Fluid‐based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases

• Published in: Journal of neurochemistry 2019-11, Vol.151 (4), p.417-434
• Main Authors: Brinkmalm, Ann, Portelius, Erik, Brinkmalm, Gunnar, Pannee, Josef, Dahlén, Rahil, Gobom, Johan, Blennow, Kaj, Zetterberg, Henrik
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - blood; alpha-Synuclein - cerebrospinal fluid; Amyloid beta-Peptides - blood; Amyloid beta-Peptides - cerebrospinal fluid; Axons; Biomarkers; Biomarkers - blood; Biomarkers - cerebrospinal fluid; Brain; Clinical trials; CSF; Degeneration; Dementia; Dementia - metabolism; Dementia - pathology; Dementia - physiopathology; Disorders; DNA-Binding Proteins - blood; DNA-Binding Proteins - cerebrospinal fluid; Drug development; Humans; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - physiopathology; Neurosciences; Neurovetenskaper; Pathology; plasma; Proteomics; Proteomics - methods; serum; Signs and symptoms; Synapses; tau Proteins - blood; tau Proteins - cerebrospinal fluid
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.14594

Neurodegenerative dementias constitute a broad group of diseases in which abnormally folded proteins accumulate in specific brain regions and result in tissue reactions that eventually cause neuronal dysfunction and degeneration. Depending on where in the brain this happens, symptoms appear which may be used to classify the disorders on clinical grounds. However, brain changes in neurodegenerative dementias start to accumulate many years prior to symptom onset and there is a poor correlation between the clinical picture and what pathology that is the most likely to cause it. Thus, novel drug candidates having disease‐modifying effects that is targeting the underlying pathology and changes the course of the disease needs to be defined using objective biomarker‐based measures since the clinical symptoms are often non‐specific and overlap between different disorders. Furthermore, the treatment should ideally be initiated as soon as symptoms are evident or when biomarkers confirm an underlying pathology (pre‐clinical phase of the disease) to reduce irreversible damage to, for example, neurons, synapses and axons. Clinical trials in the pre‐clinical phase bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not yet clinically affected. Here, we discuss neuropathological changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid‐based biomarkers and how more of them could be identified using targeted proteomics approaches. This article is part of the special issue "Proteomics". The review by Brinkmalm and colleagues discusses neuropathological and cellular changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid‐based biomarkers. A major part of the paper deals with targeted proteomics approaches to biomarker development and validation. Both affinity‐ and mass spectrometry‐based technologies are covered. This article is part of the special issue "Proteomics".