Fluid diagnosis for dementiaMarch 7, 2019
A typical diagnosis of dementia is based on a history of illness, cognitive deficits and their patterns. Along with the above-mentioned tests, there is now a shift towards diagnosing specific forms of Alzheimer’s disease (AD) using molecular biomarkers. There has been enormous progress in identifying fluid biomarkers for AD in the past 20 years. Pathologically, AD is defined by 1. a neuronal loss of brain regions, specifically in medial temporal lobe structures and temporoparietal cortices, 2. neurofibrillary tangles composed of truncated and hyperphosphorylated tau protein, 3. the extracellular neuritic plaques with deposits of -amyloid peptides. There are several subtypes of dementia which are diagnosed using different biomarkers to evolve better therapy and precision medicine.
In -amyloid pathology, the 42-amino-acid isoform of -amyloid (A42) forms the major component of senile plaques leading to cerebral amyloid angiopathy in AD. Enzyme-linked immunosorbent assay (ELISA) based A42 concentration measurement in CSF has been verified in many studies (Olsson et al., 2016), where reduced levels reflect sequestration to senile plaques as was also shown in positron emission tomography (PET) imaging. These reduced levels of A42 can indicate pre-clinical stages of AD or dementia with Lewy bodies (DLB), commonly associated with cerebral A aggregation. In order to make diagnostics more accessible, blood is preferable, and plasma A42 measurement using Single Molecule Array (Simoa) technique could quantify to sub-picogram per mL levels (limit of quantification of 0.04pg/mL). A large-scale Swedish BioFINDER study found weak, but significant, correlations between both plasma AB42 and AB42/40 ratio to corresponding CSF measurements.
The abnormal phosphorylation and truncation of tau proteins, which constitute major neurofibrillary tangles in AD, are also detectable in blood samples. It has been shown that increased levels of plasma tau levels may correlate with AD. Longitudinal studies have shown that increased plasma tau levels have significant correlation with future cognitive decline as well as in hypometabolism measured by FDG PET. However, many clinical studies reported that there is a large overlap of tau levels between cases of tauopathies and controls, suggesting that more studies may be needed to take it into clinical practice. Alternatively, T-tau or P-tau measurement in neuron-enriched exosomes may help as a better biomarker.
Neurogranin and cognitive decline
One of the key features of AD is axonal degeneration, which is linked with the onset of cognitive decline and A pathology. It has been demonstrated that higher levels of CSF T-tau lead to increased intensity of neurodegeneration. Some more markers like fatty acid-binding protein (FABP) family and visinin-like protein 1 (VLP-1; VSNL1) do show a weak but significant association to AD. T-tau and neurofilament-light (NF-L) assays are also being used for performing ultrasensitive blood tests, but these are in early stages of development. A recent study on a cohort of Alzheimer’s Disease Neuroimaging Initiative (ADNI) study showed a marked increase in plasma NF-L levels, with receiver operating curve (ROC) area under the curve (AUC) of 0.87, which is comparable to CSF AD biomarkers.
One of the earliest clinical characteristic of AD is memory impairment due to subtle alterations in synaptic efficiency in the hippocampus prior to frank neuronal degeneration. One of the most important proteins, called neurogranin (Ng; NRGN), is a dendritic protein highly abundant in neurons. It is involved in long term potentiation of synapses, particularly in hippocampus and basal forebrain. CSF Ng concentrations were observed to be increased in AD (Hellwig et al, 2015; Kvartsberg et al., 2015a,b; Thorsell et al., 2010; Kester et al., 2015), but not in other neurodegenerative diseases. New studies have also reported that there is a strong correlation between higher levels of Ng and cognitive decline and brain atrophy (Tarawneh et al., 2016). Some of the novel emerging biomarkers include synaptosomal-associated protein 25 (SNAP25) and Ras-related protein RAB3A.
Glial cells in the brain are important for normal nutrient supply and form part of the blood-brain barrier. These cells play important roles in repair following CNS injury and resident macrophages microglia form the primary active defense players. Loss of synaptic plasticity and neuronal function in AD can be linked to activation of both cell types, but more so the glial cells. Interesting findings related to variants of myeloid cells 2 (TREM2; TREML2) gene specifically expressed in microglia cells has raised interest in the possibility of identifying better biomarkers for glial activation (Lue et al., 2015; Guerrerio et al., 2013; Jonsson et al., 2013). Increased levels of secreted ectodomain of TREM2 in CSF were in concordance with that of T-tau and P-tau levels in AD patients. Similarly, several other biomarkers of astrocytes, microglia and macrophage-derived proteins, like CD14, YKL-40 and C-C chemokine receptor 2 with its ligand C-C chemokine ligand 2 (CCL2) levels were present in increased levels in AD patients CSF. The validation of these biomarkers in blood has not yet resulted in any conclusive outcomes. Approximately 50% of frontotemporal dementia (FTD) cases are reported to show increased levels of hyperphosphorylated TDP-43 proteinopathy. It has also been observed to be associated with the impairment of cognitive capabilities of aging patients.
Obviously, CSF has proven to be the best source of biomarkers for detecting tangle and plaque pathology for clinical utility, but there are emerging biomarkers that are reshaping the diagnosis and therapeutic approaches in AD. The new discoveries and findings do suggest that, for now, a combination of CSF, blood and PET may be the best option. However, blood biomarkers are on brink of being a viable option for the screening and early clinical management of patients with AD. The last 20 years of research on fluid biomarkers has given extraordinary results and ADCSF biomarker toolbox looks set to better define precision medicine.