Quantification of neurodegeneration by measurement of brain-specific proteins (original) (raw)
Scientific Reports, 2021
Various proteins play a decisive role in the pathology of different neurodegenerative diseases. Nonetheless, most of these proteins can only be detected during a neuropathological assessment, although some non-specific biomarkers are routinely tested for in the cerebrospinal fluid (CSF) as a part of the differential diagnosis of dementia. In antemortem CSF samples from 117 patients with different types of neuropathologically confirmed neurodegenerative disease with dementia, we assessed total-tau (t-tau), phosphorylated-tau (181P) (p-tau), amyloid-beta (1–42) (Aβ42), TAR DNA binding protein (TDP)-43, progranulin (PGRN), and neurofilament light (NfL) chain levels, and positivity of protein 14-3-3. We found t-tau levels and the t-tau/p-tau ratios were significantly higher in prion diseases compared to the other neurodegenerative diseases. Statistically significant differences in the t-tau/Aβ42 ratio predominantly corresponded to t-tau levels in prion diseases and Aβ42 levels in AD. TDP-43 levels were significantly lower in prion diseases. Additionally, the TDP-43/Aβ42 ratio was better able to distinguish Alzheimer’s disease from other neurodegenerative diseases compared to using Aβ42 alone. In frontotemporal lobar degeneration, PRGN levels were significantly higher in comparison to other neurodegenerative diseases. There is an increasing need for biomarkers suitable for diagnostic workups for neurodegenerative diseases. It appears that adding TDP-43 and PGRN to the testing panel for neurodegenerative diseases could improve the resolution of differential diagnoses.
A Prospective Viewpoint on Neurological Diseases and Their Biomarkers
Molecules
Neurodegenerative diseases (NDDs) are disorders that affect both the central and peripheral nervous systems. To name a few causes, NDDs can be caused by ischemia, oxidative and endoplasmic reticulum (ER) cell stress, inflammation, abnormal protein deposition in neural tissue, autoimmune-mediated neuron loss, and viral or prion infections. These conditions include Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease (PD). The formation of β-sheet-rich aggregates of intra- or extracellular proteins in the CNS hallmarks all neurodegenerative proteinopathies. In systemic lupus erythematosus (SLE), numerous organs, including the central nervous system (CNS), are affected. However, the inflammatory process is linked to several neurodegenerative pathways that are linked to depression because of NDDs. Pro-inflammatory signals activated by aging may increase vulnerability to neuropsychiatric disorders. Viruses may increase macrophages and CCR5+ T cells within the CNS d...
Journal of Clinical Laboratory Analysis, 1990
A simple, fast, and reliable immunoassay has been developed to detect and measure Alzheimer's disease-associated proteins (ADAPs) in human brain tissue. This assay, called ALZ-EIA (brain), was developed for Abbott's quantum system, in which li4-in. beads are used as solid phase. The beads were coated with polyclonal IgG purified from sera obtained from rabbits immunized with a highly enriched Alzheimer's disease brain protein fraction for ADAP. The antigen (ADAP) is effectively captured by the polyclonal IgG coated on the beads. ALZ-50 (a mouse monoclonal IgM) is used as the detection antibody, and bound ALZ-50 is subsequently quantified by a horseradish peroxidase-linked goat antimouse IgM and appropriate substrate. The assay is linear up to 0.5 absorbance units (r = 0.!3), reproducible (CV less than lo%), sensitive, and specific. With preformulated reagents and standard supplies, the assay is simple and rapid; 120 data points can readily be generated in about 4 hr.
Neuro biomarker levels measured with high-sensitivity digital ELISA differ between serum and plasma
Bioanalysis, 2019
Aim: Digital ELISA-based assays for blood biomarkers of neurological disease are on the verge of clinical use. Here, we aimed to determine whether different preanalytical blood processing techniques influence results. Materials & methods: Concentrations of neurofilament light chain (NfL), Tau and amyloid beta (Aβ) were measured in human plasma and serum specimens using digital ELISA and compared between blood products. Measured levels of NfL were highly equivalant between serum and plasma in all analyses, however, measured levels of Tau and Aβ were consistently lower in serum relative to plasma. Conclusion: Tau and Aβ are likely lost during clotting in serum preparations, and should be assayed in plasma to get an accurate measure of circulating levels.
Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics
Nature Reviews Drug Discovery, 2007
Alzheimer's disease (AD) and many other neurodegenerative disorders share common mechanisms that are linked to the pathological aggregation of misfolded proteins that accumulate as fibrillar amyloid deposits in selectively vulnerable regions of the central nervous system (for reviews, see REFS 1-4). The defining lesions of AD are neurofibrillary tangles (NFTs) and senile plaques formed by neuronal accumulations of abnormal tau filaments and extracellular deposits of Aβ fibrils, respectively, both of which are implicated in mechanisms of AD brain degeneration 2-4 . On the other hand, Lewy bodies (LBs) composed of abnormal α-synuclein filaments are pathological signatures of Parkinson's disease (PD), and growing evidence implicates abnormal α-synuclein in the pathogenesis of PD (for reviews, see REFS 5-9). For these and other reasons the progressive conversion of normal soluble tau and Aβ fibrils in AD and α-synuclein in PD to form insoluble oligomers, protofibrils and fully formed amyloid fibrils is increasingly the focus of drug discovery to identify disease-modifying therapies for AD, PD and related neurodegenerative brain amyloidoses 4 . Moreover, transgenic animal models of these disorders enable proof-of-concept studies of compounds that target disease-specific amyloidogenic pathways, and many of these compounds are entering clinical trials 4 . This progress in neurodegenerative disease research notwithstanding, a major impediment to the conduct of cost-effective and informative clinical trials of potential disease-modifying therapies is the absence of robust biomarkers for the early diagnosis of these disorders, when therapy is likely to have the greatest impact, and for monitoring patient responses to new therapeutic interventions in clinical trials. A daunting challenge to overcoming this obstacle is the complexity of neurodegenerative diseases, a number of which overlap 2,7,9 . This overlap is exemplified by neurodegenerative tauopathies characterized by AD-like fibrillary tau lesions, many of which manifest clinically as frontotemporal dementia (FTD). As illustrated in FIG. 2, various mechanistically diverse neurodegenerative diseases could underlie the clinical manifestations of FTD. Indeed, in 15-30% of patients meeting clinical criteria for FTD, the underlying disorder is AD on post-mortem examination 10 . Furthermore, AD and PD commonly co-occur, and the most common subtype of AD is the LB variant of AD, while >50% of AD patients show LBs in addition to senile plaques and NFTs . In addition, although PD is a neurodegenerative α-synucleinopathy that manifests principally as a movement disorder, PD with dementia is common; when dementia precedes Parkinsonism and there are abundant cortical as well as subcortical LBs, the disorder is designated dementia with LBs 11 . FIGURE 3 illustrates the complexity of neurodegenerative movement disorders and the overlap of PD and AD.
Mechanism and biomarkers for neurodegenerative diseases: A systematic review
IP innovative publication pvt ltd, 2020
Neurodegenerative disease such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Multiple sclerosis (MS), Huntington’s disease (HD) are characterized by progressive loss of cognitive function, dementia and problems with movement. Neuronal loss is associated with extra and intercellular accumulation of misfolding proteins, oxidative stress, free radical formation, mitochondrial dysfunction, disruption of neuronal golgi apparatus, impaired bioenergetics, dysfunction of neurotrophins. Biomarkers that might aid in the diagnosis of these devastating and globally important disease are urgently sought and required. Therefore, range of biomarkers are explained for neurodegenerative disease.
Upcoming diagnostic biomarkers with promising prospects in neurological disorders
Clinical and Experimental Pharmacology and Physiology
In accordance with a systematic analysis for the Global Burden of Disease Study 2015, reported in Lancet Neurology, neurological disorders are ranked as the second-leading cause of deaths (9.4 million, comprising 16.8% of global deaths). These reports reflect the massive rise (36.7% increase between 1990 and 2015) in mortality due to neurological disorders. 1 The data evidently indicate that neurological disorders are becoming one of the prime causes of disability and death worldwide. Owing to such an alarming rise in neurological disorders over the past 25 years, the scenario demands substantial steps to be taken for their prevention and treatment. Neurological disorders include cognitive impairment, stroke, Alzheimer's disease (AD), and Parkinson's disease (PD). 2 It seems that each of these neurological conditions has a unique pathophysiology and therefore should be identified as distinguished conditions for their appropriate diagnosis and treatment. However, it has been well demonstrated in preceding research studies that these neurological disorders reflect similar symptoms and aetiology, ending up with an exhaustive and challenging diagnosis. Nevertheless, current investigation studies are coming up to objectively evaluate profoundly the molecular mechanisms that cause these neurological disorders, which would in turn aid in their proper diagnosis and treatment. The pathogenesis of neurodegenerative disorder is marked by various pathological alterations co-occurring in a particular brain tissue owing to the deposition of proteins or interactions happening therein that result in cognitive decline and clinical manifestation of that neurological disorder. 3 Therefore, the diagnosis of such neurodegenerative condition is mainly based on the identification of the pattern of
Advances in Diagnostics for Neurodegenerative Disorders
Neurodegenerative Disorders, 2011
In this chapter, the established investigative techniques for aiding diagnosis in neurodegenerative disease are reviewed. Beginning with neuropsychological analysis, this review ranges though structural (anatomic), dynamic, and functional brain imaging using MRI and radio-nucleotide scanning to complex neurophysiological applications. In each section, the increasing likelihood of developing true noninvasive biomarkers is addressed. The future of multi-modality imaging and its contribution to, not only to diagnosis, but to classification, prognosis, and treatment outcome in neurodegeneration is considered.