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

Abstract

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.

Cerebrospinal Fluid Levels of Neurogranin in Parkinsonian Disorders

“…Ng has been extensively investigated in AD where studies, consistent with results in the present study, have shown increased levels of Ng in AD . Furthermore, increased Ng has been linked to cognitive decline and conversion from MCI to AD .…”

“…Ng has been extensively investigated in AD where studies, consistent with results in the present study, have shown increased levels of Ng in AD. 2,[4][5][6][7][8][9][10][11]16 Furthermore, increased Ng has been linked to cognitive decline and conversion from MCI to AD. 6,7 In this study focusing on parkinsonian disorders, confirming some studies but contradicting others, 9,13,14 we find decreased levels of Ng in PD compared to controls.…”

“…In Parkinson's disease (PD), α‐synuclein (α‐syn)‐containing intraneuronal inclusions are believed to lead to synaptic dysfunction, interfere with axonal transport, and lead to damage of dopaminergic neurons . Cerebrospinal fluid (CSF) concentration of the dendritic protein, neurogranin (Ng), has been suggested as a potential biomarker for synapse loss or dysfunction . Ng is a small neuronal postsynaptic protein located in the cell bodies and dendritic processes of neurons foremost in the cerebral cortex, hippocampus, and striatum …”

“…CSF Ng levels have been extensively investigated in Alzheimer's disease (AD), where they are increased compared to controls, increased in amyloid‐beta (Aβ) + mild cognitive impairment (MCI), and linked to cognitive decline and progression from MCI to AD dementia . A recent postmortem, human brain proteome study on patiens with and without dementia found that synaptic proteins, but not any individual protein, could differentiate PD with dementia (PDD) and dementia with Lewy bodies (DLB) from controls and AD and that cognitive impairment and decline in life correlated with loss of synaptic proteins …”

“…1 Cerebrospinal fluid (CSF) concentration of the dendritic protein, neurogranin (Ng), has been suggested as a potential biomarker for synapse loss or dysfunction. 2 Ng is a small neuronal postsynaptic protein located in the cell bodies and dendritic processes of neurons foremost in the cerebral cortex, hippocampus, and striatum. 3 CSF Ng levels have been extensively investigated in Alzheimer's disease (AD), 2 where they are increased compared to controls, 4-9 increased in amyloid-beta (Aβ) + mild cognitive impairment (MCI), and linked to cognitive decline and progression from MCI to AD dementia.…”