Biomarkers of Alzheimer’s disease in body fluids

Various innovative diagnostic methods for Alzheimer’s disease (AD) have been developed in view of the increasing preva-lence and consequences of later-life dementia. Biomarkers in cerebrospinal fluid (CSF) and blood for AD are primarily based on the detection of components derived from amyloid plaques and neurofibrillary tangles (NFTs). Published reports on CSF and blood biomarkers in AD indicate that although biomarkers in body fluids may be utilized in the clinical diagnosis of AD, there are no specific markers that permit accurate and reliable diagnosis of early-stage AD or the monitoring of disease pro-gression.     

CSF total tau, Aβ42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease

With the arrival of effective symptomatic treatments and the promise of drugs that may delay progression, we now need to identify Alzheimer’s disease (AD) at an early stage of the disease. To diagnose AD earlier and more accurately, attention has been directed toward peripheral biochemical markers. This article reviews promising potential cerebrospinal fluid (CSF) biomarkers for AD focussing on their role in clinical diagnosis. In particular, two biochemical markers, CSF total tau (t-tau) protein and the 42 amino acid form of β-amyloid (Aβ42), perform satisfactorily enough to achieve a role in the clinical diagnostic settings of patients with dementia together with the cumulative information from basic clinical work-up, genetic screening, and brain imaging. These CSF markers are particularly useful to discriminate early or incipient AD from age-associated memory impairment, depression, and some secondary dementias. In order to discriminate AD from other primary dementia disorders, however, more accurate and specific markers are needed. Preliminary evidence strongly suggests that quantification of tau phosphorylated at specific sites in CSF improves early detection, differential diagnosis, and tracking of disease progression in AD.     

V3 Recombinants Indicate a Central Role for CCR5 as a Coreceptor in Tissue Infection by Human Immunodeficiency Virus Type 1

Binding of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 to both CD4 and one of several chemokine receptors (coreceptors) permits entry of virus into target cells. Infection of tissues may establish latent viral reservoirs as well as cause direct pathologic effects that manifest as clinical disease such as HIV-associated dementia. We sought to identify the critical coreceptors recognized by HIV-1 tissue-derived strains as well as to correlate these coreceptor preferences with site of infection and dementia diagnosis. To reconstitute coreceptor use, we cloned HIV-1 envelope V3 sequences encoding the primary determinants of coreceptor specificity from 13 brain-derived and 6 colon-derived viruses into an isogenic (NL4-3) viral background. All V3 recombinants utilized the chemokine receptor CCR5 uniformly and efficiently as a coreceptor but not CXCR4, BOB/GPR15, or Bonzo/STRL33. Other receptors such as CCR3, CCR8, and US28 were inefficiently and variably used as coreceptors by various envelopes. CCR5 without CD4 present did not allow for detectable infection by any of the tested recombinants. In contrast to the pathogenic switch in coreceptor specificity frequently observed in comparisons of blood-derived viruses early after HIV-1 seroconversion and after onset of AIDS, the characteristics of these V3 recombinants suggest that CCR5 is a primary coreceptor for brain- and colon-derived viruses regardless of tissue source or diagnosis of dementia. Therefore, tissue infection may not depend significantly on viral envelope quasispeciation to broaden coreceptor range but rather selects for CCR5 use throughout disease progression.     

Cyclooxygenase as a target for the antiamyloidogenic activities of nonsteroidal anti-inflammatory drugs in Alzheimer's disease

A large number of epidemiological studies have addressed the possible protective effect of anti-inflammatory drug use with regard to Alzheimer's disease (AD). The most convincing of these studies--the Baltimore Longitudinal Study of Aging--utilized data collected prospectively, thereby minimizing recall bias issues. However, despite this evidence, therapeutic studies investigating nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-1 (COX-1) and COX-2 inhibitors and steroids, do not support this hypothesis. This discrepancy may be due to the fact that the bulk of epidemiological evidence has examined the likely incidence of AD prior to the onset of clinical symptoms of disease. On the basis of this information, the article will attempt to formulate a possible scenario, in which optimal NSAIDs might be tested in the most favorable clinical therapeutic conditions in order to determine whether NSAIDs can provide beneficial treatment for the clinical progression of AD dementia.     

Humanin and the Receptors for Humanin

Alzheimer’s disease (AD) is a prevalent dementia-causing neurodegenerative disease. Neuronal death is closely linked to the progression of AD-associated dementia. Accumulating evidence has established that a 24-amino-acid bioactive peptide, Humanin, protects neurons from AD-related neuronal death. A series of studies using various murine AD models including familial AD gene-expressing transgenic mice have shown that Humanin is effective against AD-related neuronal dysfunction in vivo. Most recently, it has been shown that Humanin inhibits neuronal cell death and dysfunction by binding to a novel IL-6-receptor-related receptor(s) on the cell surface involving CNTFRα, WSX-1, and gp130. These findings suggest that endogenous Humanin [or a Humanin-like substance(s)] may suppress the onset of AD-related dementia by inhibiting both AD-related neuronal cell death and dysfunction.     

Fatal hepatitis E viral infection in pregnant women in Ghana: a case series

ABSTRACT: BACKGROUND: Viral infections during pregnancy can pose serious threats to mother and fetus from the time of conception to the time of delivery. These lead to congenital defects, spontaneous abortion and even death. The definitive diagnosis and management of pregnancy-related viral infections may be challenging especially in less resourced countries. CASE PRESENTATION: We present clinical and laboratory responses to the diagnosis and management of three cases of fulminant hepatitis secondary to Hepatitis E viral infection in pregnancy.Case 1 was a 31-year-old Ghanaian woman who presented with a week's history of passing dark urine as well as yellowish discoloration of the eyes. She subsequently developed fulminant hepatitis secondary to Hepatitis E viral infection, spontaneously aborted at 24 weeks of gestation and later died.Case 2 was also a 31-year-old Ghanaian woman who was admitted with a four-day history of jaundice. She had low grade fever, but no history of abdominal pain, haematuria, pale stool or pruritus. She next developed fulminant hepatitis secondary to Hepatitis E viral infection. However, she did not miscarry but died at 28 weeks of gestation.Case 3 was a 17-year-old Ghanaian woman who was referred to the tertiary health facility on account of jaundice and anaemia. She had delivered a live male infant at maturity of 32 weeks but noticed she was jaundiced and had a presentation of active disease 3 days prior to delivery. The baby was icteric at birth and on evaluation, had elevated bilirubin (mixed type) with normal liver enzymes. Hepatitis E virus infection was confirmed in both mother and baby. However, the jaundice and the hepatomegaly resolved in mother and baby after 5 and 12 days respectively. CONCLUSION: To the best of our knowledge, these are the first documented cases of fatal fulminant hepatic failures resulting from HEV infection in Ghana.     

The extent of early viral replication is a critical determinant of the natural history of simian immunodeficiency virus infection.

Different patterns of viral replication correlate with the natural history of disease progression in humans and macaques infected with human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), respectively. However, the viral and host factors influencing these patterns of viral replication in vivo are poorly understood. We intensively studied viral replication in macaques receiving identical inocula of SIV. Marked differences in viral replication patterns were apparent within the first week following inoculation, a time prior to the development of measurable specific immune effector responses to viral antigens. Plasma viral RNA levels measured on day 7 postinoculation correlated with levels measured in the postacute phase of infection. Differences in the susceptibility of host cells from different animals to in vitro SIV infection correlated with the permissiveness of the animals for early in vivo viral replication and hence with the postacute set point level of plasma viremia. These results suggest that host factors that exert their effects prior to full development of specific immune responses are critical in establishing the in vivo viral replication pattern and associated clinical course in subjects infected with SIV and, by extension, with HIV-1.     

Gene Expression Alterations in the Sphingolipid Metabolism Pathways during Progression of Dementia and Alzheimer’s Disease: A Shift Toward Ceramide Accumulation at the Earliest Recognizable Stages of Alzheimer’s Disease?

There is mounting evidence linking Aβ₄₂ generation in Alzheimer’s disease (AD) with sphingomyelin catabolism. Using microarray technology to study 17 brain regions from subjects with varying severity of AD and dementia we detected multiple gene expression abnormalities of the key enzymes that control sphingolipid metabolism. These changes were correlated with the progression of clinical dementia. The upregulation of gene expression of the enzymes controlling synthesis de novo of Cer and the downregulation of the enzymes involved in glycosphingolipid synthesis was evident as early in disease progression as in mild dementia. Together these changes suggest a shift in sphingolipid metabolism towards accumulation of Cer, depletion of glycosphingolipids and the reduction of synthesis of the anti-apoptosis signaling lipid—sphingosine 1-phosphate as a function of disease progression. This disrupted balance within the sphingolipid metabolism may trigger signaling events promoting neurodegeneration across cortical regions. This potential mechanism may provide a link between lipid metabolism disturbance and AD. Special issue dedicated to John P. Blass.     

Increased viral burden and cytopathicity correlate temporally with CD4+ T-lymphocyte decline and clinical progression in human immunodeficiency virus type 1-infected individuals.

The rate of clinical progression is variable among individuals infected with human immunodeficiency virus type 1 (HIV-1). Changes in viral burden which correlate with disease status have been demonstrated in cross-sectional studies; however, a detailed longitudinal study of the temporal relationship between viral burden, CD4+ T-cell numbers, and clinical status throughout the course of infection has not been reported. Multiple longitudinal blood samples were obtained from four HIV-1-infected individuals with clinically divergent profiles. Levels of HIV-1 were measured in sequential samples of peripheral blood mononuclear cells, using both end-point dilution cultures and quantitative polymerase chain reaction methods. Serial HIV-1 isolates from each case were also evaluated to determine their biological properties in vitro. For the three patients with clinical progression, a dramatic increase in the level of HIV-1 was observed concurrent with or prior to a marked drop in CD4+ T lymphocytes. This increase in viral burden was temporally associated with the emergence of a more cytopathic viral phenotype. In contrast, consistently low levels of HIV-1 were observed in the one patient who was clinically and immunologically stable for more than a decade. Moreover, viral isolates from this patient were less cytopathic in vitro compared with HIV-1 isolates from those patients with disease progression. The temporal association between increased viral burden and CD4+ T-cell decline suggests a direct role for HIV-1 in the cytopathology of CD4+ T cells in vivo. Our results indicate that the pathogenic mechanisms responsible for CD4+ T-cell depletion may be related to both quantitative and qualitative changes in HIV-1.     

Mild cognitive impairment: searching for the prodrome of Alzheimer's disease

The concept of mild cognitive impairment (MCI) identifies persons who are neither cognitively normal nor demented. There is increasing evidence that MCI defines a group of persons who are at near-term risk of developing dementia and particularly Alzheimer''s disease (AD). MCI thus constitutes an attractive target population for preventive treatments of AD. MCI is associated with aging and is more prevalent than dementia. There are several clinical and biological markers that are predictive of MCI prognosis, including depressive symptoms, cognitive deficits, brain imaging and neurochemical findings. The clinician needs to be especially alert to depressive and other mood symptoms which are common in MCI and potentially treatable. Trials of current medications for prevention of MCI progression to dementia have been largely negative. There are observational data suggesting that lifestyle modifications including exercise, leisure activities, cognitive stimulation, and social activities may be effective for prevention of MCI progression. There are many novel therapies currently in trials for early AD, and if effective they may prove to be helpful in prevention of MCI progression as well.     

综述:靶向淀粉样蛋白的阿尔茨海默病药物研究进展

淀粉样蛋白级联假说是阐释阿尔茨海默病(Alzheimer's disease,AD)发病机制的主要学说之一,即脑内过量的β-淀粉样蛋白(β-amyloid,Aβ)是促发AD的核心因素．因此,靶向Aβ形成、聚集和清除等关键环节的药物开发是目前药物研究的热点．但近年来AD新药临床试验屡屡失败,至今尚未得到一种切实有效的治疗药物．淀粉样蛋白级联假说的局限性和痴呆期患者疾病进程的难以逆转,可能是临床试验反复失败的两个主要原因．借助AD早期诊断技术的发展,将药物干预的时间窗口前移,重视痴呆前期病理机制与治疗的研究,可能是研制延缓AD发生和发展有效药物的新途径．     

Accumulation of spectrin and calpain-cleaved spectrin breakdown products in CSF after traumatic brain injury in rats

The introduction of acetylcholine esterase inhibitors for symptomatic treatment of Alzheimer's disease, and the promise of drugs that may delay disease progression, has created a great need for reliable diagnostic tools. However, current criteria for the clinical diagnosis of AD are largely based on the exclusion of other dementia disorders and disease markers are lacking. Since biochemical changes in the brain are reflected in the cerebrospinal fluid (CSF), the search for diagnostic tools for AD has been directed toward CSF markers. CSF markers for AD should reflect the central pathogenic processes of the disorder, i.e. the mismetabolism of β-amyloid (Aβ) and the hyperphosphorylation of tau. Several studies have found that the CSF level of Aβ42 is decreased, and the CSF levels of total tau and phosphorylated tau are increased in AD as compared with normal controls. Thus, the sensitivity of these changes in AD is high. But changes in CSF-Ab42 and CSF-tau have been found in other neurodegenerative disorders and therefore, the specificity seems to be moderately high. Other potential markers that may increase the clinical diagnostic accuracy include the CSF/serum albumin ratio (for identification of blood–brain barrier damage related to disturbances in the small intracerebral vessels), CSF-sulfatide (for identification of ongoing demyelination related to white matter changes and CSF-neurofilament light protein (NFL) [for identification of ongoing axonal (tau and NFL) degeneration]. Use of the summarized information from analyses of several CSF biochemical markers, from the clinical examination, and from brain imaging (SPECT, CT/MRI) may increase the accuracy of the clinical diagnosis.     

Exploiting natural antiviral immunity for the control of pandemics: Lessons from Covid-19

The outbreak of coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disruptive global consequences in terms of mortality and social and economic crises, have taught lessons that may help define strategies to better face future pandemics. Innate and intrinsic immunity form the front-line natural antiviral defense. They involve both tissue-resident and circulating cells, which can produce anti-viral molecules shortly after viral infection. Prototypes of these factors are type I interferons (IFN), antiviral cytokines with a long record of clinical use. During the last two years, there has been an impressive progress in understanding the mechanisms of both SARS-CoV-2 infection and the cellular and soluble antiviral responses occurring early after viral exposure. However, this information was not sufficiently translated into therapeutic approaches. Insufficient type I IFN activity probably accounts for disease progression in many patients. This results from both the multiple interfering mechanisms developed by SARS-CoV-2 to decrease type I IFN response and various pre-existing human deficits of type I IFN activity, inherited or auto-immune. Emerging data suggest that IFN-I-mediated boosting of patients’ immunity, achieved directly through the exogenous administration of IFN-β early post viral infection, or indirectly following inoculation of heterologous vaccines (e.g., Bacillus Calmette Guerin), might play a role against SARS-CoV-2. We review how recent insights on the viral and human determinants of critical COVID-19 pneumonia can foster clinical studies of IFN therapy. We also discuss how early therapeutic use of IFN-β and prophylactic campaigns with live attenuated vaccines might prevent a first wave of new pandemic viruses.     

Vascular Cognitive Disorder. A Biological and Clinical Overview

Although vascular dementia (VaD) represents the second most common cause of dementia after Alzheimer’s disease (AD) in the elderly, and is referred as the “silent epidemic of the twenty-first century”, there is still a controversy on terminology, classification and diagnostic criteria of VaD. The diagnosis of VaD resides in clinical criteria determining a cognitive impairment, the presence of cerebrovascular disease and, only in the case of post-stroke dementia or multi-infarct dementia, a temporal relationship between these. The search for a reliable biochemical tests helping in the diagnosis of VaD is so far not available. Several vascular risk factors have a role in the development of VaD and their identification and treatment are among the major aspects of management of VaD. A new line of research in this field is the study of genetic factors underlying vascular cognitive impairment which are: (1) genes predisposing to cerebrovascular disease, and (2) genes that influence brain tissue responses to cerebrovascular lesions. Evidence in favour of a coexistence of vascular and degenerative components in the pathogenesis of dementia in an elderly population comes from neuropathological and epidemiological studies. There is now a great debate whether VaD and AD are more than common coexisting unrelated pathologies and, instead, represent different results of synergistic pathological mechanisms. Preventive approaches aiming at reducing incident VaD by targeting patients at risk of cerebrovascular disease (primary prevention), or acting on patients after a stroke (secondary prevention) to prevent stroke recurrence and the progression of brain changes associated with cognitive impairment are mandatory therapeutic strategies.     

Role of dendritic cells in differential susceptibility to viral demyelinating disease

Although persistent viral diseases are a global health concern, the mechanisms of differential susceptibility to such infections among individuals are unknown. Here, we report that differential interactions between dendritic cells (DCs) and virus are critical in determining resistance versus susceptibility in the Theiler murine encephalomyelitis virus-induced demyelinating disease model of multiple sclerosis. This virus induces a chronic demyelinating disease in susceptible mice, whereas the virus is completely cleared in resistant strains of mice. DCs from susceptible mice are more permissive to viral infection, resulting in severe deficiencies in development, expansion, and function, in contrast to DCs from resistant mice. Although protective prior to viral infection, higher levels of type I interferons (IFNs) and IFN-gamma produced by virus-infected DCs from susceptible mice further contribute to the differential inhibition of DC development and function. An increased DC number and/or acquired resistance of DCs to viral infection render susceptible mice resistant to viral persistence and disease progression. Thus, the differential permissiveness of DCs to infectious agents and its subsequent functional and developmental deficiencies determine the outcome of infection- associated diseases. Therefore, arming DCs against viral infection-induced functional decline may provide a useful intervention for chronic infection-associated diseases.     

Hepatitis B viral factors and clinical outcomes of chronic hepatitis B

Hepatitis B virus (HBV) infection is an important health problem and the major cause of chronic hepatitis, cirrhosis as well as hepatocellular carcinoma (HCC) worldwide. The natural history of chronic HBV infection can be divided into 4 dynamic phases in HBV carriers who acquire the virus early in life. In general, the frequency and severity of hepatitis flares in the immune clearance or reactivation phase predict disease progression in HBV carriers, and early HBeAg seroconversion typically confers a favorable outcome. In contrast, late or absent HBeAg seroconversion after multiple hepatitis flares accelerates the progression of chronic hepatitis to cirrhosis. Recently, several hepatitis B viral factors predictive of clinical outcomes have been identified. For example, serum HBV DNA level at enrollment is the best predictor of adverse outcomes (cirrhosis, HCC and death from liver disease) in adults with chronic HBV infection. In addition, HBV genotype C, basal core promoter (BCP) mutant and pre-S deletion mutant are associated with increased risk of HCC development. In conclusion, hepatitis B viral factors such as serum HBV DNA level, genotype and mutants have already been clarified to influence disease progression of chronic hepatitis B. Further studies are needed to investigate the pathogenic mechanism of each viral factor.     

Neuronal LR11 Expression Does Not Differentiate between Clinically-Defined Alzheimer's Disease and Control Brains

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Because the pathological changes underlying this disease can begin decades prior to the onset of cognitive impairment, identifying the earliest events in the AD pathological cascade has critical implications for both the diagnosis and treatment of this disease. We previously reported that compared to autopsy confirmed healthy control brain, expression of LR11 (or SorLA) is markedly reduced in AD brain as well as in a subset of people with mild cognitive impairment (MCI), a prodromal clinical stage of AD. Recent studies of the LR11 gene SORL1 have suggested that the association between SORL1 single nucleotide polymorphisms (SNPs) and AD risk may not be universal. Therefore, we sought to confirm our earlier findings in a population chosen solely based on clinical criteria, as in most genetic studies. Quantitative immunohistochemistry was used to measure LR11 expression in 43 cases from the Religious Orders Study that were chosen based on a final pre-mortem clinical diagnosis of MCI, mild/moderate AD or no cognitive impairment (NCI). LR11 expression was highly variable in all three diagnostic groups, with no significant group differences. Low LR11 cases were identified using the lowest tertile of LR11 expression observed across all cases as a threshold. Contrary to previous reports, low LR11 expression was found in only 29% of AD cases. A similar proportion of both the MCI and NCI cases also displayed low LR11 expression. AD-associated lesions were present in the majority of cases regardless of diagnostic group, although we found no association between LR11 levels and pathological variables. These findings suggest that the relationship between LR11 expression and the development of AD may be more complicated than originally believed.     

Dementia: Alzheimer pathology and vascular factors: From mutually exclusive to interaction

Alzheimer's disease (AD) is the most common type of dementia. Both its incidence and prevalence are expected to increase exponentially as populations' age worldwide. Despite impressive efforts of research worldwide, neither cure nor effective preventive strategy is available for this devastating disease. Currently there are several hypotheses on what causes AD, with the amyloid hypothesis being the most investigated and accepted hypothesis over the past 20 years. However the exact role of amyloid-β in the onset and progression of AD is not yet fully understood, and even the validity of the amyloid hypothesis itself is still being discussed. This debate is fuelled by the vascular hypothesis, as increasing epidemiological, neuroimaging, pathological, pharmacotherapeutic and clinical studies suggest that vascular pathology plays a key role in the onset and progression of AD. We here will discuss arguments in favor and limitations of both hypotheses within the framework of available literature, but also provide arguments for convergence of both hypotheses.Finally we propose approaches that may aid in unraveling the etiology and treatment of AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

The impact of cerebrospinal fluid biomarkers on the diagnosis of Alzheimer's disease

The cerebrospinal fluid (CSF) biomarkers β-amyloid(1-42) (Aβ(1-42)), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau(181P)) are gradually finding their way into routine clinical practice as an affirmative diagnostic tool for Alzheimer's disease (AD). These biomarkers have also been implemented in the revised diagnostic criteria for AD. The combination of the CSF biomarkers Aβ(1-42), T-tau, and P-tau(181P) leads to high (around 80%) levels of sensitivity, specificity, and diagnostic accuracy for discrimination between AD and controls (including psychiatric disorders like depression) and can be applied for diagnosing AD in the predementia phases of the disease (mild cognitive impairment). The added value of CSF biomarkers could lie within those cases in which the clinical diagnostic work-up is not able to discriminate between AD and non-AD dementias. However, their discriminatory power for the differential diagnosis of dementia is suboptimal. Other CSF biomarkers, especially those that are reflective of the pathology of non-AD dementia etiologies, could improve the accuracy of differential dementia diagnosis. CSF biomarkers will be of help to establish a correct and early AD diagnosis, even in the preclinical stages of the disease, which will be of importance once disease-modifying drugs for AD become available. Variation in biomarker measurements still jeopardize the introduction of CSF biomarkers into routine clinical practice and clinical trials, but several national and international standardization initiatives are ongoing.     

Septic tularemia in 2 cottontop tamarins(Sanguinus oedipus)

Two captive cottontop tamarins (Sanguinus oedipus) died within 5 d of each other from systemic infection by Francisella tularensis (tularemia). One tamarin experienced mild clinical signs, including malaise, anorexia, and a mucoid nasal discharge for 4 d before death, whereas the other experienced a more rapid progression of disease that lasted less than 24 h. Differential diagnoses included gram-negative septicemia by an organism such as Escherichia coli, Salmonella, or Yersinia; protozoal infection such as Toxoplasma gondii or an acute viral infection such as lymphocytic choriomeningitis. F. tularensis infection was identified by F. tularensis-specific PCR in both primates. Possible sources of infection include aerosol, biting arthropod vectors, and transmission via a rodent reservoir. This case report highlights the importance of tularemia as a differential diagnosis in acute febrile illness in captive nonhuman primates.