Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results.
Objective:
We investigated the relationship between CSF amyloid-β protein (Aβ) and vascular pathological findings to elucidate the mechanisms of Aβ elimination from the brain in CAA-ri.
Methods:
We examined Aβ40 and Aβ42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer’s disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aβ40 and Aβ42 depositions on the leptomeningeal blood vessels (arteries, arterioles, and veins) using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri.
Results:
The median Aβ40 and Aβ42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aβ40, 6837 pg/ml; Aβ42, 324 pg/ml) and AD-CAA (Aβ40, 7669 pg/ml, p = 0.345; Aβ42, 355 pg/ml, p = 0.760). Aβ40 and Aβ42 levels in patients with post-treatment CAA-ri (Aβ40, 1770 pg/ml, p = 0.056; Aβ42, 167 pg/ml, p = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aβ40 and Aβ42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aβ-deposited blood vessels than postmortem CAA-ri cases (Aβ40, 20.8% versus 3.9%, p = 0.0714; Aβ42, 27.4% versus 2.0%, p = 0.0714, respectively).
Conclusion:
Lower levels of CSF Aβ40 and Aβ42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function.
AlbargothyNJ, JohnstonDA, MacGregor-SharpM, WellerRO, VermaA, HawkesCA, CarareRO (2018) Convective influx/glymphatic system: Tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathol136, 139–152.
3.
RasmussenMK, MestreH, NedergaardM (2018) The glymphatic pathway in neurological disorders. Lancet Neurol17, 1016–1024.
4.
WellerRO, DjuandaE, YowHY, CarareRO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol117, 1–14.
5.
ScoldingNJ, JosephF, KirbyPA, MazantiI, GrayF, MikolJ, EllisonD, HiltonDA, WilliamsTL, MacKenzieJM, XuerebJH, LoveS (2005) Abeta-related angiitis: Primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain128, 500–515.
PlotzkerAS, HensonRL, FaganAM, MorrisJC, DayGS (2021) Clinical and paraclinical measures associated with outcome in cerebral amyloid angiopathy with related inflammation. J Alzheimers Dis80, 133–142.
15.
BravoGÁ, CireraLS, TorrentàLR (2021) Clinical and radiological features of cerebral amyloid angiopathy-related inflammation. Neurol Sci42, 5353–5358.
16.
ChungKK, AndersonNE, HutchinsonD, SynekB, BarberPA (2011) Cerebral amyloid angiopathy related inflammation: Three case reports and a review. J Neurol Neurosurg Psychiatry82, 20–26.
17.
AurielE, CharidimouA, GurolME, NiJ, Van Etten ES, Martinez-RamirezS, BoulouisG, PiazzaF, DiFrancescoJC, FroschMP, Pontes-NetoOM, ShoamaneshA, ReijmerY, VashkevichA, AyresAM, SchwabKM, ViswanathanA, GreenbergSM (2016) Validation of clinicoradiological criteria for the diagnosis of cerebral amyloid angiopathy-related inflammation. JAMA Neurol73, 197–202.
18.
SakaiK, HayashiS, SanpeiK, YamadaM, TakahashiH (2012) Multiple cerebral infarcts with a few vasculitic lesions in the chronic stage of cerebral amyloid angiopathy-related inflammation. Neuropathology32, 551–556.
19.
KoikeY, OuchiH, SatoT, ShimboJ, SatoA, SasakiO, ShibuyaH, OkamotoK, KakitaA, IgarashiS (2013) . Amyloid beta-related angiitis: Brain lesions showing leptomeningeal gadolinium enhancement on MRI and characteristuc surgical pathologic features. Brain Nerve65, 693–697(in Japanse with English abstract).
20.
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, 939–44.
21.
KnudsenKA, RosandJ, KarlukD, GreenbergSM (2001) Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria. Neurology56, 537–539.
RobertsKF, ElbertDL, KastenTP, PattersonBW, SigurdsonWC, ConnorsRE, OvodV, MunsellLY, MawuenyegaKG, Miller-ThomasMM, MoranCJ, CrossDT,
3rdDerdeynCP, BatemanRJ (2014) Amyloid-β efflux from the central nervous system into the plasma. Ann Neurol76, 837–844.
26.
SperlingR, SallowayS, BrooksDJ, TampieriD, BarakosJ, FoxNC, RaskindM, SabbaghM, HonigLS, PorsteinssonAP, LieberburgI, ArrighiHM, MorrisKA, LuY, LiuE, GreggKM, BrashearHR, KinneyGG, BlackR, GrundmanM (2012) Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: A retrospective analysis. Lancet Neurol11, 241–249.
27.
SmithAJ, YaoX, DixJA, JinBJ, VerkmanAS (2017) Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. Elife6, e27679.
28.
AbbottNJ, PizzoME, PrestonJE, JanigroD, ThorneRG (2018) The role of brain barriers in fluid movement in the CNS: Is there a ‘glymphatic’ system? . Acta Neuropathol135, 387–407.
29.
McInteeFL, GiannoniP, BlaisS, SommerG, NeubertTA, RostagnoA, GhisoJ (2016) differential brain clearance and catabolism of monomeric and oligomeric Alzheimer’s Aβ protein. Front Aging Neurosci8, 223.
30.
NimmoJ, JohnstonDA, DodartJC, MacGregor-SharpMT, WellerRO, NicollJAR, VermaA, CarareRO (2020), Peri-arterial pathways for clearance of α-Synuclein and tau from the brain:, Imlications for the pathogenesis of dementias and for immunotherapy, Alzheimers Dement12, e12070.
31.
IshidaK, YamadaK, NishiyamaR, HashimotoT, NishidaI, AbeY, YasuiM, IwatsuboT (2022) Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med219, e20211275.
32.
Castillo-CarranzaDL, NilsonAN, Van Skike CE, JahrlingJB, PatelK, GarachP, GersonJE, SenguptaU, AbisambraJ, NelsonP, TroncosoJ, UngvariZ, GalvanV, KayedR (2017) Cerebral microvascular accumulation of tau oligomers in Alzheimer’s disease and related tauopathies. Aging Dis8, 257–266.
