New cerebrospinal fluid biomarkers in Alzheimer’s disease

Abstract

Future NeurologyVol. 12, No. 2 EditorialFree AccessNew cerebrospinal fluid biomarkers in Alzheimer’s diseaseJennifer T Burchell & Peter K PanegyresJennifer T Burchell Neurodegenerative Disorders Research Pty Ltd, 4 Lawrence Avenue, West Perth, Western Australia 6005, AustraliaSearch for more papers by this author & Peter K Panegyres*Author for correspondence: E-mail Address: research@ndr.org.au Neurodegenerative Disorders Research Pty Ltd, 4 Lawrence Avenue, West Perth, Western Australia 6005, AustraliaSearch for more papers by this authorPublished Online:5 May 2017https://doi.org/10.2217/fnl-2017-0009AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: α-synucleinAlzheimer’s diseaseautotaxincomplementdementiamild cognitive impairmentneurofilament lightParkinson’s diseaseTGF-βFirst draft submitted: 7 March 2017; Accepted for publication: 20 March 2017; Published online: 5 May 2017In 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-βTGF-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.Neurofilament light polypeptideNeurofilaments are a group of heteropolymers found in the nervous systems and are responsible for the radial growth of axons during development, maintenance of axon caliber and neural transmission. One member of the family of neurofilaments is called neurofilament light polypeptide and is thought to correlate with axonal degeneration. CSF NFL levels have been reported to be associated with age [6], white matter lesions [7], AD [8] and other neurodegenerative diseases. A recent study of CSF NFL subunit levels in patients with MCI showed a positive correlation between NFL levels and hippocampal atrophy, suggesting that CSF NFL might offer promise as a marker for progression to AD [9].The hippocampus is one of the areas of the brain with the highest atrophy rate in aging. In a study of 144 cognitively healthy older individuals, Idland et al. reported that NFL levels predicted neurodegeneration as measured by hippocampal atrophy rate independently of age, β-amyloid 1–42 and p-tau [10]. They concluded that NFL was likely to be a biomarker of neurodegeneration independent of AD or age; however, further research is required to test the predictive value of NFL in the onset and progression of prodromal AD.AutotaxinEctonucleotide pyrophosphatase/phosphodiesterase 2, also known as autotaxin, is produced by beige adipose tissue and acts to regulate energy metabolism. Autotaxin gene expression was increased in the frontal cortices of AD patients compared with non-AD patients, with a tendency for higher gene expression in patients with the ApoE ε3/ε4 genotype compared with the ApoE ε3/ε3 genotype [11]. Recently, elevated autotaxin levels have been found in the CSF of MCI and AD patients compared with healthy controls [12]. Interestingly, autotaxin was also positively correlated with levels of T-tau, p-Tau181, T-tau/Aβ1–42 as well as p-Tau181/Aβ1–42, although to a lesser degree. These results suggest that autotaxin could predict neuropathology and cognitive deficits in AD.α-synα-syn is involved in the regulation of synaptic plasticity, dopamine synthesis and neuronal differentiation. Abnormal accumulation of α-syn in the brain is a pathological hallmark of PD and DLB, and can be found in the brains of individuals with AD. Therefore, there has been recent interest in developing an assay for the detection of α-syn as a biomarker for neurodegenerative disorders. A simple ELISA-based method of detecting total α-syn in CSF has recently been developed and validated using electrochemiluminescence technology in 50 CSF samples [13]. This assay offers promise for use as a biomarker not only in AD, but also in other neurodegenerative disorders including PD and prion disease [14]. As α-syn is found in other neurodegenerative conditions, its use as a marker to distinguish AD from other diseases is probably restricted.ComplementComplement is an integral part of the innate immune system whose role is to recognize a target and opsonize it for engulfment and destruction by phagocytes. This is achieved by complement assembling the membrane attack complex which acts to create holes in a foreign pathogen’s protective membrane. One major fault of this system is that complement can mistakenly attack host tissue which is known as bystander lysis. This mechanism can possibly contribute to the pathogenesis of AD.Three decades ago, it was discovered that complement could opsonize Aβ deposits in the brain of AD patients [15] and, soon after, it was reported that the membrane attack complex could attack dystrophic neurites [16]. The genes for C1q, C3 and C4 are expressed in the brain and have been reported to be upregulated more than threefold in AD [17]. Rogers et al. subsequently reported that C1q binds strongly to the Aβ peptide suggesting that the classical pathway could be activated by any tissue component recognized by complement [18]. Extracellular Aβ deposits in the brain have been reported to directly activate the complement system by associating with the opsonizing components of complement. Specifically, C1q can bind to Aβ and its N-terminal fragments which can potentially trigger the inflammatory cascade of AD [19]. Moreover, levels of complement components C3 and C4 and complement receptor 1 (CR1) have been reported to be elevated in the CSF of AD patients [20]. Daborg et al. reported that CSF levels of C3 and C4 were elevated in AD patients when compared with MCI patients who progressed to AD [20]. In addition, CSF levels of CR1 were elevated after combining MCI and AD groups compared with controls. These results, while promising, were deemed not useful for diagnostic purposes due to the small changes detected and could be strengthened by involving larger numbers of patients in future studies.ConclusionThere have been some interesting and promising recent advances in detecting and validating potential CSF biomarkers for use in AD and other neurodegenerative disorders. A recent emphasis has been on immunological factors. TGF-β is reported to be increased in the cortex of AD and DLB patients and correlates with neuropathological and clinical markers of disease severity, and therefore has potential for use as a biomarker for AD. NFL could potentially be developed as a biomarker for neurodegeneration which is independent of age or AD status; therefore, it might be helpful to distinguish AD from other neurodegenerative disorders. Recent studies report increased gene expression of autotaxin in the frontal cortex of AD patients and increased levels in the CSF of MCI and AD patients which could predict neuropathology and cognitive deficits in AD. α-syn has been shown to be increased in the CSF of AD, PD and prion disease patients, and is, therefore, a useful marker for neurodegeneration but might not help in distinguishing these conditions. Other studies have demonstrated increased levels of complement C3 and C4, as well as CR1, in the CSF of AD patients. Taken together these studies not only offer hope for the development of biomarkers to detect AD and its progression, but also the advancement of therapeutic targets to limit disease progression.Financial & competing interests disclosureThis work was funded by Neurodegenerative Disorders Research Pty Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Burchell JT, Panegyres PK. Novel CSF biomarkers for Alzheimer’s disease. Future Neurol. 10(6), 511–514 (2015).Link, CAS, Google Scholar2 Böttner M, Krieglstein K, Unsicker K. The transforming growth factor-βs: structure, signaling, and roles in nervous system development and functions. J. Neurochem. 75(6), 2227–2240 (2000).Crossref, Medline, CAS, Google Scholar3 Zetterberg H, Andreasen N, Blennow K. Increased cerebrospinal fluid levels of transforming growth factor-β1 in Alzheimer’s disease. Neurosci. Lett. 367(2), 194–196 (2004).Crossref, Medline, CAS, Google Scholar4 Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P, Nagatsu T. Transforming growth factor-β1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson’s disease. Neurosci. Lett. 193(2), 129–132 (1995).Crossref, Medline, CAS, Google Scholar5 Chong JR, Chai YL, Lee JH et al. Increased transforming growth factor β2 in the neocortex of Alzheimer’s disease and dementia with Lewy bodies is correlated with disease severity and soluble Aβ42 load. J. Alzheimers Dis. 56(1), 157–166 (2016).Crossref, Google Scholar6 Vågberg M, Norgren N, Dring A et al. Levels and age dependency of neurofilament light and glial fibrillary acidic protein in healthy individuals and their relation to the brain parenchymal fraction. PLoS ONE 10(8), e0135886 (2015).Crossref, Medline, Google Scholar7 Sjögren M, Blomberg M, Jonsson M et al. Neurofilament protein in cerebrospinal fluid: a marker of white matter changes. J. Neurosci. Res. 66(3), 510–516 (2001).Crossref, Medline, CAS, Google Scholar8 Olsson B, Lautner R, Andreasson U et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 15(7), 673–684 (2016).Crossref, Medline, CAS, Google Scholar9 Zetterberg H, Skillbäck T, Mattsson N et al. Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression. JAMA Neurol. 73(1), 60–67 (2016).Crossref, Medline, Google Scholar10 Idland AV, Sala-Llonch R, Borza T et al. CSF neurofilament light levels predict hippocampal atrophy in cognitively healthy older adults. Neurobiol. Aging 49, 138–144 (2017).Crossref, Medline, CAS, Google Scholar11 Umemura K, Yamashita N, Yu X et al. Autotaxin expression is enhanced in frontal cortex of Alzheimer-type dementia patients. Neurosci. Lett. 400(1–2), 97–100 (2006).Crossref, Medline, CAS, Google Scholar12 McLimans KE, Willette AA. Autotaxin as a CSF biomarker for central dysmetabolism and Alzheimer’s disease outcomes. Alzheimers Dement. 12(7), 83 (2016).Crossref, Google Scholar13 Førland MG, Öhrfelt A, Oftedal LS. Validation of a new assay for α-synuclein detection in cerebrospinal fluid. Clin. Chem. Lab. Med. 55(2), 254–260 (2017).Crossref, Medline, CAS, Google Scholar14 Llorens F, Kruse N, Schmitz M et al. Evaluation of α-synuclein as a novel cerebrospinal fluid biomarker in different forms of prion diseases. Alzheimers Dement. doi:10.1016/j.jalz.2016.09.013 (2016) (Epub ahead of print).Crossref, Google Scholar15 Eikelenboom P, Stam FC. Immunoglobulins and complement factors in senile plaques. Acta Neuropathol. 57(2–3), 239–242 (1982).Crossref, Medline, CAS, Google Scholar16 McGeer PL, Akiyama H, Itagaki S et al. Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci. Lett. 107(1), 341–346 (1989).Crossref, Medline, CAS, Google Scholar17 Walker DG, McGeer PL. Complement gene expression in human brain: comparison between normal and Alzheimer disease cases. Brain Res. Mol. Brain Res. 14(1–2), 109–116 (1992).Crossref, Medline, CAS, Google Scholar18 Rogers J, Cooper NR, Webster S et al. Complement activation by beta-amyloid in Alzheimer disease. Proc. Natl Acad. Sci. USA 89(21), 10016–10020 (1992).Crossref, Medline, CAS, Google Scholar19 Yasojima K, Schwab C, McGeer EG et al. Upregulated production and activation of the complement system in Alzheimer disease brain. Am. J. Pathol. 154(3), 927–936 (1999).Crossref, Medline, CAS, Google Scholar20 Daborg J, Andreasson U, Pekna M et al. Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer’s disease. J. Neural Transm. (Vienna) 119(7), 789–797 (2012).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByDeveloping Effective Alzheimer’s Disease Therapies: Clinical Experience and Future DirectionsJournal of Alzheimer's Disease, Vol. 71, No. 3Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease?6 March 2018 | BMC Medicine, Vol. 16, No. 1Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts and controversies8 December 2017 | Journal of Neural Transmission, Vol. 125, No. 4 Vol. 12, No. 2 Follow us on social media for the latest updates Metrics History Published online 5 May 2017 Published in print May 2017 Information© Future Medicine LtdKeywordsα-synucleinAlzheimer’s diseaseautotaxincomplementdementiamild cognitive impairmentneurofilament lightParkinson’s diseaseTGF-βFinancial & competing interests disclosureThis work was funded by Neurodegenerative Disorders Research Pty Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download