New cerebrospinal fluid biomarkers in Alzheimer’s disease

Written by Burchell JT, Panegyres PK

In 2015, we published a review on novel cerebrospinal fluid (CSF) biomarkers for detecting Alzheimer’s disease (AD) [1]. We summarized the main potential CSF biomarkers as low amyloid β1–42 (Aβ1–42) and a high total tau (T-tau) and phosphorylated tau (p-tau). We discussed a number of other potential biomarkers, including those involving blood–brain barrier integrity (PDGFR-β), mitochondrial DNA (mtDNA), VEGF family members, calcium-sensor protein VILIP-1, β-site APP-cleaving enzyme 1 and the astrocyte marker YKL-40. More recently, a number of studies have focused on the potential use of other biomarkers such as TGF-β, neurofilament light polypeptide (NFL), autotaxin, α-syn and complement. These modules offer promise for earlier detection of AD and other neurodegenerative disorders including Parkinson’s disease (PD) and mild cognitive impairment (MCI).

TGF-β are multifunctional cytokines that are secreted into the CSF to regulate the development of a number of cell types including the differentiation, proliferation and apoptosis of neuronal cells [2]. There are three different isoforms of TGF-β in mammals: TGF-β1, TGF-β2 and TGF-β3. Increased levels of TGF-β1 have been reported in lumbar CSF from AD patients [3] and in ventricular CSF from patients with PD [4], suggesting a possible use for TGB-β1 as a biomarker for AD. TGF-β2 has been reported to regulate Aβ-mediated neuronal death but it is unclear what precise role it plays in AD and Lewy body disease (LBD). Chong et al. [5] reported a significant increase in neocortical levels of TGF-β2 in AD and LBD patients but not in PD patients. Interestingly, TGF-β2 levels also correlated with neurofibrillary tangle scores, Lewy bodies (in the LBD group), dementia severity and soluble Aβ42 concentration. This study demonstrates that TGF-β2 is increased in the cortex of AD and dementia with Lewy bodies (DLB) patients and correlates with neuropathological and clinical markers of disease severity; and, therefore, has potential for use as a biomarker or as a target for pharmacological approaches to AD and DLB. TGF-β has been shown to be increased in CSF of patients with PD and AD but is thought to be an unreliable marker for other neurodegenerative disorders, such as amyotrophic lateral sclerosis, spinocerebellar degeneration and multiple system atrophy-cerebellar subtype. For this reason, it might be a helpful biomarker that could be used to distinguish between AD and PD from other neurodegenerative disorders.

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