Biomarkers for Microglial Activation in Alzheimer's Disease

Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques

Cerebrospinal fluid analyses for the diagnosis of subarachnoid haemorrhage and experience from a Swedish study. What method is preferable when diagnosing a subarachnoid haemorrhage?

Subarachnoid haemorrhage (SAH) has a high mortality and morbidity rate. Early SAH diagnosis allows the early treatment of a ruptured cerebral aneurysm, which improves the prognosis. Diagnostic cerebrospinal fluid (CSF) analyses may be performed after a negative computed tomography scan, but the precise analytical methods to be used have been debated. Here, we summarize the scientific evidence for different CSF methods for SAH diagnosis and describe their implementation in different countries. The principle literature search was conducted using PubMed and Scopus with the search items "cerebrospinal fluid”, "subarachnoid haemorrhage”, and "diagnosis”. CSF analyses for SAH include visual examination, red blood cell counts, spectrophotometry for oxyhaemoglobin or bilirubin determination, CSF cytology, and ferritin measurement. The methods vary in availability and performance. There is a consensus that spectrophotometry has the highest diagnostic performance, but both oxyhaemoglobin and bilirubin determinations are susceptible to important confounding factors. Visual inspection of CSF for xanthochromia is still frequently used for diagnosis of SAH, but it is advised against because spectrophotometry has a superior diagnostic accuracy. A positive finding of CSF bilirubin is a strong indicator of an intracranial bleeding, whereas a positive finding of CSF oxyhaemoglobin may indicate an intracranial bleeding or a traumatic tap. Where spectrophotometry is not available, the combination of CSF cytology for erythrophages or siderophages and ferritin is a promising alternativ

Apolipoprotein E Genotype and the Diagnostic Accuracy of Cerebrospinal Fluid Biomarkers for Alzheimer Disease.

Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown

Biomarkers for Alzheimer's disease and the APOE polymorphism

Alzheimer’s disease (AD) is the most common form of dementia and cerebrospinal fluid (CSF) biomarkers reflecting the core pathology of AD are now widely used for diagnosis making, in particular β-amyloid[1-42] (Aβ42) reflecting amyloid plaque pathology, phosphorylated tau (P-tau) reflecting neurofibrillary tangle pathology and total tau (T-tau) reflecting general neurodegeneration. In addition, blood-based biomarkers for AD are in the pipeline with recent studies showing promising diagnostic potential. The most important genetic risk factor for sporadic AD is the ε4 allele of the apolipoprotein E (APOE) polymorphism, increasing risk for AD diagnosis in a dose-dependent manner as well as lowering the age of onset. We conducted a comprehensive meta-analysis of the AD biomarker literature from 1984 to 2014, which could confirm the robust diagnostic performance of the above-mentioned established CSF biomarker triad for AD, and also revealed possible new biomarker candidates in both CSF and blood that could contribute to the diagnostic work-up of the disease as well as serve as tools for monitoring new disease-modifying treatments. In a large multicentre study, we confirmed the strong association between the APOE ε4 genotype and AD and showed that the ε4 allele also affects concentrations of CSF Aβ42 in a dose-dependent manner. However, the APOE polymorphism does not blur the diagnostic accuracy of the established AD biomarkers and CSF Aβ42 was shown to reflect cerebral amyloid pathology irrespective of the APOE genotype. In another multicentre cohort consisting of solely cognitively healthy subjects, we showed that the dose-dependent effect of APOE ε4 on CSF Aβ42 was absent in younger subjects and CSF Aβ42 concentrations started to drop around age 50 and even earlier in ε4-carriers, pinpointing the earliest disturbances in amyloid homeostasis, long before cognitive impairment becomes apparent. Taken together, the results from this thesis underline the usefulness of AD biomarkers as well as their robust diagnostic performance irrespective of the most prominent genetic risk factor. In addition, since biomarkers (in particular CSF Aβ42) can reflect pathological changes already in the preclinical stage of the disease, they could become valuable in future AD prevention, once disease-modifying therapies become available

Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer's disease

Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers A beta 42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful

Apolipoprotein E genotypes and longevity across dementia disorders

Introduction: The ε4 allele of the apolipoprotein E (APOE) gene is a prominent risk factor for Alzheimer's disease (AD), but its implication in other dementias is less well studied. Methods: We used a data set on 2858 subjects (1098 AD, 260 vascular dementia [VaD], 145 mixed AD and VaD, 90 other dementia diagnoses, and 1265 controls) to examine the association of APOE polymorphisms with clinical dementia diagnoses, biomarker profiles, and longevity. Results: The ε4 allele was associated with reduced longevity as ε4 versus ε3 homozygotes lived on average 2.6 years shorter (P =.006). In AD, ε4 carriers lived 1.0 years shorter than noncarriers (P =.028). The ε4 allele was more prevalent in AD, mixed AD and VaD, and VaD patients compared to controls, but not in other dementia disorders. Discussion: The APOE ε4 allele is influential in AD but might also be of importance in VaD and in mixed AD and VaD, diseases in which concomitant AD pathology is common

Microglial Markers are Elevated in the Prodromal Phase of Alzheimer's Disease and Vascular Dementia

Microglia manage immunosurveillance and mediate inflammation, both suggested to be important in Alzheimer's disease (AD). The aim of this study was to investigate if microglial markers could differentiate, firstly between AD and controls, and secondly between stable mild cognitive impairment (MCI) and those progressing to AD and vascular dementia (VaD). Furthermore, we investigated if these markers were sufficiently stable to be used in clinical trials. We quantified YKL-40 and sCD14 in cerebrospinal fluid (CSF) from 96 AD patients, 65 healthy controls, and 170 patients with MCI from baseline and over 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six-month interval in between. YKL-40, but not sCD14, was significantly elevated in AD compared with healthy controls (p=0.003). Furthermore, YKL-40 and sCD14 were increased in MCI patients who converted to VaD (p=0.029 and p=0.008), but not to AD according to NINCDS-ADRDA. However, when stratified according to CSF levels of tau and A beta(42), YKL-40 was elevated in those with an AD-indicative profile compared with stable MCI with a normal profile (p=0.037). In addition, YKL-40 and sCD14 were very stable in AD patients with good correlation between time-points (r=0.94, p=3.4x10(-25); r=0.77, p=2.0x10(-11)) and the cortical damage marker T-tau. Thus, microglial markers are stable and may be used as safety markers for monitoring CNS inflammation and microglia activation in clinical trials. Moreover, YKL-40 differentiates between AD and controls and between stable MCI and those that convert to AD and VaD

Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations

Abstract Background From earlier studies it is known that the APOE ε2/ε3/ε4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1–42 (Aβ42) in patients with cognitive decline due to Alzheimer’s disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17–99 from nine different clinical research centers. Results CSF concentrations of Aβ42 were lower in APOE ε4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ε4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ε4-negative individuals and 43 years in heterozygous APOE ε4 carriers. Homozygous APOE ε4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. Conclusions People possessing the APOE ε4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ε4 noncarriers already in early middle age. Homozygous APOE ε4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ε4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline