidence suggest that cortisol can promote inflammation. However, less is known on the interaction of cortisol with neuroinflammation in the context of AD, and to the best of our knowledge there are no human studies that have systematically explored the association of these two systems in AD patients so far. The aim of this study was to investigate levels of cerebrospinal fluid (CSF) biomarkers of neuroinflammation and their relationship to salivary cortisol in a memory clinic cohort.MethodA total of 108 memory clinic patients with subjective cognitive decline (SCI, n = 40), mild cognitive impairment (MCI, n = 39) and AD (n = 29), from the Karolinska University Hospital in Stockholm, Sweden, were included in this study. Salivary cortisol was collected at six timepoints during the day on two days, to quantify awakening cortisol, cortisol awakening response (CAR), bedtime cortisol and total cortisol. CSF levels of 37 neuroinflammation and cerebrovascular dysfunction biomarkers were determined by a multiplex immunoassay. Associations among cortisol and neuroinflammation markers were assessed by linear regression models adjusting for age and diagnosis. ANCOVA tests were used to compare biomarker levels between the diagnostic groups.ResultAwakening cortisol was significantly elevated in the AD group compared to the SCI and MCI participants. Higher IP‐10 and placental growth factor (PlGF) levels were associated with decreased CAR independent of age and diagnosis. Thymus and activation‐regulated chemokine (TARC), CRP, intracellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) levels were upregulated in MCI participants compared to SCI and AD.ConclusionWe provide evidence that the HPA axis is altered in AD. Moreover, salivary cortisol is associated to neuroinflammation in an age and diagnosis independent manner. Finally, neuroinflammatory and vascular dysfunction regulators are increased in CSF during MCI stages followed by a drop in their levels in AD participants, presumably reflecting a more active role of neuroinflammation at an early state.

Association between Cerebrospinal Fluid and Serum Biomarker Levels and Diagnosis, Injury Severity, and Short-Term Outcomes in Patients with Acute Traumatic Spinal Cord Injury.

Acute traumatic spinal cord injury (SCI) is recognized as a global problem that can lead to a range of acute and secondary complications impacting morbidity and mortality. There is still a lack of reliable diagnostic and prognostic biomarkers in patients with SCI that could help guide clinical care and identify novel therapeutic targets for future drug discovery. The aim of this prospective controlled study was to determine the cerebral spinal fluid (CSF) and serum profiles of 10 biomarkers as indicators of SCI diagnosis, severity, and prognosis to aid in assessing appropriate treatment modalities. CSF and serum samples of 15 SCI and ten healthy participants were included in the study. The neurological assessments were scored on admission and at discharge from the hospital using the American Spinal Injury Association Impairment Score (AIS) grades. The CSF and serum concentrations of SBDP150, S100B, GFAP, NF-L, UCHL-1, Tau, and IL-6 were significantly higher in SCI patients when compared with the control group. The CSF GBDP 38/44K, UCHL-L1, S100B, GFAP, and Tau levels were significantly higher in the AIS A patients. This study demonstrated a strong correlation between biomarker levels in the diagnosis and injury severity of SCI but no association with short-term outcomes. Future prospective controlled studies need to be done to support the results of this study.

Proteomic Signatures Associated with Genetic and Clinical Subtypes of Parkinson’s Disease (S42.006)

<h3>Objective:</h3> Identify proteomic signatures associated with Parkinson9s disease (PD) patients9 genetic status, movement and cognitive tests, neuroimaging, and cerebrospinal fluid (CSF) phosphorylated-tau, total-tau, alpha-synuclein, and amyloid-beta levels. Prioritize protein signatures by integrating genome-wide genotyping and CSF proteomic data. <h3>Background:</h3> PD is a heterogeneous disorder with identifiable clinical-pathological subtypes based on symptom severity and predominance. An accurate molecular profile could reduce PD clinical heterogeneity. Few studies have applied a proteogenomic approach to samples from PD patients to identify proteins associated with clinical, neuroimaging, or neuropathological subtypes. <h3>Design/Methods:</h3> We used data from the Parkinson9s Progression Markers Initiative (PPMI) cohort (N = 1158); 683 individuals passed quality control for pQTL analysis. Differentially expressed proteins in LRRK2+, GBA1+, or sporadic PD (sPD) were curated using F-test, adjusting for sex, age, and principal components 1–4. Weighted correlation network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) algorithm were used to explore modules of proteins associated with CSF biomarkers and clinical and neuroimaging data. We used the data from Posavi et al. (2019) as a replication cohort. <h3>Results:</h3> We identified subgroups of proteins associated with mutation carriers in LRRK2 (n=709) and GBA1 (n=505), or sPD (n=97). The WGCNA revealed two modules of proteins associated with higher levels of CSF biomarkers in PD patients. We found 117 proteins distinguishing genetically defined PD from sPD (AUC=0.94) and identified 158 proteins that differentiate PD from controls (AUC=0.86). Our model in the replication cohort (AUC=0.92/0.71) outperformed the model with four robust biomarkers from Posavi et al. (AUC=0.88/0.63) for PD prediction. We identified genetic modifiers for TMEM106A, ITGB2, ENTPD1, OLR1, GRN, GPNMB, GREM2, C1QTNF1, and HLA-DQA2 levels in the LRRK2 locus. <h3>Conclusions:</h3> Genetically defined PD subgroups are associated with distinct proteomic signatures. Protein modules correlated to CSF biomarkers and differentiated PD from controls. Our proteome-genome approach found that LRRK2 is a pleiotropic genetic modifier. <b>Disclosure:</b> Ms. Lai has nothing to disclose. Dr. Palanisamy has nothing to disclose. Bruno Benitez has nothing to disclose.

White matter hyperintensity mediating gait disorders in iNPH patients via neurofilament light chain.

This study aimed to analyze the differences in regional white matter hyperintensities (WMH) volume and cerebrospinal fluid biomarker levels between idiopathic normal pressure hydrocephalus (iNPH) patients with or without gait disorder. Forty-eight iNPH patients undergoing bypass surgery and 20 normal senile individuals were included. The LST toolkit was used to segment all MRI fluid attenuation inversion images and quantify the WMH volume in each brain region. Cerebrospinal fluid was collected from all individuals and measured for concentrations of Aβ, t-tau, p-tau, and neurofilament light chain (NfL). Patients with iNPH were followed up for 1 year and divided categorized into a gait disorder improvement group and no improvement group according to the 3 m round-trip test time parameter improvement by more than 10%. We found that WMH in all areas of iNPH patients was higher than that in the control group. CSF levels of Aβ, t-tau, and p-tau were lower than those in the control group, while NfL levels were higher than those in the control group. The gait (+) group NfL level was higher than that in gait (-), and there were no statistical differences in Aβ, t-tau, and p-tau levels. The gait (+) group of frontal and parietal lobe WMH volume PVH above the gait (-) group. The mediating effect model analysis showed that PVH might affect the gait disorder of iNPH patients through NfL. A 1-year follow-up of the patients after the bypass surgery found that 24 of the 35 patients in the gait (+) group had improvements, while 11 had no significant improvements. The comparison of CSF marker levels between the two groups showed that the CSF NfL level in the improved group was lower than that in the non-improved group. The WMH volume and PVH in the frontal-parietal lobe of the improved group were lower than those of the non-improved group. iNPH patients have more serious frontoparietal and periventricular white matter lesions, and WMH volume in the frontoparietal may mediate the occurrence of gait disorder in iNPH patients through the increase of NfL level.

Genetic Polymorphisms in Oxidative Stress and Inflammatory Pathways as Potential Biomarkers in Alzheimer's Disease and Dementia.

Oxidative stress and neuroinflammation are important processes involved in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Numerous risk factors, including genetic background, can affect the complex interplay between those mechanisms in the aging brain and can also affect typical AD hallmarks: amyloid plaques and neurofibrillary tangles. Our aim was to evaluate the association of polymorphisms in oxidative stress- and inflammation-related genes with cerebrospinal fluid (CSF) biomarker levels and cognitive test results. The study included 54 AD patients, 14 MCI patients with pathological CSF biomarker levels, 20 MCI patients with normal CSF biomarker levels and 62 controls. Carriers of two polymorphic IL1B rs16944 alleles had higher CSF Aβ1-42 levels (p = 0.025), while carriers of at least one polymorphic NFE2L2 rs35652124 allele had lower CSF Aβ1-42 levels (p = 0.040). Association with IL1B rs16944 remained significant in the AD group (p = 0.029). Additionally, MIR146A rs2910164 was associated with Aβ42/40 ratio (p = 0.043) in AD. Significant associations with cognitive test scores were observed for CAT rs1001179 (p = 0.022), GSTP1 rs1138272 (p = 0.005), KEAP1 rs1048290 and rs9676881 (both p = 0.019), as well as NFE2L2 rs35652124 (p = 0.030). In the AD group, IL1B rs1071676 (p = 0.004), KEAP1 rs1048290 and rs9676881 (both p = 0.035) remained associated with cognitive scores. Polymorphisms in antioxidative and inflammation genes might be associated with CSF biomarkers and cognitive test scores and could serve as additional biomarkers contributing to early diagnosis of dementia.

Identifying the dataset to define the optimal timing of histopathological examination for central nervous system toxicity in MPTP-induced Parkinson's disease monkey model.

Determining the optimal timing for histopathological examination following exposure to a test article is crucial for assessing neurotoxicity. However, no study has focused on identifying an ideal dataset to define the optimal timing for histopathological examination of central nervous system (CNS) toxicity in monkeys. Therefore, this study aimed to define a predictive endpoint that would guide us in selecting the optimal timing for histopathological examination of CNS toxicity in monkeys. Four cynomolgus monkeys were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously at a dosage of 0.6 mg/kg twice at 1-week intervals. Necropsies were performed 1 week after the final dose. The Parkinsonian rating (PR) score and temporal changes in neurofilament light chain and glial fibrillary acidic protein concentrations in the cerebrospinal fluid (CSF) and serum were evaluated and compared with the histopathological findings in the brain. The PR score of all animals administered MPTP increased from days 10 to 11, with some degree of individual variability. Microscopically, all animals showed axonal swelling and vacuolation, with or without microgliosis in the nigrostriatal bundle. However, substantial neurodegenerative findings were observed only in animals with high PR scores at necropsy. A slight increase in CSF biomarker levels at necropsy was also observed in animals with high PR scores. However, their correlation with microscopic findings in these animals was unclear. These data suggest that comprehensive clinical observations, such as PR score alone or combined with other CSF biomarkers, could be further evaluated as potential indicators for triggering anatomic CNS evaluations in monkeys following toxic insults.