Alzheimer's Disease Cerebrospinal Fluid Research Articles

Longitudinal trajectories of Alzheimer's disease CSF biomarkers and blood pressure in cognitively healthy subjects.

We examined whether hypertension (HTN) was associated with Alzheimer's disease-related biomarkers in cerebrospinal fluid (CSF) and how changes in blood pressure (BP) related to changes in CSF biomarkers over time. A longitudinal observation of cognitively healthy normotensive subjects (n=134, BP<140/90, withno antihypertensive medication), controlled HTN(n=36, BP<140/90, taking antihypertensive medication), and 35 subjects with uncontrolled HTN (BP ≥ 140/90). The follow-up range was 0.5to15.6 years. Total tau (T-tau) and phospho-tau181 (P-tau 181) increased in allbut controlled HTN subjects (group×timeinteraction: p<0.05 for both), but no significant Aβ42 changes were seen. SignificantBP reduction wasobserved in uncontrolled HTN, andit was related to increase in T-tau (p=0.001) and P-tau 181 (p<0.001). Longitudinal increases in T-tau and P-tau 181 were observed in most subjects; however, onlyuncontrolled HTN had both markers increase alongside BPreductions. We speculatecumulative vascular injury renders thebrain susceptible to relative hypoperfusion with BP reduction. Over the course of the study, participants with uncontrolled HTN at baseline showed greater accumulation of CSF total tau and phospho-tau181 (P-tau 181) than subjects with normal BP or with controlled HTN. In the group with uncontrolled HTN, increases in total tau and P-tau 181 coincided with reduction in BP. We believe this highlights the role of HTN in vascular injury and suggests decline in cerebral perfusion resulting in increased biomarker concentrations in CSF. Medication use was the main factor differentiating controlled from uncontrolled HTN, indicating that earlier treatment was beneficial for preventing accumulations of pathology.

Predictive value for cerebrospinal fluid Alzheimer's disease profile of different measures of verbal episodic memory in patients with MCI

Neuropsychological evidence of memory impairment represents the main feature of the clinical onset of typical Alzheimer’s disease (AD). Rey’s Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) are two tests both assessing verbal episodic memory, widely used in clinical practice. Our aim was to investigate the added value of their combined use in predicting cerebrospinal fluid (CSF) AD biomarkers positivity in a retrospective consecutive series of patients with mild cognitive impairment (MCI). 169 MCI patients were included. For all of them neuropsychological assessment and CSF analysis were available. According to CSF A/T/(N) profile, 109 were defined as MCI due to AD (A+T+), and 60 were non-AD MCI (A−T−). Logistic regression model and receiver-operating characteristic (ROC) curves were analyzed to evaluate the discriminatory power of single and combined sub-measures between AD and non-AD patients. The combination of RAVLT-del with LM could acceptably discriminate the two groups (AUC: 0.69, CI 95% 0.617–0.761, sens: 0.75, spec. 0.58, p < 0.001), while the single tests did not show sufficient discriminative performance. Our study shows that the combination of RAVLT delayed recall with LM better predicts the biological AD diagnosis (A+T+), showing a good discriminative power between MCI-AD from non-AD MCI. Since RAVLT and LM assess different components of verbal episodic memory, they should be considered as complementary, rather than interchangeable, tests.

Scottish Intercollegiate Guidelines Network (SIGN) Guidance on Dementia. The investigation of suspected dementia (SIGN 168) with focus on biomarkers.

This is an executive summary of the recent guidance produced by the SIGN dementia guideline group with regards to the investigation of suspected dementia. This is a sub-section of the broader SIGN 168 guideline released in November 2023. The guideline group included clinicians with expertise in Old Age Psychiatry, Neurology, Radiology and Nuclear Medicine supported by colleagues from the SIGN and Healthcare Improvement Scotland (HIS) teams. There was representation from carers and support organisations with experience of dementia, to ensure the recommendations were appropriate from the perspective of the people being assessed for possible dementia and their carers. As the 2018 National Institute for Health and Clinical Excellence (NICE) dementia review, included a review of the evidenced investigation of dementia, the SIGN guideline development group decided to focus on a review on the up to date evidence regarding the role of imaging and fluid biomarkers in the diagnosis of dementia. In order to give context to the consideration of more advanced diagnostic biomarker investigations, the guideline and this summary includes the NICE guidance on the use of standard investigations as well as more specialist investigations. The evidence review supports consideration of the use of structural imaging, nuclear medicine imaging and established Alzheimer's cerebrospinal fluid (CSF) biomarkers (amyloid and tau) in the diagnosis of dementia. Although routine use of amyloid PET imaging was not recommended, its potential use, under specialist direction, in patients with atypical or young onset presentations of suspected Alzheimer's dementia was included as a clinical good practice point.

Relationship Between Cerebrospinal Fluid Alzheimer's Disease Biomarker Values Measured via Lumipulse Assays and Conventional ELISA: Single-Center Experience and Systematic Review.

Although Lumipulse assays and conventional ELISA are strongly correlated, the precise relationship between their measured values remains undetermined. To determine the relationship between Lumipulse and ELISA measurement values. Patients who underwent cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker measurements and consented to biobanking between December 2021 and June 2023 were included. The relationship between values measured via Lumipulse assays and conventional ELISA were evaluated by Passing-Bablok analyses for amyloid-β 1-42 (Aβ 42), total tau (t-tau), and phospho-tau 181 (p-tau 181). Studies using both assays were systematically searched for in PubMed and summarized after quality assessment. Regression line slopes and intercepts were 1.41 (1.23 to 1.60) and -77.8 (-198.4 to 44.5) for Aβ 42, 0.94 (0.88 to 1.01) and 98.2 (76.9 to 114.4) for t-tau, and 1.60 (1.43 to 1.75) and -21.1 (-26.9 to -15.6) for p-tau181. Spearman's correlation coefficients were 0.90, 0.95, and 0.95 for Aβ 42, t-tau, and p-tau181, respectively. We identified 13 other studies that included 2,117 patients in total. Aβ 42 slope varied among studies, suggesting inter-lab difference of ELISA. The slope and intercept of t-tau were approximately 1 and 0, respectively, suggesting small proportional and systematic differences. Conversely, the p-tau181 slope was significantly higher than 1, distributed between 1.5-2 in most studies, with intercepts significantly lower than 0, suggesting proportional and systematic differences. We characterized different relationship between measurement values for each biomarker, which may be useful for understanding the differences in CSF biomarker measurement values on different platforms and for future global harmonization.

Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid.

Cerebrovascular dysfunction is a pathological hallmark of Alzheimer's disease (AD). Nevertheless, detecting cerebrovascular changes within bulk tissues has limited our ability to characterize proteomic alterations from less abundant cell types. We conducted quantitative proteomics on bulk brain tissues and isolated cerebrovasculature from the same individuals, encompassing control (N=28), progressive supranuclear palsy (PSP) (N=18), and AD (N=21) cases. Protein co-expression network analysis identified unique cerebrovascular modules significantly correlated with amyloid plaques, cerebrovascular amyloid angiopathy (CAA), and/or tau pathology. The protein products within AD genetic risk loci were concentrated within cerebrovascular modules. The overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with cerebrovascular network highlighted a significant increase of matrisome proteins, SMOC1 and SMOC2, in CSF, plasma, and brain. These findings enhance our understanding of cerebrovascular deficits in AD, shedding light on potential biomarkers associated with CAA and vascular dysfunction in neurodegenerative diseases.

Characteristics of T Cells in Single-Cell Datasets of Peripheral Blood and Cerebrospinal Fluid in Alzheimer's Disease Patients.

Alzheimer's disease (AD) is the most common type of dementia, causing a huge socioeconomic burden. In parallel with the widespread uptake of single-cell RNA sequencing (scRNA-seq) technology, there has been a rapid accumulation of data produced by researching AD at single-cell resolution, which is more conductive to explore the neuroimmune-related mechanism of AD. To explore the potential features of T cells in the peripheral blood and cerebrospinal fluid of AD patients. Two datasets, GSE181279 and GSE134578, were integrated from GEO database. Seurat, Monocle, CellChat, scRepertoire, and singleR packages were mainly employed for data analysis. Our analysis demonstrated that in peripheral blood, T cells were significantly expanded, and these expanded T cells were possessed effector function, such as CD8+TEMRA, CD4+TEMRA, and CD8+TEM. Interestingly, CD8+TEMRA and CD4+TEMRA cells positioned adjacently after dimensions reduction and clustering. Notably, we identified that the expanded T cells were developed from Naïve T cells and TCM cells, and TEM cells was in the intermediate state of this developing process. Additionally, in cerebrospinal fluid of AD patients, the amplified T cells were mainly CD8+TEMRA cells, and the number and strength of communication between CD4+TEM, CD8+TEM, and CD8+TEMRA were decreased in AD patients. Our comprehensive analyses identified the cells in cerebrospinal fluid from AD patients are expanded TEMRA or TEM cells and the TEMRA cells communicating with other immune cells is weakened, which may be an important immune feature that leads to AD.

Compromised Plasma Membrane Repair Contributes to Neuronal Cell Death and Neurodegeneration During Alzheimer’s Disease

Alzheimer’s Disease (AD) is the most common neurodegenerative disease and involves accumulation of intracellular amyloid beta (Aβ) in the early stages of the disease. Aβ has been shown to compromise neuronal cell membrane integrity by increasing membrane permeability, elevating intracellular calcium concentrations, and Aβ directly penetrating and damaging the neuronal cell membrane. Damage to the cell membrane requires a rapid and effcient repair mechanism to restore the barrier function of the membrane and avoid cell death. Here, we aimed to study the effects of intracellular Aβ on neuronal cell membrane repair. To determine if membrane permeability is compromised in vivo, we stained 6-month FVB and APP/PS1 brain sections with anti-IgG. We observed a significant increase in IgG positivity in the APP/PS1 tissue as compared to the FVB brains. We repeated this with post-mortem frontal lobe tissue and observed a significant increase in IgG-positivity in the AD samples as compared to the non-AD. To assess the effect of neuronal membrane repair in AD patients, we treated mouse neuroblastomas (N2A) and primary mouse hippocampal neurons with non-AD and AD patient cerebrospinal fluid (CSF) at a 1:100 dilution or 1μM recombinant human Aβ42. We conducted laser damage assays and observed a membrane repair defect in these neuronal cell models. We explored the biochemical components of the CSF that may be contributing to this induced repair defect, we measured the Aβ42 by ELISA and stratified Aβ42 concentration by the corresponding CSF AUC. We observed a positive correlation between Aβ42 concentrations and reduced membrane repair capacity. We sought to determine the mechanism of the reduced membrane repair capacity by assessing the expression levels of membrane repair proteins and observed decreased dysferlin in cell models, 6-month APP/PS1 mouse models, and human postmortem tissues with high levels of Aβ. Overexpression of dysferlin in the AD cell models can increase dysferlin expression and restore membrane repair capacity in neurons treated with AD CSF samples or recombinant Aβ42. We have determined this reduction in repair capacity is due to reduced dysferlin expression, and future studies will determine the mechanism leading to dysferlin downregulation. This work was supported by The Ohio State University College of Medicine Dean’s Discovery Grants Program. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Personal value of Alzheimer's disease biomarker testing and result disclosure from the patient and care partner perspective.

We described patients' and care partners' experiences with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing and result disclosure in routine care. IMPACT-AD BC is an observational study of clinic patients who underwent AD CSF biomarker testing as part of their routine medical care (n = 142). In the personal utility arm of the study, semi-structured phone interviews were conducted with a subset of patients (n = 34), and separately with their care partners (n = 31). Post-disclosure interviews were conducted ∼1 month and ∼6 months after biomarker result disclosure and investigated the patients' decision-making process around testing, impact of receiving results, wellness and lifestyle changes, and future planning. A majority of patients (90%) rated their decision to undergo testing as "easy." Post-disclosure, the majority (82%) reported overall positive feelings from having greater certainty and the ability to plan ahead, and results spurred them to adopt/continue healthy behaviors such as exercise (84%) and cognitive activities (54%). Care partners expressed relief from having more diagnostic certainty, increased appreciation of future caregiving responsibilities, and a desire to connect with support resources. Perspectives of persons with lived experience in dementia provide new insight into the value of biomarker testing and should be included as part of evidence-guided considerations for pre-test counseling and result disclosure. Moreover, study findings identify an interval when patients and care partners are highly receptive to positive lifestyle and medical interventions.

Clinical value of Alzheimer's disease biomarker testing.

In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. Patients with completed management questionnaires (n = 142) had a median age of 64 (interquartile range: 59-69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (-52.0%) and detailed neuropsychological assessments (-63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and -50.0% in biomarker-positive and -negative cases, respectively). AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.

Amyloid pathology mediates the associations between plasma fibrinogen and cognition in non-demented adults.

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aβ42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aβ42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aβ42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aβ pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aβ pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aβ pathology. Fibrinogen was associated with both cognition and Aβ pathology. Aβ pathology may be a critical mediator for impacts of fibrinogen on cognition.

Cognitive and Cerebrospinal Fluid Alzheimer's Disease-related Biomarker Trajectories in Older Surgical Patients and Matched Nonsurgical Controls.

Anesthesia and/or surgery accelerate Alzheimer's disease pathology and cause memory deficits in animal models, yet there is a lack of prospective data comparing cerebrospinal fluid (CSF) Alzheimer's disease-related biomarker and cognitive trajectories in older adults who underwent surgery versus those who have not. Thus, the objective here was to better understand whether anesthesia and/or surgery contribute to cognitive decline or an acceleration of Alzheimer's disease-related pathology in older adults. The authors enrolled 140 patients 60 yr or older undergoing major nonneurologic surgery and 51 nonsurgical controls via strata-based matching on age, sex, and years of education. CSF amyloid β (Aβ) 42, tau, and p-tau-181p levels and cognitive function were measured before and after surgery, and at the same time intervals in controls. The groups were well matched on 25 of 31 baseline characteristics. There was no effect of group or interaction of group by time for baseline to 24-hr or 6-week postoperative changes in CSF Aβ, tau, or p-tau levels, or tau/Aβ or p-tau/Aβ ratios (Bonferroni P > 0.05 for all) and no difference between groups in these CSF markers at 1 yr (P > 0.05 for all). Nonsurgical controls did not differ from surgical patients in baseline cognition (mean difference, 0.19 [95% CI, -0.06 to 0.43]; P = 0.132), yet had greater cognitive decline than the surgical patients 1 yr later (β, -0.31 [95% CI, -0.45 to -0.17]; P < 0.001) even when controlling for baseline differences between groups. However, there was no difference between nonsurgical and surgical groups in 1-yr postoperative cognitive change in models that used imputation or inverse probability weighting for cognitive data to account for loss to follow up. During a 1-yr time period, as compared to matched nonsurgical controls, the study found no evidence that older patients who underwent anesthesia and noncardiac, nonneurologic surgery had accelerated CSF Alzheimer's disease-related biomarker (tau, p-tau, and Aβ) changes or greater cognitive decline.

Translating NIA-AA criteria into usual practice: Report from the ReDeMa Project.

Biomarker-informed criteria were proposed for the diagnosis of Alzheimer's disease (AD) by the National Institute on Aging and the Alzheimer's Association (NIA-AA) in 2011; however, the adequacy of this criteria has not been sufficiently evaluated. ReDeMa (Red de Demencias de Madrid) is a regional cohort of patients attending memory and neurology clinics. Core cerebrospinal fluid biomarkers were obtained, NIA-AA diagnostic criteria were considered, and changes in diagnosis and management were evaluated. A total of 233 patients were analyzed (mean age 70 years, 50% women, 73% AD). The diagnostic language was modified significantly, with a majority assumption of NIA-AA definitions (69%). Confidence in diagnosis increased from 70% to 92% (p < 0.0005) and management was changed in 71% of patient/caregivers. The influence of neurologist's age or expertise on study results was minimal. The NIA-AA criteria are adequate and utile for usual practice in memory and neurology clinics, improving diagnostic confidence and significantly modifying patient management. Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers increase diagnostic certainty regardless of the neurologist.AD CSF biomarkers lead to changes in disease management .Biomarker-enriched, 2011 NIA-AA diagnostic criteria are adequate for usual practice.

Exploration of novel biomarkers for neurodegenerative diseases using ligand‐binding assays

AbstractBackgroundNeurodegeneration is a complex area involving multiple pathways and often has a long prodromal phase. Reliable biomarkers are needed to allow earlier diagnosis, monitoring of the disease progression, and studying the impact of therapeutic approaches.MethodTherefore, a screening was performed by Sciomics GmbH to identify potential protein biomarkers. The most promising analytes were selected, including cluster of differentiation 14 (CD14), osteopontin (OPN), vascular endothelial growth factor A (VEGF‐A), cancer antigen 15‐3 (CA15‐3) and carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM‐1). Using quantitative ligand‐binding assays based on fluorescence or electrochemiluminescence these analytes were investigated regarding up‐ or downregulation in the presence of Alzheimer´s disease (AD), Parkinson´s disease (PD), Multiple Sclerosis (MS) or Amyotrophic Lateral Sclerosis (ALS) compared to healthy patients.ResultThe quantitative assays confirmed the screening in that CD14 levels were elevated in cerebrospinal fluid (CSF) of AD patients and that OPN levels were increased in CSF of PD patients. In addition, the following significant changes were observed: OPN was elevated in plasma of PD and MS patients, while it was decreased in CSF of MS patients. VEGF‐A levels were increased in the plasma of ALS patients and decreased in CSF of MS patients.ConclusionIncreased CD14 levels in AD CSF are in agreement with studies suggesting that CD14, a co‐receptor of toll like receptor 4 (TLR4) expressed on the surface of e.g. microglia, might mediate the interaction of fibrillar Aβ to TLR4 and thus induce inflammation. OPN has already been shown to be increased in CSF and blood of PD patients previously and it is suggested to be involved in PD pathogenesis due to its role in oxidative stress, apoptosis, mitochondrial dysfunction, and cytokine regulation. Other studies have shown increased levels of OPN in plasma of MS patients potentially due to its expression in activated T‐cells. However, some studies also show increased MS CSF levels in contrast to our findings, where OPN levels are lower in MS CSF. Literature data for VEGF‐A is more conflicting possibly due to different assays detecting different isoforms. To further solidify these findings, large‐scale analyses using well characterized samples should be done in the future.

The cerebrospinal fluid soluble TREM‐1 concentration in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI)

AbstractBackgroundThe most prevalent form of dementia in the world is Alzheimer Disease (AD), a common neurodegenerative condition. Amyloid peptides, phosphorylated tau proteins, and neuroinflammation are the disease’s hallmarks. Finding new biomarkers that can assist in early AD detection is crucial due to the late appearance of the disease symptoms. Triggering receptor expressed on myeloid cell 1 (TREM‐1) is hypothesized that may contribute to the development of AD by causing neuroinflammation. Due of its significance in inflammatory responses, it has been regarded as a promising biomarker. Literature data indicate that TREM‐1 could be potential biomarker of AD severity. Therefore the purpose of our research was to measure the concentration of soluble TREM‐1 in cerebrospinal fluid of AD and MCI patients and non‐demented controls and compare it with classical AD biomarkers.MethodThe concentrations of TREM‐1 were measured in cerebrospinal fluid (CSF) of 20 AD patients and 15 MCI patients as well as 11 non‐demented controls using multiplexing method. Classical biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181 were assessed by immunoenzyme assays.ResultTREM‐1 concentrations were significantly higher in AD and MCI patients in comparison to non‐demented controls. Moreover, in MCI patients, the levels of this protein were significantly higher than in AD patients. Additionally, increased CSF levels of TREM‐1 correlated positively with Tau, pTau181 in the whole study group.ConclusionFindings of our research suggest that TREM‐1 could be early indicator of AD pathology. However, follow‐up studies on larger study group are needed.

Single domain antibodies as promising tools for the selective detection and neutralization of neurotoxic Aβ42 oligomers in the cerebrospinal fluid of Alzheimer’s disease patients

AbstractBackgroundExtracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles of the hyperphosphorylated tau protein are the main hallmarks of Alzheimer’s disease (AD). Small, soluble oligomers, rather than mature fibrils, are the major neurotoxic agents. The heterogeneous structures and the transient nature of these oligomers make their isolation and characterization very challenging. Single domain Abs (sdAbs), composed only of a variable domain of the heavy chain with high specificity and affinity, appear as promising tools for an early diagnosis and therapy for AD.MethodsPerforming an in vitro and in vivo screening of different sdAbs, we selected those targeting Aβ42 oligomers or fibrils with high specificity using dot‐blot, ELISA assay and the super resolution stimulated emission depletion (STED) microscopy. The potential of sdAbs was also investigated in preventing Aβ42 oligomer‐induced cytotoxicity in cultured neuronal cells. Then, the sdAbs were used to selectively detect Aβ42 species in the cerebrospinal fluid (CSF) of AD patients and control subjects and to neutralize their associated harmful effects following cell exposure to CSF samples.ResultssdAbs can selectively detect Aβ42 oligomers or fibrils both in vitro and in cultured cells, preventing the neurotoxicity induced by small oligomers. Moreover, sdAbs can significantly identify Aβ42 oligomers in the CSF of AD patients counteracting their induced toxicity in our cell models.ConclusionsAll these data provide a solid foundation for the development of sdAbs‐based immunodiagnostic tools that can selectively detect toxic aggregates in human body fluids for an early differential diagnosis of protein deposition diseases, such as AD. Furthermore, our results contribute to the improvement of the current therapeutic approaches against AD.The study was supported by Airalzh (AGYR 2020 to R.C.).

Blood proteomics to identify AD CSF molecular subtypes

AbstractBackgroundWe identified three distinct molecular subtypes in Alzheimer’s disease (AD) using cerebrospinal fluid (CSF) proteomics: one subtype was characterised by neuronal hyperplasticity with increased amyloid metabolism, the second subtype was characterised by innate immune activation and the third subtype by a disrupted blood‐brain barrier. Each subtype will likely need specific treatment, but for patient selection CSF proteomics might be impractical. Here we investigated if AD molecular subtypes can also be detected in blood.MethodWe selected from EMIF‐AD MBD 149 individuals with AD across the clinical spectrum who had plasma proteomics as well as a CSF subtype definition available. We compared CSF subtypes on plasma levels using general linear models. We selected a subset of proteins that best predicted AD subtype by trying a random forest classifier on 70% of the patient sample, and computed prediction accuracy statistics on patients that were left out.ResultPlasma levels of 407 (13%) proteins differed between AD subtypes (figure). The plasma profiles specific to AD subtype showed altered levels for corresponding molecular processes: The CSF hyperplasticity subtype (n = 53) showed low plasma levels of 76 proteins associated with neuron development and axon guidance. The CSF innate immune activation subtype (n = 48) showed low plasma levels of 142 proteins related to regulation of immune response. The CSF blood‐brain barrier subtype (n = 48) showed the low plasma levels of 189 proteins associated with blood vessel morphogenesis. The random forest could classify subtypes with an overall accuracy of 77% (range 70%‐85%), and the top 5 contributing proteins were FGF10, CTCF, TCN2, PLXNA1, and EMILIN3.ConclusionIt is possible to detect distinct AD CSF molecular subtypes in blood. The next step is to validate this in independent cohorts, and to test if subtypes are related to different treatment responses.

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.

Levels of nicastrin species are increased in Alzheimer’s disease cerebrospinal fluid

AbstractBackgroundPrevious studies demonstrated that presenilin‐1 (PS1), the active component of the intramembrane γ‐secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The γ‐secretase components, APH‐1 (anterior pharynx‐defective 1) and PEN‐2 (presenilin enhancer 2), co‐exist within these CSF complexes, while nicastrin is not detected. Nicastrin plays a role in the complex regulation, and substrate recognition, being the unique γ‐secretase component that is a Type I, single‐pass transmembrane protein. Here, we aim to characterize and compare the levels of CSF nicastrin in Alzheimer’s disease (AD) and non‐AD control patients.MethodNicastrin levels were analyzed in the CSF by western blotting using antibodies against the ectodomain and the intracellular domain to identify the different species of the protein that are present in human CSF. Core AD CSF biomarkers (Aβ1‐42, T‐tau, and p‐Tau) were determined. We also assessed whether CSF nicastrin and PS1 are present in extracellular vesicles (EVs).ResultWe show that nicastrin is present in CSF as full‐length species of 130, 110, and 105 kDa. We demonstrated that nicastrin full‐length species are increased in AD patients (n = 21) in comparison with non‐AD controls (n = 21), and that the levels of the three species positively correlated with T‐tau and p‐Tau levels in AD patients. Nicastrin was also found to be present in EVs, different from PS1.ConclusionThe increased levels of nicastrin in the CSF of AD patients confirmed the potential alteration of γ‐secretase subunits during pathology progression. Further studies are required to evaluate whether these proteins could act as biomarkers to facilitate AD diagnosis and/or prognosis.

Neuroimaging Correlates of Alzheimer’s Disease biomarkers in a mid‐life, racially diverse high‐risk cohort

AbstractBackgroundClinicians and researchers utilize neuroimaging (NI) biomarkers of Alzheimer’s disease (AD) at an increasing rate. It is crucial that we determine whether these biomarkers generalize to underrepresented populations, particularly Black Americans (BAs), as they are 64% more likely as white individuals to develop AD. BAs may exhibit unique AD biomarker profiles across disease states, including NI biomarkers. Investigating biomarkers in at‐risk individuals may allow for early identification and intervention. Here we analyze comprehensive NI biomarkers including resting state fMRI, white matter lesions, and hippocampal volumes in conjunction with cerebrospinal fluid (CSF) markers in a midlife, racially diverse, cognitively normal cohort with a parental history of AD.MethodData included 57 cognitively normal, middle‐aged individuals, 14 BAs and 43 white. CSF was acquired via lumbar puncture to determine CSF t‐tau and Aβ1‐42 concentrations. Using resting state fMRI data, we analyzed default mode network connectivity between the posterior cingulate &amp; precuneus, parrahippocampal gyrus (PHG), temporal pole, hippocampus, and lateral temporal cortex. We obtained regional WMH data from FLAIR images using an in‐house algorithm, and hippocampal volumes from Freesurfer. In our multivariate model, outcome variables were connectivity values, regional WMH and hippocampal volumes, with race and CSF t‐tau and Aβ1‐42 as our independent variables with a race X CSF interaction term.ResultWe identified a significant race X t‐tau and race X Aβ1‐42 interaction term for temporal and parietal WMH volumes and connectivity between PHG and temporal pole. Higher AD CSF biomarkers negatively correlated with brain connectivity (p = 0.01), and positively with WMH volume (p&lt;0.001) in BAs.ConclusionWe extend our previous work to a middle‐aged cohort to show that DMN connectivity may be a predictor of AD risk in middle‐age, particularly for BAs, and that BAs may exhibit earlier vulnerability to vascular lesions. We support previous work that the temporal lobe is the first region to experience AD‐related connectivity changes, and that WMHs may predispose this region to AD vulnerability. This study emphasizes the need for recruitment of diverse cohorts in NI studies of AD.