Blood biomarkers in mild cognitive impairment patients: Relationship between analytes and progression to Alzheimer disease dementia

Background and purpose

Blood-based biomarkers are promising tools for the diagnosis of Alzheimer disease (AD) at prodromal stages (mild cognitive impairment [MCI]) and are hoped to be implemented as screening tools for patients with cognitive complaints. In this work, we evaluated the potential of peripheral neurological biomarkers to predict progression to AD dementia and the relation between blood and cerebrospinal fluid (CSF) AD markers in MCI patients referred from a general neurological department.

Methods

A group of 106 MCI patients followed at the Neurology Department of Coimbra University Hospital was included. Data regarding baseline neuropsychological evaluation, CSF levels of amyloid β 42 (Aβ42), Aβ40, total tau (t-Tau), and phosphorylated tau 181 (p-Tau181) were available for all the patients. Aβ42, Aβ40, t-Tau, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels were determined in baseline stored serum and plasma samples by commercial SiMoA (Single Molecule Array) assays. Progression from MCI to AD dementia was assessed at follow-up (mean = 5.8 ± 3.4 years).

Results

At baseline, blood markers NfL, GFAP, and p-Tau181 were significantly increased in patients who progressed to AD at follow-up (p < 0.001). In contrast, plasma Aβ42/40 ratio and t-Tau showed no significant differences between groups. NfL, GFAP, and p-Tau181 demonstrated good diagnostic accuracy to identify progression to AD dementia (area under the curve [AUC] = 0.81, 0.80, and 0.76, respectively), which improved when combined (AUC = 0.89). GFAP and p-Tau181 were correlated with CSF Aβ42. Association of p-Tau181 with NfL was mediated by GFAP, with a significant indirect association of 88% of the total effect.

Conclusions

Our findings highlight the potential of combining blood-based GFAP, NfL, and p-Tau181 to be applied as a prognostic tool in MCI.     

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers

Introduction

Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ₄₂ and Aβ₄₀ in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers.

Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects

Objective

Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects.

Methods

Amyloid‐β 1 to 42 peptide (Aβ_1–42), total tau (t‐tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy‐confirmed AD cases and 52 age‐matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t‐tau and Aβ_1–42 in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy‐confirmed CSF data.

Results

CSF Aβ_1–42 was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for Aβ_1–42, t‐tau, and APOε4 allele count provided the best assessment delineation of mild AD. An AD‐like baseline CSF profile for t‐tau/Aβ_1–42 was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study.

Interpretation

The CSF biomarker signature of AD defined by Aβ_1–42 and t‐tau in the autopsy‐confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD. Ann Neurol 2009     

Patients with mild cognitive impairment and a reduced CSF Aβ₁₋₄₂ protein progress rapidly to Alzheimer's disease

Introduction

Some studies have shown that CSF amyloid-beta 1-42 (Aβ_1-42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau_181p) proteins are useful diagnostic markers for distinguishing between clinically stable mild cognitive impairment (MCI) patients and those who will develop Alzheime?s disease (AD).Our objective was to test the ability of this technique to discriminate in our cohort of MCI patients, according to the clinical outcome, one year after the lumbar puncture.

Material and methods

A total of 36 MCI patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we measured CSF Aβ_1-42, T-tau and P-tau_181p proteins, and calculated the T-tau/Aβ_1-42 y P-tau_181p/Aβ_1-42 ratios. This project was approved by the local ethics committee.

Results

One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients had lower Aβ _1-42 protein levels (285.3 vs 377 ng/ml, P < .02) and higher P-tau_181p/Aβ_1-42 ratio (0,25 vs 0,16, p < .02) than the clinically stable patients.

Conclusions

Our MCI patients with lower Aβ_1-42 protein levels and an increased P-tau_181p /Aβ_1-42 ratio progressed quickly to AD. These results may help to identify those MCI patients with a poorer prognosis.     

Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

Background

Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects.

Objective

To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders.

Methods

Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n₁ = 51, n₂ = 101), corticobasal degeneration (CBD) (n₁ = 11, n₂ = 3), progressive supranuclear palsy (PSP) (n₁ = 22, n₂ = 21), multiple system atrophy (MSA) (n₁ = 31, n₂ = 26), and healthy control (HC) (n₁ = 48, n₂ = 30) participants, as well as Alzheimer's disease (AD) (n₂ = 23) patients in the second cohort.

Results

Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25–0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate = −0.025 to −0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate = 0.32, P = 0.021).

Conclusions

These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Basic and Clinical Studies on the Measurement of β-amyloid(1–42) in Cerebrospinal Fluid as a Diagnostic Marker for Alzheimer's Disease and Related Disorders: Multi Center Study in Japan

Background : The development of diagnostic markers for earlier and more accurate clinical diagnosis of Alzheimer's disease (AD) is essential to identify unequivocally AD patients during life. This study is to investigate the basic performance and clinical significance of β‐amyloid_(1–42) (Aβ₄₂) level measurement in cerebrospinal fluid (CSF) alone or in combination with CSF tau for distinguishing AD from non‐AD disorders. Methods : The basic characteristics of the reagent for measuring Aβ₄₂, which used Sandwich ELISA, was examined. The clinical studies were done at 5 centers in Japan. CSF samples from 353 patients were collected and classified into the following six groups; AD (n=189), Mild Cognitive Impairment (MCI: n=25), Neurodegenerative disorders without AD (ND: n=66), Cerebrovascular disturbance (CVD: n=28), Other neurological disorders (OND: n=18) and Neurological control (NC: n=27) group. Results : Mean levels of Aβ₄₂ in CSF were significantly lower in AD (395 pg/mL) than MCI (586 pg/mL;p<0.001), ND (530 pg/mL; p<0.001), CVD (504 pg/mL; p<0.001) and NC (605 pg/mL; p<0.001), respectively. Mean levels of AD unit (tau/Aβ₄₂) were significantly higher in AD (1.63) than MCI (0.79; p<0.001), ND (0.56; p<0.001), CVD (0.34; p<0.001) and NC (0.19; p<0.001), respectively. Discrimination of AD from other related disorders was significantly improved by the combined assessment of Aβ₄₂ and tau. When the cut‐off level of an AD unit was 0.67, the sensitivity for AD was 80% and the specificity for other related disorders was 86%. The positive rate (AD unit>0.67) of MCI patients who had progressed to AD within a few years was 79% (15/19). Conclusion : The combined measurement of CSF Aβ₄₂ and tau is clinically a useful diagnostic marker to discriminate AD at an early stage including MCI from normal aging and other related disorders.     

CSF phospho-tau is independent of age, cognitive status and gender of neurological patients

CSF phospho-tau (p-tau₁₈₁) levels have shown good diagnostic utility in differential diagnosis of Alzheimer disease (AD). Unlike total-tau (t-tau), age related changes of this promising biomarker are sparsely studied. The aim of the study was to determine whether p-tau₁₈₁ is dependent on age, cognitive status or gender in patients with different neurological diseases who underwent diagnostic lumbar puncture and who had no clinical evidence of neurodegenerative diseases. CSF levels of p-tau₁₈₁ and total-tau (t-tau) of 46 neurologic patients (age range 22–89 years; 22 male, 24 female) were analyzed. Clinical diagnoses were cerebral ischaemia (n = 6), multiple sclerosis (n = 13), epileptic seizures (n = 3), polyneuropathy (n = 9) and other neurological diagnoses (n = 15). Cognitive performance was assessed by the German version of the CERAD battery. The mean level of p-tau₁₈₁ was in accordance with previous findings in neurological patients (42.8 ± 15.3 pg/ml) and did not differ between neurological diseases. In contrast to t-tau (r = 0.38; P = 0.009), p-tau₁₈₁ did not correlate significantly to age (r = 0.15; P = 0.308). No influence of cognitive status or gender on p-tau₁₈₁ levels could be detected. The study corroborates the independence of p-tau₁₈₁ from age, cognitive status, gender and a wide spectrum of neurological diseases. The findings suggest that neither age related neurodegenerative processes nor ischaemic or inflammatory processes are accompanied by tau protein phosphorylation. In contrast, the data support the view that p-tau₁₈₁ seems to be a sign of the highly AD-specific pattern of tau phosphorylation during formation of neurofibrillary tangles.     

Association of antidiabetic medication use,cognitive decline,and risk of cognitive impairment in older people with type 2 diabetes: Results from the population‐based Mayo Clinic Study of Aging

Objective

To determine the cross‐sectional and longitudinal associations between diabetes treatment type and cognitive outcomes among type II diabetics.

Methods

We examined the association between metformin use, as compared to other diabetic treatment (ie, insulin, other oral medications, and diet/exercise) and cognitive test performance and mild cognitive impairment (MCI) diagnosis among 508 cognitively unimpaired at baseline type II diabetics enrolled in the Mayo Clinic Study of Aging. We created propensity scores to adjust for treatment effects. We used multivariate linear and logistic regression models to investigate the cross‐sectional association between treatment type and cognitive test z scores, respectively. Mixed effects models and competing risk regression models were used to determine the longitudinal association between treatment type and change in cognitive test z scores and risk of developing incident MCI.

Results

In linear regression analyses adjusted for age, sex, education, body mass index, APOE ε4, insulin treatment, medical comorbidities, number of medications, duration of diabetes, and propensity score, we did not observe an association between metformin use and cognitive test performance. Additionally, we did not observe an association between metformin use and cognitive test performance over time (median = 3.7‐year follow‐up). Metformin was associated with an increased risk of MCI (subhazard ratio (SHR) = 2.75; 95% CI = 1.64, 4.63, P < .001). Similarly, other oral medications (SHR = 1.96; 95% CI = 1.19, 3.25; P = .009) and insulin (SHR = 3.17; 95% CI = 1.27, 7.92; P = .014) use were also associated with risk of MCI diagnosis.

Conclusions

These findings suggest that metformin use, as compared to management of diabetes with other treatments, is not associated with cognitive test performance. However, metformin was associated with incident MCI diagnosis.

     

White matter hyperintensities are associated with disproportionate progressive hippocampal atrophy

This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial volumetric 1.5‐T MRI. CSF Aβ₄₂ and total tau were measured (n = 353). Brain and hippocampal loss were quantified from serial MRI using the boundary shift integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for (a) concurrent brain/hippocampal atrophy rates and (b) CSF Aβ₄₂ and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls (P = 0.002) and MCI subjects (P = 0.03), and with brain atrophy rate in controls (P = 0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls (P = 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in nondemented older adults. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Increased Cerebrospinal Fluid F<Subscript>2</Subscript>-Isoprostanes are Associated with Aging and Latent Alzheimer’s Disease as Identified by Biomarkers

Alzheimer’s disease (AD) is a common age-related chronic illness with latent, prodrome, and fully symptomatic dementia stages. Increased free radical injury to regions of brain is one feature of prodrome and dementia stages of AD; however, it also is associated with advancing age. This raises the possibility that age-related free radical injury to brain might be caused in part or in full by latent AD. We quantified free radical injury in the central nervous system with cerebrospinal fluid (CSF) F₂-isoprostanes (IsoPs) in 421 clinically normal individuals and observed a significant increase over the adult human lifespan (P < 0.001). Using CSF amyloid (A) β₄₂ and tau, we defined normality using results from 28 clinically normal individuals <50 years old, and then stratified 74 clinically normal subjects ≥60 years into those with CSF that had normal CSF Aβ₄₂ and tau (n = 37); abnormal CSF Aβ₄₂ and tau, the biomarker signature of AD (n = 24); decreased Aβ₄₂ only (n = 4); or increased tau only (n = 9). Increased CSF F₂-IsoPs were present in clinically normal subjects with the biomarker signature of AD (P < 0.05) and those subjects with increased CSF tau (P < 0.001). Finally, we analyzed the relationship between age and CSF F₂-IsoPs for those clinically normal adults with normal CSF (n = 37) and those with abnormal CSF Aβ₄₂ and/or tau (n = 37); only those with normal CSF demonstrated a significant increase with age (P < 0.01). These results show that CSF F₂-IsoPs increased across the human lifespan and that this age-related increase in free radical injury to brain persisted after culling those with laboratory evidence of latent AD.     

Does statin use affect amyloid beta deposition and brain metabolism?

Background

There are contradictory findings regarding the effect of statin drugs on amyloid β (Aβ) deposition as one of the main hallmarks of Alzheimer's disease (AD), along with tau pathology. We aimed to longitudinally investigate the therapeutic and preventive role of statin drugs by examining the brain Aβ deposition and metabolism rate in AD, mild cognitive impairment (MCI), and healthy controls (HC).

Methods

The data of 828 subjects including 178 HC, 492 MCI, and 158 AD individuals were obtained from ADNI. The baseline and longitudinal [¹⁸F] AV45 and 18-fluorodeoxyglucose (FDG) PET standard uptake value ratio (SUVR) measures were investigated among statin users and non-users.

Results

Our results showed that there is no significant difference in baseline Aβ deposition and metabolism rate between statin users and non-users among HC, MCI, and AD subjects. While there was no significant effect of statin on metabolism rate, there was a significant difference in Aβ deposition change after 4 years (from baseline) between statin users and non-users within HC subjects (p = 0.011). The change of Aβ deposition at 4 years from baseline was −2.0 ± 6.3% for statin users and 1.4 ± 4.7% for non-users. There was no significant association between statin duration use with baseline and longitudinal Aβ deposition and metabolism rate. However, statin dosage was significantly associated with Aβ deposition in 2 years (r = −0.412, p = 0.021) in the HC group. Moreover, our analysis showed a significant correlation between total statin exposure (duration×dosage) and Aβ deposition in 2 years visit (r = −0.198, p = 0.037) in HC subjects. Furthermore, we investigated the longitudinal changes within each group of statin users and non-users separately in linear mixed models. Our findings showed that there are no significant changes in AV45 and FDG SUVR among both groups.

Conclusion

The present longitudinal analysis revealed that using statins might be beneficial in slowing down or stabilizing the Aβ deposition due to aging in subjects without cognitive impairment. However, once the clinical symptoms of cognitive impairment appear, statins fail to slow down Aβ deposition. Overall, our findings revealed that statin users might have slower Aβ aggregation than non-users.     

Plasma tau as a window to the brain—negative associations with brain volume and memory function in mild cognitive impairment and early alzheimer's disease

Neurofibrillary tangles are associated with cognitive dysfunction, and hippocampal atrophy with increased CSF tau markers. However, the plasma tau levels of Alzheimer's disease (AD) have not been well studied. We investigated plasma tau by using an immunomagnetic reduction assay in 20 patients with mild cognitive impairment (MCI) due to AD, 10 early AD dementia, and 30 healthy elders (HE). All received a 3D‐brain MRI scan and a set of cognitive function test. We explored their relationships with both brain structure and cognitive functions. Images were analyzed to determine the brain volumes and gray matter densities. Patients with MCI or early AD had significantly increased plasma tau levels compared with HE. Plasma tau levels were negatively associated with the performance of logical memory, visual reproduction, and verbal fluency; also negatively associated with volume of total gray matter, hippocampus, amygdala; and gray matter densities of various regions. Regression analyses indicated that logical memory explained 0.394 and hippocampus volume predicted .608 of the variance of plasma tau levels, both P < 0.001. Education years were negatively associated with the gray matter densities of the supramarginal (r = ?0.407), middle temporal gyrus (r = ?0.40) and precuneus (r = ?0.377; all P < 0.05) in HE; and negatively associated with plasma tau levels in patients (r = ?0.626). We propose that plasma tau may serve as a window to both structure and function of the brain. Higher education is a protective factor against AD and is associated with lower plasma tau levels in patients. Hum Brain Mapp 35:3132–3142, 2014. © 2013 Wiley Periodicals, Inc.     

Inverse association of cortisol serum levels with T-tau,P-tau 181 and P-tau 231 peptide levels and T-tau/Aβ 1–42 ratios in CSF in patients with mild Alzheimer’s disease dementia

Hypercortisolemia and increased levels of hyperphosphorylated tau proteins in cerebrospinal fluid (CSF) are common features with pathogenic relevance in Alzheimer`s disease (AD). Experimental studies point to an influence of cortisol on Aβ and tau pathology in AD. Association of both parameters have not yet been described in a sample of AD patients. In the present study, serum levels of cortisol were determined in 26 patients with mild AD dementia and 20 age-matched healthy elderly controls by ELISA. In addition, we measured in AD patients CSF levels of cortisol, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau 181), tau protein phosphorylated at threonine 231 (P-tau 231) and beta-Amyloid (Aβ) 1–42 and determined T-tau/Aβ 1–42 ratios in CSF. We found in AD patients significantly increased cortisol serum levels (551.4 ± 146.1 nmol/l; P = 0.002) as compared to healthy controls (435.3 ± 83.9 nmol/l). In AD patients, cortisol serum levels were significantly inversely correlated with T-tau (r = −0.496; P = 0.01), P-tau 181 (r = −0.558; P = 0.003) and P-tau 231 (−0.500; P = 0.009) protein levels and T-tau/Aβ 1–42 ratios (r = −0.450; P = 0.021) in CSF. In addition, cortisol serum levels showed a trend of positive correlation with Aβ 1–42 CSF levels (r = 0.386; P = 0.052). However, no significant correlations of cortisol serum with CSF levels as well as cortisol CSF levels with CSF biomarkers could be detected in AD patients. In conclusion, our results show that increased cortisol serum but not CSF levels are associated with minor signs of AD pathology in CSF, indicating a putative neuroprotective effect of moderately elevated cortisol serum levels in patients with mild AD dementia.     

CSF Aβ42 and tau in Parkinson's disease with cognitive impairment

We tested the hypothesis that the CSF biomarker signature associated with Alzheimer's disease (AD) is present in a subset of individuals with Parkinson's disease and Dementia (PD‐D) or with PD and Cognitive Impairment, Not Dementia (PD‐CIND). We quantified CSF Aβ₄₂, total tau (T‐tau), and phospho‐tau (P181‐tau) using commercially available kits. Samples were from 345 individuals in seven groups (n): Controls ≤50 years (35), Controls >50 years (115), amnestic Mild Cognitive Impairment (aMCI) (24), AD (49), PD (49), PD‐CIND (62), and PD‐D (11). We observed expected changes in AD or aMCI compared with age‐matched or younger controls. CSF Aβ₄₂ was reduced in PD‐CIND (P < 0.05) and PD‐D (P < 0.01), whereas average CSF T‐tau and P181‐tau were unchanged or decreased. One‐third of PD‐CIND and one‐half of PD‐D patients had the biomarker signature of AD. Abnormal metabolism of Aβ₄₂ may be a common feature of PD‐CIND and PD‐D. © 2010 Movement Disorder Society     

The impact of anxiety on the progression of mild cognitive impairment to dementia in Chinese and English data bases: a systematic review and meta‐analysis

Objective

It remains unclear whether or not anxiety increases the risk of dementia in people with mild cognitive impairment (MCI). The aim of this systematic review and meta‐analysis was to investigate the risk of dementia among people with MCI and anxiety compared with those with MCI and no anxiety.

Methods

The hazard ratio of conversion to dementia in people with anxiety and MCI was compared with those without anxiety and was calculated using a generic inverse variance method with fixed effect models.

Results

Eleven studies from the English and Chinese databases were included, seven of which were included in the meta‐analysis. The pooled hazard ratio of conversion to dementia was 1.18 95% CI [1.07, 1.31] (p = 0.002) in the group of MCI plus anxiety compared with those without anxiety.

Conclusion

The results suggest that anxiety increases the risk of progression to dementia in people with MCI. Future interventions targeting anxiety management in vulnerable people with MCI may reduce the risk of dementia. Copyright © 2017 John Wiley & Sons, Ltd.     

Cerebrospinal fluid markers for Alzheimer's disease in a cognitively healthy cohort of young and old adults

BackgroundLow amyloid β₄₂ (Aβ₄₂) and high total tau and phosphorylated tau (p-tau) concentrations in the cerebrospinal fluid (CSF) are biomarkers of Alzheimer’s disease (AD), reflecting brain deposition of amyloid plaques and tangles. Age and apolipoprotein E allele E4 are two strong risk factors for AD, but few data are still available on their effect on CSF markers in normal aging.ObjectiveTo study the effect of age on CSF Aβ₄₂, total tau, and p-tau levels in a well-characterized group of cognitively normal subjects.MethodsCSF Aβ₄₂ levels of 81 subjects (27% female, 53 ± 15.3 years, range: 21–88) were determined with sandwich enzyme-linked immunosorbent assay; of these, total tau and p-tau levels were measured in 61 (75%) and 42 (52%) cases, respectively. A linear regression analysis between age and CSF markers was carried out on the whole sample and separately in apolipoprotein E allele ɛ4 carriers and noncarriers.ResultsThe median levels of all markers were significantly different between young (<65 years) and old (≥65 years) subjects (Aβ₄₂: P = .03; tau: P = .02; p-tau: P = .002; tau/Aβ₄₂: P = .004; p-tau/Aβ₄₂: P = .03). The association of marker levels with age was confirmed in linear regression models, where a positive relationship with age was observed for total tau (B = 2.3; 95% confidence interval [CI]: 0.89 to 3.7; P = .002), p-tau (B = 0.5; 95% CI: 0.1 to 0.9; P = .02), and tau/Aβ₄₂ ratio (B = 0.006; 95% CI: 0.002 to 0.01; P = .002). No subjects showed abnormal tau, whereas 19% showed abnormal CSF Aβ₄₂ concentrations.ConclusionIn cognitively normal subjects, the concentrations of CSF biomarkers of AD are associated with age. Further longitudinal studies could clarify whether Aβ₄₂ low levels represent a preclinical AD biomarker.     

CSF Apo-E levels associate with cognitive decline and MRI changes

Apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for Alzheimer’s disease (AD) and it is thought to do so by modulating levels of its product, apolipoprotein E (Apo-E), and regulating amyloid-β (Aβ) clearance. However, information on clinical and biomarker correlates of Apo-E proteins is scarce. We examined the relationship of cerebrospinal fluid (CSF) and plasma Apo-E protein levels, and APOE genotype to cognition and AD biomarker changes in 311 AD neuroimaging initiative subjects with CSF Apo-E measurements and 565 subjects with plasma Apo-E measurements. At baseline, higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. CSF Apo-E levels were associated with longitudinal cognitive decline, MCI conversion to dementia, and gray matter atrophy rate in total tau/Aβ_1–42 ratio and APOE genotype-adjusted analyses. In analyses stratified by APOE genotype, our results were only significant in the group without the ε4 allele. Baseline CSF Apo-E levels did not predict longitudinal CSF Aβ or tau changes. Plasma Apo-E levels show a mild correlation with CSF Apo-E levels, but were not associated with longitudinal cognitive and MRI changes. Based on our analyses, we speculate that increased CSF Apo-E2 or -E3 levels might represent a protective response to injury in AD and may have neuroprotective effects by decreasing neuronal damage independent of tau and amyloid deposition in addition to its effects on amyloid clearance.     

Redefining primary headaches

To assess the role of tau protein, beta-amyloid_(1–42) and cystatin C in the diagnostics of Alzheimer dementia (AD) and other neurodegenerative diseases (ND) by comparing to the control groups (CG). The levels of tau protein, beta-amyloid_(1–42) and cystatin C were assessed in the set of 69 patients (AD + ND, 33 males, 36 females, aged 22–90, mean 60.5 + 16.1 years), and in a control group of 69 subjects without the affection of the central nervous system (CGAD + CGND, 33 males, 36 females, aged 20–91, mean 60.5 + 16.0 years). Statistically significant increased tau protein levels (P = 0.0001) and index tau/beta-amyloid_(1–42) levels (P = 0.0002) were shown in the group of AD patients, compared to the group of ND patients. One-way ANOVA analysis with Bonferonni post hoc test did not show any significant differences of the cystatin C values between any of the compared groups. ROC analysis showed at least one tie between the positive actual state group (AD) and the negative actual state group (ND) by CSF cystatin C and at least one tie between the positive actual state group and the negative actual state group by CSF tau protein. Our study confirmed previously reported results only in part. While tau protein seems to be quite a reliable marker of AD, the role of beta-amyloid_(1–42) and cystatin C in AD diagnosis remains at least questionable.     

Discriminatory and predictive capabilities of enzyme-linked immunosorbent assay and multiplex platforms in a longitudinal Alzheimer’s disease study

BackgroundMultiplex assays such as xMAP have been proposed for the assessment of Alzheimer’s disease (AD) biomarkers amyloid β 42 (Aβ₄₂), tau (Tau), and phosphorylated tau (pTau) in cerebrospinal fluid (CSF). Here, we compared the traditional enzyme-linked immunosorbent assay (ELISA) and xMAP with respect to their: (1) absolute biomarker concentration, (2) ability to distinguish AD from nondemented subjects, (3) ability to monitor AD longitudinally, and (4) ability to predict progression from mild cognitive impairment (MCI) to AD.MethodsWe selected 68 AD, 62 MCI, and 24 nondemented subjects, performed clinical examinations, and obtained CSF at baseline and 2 years later. Aβ₄₂, Tau, and pTau were measured with both ELISA and xMAP.ResultsBiomarker levels differed considerably between the two assays, and the differences were concentration dependent. No differences were observed in ability to distinguish nondemented subjects from AD patients between ELISA (area under curve of 0.84 for Aβ₄₂, 0.79 for Tau, and 0.75 for pTau) and xMAP (area under curve of 0.82 for Aβ₄₂, 0.75 for Tau, and 0.73 for pTau), all P < .05. Increased Aβ₄₂ levels of AD patients at follow-up compared with baseline were detected with ELISA, whereas increased Tau levels for nondemented subjects and MCI patients were only detected with xMAP. The hazard ratios for progression from MCI to AD did not differ between the assays.ConclusionBoth ELISA and multiplex assays can be used to measure AD biomarker levels in CSF to support clinical diagnosis and predict progression from MCI to AD with similar accuracy. Importantly, the assays’ output in absolute biomarker concentrations is remarkably different, and this discrepancy cannot be reconciled with simple correction factors.     

Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI

The dynamics of cerebrospinal fluid (CSF) tau and Aβ biomarkers over time in Alzheimer’s disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyzed the longitudinal CSF tau and Aβ biomarker data from 142 of the AD Neuroimaging Initiative (ADNI) study subjects [18 AD, 74 mild cognitive impairment (MCI), and 50 cognitively normal subjects (CN)]. Yearly follow-up CSF collections and studies were conducted for up to 48 months (median = 36 months) for CSF Aβ_1–42, phosphorylated tau (p-tau₁₈₁), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Aβ_1–42 and p-tau₁₈₁ biomarkers there was a group of subjects with stable longitudinal CSF biomarkers measures and a group of subjects who showed a decrease (Aβ_1–42, mean = ?9.2 pg/ml/year) or increase (p-tau₁₈₁, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Aβ_1–42 values were associated with longitudinal increases in p-tau₁₈₁. Conversely, high baseline p-tau₁₈₁ values were not associated with changes in Aβ_1–42 levels. When the subjects with normal baseline biomarkers and stable concentrations during follow-up were excluded, the expected time to reach abnormal CSF levels and the mean AD values was significantly shortened. Thus, our data demonstrate for the first time that there are distinct populations of ADNI subjects with abnormal longitudinal changes in CSF p-tau₁₈₁ and Aβ_1–42 levels, and our longitudinal results favor the hypothesis that Aβ_1–42 changes precede p-tau₁₈₁ changes.