Neurodegenerative diseases require characterization based on underlying biology using biochemical biomarkers. Mixed pathology complicates discovery of biomarkers and characterization of cohorts, but inclusion of greater numbers of patients with different, related diseases with frequently co-occurring pathology could allow better accuracy. Combining cohorts collected from different studies would be a more efficient use of resources than recruiting subjects from each population of interest for each study.
Objective:
To explore the possibility of combining existing datasets by controlling pre-analytic variables in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Parkinson’s Progression Markers Initiative (PPMI) studies.
Methods:
Cerebrospinal fluid (CSF) was collected and processed from 30 subjects according to both the ADNI and PPMI protocols. Relationships between reported levels of Alzheimer’s disease (AD) and Parkinson’s disease (PD) biomarkers in the same subject under each protocol were examined.
Results:
Protocol-related differences were observed for Aβ, but not t-tau or α-syn, and trended different for p-tau and pS129. Values of α-syn differed by platform. Conversion of α-syn values between ADNI and PPMI platforms did not completely eliminate differences in distribution.
Discussion:
Factors not captured in the pre-analytical sample handling influence reported biomarker values. Assay standardization and better harmonized characterization of cohorts should be included in future studies of CSF biomarkers.
TapiolaT, AlafuzoffI, HerukkaSK, ParkkinenL, HartikainenP, SoininenH, PirttilaT (2009) Cerebrospinal fluid beta-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol66, 382–389.
2.
MulderC, VerweyNA, van der FlierWM, BouwmanFH, KokA, van ElkEJ, ScheltensP, BlankensteinMA (2010) Amyloid-beta(1–42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. Clin Chem56, 248–253.
RahimiJ, KovacsGG (2014) Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther6, 82.
5.
HamiltonRL (2000) Lewy bodies in Alzheimer’s disease: A neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol10, 378–384.
6.
LippaCF, FujiwaraH, MannDM, GiassonB, BabaM, SchmidtML, NeeLE, O’ConnellB, PollenDA, St George-HyslopP, GhettiB, NochlinD, BirdTD, CairnsNJ, LeeVM, IwatsuboT, TrojanowskiJQ (1998) Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol153, 1365–1370.
7.
LippaCF, SchmidtML, LeeVM, TrojanowskiJQ (1999) Antibodies to alpha-synuclein detect Lewy bodies in many Down’s syndrome brains with Alzheimer’s disease. Ann Neurol45, 353–357.
LeeJH, KimSH, KimGH, SeoSW, ParkHK, OhSJ, KimJS, CheongHK, NaDL (2011) Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B. Neurology77, 18–25.
10.
KorffA, LiuC, GinghinaC, ShiM, ZhangJ (2013) alpha-Synuclein in Cerebrospinal Fluid of Alzheimer’s Disease and Mild Cognitive Impairment. J Alzheimers Dis36, 679–688.
11.
ToledoJB, KorffA, ShawLM, TrojanowskiJQ, ZhangJ (2013) CSF alpha-synuclein improves diagnostic and prognostic performance of CSF tau and Abeta in Alzheimer’s disease. Acta Neuropathol126, 683–697.
12.
WangH, StewartT, ToledoJB, GinghinaC, TangL, AtikA, AroP, ShawLM, TrojanowskiJQ, GalaskoDR, EdlandS, JensenPH, ShiM, ZhangJ (2018) A longitudinal study of total and phosphorylated alpha-synuclein with other biomarkers in cerebrospinal fluid of Alzheimer’s disease and mild cognitive impairment. J Alzheimers Dis61, 1541–1553.
13.
KangJH, IrwinDJ, Chen-PlotkinAS, SiderowfA, CaspellC, CoffeyCS, WaligorskaT, TaylorP, PanS, FrasierM, MarekK, KieburtzK, JenningsD, SimuniT, TannerCM, SingletonA, TogaAW, ChowdhuryS, MollenhauerB, TrojanowskiJQ, ShawLM (2013) Association of cerebrospinal fluid beta-amyloid 1–42,-tau,-tau181, and alpha-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. JAMA Neurol70, 1277–1287.
14.
GodynJ, JonczykJ, PanekD, MalawskaB (2016) Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep68, 127–138.
15.
DoodyRS, ThomasRG, FarlowM, IwatsuboT, VellasB, JoffeS, KieburtzK, RamanR, SunX, AisenPS, SiemersE, Liu-SeifertH, MohsR (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med370, 311–321.
VandenbergheR, RinneJO, BoadaM, KatayamaS, ScheltensP, VellasB, TuchmanM, GassA, FiebachJB, HillD, LobelloK, LiD, McRaeT, LucasP, EvansI, BoothK, LuscanG, WymanBT, HuaL, YangL, BrashearHR, BlackRS (2016) Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther8, 18.
18.
HenleyDB, SundellKL, SethuramanG, DowsettSA, MayPC (2014) Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin30, 2021–2032.
19.
KnopmanDS, HaeberleinSB, CarrilloMC, HendrixJA, KerchnerG, MargolinR, MaruffP, MillerDS, TongG, TomeMB, MurrayME, NelsonPT, SanoM, MattssonN, SultzerDL, MontineTJ, JackCRJr., KolbH, PetersenRC, VemuriP, CanniereMZ, SchneiderJA, ResnickSM, RomanoG, van HartenAC, WolkDA, BainLJ, SiemersE (2018) The National Institute on Aging and the Alzheimer’s Association Research Framework for Alzheimer’s disease: Perspectives from the Research Roundtable. Alzheimers Dement14, 563–575.
20.
ToombsJ, PatersonRW, LunnMP, NicholasJM, FoxNC, ChapmanMD, SchottJM, ZetterbergH (2013) Identification of an important potential confound in CSF AD studies: Aliquot volume. Clin Chem Lab Med51, 2311–2317.
21.
VandersticheleH, DemeyerL, JanelidzeS, CoartE, StoopsE, MaurooK, HerbstV, FrancoisC, HanssonO (2017) Recommendations for cerebrospinal fluid collection for the analysis by ELISA of neurogranin trunc P75, alpha-synuclein, and total tau in combination with Abeta(1–42)/Abeta(1–40). Alzheimers Res Ther9, 40.
22.
ToombsJ, PatersonRW, SchottJM, ZetterbergH (2014) Amyloid-beta 42 adsorption following serial tube transfer. Alzheimers Res Ther6, 5.
LewczukP, BeckG, EsselmannH, BruckmoserR, ZimmermannR, FiszerM, BiblM, MalerJM, KornhuberJ, WiltfangJ (2006) Effect of sample collection tubes on cerebrospinal fluid concentrations of tau proteins and amyloid beta peptides. Clin Chem52, 332–334.
26.
HongZ, ShiM, ChungKA, QuinnJF, PeskindER, GalaskoD, JankovicJ, ZabetianCP, LeverenzJB, BairdG, MontineTJ, HancockAM, HwangH, PanC, BradnerJ, KangUJ, JensenPH, ZhangJ (2010) DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain133, 713–726.
27.
ShiM, ZabetianCP, HancockAM, GinghinaC, HongZ, YearoutD, ChungKA, QuinnJF, PeskindER, GalaskoD, JankovicJ, LeverenzJB, ZhangJ (2010) Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson’s disease. Neurosci Lett480, 78–82.
28.
GibbWR, LeesAJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry51, 745–752.
29.
McKhannG, DrachmanD, FolsteinM, KatzmanR, PriceD, StadlanEM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34, 939–944.
SchoonenboomNS, MulderC, VandersticheleH, Van ElkEJ, KokA, Van KampGJ, ScheltensP, BlankensteinMA (2005) Effects of processing and storage conditions on amyloid beta (1–42) and tau concentrations in cerebrospinal fluid: Implications for use in clinical practice. Clin Chem51, 189–195.
SmachMA, CharfeddineB, Ben OthmanL, LammouchiT, DridiH, NafatiS, LtaiefA, BennamouS, LimemK (2009) Evaluation of cerebrospinal fluid tau/beta-amyloid(42) ratio as diagnostic markers for Alzheimer disease. Eur Neurol62, 349–355.
34.
KangJH, MollenhauerB, CoffeyCS, ToledoJB, WeintraubD, GalaskoDR, IrwinDJ, Van DeerlinV, Chen-PlotkinAS, Caspell-GarciaC, WaligorskaT, TaylorP, ShahN, PanS, ZeroP, FrasierM, MarekK, KieburtzK, JenningsD, TannerCM, SimuniT, SingletonA, TogaAW, ChowdhuryS, TrojanowskiJQ, ShawLM (2016) CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: The Parkinson’s Progression Markers Initiative study. Acta Neuropathol131, 935–949.
35.
ParnettiL, CicognolaC, EusebiP, ChiasseriniD (2016) Value of cerebrospinal fluid alpha-synuclein species as biomarker in Parkinson’s diagnosis and prognosis. Biomark Med10, 35–49.
36.
HallS, OhrfeltA, ConstantinescuR, AndreassonU, SurovaY, BostromF, NilssonC, HakanW, DecraemerH, NaggaK, MinthonL, LondosE, VanmechelenE, HolmbergB, ZetterbergH, BlennowK, HanssonO (2012) Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol69, 1445–1452.
37.
Glodzik-SobanskaL, PirragliaE, BrysM, de SantiS, MosconiL, RichKE, SwitalskiR, Saint LouisL, SadowskiMJ, MartiniukF, MehtaP, PraticoD, ZinkowskiRP, BlennowK, de LeonMJ (2009) The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer’s disease. Neurobiol Aging30, 672–681.
38.
PeskindER, LiG, ShoferJ, QuinnJF, KayeJA, ClarkCM, FarlowMR, DeCarliC, RaskindMA, SchellenbergGD, LeeVM, GalaskoDR (2006) Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Arch Neurol63, 936–939.
39.
MattssonN, RosenE, HanssonO, AndreasenN, ParnettiL, JonssonM, HerukkaSK, van der FlierWM, BlankensteinMA, EwersM, RichK, KaiserE, VerbeekMM, Olde RikkertM, TsolakiM, MulugetaE, AarslandD, VisserPJ, SchroderJ, MarcussonJ, de LeonM, HampelH, ScheltensP, WallinA, Eriksdotter-JonhagenM, MinthonL, WinbladB, BlennowK, ZetterbergH (2012) Age and diagnostic performance of Alzheimer disease CSF biomarkers. Neurology78, 468–476.
40.
SjogrenM, VandersticheleH, AgrenH, ZachrissonO, EdsbaggeM, WikkelsoC, SkoogI, WallinA, WahlundLO, MarcussonJ, NaggaK, AndreasenN, DavidssonP, VanmechelenE, BlennowK (2001) Tau and Abeta42 in cerebrospinal fluid from healthy adults 21–93 years of age: Establishment of reference values. Clin Chem47, 1776–1781.
