Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer’s disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = –0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = –0.15; p-tau: r = –0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.
BlennowK, de LeonMJ, ZetterbergH (2006) Alzheimer’s disease. Lancet368, 387–403.
2.
BeachTG, MonsellSE, PhillipsLE, KukullW (2012) Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol71, 266–273.
3.
WangHF, TanL, CaoL, ZhuXC, JiangT, TanMS, LiuY, WangC, TsaiRM, JiaJP, YuJT, Alzheimer’s Disease Neuroimaging Initiative (2016) Application of the IWG12 diagnostic criteria for Alzheimer’s disease to the ADNI. J Alzheimers Dis51, 227–236.
4.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCRJr, KawasCH, KlunkWE, KoroshetzWJ, ManlyJJ, MayeuxR, MohsRC, MorrisJC, RossorMN, ScheltensP, CarrilloMC, ThiesB, WeintraubS, PhelpsCH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 263–269.
5.
AlbertMS, DeKoskyST, DicksonD, DuboisB, FeldmanHH, FoxNC, GamstA, HoltzmanDM, JagustWJ, PetersenRC (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 270–279.
6.
NordbergA, RinneJO, KadirA, LangstromB (2010) The use of PET in Alzheimer disease. Nat Rev Neurol6, 78–87.
7.
EisenmengerLB, HuoEJ, HoffmanJM, MinoshimaS, MatesanMC, LewisDH, LoprestiBJ, MathisCA, OkonkwoDO, MountzJM (2016) Advances in PET imaging of degenerative, cerebrovascular, and traumatic causes of dementia. Semin Nucl Med46, 57–87.
8.
BarthelH, SchroeterML, HoffmannK-T, SabriO (2015) PET/MR in dementia and other neurodegenerative diseases. Semin Nucl Med45, 224–233.
9.
JackCRJr, AlbertMS, KnopmanDS, McKhannGM, SperlingRA, CarrilloMC, ThiesB, PhelpsCH (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 257–262.
10.
NestorSM, RupsinghR, BorrieM, SmithM, AccomazziV, WellsJL, FogartyJ, BarthaR, Alzheimer’s Disease Neuroimaging Initiative (2008) Ventricular enlargement as a possible measure of Alzheimer’s disease progression validated using the Alzheimer’s disease neuroimaging initiative database. Brain131, 2443–2454.
11.
ClarkCM, XieS, ChittamsJ, EwbankD, PeskindE, GalaskoD, MorrisJC, McKeelDW, FarlowM, WeitlaufSL (2003) Cerebrospinal fluid tau and β-amyloid: How well do these biomarkers reflect autopsy-confirmed dementia diagnoses?Arch Neurol60, 1696–1702.
12.
BlennowK, DuboisB, FaganAM, LewczukP, de LeonMJ, HampelH (2015) Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers Dement11, 58–69.
13.
DinizBSO, PintoJA, ForlenzaOV (2008) Do CSF total tau, phosphorylated tau, and β-amyloid 42 help to predict progression of mild cognitive impairment to Alzheimer’s disease? A systematic review and meta-analysis of the literature. World J Biol Psychiatry9, 172–182.
14.
JansenWJ, OssenkoppeleR, KnolDL, TijmsBM, ScheltensP, VerheyFR, VisserPJ, AaltenP, AarslandD, AlcoleaD, AlexanderM, AlmdahlIS, ArnoldSE, BaldeirasI, BarthelH, van BerckelBN, BibeauK, BlennowK, BrooksDJ, van BuchemMA, CamusV, CavedoE, ChenK, ChetelatG, CohenAD, DrzezgaA, EngelborghsS, FaganAM, FladbyT, FleisherAS, van der FlierWM, FordL, ForsterS, ForteaJ, FoskettN, FrederiksenKS, Freund-LeviY, FrisoniGB, FroelichL, GabryelewiczT, GillKD, GkatzimaO, Gomez-TortosaE, GordonMF, GrimmerT, HampelH, HausnerL, HellwigS, HerukkaSK, HildebrandtH, IshiharaL, IvanoiuA, JagustWJ, JohannsenP, KandimallaR, KapakiE, Klimkowicz-MrowiecA, KlunkWE, KohlerS, KoglinN, KornhuberJ, KrambergerMG, Van LaereK, LandauSM, LeeDY, de LeonM, LisettiV, LleoA, MadsenK, MaierW, MarcussonJ, MattssonN, de MendoncaA, MeulenbroekO, MeyerPT, MintunMA, MokV, MolinuevoJL, MollergardHM, MorrisJC, MroczkoB, Van der MusseleS, NaDL, NewbergA, NordbergA, NordlundA, NovakGP, ParaskevasGP, ParnettiL, PereraG, PetersO, PoppJ, PrabhakarS, RabinoviciGD, RamakersIH, RamiL, Resende de OliveiraC, RinneJO, RodrigueKM, Rodriguez-RodriguezE, RoeCM, RotU, RoweCC, RutherE, SabriO, Sanchez-JuanP, SantanaI, SarazinM, SchroderJ, SchutteC, SeoSW, SoeteweyF, SoininenH, SpiruL, StruyfsH, TeunissenCE, TsolakiM, VandenbergheR, VerbeekMM, VillemagneVL, VosSJ, van Waalwijk van DoornLJ, WaldemarG, WallinA, WallinAK, WiltfangJ, WolkDA, ZbochM, ZetterbergH (2015) Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis. JAMA313, 1924–1938.
15.
VandersticheleH, BiblM, EngelborghsS, Le BastardN, LewczukP, MolinuevoJL, ParnettiL, Perret-LiaudetA, ShawLM, TeunissenC, WoutersD, BlennowK (2012) Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: A consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement8, 65–73.
del CampoM, MollenhauerB, BertolottoA, EngelborghsS, HampelH, SimonsenAH, KapakiE, KruseN, Le BastardN, LehmannS, MolinuevoJL, ParnettiL, Perret-LiaudetA, Saez-ValeroJ, SakaE, UrbaniA, VanmechelenE, VerbeekM, VisserPJ, TeunissenC (2012) Recommendations to standardize preanalytical confounding factors in Alzheimer’s and Parkinson’s disease cerebrospinal fluid biomarkers: An update. Biomark Med6, 419–430.
18.
JohansonCE, DuncanJA 3rd, KlingePM, BrinkerT, StopaEG, SilverbergGD (2008) Multiplicity of cerebrospinal fluid functions: New challenges in health and disease. Cerebrospinal Fluid Res5, 10.
HodelJ, LebretA, PetitE, LeclercX, ZinsM, VignaudA, DecqP, RahmouniA (2013) Imaging of the entire cerebrospinal fluid volume with a multistation 3D SPACE MR sequence: Feasibility study in patients with hydrocephalus. Eur Radiol23, 1450–1458.
21.
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, 939–939.
22.
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (DSM). American Psychiatric Association, Washington, DC pp. 143–147.
23.
DuboisB, FeldmanHH, JacovaC, DeKoskyST, Barberger-GateauP, CummingsJ, DelacourteA, GalaskoD, GauthierS, JichaG (2007) Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS–ADRDA criteria. Lancet Neurol6, 734–746.
24.
DuboisB, FeldmanHH, JacovaC, CummingsJL, DeKoskyST, Barberger-GateauP, DelacourteA, FrisoniG, FoxNC, GalaskoD (2010) Revising the definition of Alzheimer’s disease: A new lexicon. Lancet Neurol9, 1118–1127.
RascovskyK, HodgesJR, KnopmanD, MendezMF, KramerJH, NeuhausJ, van SwietenJC, SeelaarH, DopperEG, OnyikeCU (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain134, 2456–2477.
29.
KemptonMJ, UnderwoodTSA, BruntonS, StyliosF, SchmechtigA, EttingerU, SmithMS, LovestoneS, CrumWR, FrangouS, WilliamsSCR, SimmonsA (2011) A comprehensive testing protocol for MRI neuroanatomical segmentation techniques: Evaluation of a novel lateral ventricle segmentation method. Neuroimage58, 1051–1059.
30.
MolinuevoJL, GispertJD, PujolJ, RojasS, LladoA, BalasaM, AntonellA, Sanchez-ValleR, RamiL (2012) A new approach to the Alzheimer’s disease diagnosis with biomarkers: Description of the AD-CSF-Index. Rev Neurol54, 513–522.
31.
MolinuevoJL, GispertJD, DuboisB, HenekaMT, LleoA, EngelborghsS, PujolJ, de SouzaLC, AlcoleaD, JessenF, SarazinM, LamariF, BalasaM, AntonellA, RamiL (2013) The AD-CSF-index discriminates Alzheimer’s disease patients from healthy controls: A validation study. J Alzheimers Dis36, 67–77.
32.
ScheltensP, LeysD, BarkhofF, HugloD, WeinsteinHC, VermerschP, KuiperM, SteinlingM, WoltersEC, ValkJ (1992) Atrophy of medial temporal lobes on MRI in “probable” Alzheimer’s disease and normal ageing: Diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry55, 967–972.
33.
JackCR, WisteHJ, KnopmanDS, VemuriP, MielkeMM, WeigandSD, SenjemML, GunterJL, LoweV, GreggBE, PankratzVS, PetersenRC (2014) Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration. Neurology82, 1605–1612.
34.
HennemanWJ, SluimerJD, BarnesJ, van der FlierWM, SluimerIC, FoxNC, ScheltensP, VrenkenH, BarkhofF (2009) Hippocampal atrophy rates in Alzheimer disease: Added value over whole brain volume measures. Neurology72, 999–1007.
35.
FaganAM, HeadD, ShahAR, MarcusD, MintunM, MorrisJC, HoltzmanDM (2009) Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol65, 176–183.
36.
SusantoTA, PuaEP, ZhouJ (2015) Cognition, brain atrophy, and cerebrospinal fluid biomarkers changes from preclinical to dementia stage of Alzheimer’s disease and the influence of apolipoproteine. J Alzheimers Dis45, 253–268.
37.
ChouYY, LeporeN, AvedissianC, MadsenSK, ParikshakN, HuaX, ShawLM, TrojanowskiJQ, WeinerMW, TogaAW, ThompsonPM (2009) Mapping correlations between ventricular expansion and CSF amyloid and tau biomarkers in 240 subjects with Alzheimer’s disease, mild cognitive impairment and elderly controls. Neuroimage46, 394–410.
38.
CarmichaelOT, KullerLH, LopezOL, ThompsonPM, DuttonRA, LuA, LeeSE, LeeJY, AizensteinHJ, MeltzerCC, LiuY, TogaAW, BeckerJT (2007) Cerebral ventricular changes associated with transitions between normal cognitive function, mild cognitive impairment, and dementia. Alzheimer Dis Assoc Disord21, 14–24.
39.
HanSD, GruhlJ, BeckettL, DodgeHH, StrickerNH, FariasS, MungasD (2012) Beta amyloid, tau, neuroimaging, and cognition: Sequence modeling of biomarkers for Alzheimer’s disease. Brain Imaging Behav6, 610–620.
40.
VemuriP, WisteHJ, WeigandSD, KnopmanDS, TrojanowskiJQ, ShawLM, BernsteinMA, AisenPS, WeinerM, PetersenRC, JackCRJr (2010) Serial MRI and CSF biomarkers in normal aging, MCI, and AD. Neurology75, 143–151.
