There is no consensus regarding the diagnostic value of cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers in cerebral amyloid angiopathy (CAA).
Objective:
To describe the CSF levels of Aβ42, Aβ40, total protein Tau, and phosphorylated-Tau (p-Tau) in a large series of probable CAA patients and to compare with AD patients in order to identify a specific pattern in CAA but also to look for correlations with the neuroimaging profile.
Methods:
We retrospectively included from 2 French centers probable CAA patients according to modified Boston criteria who underwent lumbar puncture (LP) with CSF AD biomarker quantifications. Two neurologists independently analyzed all MRI sequences. A logistic regression and Spearman’s correlation coefficient were used to identify correlation between MRI and CSF biomarkers in CAA.
Results:
We included 63 probable CAA and 27 AD patients. Among CAA 50.8% presented with decreased Aβ42 level associated with elevated p-Tau and/or Tau, 34.9% with isolated decreased Aβ42 level and 14.3% patients with normal Aβ42 level. Compared to AD, CAA showed lower levels of Tau (p = 0.008), p-Tau (p = 0.004), and Aβ40 (p = 0.001) but similar Aβ42 level (p = 0.07). No correlation between Aβ42 or Aβ40 levels and neuroimaging was found.
Conclusion:
CSF biomarkers may improve the accuracy of the modified Boston criteria with altered profile in 85% of the patients fulfilling revised Boston criteria for probable CAA. Aβ40 appears as an interesting selective biomarker in differential diagnosis.
SmithEE, GreenbergSM (2003) Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston criteria. Curr Atheroscler Rep5, 260–266.
4.
LinnJ, HalpinA, DemaerelP, RuhlandJ, GieseAD, DichgansM, Van BuchemMA, BruckmannH, GreenbergSM (2010) Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology74, 1346–1350.
5.
KnudsenKA, RosandJ, KarlukD, GreenbergSM (2001) Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria. Neurology56, 537–539.
6.
CharidimouA, JaunmuktaneZ, BaronJ-C, BurnellM, VarletP, PeetersA, XuerebJ, JagerR, BrandnerS, WerringDJ (2014) White matter perivascular spaces: An MRI marker in pathology-proven cerebral amyloid angiopathy?Neurology82, 57–62.
7.
GreenbergSM, CharidimouA (2018) Diagnosis of cerebral amyloid angiopathy: Evolution of the Boston criteria. Stroke49, 491–497.
8.
Martinez-RamirezS, RomeroJ-R, ShoamaneshA, McKeeAC, Van EttenE, Pontes-NetoO, MacklinEA, AyresA, AurielE, HimaliJJ, BeiserAS, DeCarliC, SteinTD, AlvarezVE, FroschMP, RosandJ, GreenbergSM, GurolME, SeshadriS, ViswanathanA (2015) Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage. Alzheimers Dement11, 1480–1488.
9.
CharidimouA, FriedrichJO, GreenbergSM, ViswanathanA (2018) Core cerebrospinal fluid biomarker profile in cerebral amyloid angiopathy: A meta-analysis. Neurology90, e754–e762.
10.
Mouton-LigerF, WallonD, TroussièreA-C, YatimiR, DumurgierJ, MagninE, de la SayetteV, DuronE, PhilippiN, BeaufilsE, GabelleA, CroisileB, RobertP, PasquierF, HannequinD, HugonJ, PaquetC (2014) Impact of cerebro-spinal fluid biomarkers of Alzheimer’s disease in clinical practice: A multicentric study. J Neurol261, 144–151.
11.
GabelleA, DumurgierJ, VercruysseO, PaquetC, BomboisS, LaplancheJ-L, Peoc’hK, SchraenS, BuéeL, PasquierF, HugonJ, TouchonJ, LehmannS (2013) Impact of the 2008-2012 French Alzheimer Plan on the use of cerebrospinal fluid biomarkers in research memory center: The PLM Study. J Alzheimers Dis34, 297–305.
12.
OlssonB, LautnerR, AndreassonU, ÖhrfeltA, PorteliusE, BjerkeM, HölttäM, RosénC, OlssonC, StrobelG, WuE, DakinK, PetzoldM, BlennowK, ZetterbergH (2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Lancet Neurol15, 673–684.
13.
BiscettiL, SalvadoriN, FarottiL, CataldiS, EusebiP, PaciottiS, ParnettiL (2019) The added value of Aβ42/Aβ40 in the CSF signature for routine diagnostics of Alzheimer’s disease. Clin Chim Acta494, 71–73.
14.
DumurgierJ, SchraenS, GabelleA, VercruysseO, BomboisS, LaplancheJ-L, Peoc’hK, SablonnièreB, KastanenkaKV, DelabyC, PasquierF, TouchonJ, HugonJ, PaquetC, LehmannS (2015) Cerebrospinal fluid amyloid-β 42/40 ratio in clinical setting of memory centers: A multicentric study. Alzheimers Res Ther7, 30.
15.
BoulouisG, CharidimouA, PasiM, RoongpiboonsopitD, XiongL, AurielE, van EttenES, Martinez-RamirezS, AyresA, VashkevichA, SchwabKM, RosandJ, GoldsteinJN, GurolME, GreenbergSM, ViswanathanA (2017) Hemorrhage recurrence risk factors in cerebral amyloid angiopathy: Comparative analysis of the overall small vessel disease severity score versus individual neuroimaging markers. J Neurol Sci380, 64–67.
16.
CharidimouA, JägerRH, PeetersA, VandermeerenY, LalouxP, BaronJ-C, WerringDJ (2014) White matter perivascular spaces are related to cortical superficial siderosis in cerebral amyloid angiopathy. Stroke45, 2930–2935.
17.
CatakC, ZeddeM, MalikR, JanowitzD, SoricV, SeegererA, KrebsA, DüringM, OpherkC, LinnJ, WollenweberFA (2019) Decreased CSF levels of ß-amyloid in patients with cortical superficial siderosis. Front Neurol10, 439.
18.
Girard-SteinL, DumurgierJ, PaquetC, ChabriatH (2020) Clinical features related to CSF level of amyloid Aβ42 and Aβ40 proteins in presence of lobar microbleeds. Rev Neurol (Paris)176, 864–867.
19.
Martínez-LizanaE, Carmona-IraguiM, AlcoleaD, Gómez-ChocoM, VilaplanaE, Sánchez-SaudinósMB, ClarimónJ, Hernández-GuillamonM, MunueraJ, GelpiE (2015) Cerebral amyloid angiopathy-related atraumatic convexal subarachnoid hemorrhage: An ARIA before the tsunami. J Cereb Blood Flow Metab35, 710–717.
AloscoML, TripodisY, FrittsNG, HeslegraveA, BaughCM, ConneelyS, MarianiM, MartinBM, FrankS, MezJ, SteinTD, CantuRC, McKeeAC, ShawLM, TrojanowskiJQ, BlennowK, ZetterbergH, SternRA (2018) Cerebrospinal fluid tau, Aβ, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration. Alzheimers Dement14, 1159–1170.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCR, 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.
LehmannS, DumurgierJ, SchraenS, WallonD, BlancF, MagninE, BomboisS, BousigesO, CampionD, CretinB (2014) A diagnostic scale for Alzheimer’s disease based on cerebrospinal fluid biomarker profiles. Alzheimers Res Ther6, 38.
29.
PuyL, PasiM, RodriguesM, van VeluwSJ, TsivgoulisG, ShoamaneshA, CordonnierC (2021) Cerebral microbleeds: From depiction to interpretation. J Neurol Neurosurg Psychiatry92, 598–607.
30.
CharidimouA, LinnJ, VernooijMW, OpherkC, AkoudadS, BaronJ-C, GreenbergSM, JägerHR, WerringDJ (2015) Cortical superficial siderosis: Detection and clinical significance in cerebral amyloid angiopathy and related conditions. Brain138, 2126–2139.
31.
ScheltensPH, 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.
32.
FazekasF, BarkhofF, WahlundLO, PantoniL, ErkinjunttiT, ScheltensP, SchmidtR (2002) CT and MRI rating of white matter lesions. Cerebrovasc Dis13, 31–36.
33.
HortJ, O’BrienJT, GainottiG, PirttilaT, PopescuBO, RektorovaI, SorbiS, ScheltensP, on behalf of the EFNS Scientist Panel on Dementia (2010) EFNS guidelines for the diagnosis and management of Alzheimer’s disease: EFNS guidelines for Alzheimer’s disease. Eur J Neurol17, 1236–1248.
34.
MonschAU, BulaC, HermelinkM, KressigRW, MartenssonB, MosimannU, MuriR, VogeliS, von GuntenA (2013) [Consensus 2012–diagnosis and treatment of patients with dementia in Switzerland]. Rev Med Suisse9, 838–847.
35.
AlonzoNC, HymanBT, RebeckGW, GreenbergSM (1998) Progression of cerebral amyloid angiopathy: Accumulation of amyloid-beta40 in affected vessels. J Neuropathol Exp Neurol57, 353–359.
36.
HampelH, GoernitzA, BuergerK (2003) Advances in the development of biomarkers for Alzheimer’s disease: From CSF total tau and Abeta(1-42) proteins to phosphorylated tau protein. Brain Res Bull61, 243–253.
37.
BrenowitzWD, NelsonPT, BesserLM, HellerKB, KukullWA (2015) Cerebral amyloid angiopathy and its co-occurrence with Alzheimer’s disease and other cerebrovascular neuropathologic changes. Neurobiol Aging36, 2702–2708.
38.
BoylePA, YuL, NagS, LeurgansS, WilsonRS, BennettDA, SchneiderJA (2015) Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology85, 1930–1936.
39.
GreenbergSM, SalmanRA-S, BiesselsGJ, van BuchemM, CordonnierC, LeeJ-M, MontanerJ, SchneiderJA, SmithEE, VernooijM, WerringDJ (2014) Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol13, 419–428.
40.
ThalDR, RübU, OrantesM, BraakH (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology58, 1791–1800.
41.
ThalDR, GhebremedhinE, OrantesM, WiestlerOD (2003) Vascular pathology in Alzheimer disease: Correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol62, 1287–1301.
42.
MäkeläM, PaetauA, PolvikoskiT, MyllykangasL, TanskanenM (2016) Capillary amyloid-β protein deposition in a population-based study (Vantaa 85+). J Alzheimers Dis49, 149–157.
43.
BugianiO, GiacconeG, RossiG, MangieriM, CapobiancoR, MorbinM, MazzoleniG, CupidiC, MarconG, GiovagnoliA (2010) Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP. Arch Neurol67, 987–995.
44.
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.
