Author(s): Marta del Campo [*] 1 , Brit Mollenhauer 2 , Antonio Bertolotto 3 , Sebastiaan Engelborghs 4 , Harald Hampel 5 , Anja Hviid Simonsen 6 , Elisabeth Kapaki 7 , Niels Kruse 8 , Nathalie Le Bastard 9 , Sylvain Lehmann 10 , Jose L Molinuevo 11 , Lucilla Parnetti 12 , Armand Perret-Liaudet 13 , Javier Sáez-Valero 14 , Esen Saka 15 , Andrea Urbani 16 , Eugeen Vanmechelen 17 , Marcel Verbeek 18 , Pieter Jelle Visser 19 , Charlotte Teunissen 20
Alzheimer's disease; biomarkers; CSF; early diagnosis; guidelines; Parkinson's disease; preanalytical factors; recommendations; standard operating procedures
Alzheimer's disease (AD), the most common type of dementia, and Parkinson's disease (PD) are age-related irreversible neurodegenerative disorders. Recent investigations indicate that approximately two-thirds of dementia cases may be undiagnosed in nonspecialized centers  . Importantly, it has been estimated that the initial AD (but also PD) typical molecular alterations may take place even several decades before the appearance of clinical signs. Thus, owing to the long duration of this asymptomatic phase, during which pathophysiological mechanisms, together with structural and functional changes, are developing [2,3] , it is of paramount importance to detect biological markers accurately reproducing features of AD and PD pathophysiology before the expression of clinical symptoms [4,5] . Biomarkers reflecting amyloid deposition and neuronal changes in early stages of the disease can be an efficient tool for early diagnosis. Cerebrospinal fluid (CSF) is considered one of the main sources for CNS biomarker discovery, since it directly interacts with the extracellular space of the brain and mirrors biochemical alterations occurring in it  . The current AD CSF biomarker model parallels the prevailing hypothesis for its pathogenesis - that is, the amyloid cascade hypothesis characterized by an early [beta]-amyloid (A[beta]) peptide accumulation, representing the central event, followed by tangle formation, synaptic dysfunction, neurodegeneration and neuronal loss. Thus, the core CSF biomarkers for AD diagnosis are a decrease of A[beta]42 levels, which reflects senile plaque pathology, as well as an increase of total tau (T-tau) and phosphorylated tau (P-tau), which reflect axonal degeneration [7-9] . Recently, the new diagnostic criteria and guidelines for AD established by the National Institute on Aging and the Alzheimer's Association (NIA-AA) discuss the role of CSF biomarkers in AD diagnosis. The value of these biomarkers for AD diagnosis changes according to the stage of the disease  . The new NIA-AA guidelines recommend the use of those biomarkers to increase the confidence in establishing that the underlying dementia syndrome of a patient is due to an AD pathophysiological process, but not for routine diagnosis.
In parallel, in PD the core CSF biomarker is [alpha]-synuclein: its intracellular accumulation is characteristic for PD and other Parkinsonism syndromes like multiple system atrophy (MSA) and dementia with Lewy bodies. [alpha]-synuclein follows a gene dose effect, and by genome-wide association studies of sporadic PD and MSA, a strong association between disease risk and distinct single nucleotide polymorphisms in the [alpha]-synuclein coding gene, SNCA , has been shown as a risk factor for developing PD  . Therefore, misprocessing of [alpha]-synuclein is a seminal event in synucleinopathies. The quantification of [alpha]-synuclein in CSF has been described...