Plasma Lipocalin 2 in Alzheimer’s disease: potential utility in the differential diagnosis and relationship with other biomarkers

Abstract Background Lipocalin-2 is a glycoprotein that is involved in various physiological and pathophysiological processes. In the brain, it is expressed in response to vascular and other brain injury, as well as in Alzheimer’s disease in reactive microglia and astrocytes. Plasma Lipocalin-2 has been proposed as a biomarker for Alzheimer’s disease but available data is scarce and inconsistent. Thus, we evaluated plasma Lipocalin-2 in the context of Alzheimer’s disease, differential diagnoses, other biomarkers, and clinical data. Methods For this two-center case-control study, we analyzed Lipocalin-2 concentrations in plasma samples from a cohort of n = 407 individuals. The diagnostic groups comprised Alzheimer’s disease (n = 74), vascular dementia (n = 28), other important differential diagnoses (n = 221), and healthy controls (n = 84). Main results were validated in an independent cohort with patients with Alzheimer’s disease (n = 19), mild cognitive impairment (n = 27), and healthy individuals (n = 28). Results Plasma Lipocalin-2 was significantly lower in Alzheimer’s disease compared to healthy controls (p < 0.001) and all other groups (p < 0.01) except for mixed dementia (vascular and Alzheimer’s pathologic changes). Areas under the curve from receiver operation characteristics for the discrimination of Alzheimer’s disease and healthy controls were 0.783 (95%CI: 0.712–0.855) in the study cohort and 0.766 (95%CI: 0.627–0.905) in the validation cohort. The area under the curve for Alzheimer’s disease versus vascular dementia was 0.778 (95%CI: 0.667–0.890) in the study cohort. In Alzheimer’s disease patients, plasma Lipocalin2 did not show significant correlation with cerebrospinal fluid biomarkers of neurodegeneration and AD-related pathology (total-tau, phosphorylated tau protein, and beta-amyloid 1-42), cognitive status (Mini Mental Status Examination scores), APOE genotype, or presence of white matter hyperintensities. Interestingly, Lipocalin 2 was lower in patients with rapid disease course compared to patients with non-rapidly progressive Alzheimer’s disease (p = 0.013). Conclusions Plasma Lipocalin-2 has potential as a diagnostic biomarker for Alzheimer’s disease and seems to be independent from currently employed biomarkers.

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Brevican and Neurocan Peptides as Potential Cerebrospinal Fluid Biomarkers for Differentiation Between Vascular Dementia and Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201039 ◽

2020 ◽

pp. 1-13

Author(s):

Karolina Minta ◽

Gunnar Brinkmalm ◽

Erik Portelius ◽

Per Johansson ◽

Johan Svensson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Vascular Dementia ◽

Extracellular Enzymes ◽

Control Group ◽

Healthy Controls ◽

Clear Trend ◽

Cerebrospinal Fluid Biomarkers

Background: Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF). Objective: The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer’s disease (AD) and vascular dementia (VaD) compared with controls. Methods: The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry. Results: In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC = 0.83.0.93, p≤0.05) and as compared with the control group (AUC = 0.79.0.87, p ≤ 0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC = 0.86.0.91, p ≤ 0.05) and to controls (AUC = 0.80.0.82, p ≤ 0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC = 0.64.80, p > 0.05). No peptides differed between AD and controls. Conclusion: Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD.

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Kidney disease and risk of dementia: a Danish nationwide cohort study

BMJ Open ◽

10.1136/bmjopen-2021-052652 ◽

2021 ◽

Vol 11 (10) ◽

pp. e052652

Author(s):

Alisa D Kjaergaard ◽

Benjamin R Johannesen ◽

Henrik T Sørensen ◽

Victor W Henderson ◽

Christian F Christiansen

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cohort Study ◽

Kidney Disease ◽

General Population ◽

Vascular Dementia ◽

Disease Diagnosis ◽

Secondary Outcome ◽

Study Cohort ◽

Entire Study

ObjectivesIt is unclear whether kidney disease is a risk factor for developing dementia. We examined the association between kidney disease and risk of future dementia.Design and settingNationwide historical registry-based cohort study in Denmark based on data from 1 January 1995 until 31 December 2016.ParticipantsAll patients diagnosed with kidney disease and matched general population cohort without kidney disease (matched 1:5 on age, sex and year of kidney disease diagnosis).Primary and secondary outcome measuresAll-cause dementia and its subtypes: Alzheimer’s disease, vascular dementia and other specified or unspecified dementia. We computed 5-year cumulative incidences (risk) and hazard ratios (HRs) for outcomes using Cox regression analyses.ResultsThe study cohort comprised 82 690 patients with kidney disease and 413 405 individuals from the general population. Five-year and ten-year mortality rates were twice as high in patients with kidney disease compared with the general population. The 5-year risk for all-cause dementia was 2.90% (95% confidence interval: 2.78% to 3.08%) in patients with kidney disease and 2.98% (2.92% to 3.04%) in the general population. Compared with the general population, the adjusted HRs for all-cause dementia in patients with kidney disease were 1.06 (1.00 to 1.12) for the 5-year follow-up and 1.08 (1.03 to 1.12) for the entire study period. Risk estimates for dementia subtypes differed substantially and were lower for Alzheimer’s disease and higher for vascular dementia.ConclusionsPatients diagnosed with kidney disease have a modestly increased rate of dementia, mainly driven by vascular dementia. Moreover, patients with kidney disease may be underdiagnosed with dementia due to high mortality and other comorbidities of higher priority.

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A simple classification framework for predicting Alzheimer’s disease from region-based grey matter volume and APOE genotype status

Artificial Intelligence Research ◽

10.5430/air.v8n2p15 ◽

2020 ◽

Vol 8 (2) ◽

pp. 15

Author(s):

Reyhaneh Ghoreishiamiri ◽

Graham Little ◽

Matthew R. G. Brown ◽

Russell Greiner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Grey Matter ◽

Learning Algorithm ◽

Apoe Genotype ◽

Structural Mri ◽

Grey Matter Volume ◽

Healthy Controls ◽

Diagnostic Systems ◽

Initial Dataset

Alzheimer’s Disease (AD) is a prevalent neurodegenerative disease currently affecting more than 47 million people in the world. There are now many complex classifiers that can accurately distinguish AD patients from healthy controls, based on the subject’s structural magnetic resonance imaging (MRI) brain scan. Most such automated diagnostic systems are blackboxes: While their predictions are accurate, it is difficult for clinicians to interpret those predictions, due to the large number of features used by the classifier, and/or by the complexity of that classifier. This work demonstrates that an automated learning algorithm can produce a simple classifier that can correctly distinguish AD patients from healthy controls (HC) similar to its more-complex counterparts. Here we buildthis classifier from the data in the Alzheimer’s Disease Neuroimaging Initiative database, using a fairly small set of features, including grey matter volumes of 33 regions of interest derived from structural MRI, as well as the APOE genotype. We first considered three simple base-learners that each produce a classifier that is simple and interpretable. Running our overall learner, involving standard feature selection processes and these simple base-learners, on these features, produced a 7-feature elastic net model, EN7, that achieved accuracy of 89.28% on the test set. Next, we ran the same overall learner using two more-complex base-learners over the same initial dataset. The accuracy of the best model here was 90.47%, which was not statistically different from the performance of our much simpler EN7 model.

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Antioxidant Status and APOE Genotype As Susceptibility Factors for Neurodegeneration in Alzheimer's Disease and Vascular Dementia

Rejuvenation Research ◽

10.1089/rej.2012.1383 ◽

2013 ◽

Vol 16 (1) ◽

pp. 51-56 ◽

Cited By ~ 13

Author(s):

Giancarlo Zito ◽

Renato Polimanti ◽

Valentina Panetta ◽

Mariacarla Ventriglia ◽

Carlo Salustri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Vascular Dementia ◽

Antioxidant Status ◽

Apoe Genotype ◽

Susceptibility Factors

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Elevated Angiopoietin-1 Serum Levels in Patients with Alzheimer’s Disease

International Journal of Alzheimer s Disease ◽

10.1155/2012/324016 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Brigitte Schreitmüller ◽

Thomas Leyhe ◽

Elke Stransky ◽

Niklas Köhler ◽

Christoph Laske

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Serum Levels ◽

Cognitive Status ◽

Potential Candidate ◽

Healthy Controls ◽

Healthy Elderly ◽

Significant Difference ◽

Angiopoietin 1

Background. Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD is characterized by the accumulation of amyloid plaques and neurofibrillary tangles and by massive neuronal loss in the brain. There is epidemiologic and pathologic evidence that AD is associated with vascular risk factors and vascular diseases, contributing to cerebral hypoperfusion with consecutive stimulation of angiogenesis and upregulation of proangiogenic factors such as Angiopoietin-1 (Ang-1).Methods. In the present study, we measured Ang-1 serum levels in 42 patients with AD, 20 patients with mild cognitive impairment (MCI), and in 40 healthy elderly controls by ELISA.Results. We found significantly increased Ang-1 serum levels in patients with AD compared to control subjects(P=0.003). There was no significant difference between MCI patients and healthy controls(P=0.553)or between AD and MCI patients(P=0.054). The degree of cognitive impairment as measured by the mini-mental status examination (MMSE) score was significantly correlated with the Ang-1 serum levels in all patients and healthy controls.Conclusions. We found significantly increased Ang-1 serum levels in AD patients. We could also show an association between Ang-1 serum levels and the cognitive status in all patients and healthy controls. Thus, serum Ang-1 could be a potential candidate for a biomarker panel for AD diagnosis.

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Using the Disease State Fingerprint Tool for Differential Diagnosis of Frontotemporal Dementia and Alzheimer's Disease

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000447122 ◽

2016 ◽

Vol 6 (2) ◽

pp. 313-329 ◽

Cited By ~ 8

Author(s):

Miguel Ángel Muñoz-Ruiz ◽

Anette Hall ◽

Jussi Mattila ◽

Juha Koikkalainen ◽

Sanna-Kaisa Herukka ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Differential Diagnosis ◽

Frontotemporal Dementia ◽

Clinical Decision Making ◽

Apoe Genotype ◽

Disease State ◽

Diagnostic Process ◽

Computer Assisted ◽

Study Cohort

Background: Disease State Index (DSI) and its visualization, Disease State Fingerprint (DSF), form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. Aims: To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD) and Alzheimer's disease (AD). Methods: The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases. We utilized data from neuropsychological tests, volumetric magnetic resonance imaging, single-photon emission tomography, cerebrospinal fluid biomarkers and the APOE genotype. The DSI classification results were calculated with a combination of leave-one-out cross-validation and bootstrapping. A DSF visualization of a FTD patient is presented as an example. Results: The DSI distinguishes controls from FTD (area under the receiver-operator curve, AUC = 0.99) and AD (AUC = 1.00) very well and achieves a good differential diagnosis between AD and FTD (AUC = 0.89). In subsamples of autopsy-confirmed cases (AUC = 0.97) and clinically diagnosed cases (AUC = 0.94), differential diagnosis of AD and FTD performs very well. Conclusions: DSI is a promising computer-assisted biomarker approach for aiding in the diagnostic process of dementing diseases. Here, DSI separates controls from dementia and differentiates between AD and FTD.

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Lower Plasma Klotho Concentrations Are Associated with Vascular Dementia but Not Late-Onset Alzheimer’s Disease

Gerontology ◽

10.1159/000488318 ◽

2018 ◽

Vol 64 (5) ◽

pp. 414-421 ◽

Cited By ~ 5

Author(s):

Gloria Brombo ◽

Francesco Bonetti ◽

Beatrice Ortolani ◽

Mario Luca Morieri ◽

Cristina Bosi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Vascular Dementia ◽

Cardiovascular Health ◽

Late Onset ◽

Plasma Concentrations ◽

Memory Loss ◽

Multivariate Logistic Regression Analysis ◽

High Sensitivity ◽

Cognitive Status

Background: The protein Klotho is involved in biological processes related to longevity, cardiovascular health, and cognition. Serum Klotho levels have been associated with better cognition in animal models; moreover, lower Klotho concentrations in cerebrospinal fluid from subjects with late-onset Alzheimer’s disease (LOAD) have been reported. Objective: Our study aimed to examine the possible relationship between Klotho plasma concentrations and cognitive status in the elderly. Methods: We evaluated plasma Klotho levels in a sample of 320 elderly patients admitted to a Memory Clinic. Four groups of subjects were enrolled, including cognitively intact individuals complaining about memory loss (controls) and patients affected by LOAD, mild cognitive impairment, or vascular dementia (VD). The sample was stratified by plasma Klotho tertiles. Results: Lower levels of plasma Klotho (1st tertile) were associated with older age, higher prevalence of VD, single/multiple lacunar infarcts and leukoaraiosis, coronary heart disease and stroke, and higher levels of creatinine, homocysteine, and high-sensitivity C-reactive protein. On multivariate logistic regression analysis, the risk of VD was 3- and 4-fold in subjects belonging to the 1st tertile (≤514.8 pg/mL, OR 3.54, 95% CI 1.05–11.93) and 2nd tertile (> 514.8, < 659.1 pg/mL, OR 4.28, 95% CI 1.30–14.06) compared to the 3rd tertile (≥659.1 pg/mL). A significantly increased VD risk was found for Klotho values < 680 pg/mL. Conclusion: In a sample of elderly individuals, we found a significant association between low plasma Klotho levels and VD, but not LOAD. This finding suggests that, although these 2 forms of dementia might overlap, some physiopathological mechanisms related to VD and LOAD remain distinct.

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Interaction Between APOE Genotype and Diabetes in Longevity

Journal of Alzheimer s Disease ◽

10.3233/jad-210125 ◽

2021 ◽

pp. 1-8

Author(s):

Mitsuru Shinohara ◽

Kaoru Suzuki ◽

Guojun Bu ◽

Naoyuki Sato

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Interactive Effect ◽

Apoe Genotype ◽

Potential Interaction ◽

Cognitive Status ◽

Diabetic Status ◽

Clinical Records ◽

Harmful Effects

Background: While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer’s disease, their relationship remains to be elucidated. Objective: The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. Methods: We reviewed the National Alzheimer’s Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. Results: Diabetes was associated with shorter lifespan in APOE3 carriers (n = 12,415, HR = 1.29, 95%CI = 1.17–1.42, p < 0.001) and APOE2 carriers (n = 2,390, HR = 1.37, 95%CI = 1.10–1.69, p = 0.016), while such associations were weaker and not significant in APOE4 carriers (n = 9,490, HR = 1.11, 95%CI = 0.99–1.24, p = 0.162). As there is a significant interactive effect of cognitive status and diabetes on lifespan (p < 0.001), we stratified subjects by cognitive status and observed persistent APOE-dependent harmful effects of diabetes in nondemented individuals but not demented individuals. Notably, questionnaire-based activity status, with which we previously observed an association between APOE genotype and longevity, was also significantly affected by diabetes only in non-APOE4 carriers. Conclusion: The effects of diabetes on longevity vary among APOE genotype. These effects are observed in nondemented individuals and are potentially associated with activity status during their lifespan.

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P4-354: Baseline CSF BETA-AMYLOID 42 correlates with ApoE genotype and baseline cognitive status in a phase II avagacestat predementia Alzheimer's disease study

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.08.135 ◽

2012 ◽

Vol 8 (4S_Part_21) ◽

pp. S782-S782

Author(s):

Holly Soares ◽

Flora Berisha ◽

Carol Gleason ◽

George Green ◽

Jane Tiller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Phase Ii ◽

Apoe Genotype ◽

Beta Amyloid ◽

Cognitive Status ◽

Disease Study

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TDP-43 is elevated in plasma neuronal-derived exosomes of patients with Alzheimer's disease

10.21203/rs.2.17750/v1 ◽

2019 ◽

Author(s):

Nan Zhang ◽

Dongmei Gu ◽

Meng Meng ◽

Marc L. Gordon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Oldest Old ◽

Neuropsychiatric Symptoms ◽

Apoe Genotype ◽

Enzyme Linked Immunosorbent Assay ◽

Amyloid Pet ◽

Healthy Controls

Abstract Background Recently, TDP-43 has been recognized as a common proteinopathy in the “oldest old” and a neuropathological comorbidity in patients with Alzheimer’s disease (AD). However, since it has a low concentration in cerebrospinal fluid, the presence of TDP-43 in AD is rarely investigated in vivo. Methods Twenty-four patients with amyloid PET confirmed AD and 15 healthy controls (HCs) were included in this study. TDP-43 level in plasma neuronal-derived exosomes (NDEs) was measured by enzyme-linked immunosorbent assay. Results TDP-43 level was elevated in patients with AD compared with HCs (1.20 ± 0.91 ng/ml vs 0.64 ± 0.20 ng/ml, P < 0.039), after controlling for age. There was no correlation between TDP-43 level and cognitive function, neuropsychiatric symptoms or APOE genotype in patients with AD. Conclusions This study demonstrated increased TDP-43 accumulation in AD patients by examining plasma NDEs, which may provide a window into the effects of TDP-43 on AD progression.

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