Alzheimer's disease (AD) is currently diagnosed only via clinical assessments and confirmed by postmortem brain pathology. Biochemical and neuroimaging markers could facilitate diagnosis, predict AD progression from a pre-AD state of mild cognitive impairment (MCI), and be used to monitor efficacies of disease-modifying therapies. It is now clear that cerebrospinal fluid (CSF) levels of A beta 40, A beta 42, total tau and phosphorylated tau have diagnostic values in AD. Measurements of the above CSF markers in combination are useful in predicting the risk of progression from MCI to AD. Recent advances further support a notion that plasma A beta levels, expressed as an A beta 42/A beta 40 ratio, could also be of value. New potential biomarkers are emerging, and CSF or plasma marker profiles may eventually become part of the clinician's toolkit for accurate AD diagnosis and management. These biomarkers, along with clinical assessment, neuropsychological testing and neuroimaging could achieve a much higher diagnostic accuracy for AD and related disorders in the future.
Alzheimer Disease ; blood ; cerebrospinal fluid ; Amyloid beta-Peptides ; blood ; cerebrospinal fluid ; Biomarkers ; blood ; cerebrospinal fluid ; Cognition Disorders ; blood ; cerebrospinal fluid ; Humans ; tau Proteins ; blood ; cerebrospinal fluid

BACKGROUNDAn important aspect of Alzheimer's disease (AD) is loss or impairment of cholinergic neurons. It is controversial whether there is a similar cholinergic impairment and cerebral deficit of acetylcholine (ACh) in the case of vascular dementia (VD). The purpose of this study was to explore the levels of ACh and choline (Ch) in the cerebrospinal fluid (CSF) of patients with AD and VD, and their possible relationship with cognitive impairment.

METHODSTwenty-two AD patients, twenty-two VD patients, and twenty normal controls were recruited and scored with a Mini-Mental State Examination (MMSE). CSF concentrations of ACh and Ch were measured using high-performance liquid chromatography with an electrochemical detector (HPLC-ECD) and the results were then compared to cognitive status.

RESULTSACh concentrations in CSF of AD patients [(10.7 +/- 5.1) nmol/L] and VD patients [(16.8 +/- 7.4) nmol/L] were both significantly lower than in controls [(34.5 +/- 9.0) nmol/L, t = 10.67, P < 0.001; t = 6.91, P < 0.001]. Both results correlated positively with MMSE scores (rs = 0.88 and rs = 0.85, respectively, P < 0.01). The CSF concentration of Ch was significantly higher in VD patients [(887.4 +/- 187.4) nmol/L] compared to AD patients [(627.6 +/- 145.1) nmol/L, t = 6.4, P < 0.001] and controls [(716.0 +/- 159.4) nmol/L, t = 4.2, P = 0.002]. CSF Ch concentration showed no difference between AD patients and normal controls, nor did it correlate with MMSE score in any of the three groups.

CONCLUSIONSThe positive correlation between ACh deficit and cognitive impairment suggests that ACh is an important neurotransmitter for memory. The similar decrease in ACh concentration in AD and VD patients may imply a similar pathogenesis for the process of cognitive impairment involved in these two disorders. The elevated CSF levels of Ch in VD patients compared to AD patients may be useful diagnostically. Cholinesterase inhibitors may be helpful not only for AD patients, but also for VD patients.

Acetylcholine ; cerebrospinal fluid ; Aged ; Alzheimer Disease ; cerebrospinal fluid ; Blood-Brain Barrier ; Choline ; cerebrospinal fluid ; Dementia, Vascular ; cerebrospinal fluid ; Female ; Humans ; Male ; Middle Aged

This study is to investigate the influence and mechanism of action of asymmetrical dimethylarginine (ADMA) and the induced oxidative stress level on Alzheimer's disease (AD) incidence. ADMA concentration, nitric oxide, Abeta(40)/Abeta(42) ratio, inducible NO synthase (iNOS) activity and the concentrations of the induced free radicals including malondialdehyde (MDA), 3-nitrotyrosine (3-NT) and peroxynitrite (ONOO-) in the cerebrospinal fluid (CSF) from 34 neurologically normal controls and 37 AD patients were quantitatively determined and statistically compared. The results showed that the ADMA concentration significantly decreased in AD patients, and it showed negative correlation with the NO, iNOS activity, and showed positive correlation with MMSE score. ADMA concentration was negatively correlated with Abeta(40)/Abeta(42) ratio (P<0.01) with the observation that Abeta(40)/Abeta(42) ratio increased while ADMA level decreased in CSF in AD patients. The concentration levels of MDA, 3-NT and ROS significantly increased compared with the control with all the P values less than 0.05. These findings suggested that the ADMA disorder and the oxidative damage effect of the induced free radicals in CSF of AD patients are an important mechanism of AD incidence, and their joint regulation may provide new idea for the prevention and clinical treatment of AD.
Aged ; Alzheimer Disease ; cerebrospinal fluid ; Amyloid beta-Peptides ; cerebrospinal fluid ; Arginine ; analogs & derivatives ; cerebrospinal fluid ; Female ; Humans ; Male ; Malondialdehyde ; cerebrospinal fluid ; Middle Aged ; Nitric Oxide ; cerebrospinal fluid ; Nitric Oxide Synthase Type II ; cerebrospinal fluid ; Oxidative Stress ; Peptide Fragments ; cerebrospinal fluid ; Peroxynitrous Acid ; cerebrospinal fluid ; Reactive Oxygen Species ; cerebrospinal fluid ; Tyrosine ; analogs & derivatives ; cerebrospinal fluid

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.
Alzheimer Disease ; Biomarkers* ; Cerebrospinal Fluid* ; Humans ; Models, Animal ; Neurodegenerative Diseases ; Parkinson Disease ; Pathology ; Therapeutic Uses

Cerebrospinal fluid (CSF) can provide vital informative about pathological processes occurring in the brain. In particular, the CSF concentrations of Abeta42, tTau, and pTau181 are useful for the early diagnosis of Alzheimer's disease (AD). However, many studies have demonstrated that confounding factors related to the preanalytical processing of CSF can seriously influence measurements of these AD biomarkers. It is therefore important to develop a standardized protocol for the acquisition and handling of CSF, particularly with regard to the types of tube used for collection and storage, the proper aliquot volume, blood contamination, and the number of tube transfers and freeze-thaw cycles, because these aspects of the procedure have been shown to affect AD biomarker measurements. A survey of the impact of several individual preanalytical procedures on the measurement of AD biomarkers in CSF was conducted for this review article, and the implications of the differences among them are discussed. Furthermore, following a review of the procedures used in Korean and international biomarker laboratories, a consensus was reached among a cooperative Korean multicenter research group regarding a standardized protocol for the analysis of AD biomarkers in CSF. All efforts were made to be stringent regarding the controversial issues associated with this protocol, thus minimizing the confounding influence of various factors on current investigations using established AD biomarkers and on future studies using novel biomarkers of AD and other neurodegenerative disorders.
Alzheimer Disease* ; Biomarkers* ; Blood Volume ; Brain ; Cerebrospinal Fluid* ; Consensus* ; Early Diagnosis ; Korea ; Neurodegenerative Diseases ; Pathologic Processes

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β proteins (Aβ). In this study we explored the correlation of plasma Aβ40 and Aβ42 concentrations with Aβ42, total tau (tTau) and phosphorylated tau 181 (pTau181) levels in cerebrospinal fluid (CSF) in AD and control subjects to further understand the characteristics of plasma Aβ proteins levels. METHODS: The consecutive subjects (44 AD and 47 controls) in this study were recruited. The plasma levels of Aβ40 and Aβ42 were measured using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits. And the corresponding CSFs were analyzed in terms of Aβ42, tTau and pTau181 concentrations using INNOTEST ELISA kits. Further, the albumin levels were measured both in serum and CSF and albumin ratio was obtained to check the integrity of blood-brain barrier. RESULTS: CSF Aβ42 concentrations were significantly decreased while tTau and pTau181 levels were significantly increased in AD subjects. The plasma levels of Aβ42 were significantly lower (p=0.007), while the Aβ40/Aβ42 ratio was significantly higher (p<0.001) in AD patients than in controls. The overall plasma Aβ42 levels showed a positive correlation with those of CSF Aβ42 (p=0.001), but not with the others in CSF. In subgroup analysis, the CSF Aβ42 demonstrated positive correlation with not only plasma Aβ42 but also Aβ40 levels in controls. However, no significant relationship was noted between plasma and CSF Aβ proteins in AD group. CONCLUSIONS: The plasma Aβ42 and Aβ40 concentrations were shown to have a close relationship with CSF Aβ42 levels in controls, but not in AD subjects. Our results suggest that the correlation between plasma Aβ40 and CSF Aβ42 levels is perturbed in AD.
Alzheimer Disease* ; Biomarkers* ; Blood-Brain Barrier ; Cerebrospinal Fluid* ; Enzyme-Linked Immunosorbent Assay ; Humans ; Plasma* ; Statistics as Topic*

Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Abeta1-42, total tau and p-tau181 levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the
Alzheimer Disease* ; Biomarkers* ; Cerebrospinal Fluid* ; Consensus ; Decision Making ; Dementia ; Humans ; Pathology ; Quality Control

Objective: In the present study, the ABCA1 was used as a label to capture specific exosomes, the level of ABCA1-labeled exosomal microRNA-135a (miR-135a) was evaluated for the diagnosis of Alzheimer's disease (AD), especially in patients with early stages of AD. Methods: This is a preliminary research focused on the levels of ABCA1 in WBCs, RBCs, HT-22 cells, and neuron cells. The diagnostic value of ABCA1-labeled exosomal miR-135a was examined using the CSF and serum of APP/PS1 double transgenic mice, and 152 patients with SCD, 131 patients with MCI, 198 patients with DAT, and 30 control subjects. Results: The level of ABCA1 exosomes harvested from HT-22 cells and neuron culture medium was significantly higher compared to that of RBCs and WBCs ( Conclusion This study outlines a method to capture specific exosomes and detect them using immunological methods, which is more efficient for early diagnosis of AD.
ATP Binding Cassette Transporter 1/cerebrospinal fluid* ; Aged ; Aged, 80 and over ; Alzheimer Disease/cerebrospinal fluid* ; Animals ; Biomarkers/cerebrospinal fluid* ; Cell Line ; Cognitive Dysfunction/cerebrospinal fluid* ; Erythrocytes/metabolism* ; Exosomes ; Female ; Humans ; Leukocytes/metabolism* ; Male ; Mice, Transgenic ; MicroRNAs/blood* ; Neurons/metabolism*

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) could be misleading in idiopathic normal-pressure hydrocephalus (iNPH). We therefore investigated the CSF biomarkers in 18F-florbetaben amyloid-negative positron-emission tomography (PET) [amyloid PET(−)] iNPH, amyloid-positive PET [amyloid PET(+)] AD, and cognitively normal (CN) subjects. METHODS: Ten amyloid PET(+) AD patients (56.7±5.6 years old, mean±standard deviation), 10 amyloid PET(−) iNPH patients (72.8±4.5 years old), and 8 CN subjects (61.2±6.5 years old) were included. We measured the levels of β-amyloid (Aβ)40, Aβ42, total tau (t-tau) protein, and phosphorylated tau (p-tau) protein in the CSF using enzyme-linked immunosorbent assays. RESULTS: The level of Aβ42 and the Aβ42/Aβ40 ratio in the CSF were significantly lower in AD than in iNPH or CN subjects. The Aβ40 level did not differ significantly between AD and iNPH (p=1.000), but it did between AD and CN subjects (p=0.032). The levels of both t-tau and p-tau were higher in AD than in iNPH or CN subjects. The levels of Aβ42, Aβ40, t-tau, and p-tau were lower in iNPH than in CN subjects, but there was no significant difference after controlling for age. CONCLUSIONS: Our results suggest that the mechanism underlying low CSF Aβ levels differs between amyloid PET(−) iNPH and amyloid PET(+) AD subjects. The lower levels of all CSF biomarkers in iNPH patients might be due to reduced clearances from extracellular fluid and decreased brain metabolism of the periventricular zone in iNPH resulting from glymphatic dysfunction.
Alzheimer Disease ; Amyloid ; Biomarkers ; Brain ; Cerebrospinal Fluid ; Enzyme-Linked Immunosorbent Assay ; Extracellular Fluid ; Humans ; Hydrocephalus ; Metabolism ; Positron-Emission Tomography

Alzheimer's disease (AD), also called presenile dementia, is one of the most common neurodegenerative diseases in elderly people. The main pathological features of AD include senile plaques (SPs), neurofibrillary tangles (NFTs) and neuron loss. A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Class biomarkers of AD such as Abeta and phosphorylated tau have been widely used in clinical diagnosis of AD patients. Recently, novel technologies like proteomics, genomics, and imaging techniques have expanded the role of a biomarker from early diagnosis to monitoring the progression of diseases and evaluating the response to various treatments. In this article, we will review the progress of various biomarkers of AD.
Adipokines ; cerebrospinal fluid ; Alzheimer Disease ; cerebrospinal fluid ; diagnosis ; diagnostic imaging ; metabolism ; Amyloid beta-Peptides ; cerebrospinal fluid ; Biomarkers ; analysis ; Chitinase-3-Like Protein 1 ; Fluorodeoxyglucose F18 ; Humans ; Lectins ; cerebrospinal fluid ; Peptide Fragments ; cerebrospinal fluid ; Phosphorylation ; Positron-Emission Tomography ; Presenilins ; analysis ; alpha 1-Antitrypsin ; blood ; tau Proteins ; cerebrospinal fluid