The anti-aging protein, α-Klotho, may be involved in cognitive decline and has potential as a surrogate marker that reflects dementia. However, the role of α-Klotho in the brain has not been sufficiently investigated.
Objective:
Here, we investigated the association between α-Klotho and cognitive decline that is associated with cerebral deep white matter lesions (DWMLs).
Methods:
Two hundred-eighty participants (187 males and 93 females, mean age: 70.8 years old) were evaluated for DWMLs, and the Fazekas scale (Grade) was assessed following brain magnetic resonance imaging. A questionnaire concerning lifestyle and neuropsychological tests was administered, and their associations with the blood α-Klotho level were retrospectively investigated.
Results:
The α-Klotho level was 685.1 pg/mL in Grade 0 (68 subjects), 634.1 in G1 (134), 596.0 in G2 (62), and 571.6 in G3 (16), showing that the level significantly decreased with advanced grades. Significant correlations were noted between the α-Klotho level and higher brain function tests including the Mini-Mental State Examination and word fluency tests (p < 0.05). When a 90th percentile value of the level in the G0 group (400 pg/mL) or lower was defined as a low α-Klotho level, the odds ratio of the high-grade G3 group was 2.9 (95% confidence interval: 1.4–7.8) (after correction for age, sex, hypertension, and chronic kidney disease), which was significant.
Conclusion:
A reduced blood α-Klotho level was correlated with grading of cerebral DWMLs and was accompanied by cognitive decline as an independent risk factor. The α-Klotho level may serve as a useful clinical index of vascular cognitive impairment.
SekitaA, NinomiyaT, TanizakiY, DoiY, HataJ, YonemotoK, ArimaH, SasakiK, IidaM, IwakiT, KanbaS, KiyoharaY (2010) Trends in prevalence of Alzheimer’s disease and vascular dementia in a Japanese community: The Hisayama Study. Acta Psychiatr Scand122, 319–325.
2.
SchmidtR, RopeleS, EnzingerC, PetrovicK, SmithS, SchmidtH, MatthewsPM, FazekasF (2005) White matter lesion progression, brain atrophy, and cognitive decline: The Austrian stroke prevention study. Ann Neurol58, 610–616.
3.
GouwAA, van der FlierWM, FazekasF, van StraatenEC, PantoniL, PoggesiA, InzitariD, ErkinjunttiT, WahlundLO, WaldemarG, SchmidtR, ScheltensP, BarkhofF (2008) Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: The Leukoaraiosis and Disability study. Stroke39, 1414–1420.
4.
EnzingerC, FazekasF, RopeleS, SchmidtR (2007) Progression of cerebral white matter lesions –clinical and radiological considerations. J Neurol Sci257, 5–10.
5.
KuriyamaN, MizunoT, OhshimaY, YamadaK, OzakiE, ShigetaM, MitaniS, KondoM, MatsumotoS, TakedaK, NakagawaM, WatanabeY (2013) Intracranial deep white matter lesions (DWLs) are associated with chronic kidney disease (CKD) and cognitive impairment: A 5-year follow-up magnetic resonance imaging (MRI) study. Arch Gerontol Geriatr56, 55–60.
6.
TorresRV, EliasMF, SeligerS, DaveyA, RobbinsMA (2017) Risk for cognitive impairment across 22 measures of cognitive ability in early-stage chronic kidney disease. Nephrol Dial Transplant32, 299–306.
7.
DaveyA, EliasMF, RobbinsMA, SeligerSL, DoreGA (2013) Decline in renal functioning is associated with longitudinal decline in global cognitive functioning, abstract reasoning and verbal memory. Nephrol Dial Transplant28, 1810–1819.
8.
SakanH, NakataniK, AsaiO, ImuraA, TanakaT, YoshimotoS, IwamotoN, KurumataniN, IwanoM, NabeshimaY, KonishiN, SaitoY (2014) Reduced renal alpha-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism. PLoS One9, e86301.
9.
LiSA, WatanabeM, YamadaH, NagaiA, KinutaM, TakeiK (2004) Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct29, 91–99.
10.
GermanDC, KhobahyI, PastorJ, KuroOM, LiuX (2012) Nuclear localization of Klotho in brain: An anti-agingrotein. Neurobiol Aging33, 1483.
11.
ZeldichE, ChenCD, ColvinTA, Bove-FendersonEA, LiangJ, Tucker ZhouTB, HarrisDA, AbrahamCR (2014) The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem289, 24700–24715.
12.
KelesN, CaliskanM, DoganB, KelesNN, KalcikM, AksuF, KostekO, AungSM, IsbilenB, OguzA (2015) Low serum level of Klotho is an early predictor of atherosclerosis. Tohoku J Exp Med237, 17–23.
13.
KitagawaM, SugiyamaH, MorinagaH, InoueT, TakiueK, OgawaA, YamanariT, KikumotoY, UchidaHA, KitamuraS, MaeshimaY, NakamuraK, ItoH, MakinoH (2013) A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One8, e56695.
14.
KuriyamaN, MizunoT, KitaM, YamadaK, OzakiE, MatsumotoS, TakadaA, WatanabeA, KasaiT, NagakaneY, MitaniS, MatsuiD, WatanabeI, TakedaK, NakagawaM, WatanabeY (2014) TGF-beta1 is associated with the progression of intracranial deep white matter lesions: A pilot study with 5 years of magnetic resonance imaging follow-up. Neurol Res36, 47–52.
15.
OhshimaY, MizunoT, YamadaK, MatsumotoS, NagakaneY, KondoM, KuriyamaN, MiyazakiT, TakedaK, NishimuraT, NakagawaM, OzasaK, WatanabeY (2013) Low vitamin and carotenoid levels are related to cerebral white matter lesions. J Nutr Health Aging17, 456–460.
16.
InkerLA, AstorBC, FoxCH, IsakovaT, LashJP, PeraltaCA, Kurella TamuraM, FeldmanHI (2014) KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis63, 713–735.
17.
MatsuoS, ImaiE, HorioM, YasudaY, TomitaK, NittaK, YamagataK, TominoY, YokoyamaH, HishidaA (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis53, 982–992.
18.
LaurentS, BoutouyrieP, AsmarR, GautierI, LalouxB, GuizeL, DucimetiereP, BenetosA (2001) Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension37, 1236–1241.
19.
YamazakiY, ImuraA, UrakawaI, ShimadaT, MurakamiJ, AonoY, HasegawaH, YamashitaT, NakataniK, SaitoY, OkamotoN, KurumataniN, NambaN, KitaokaT, OzonoK, SakaiT, HatayaH, IchikawaS, ImelEA, EconsMJ, NabeshimaY (2010) Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun398, 513–518.
20.
FazekasF, ChawlukJB, AlaviA, HurtigHI, ZimmermanRA (1987) MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol149, 351–356.
21.
GordonBA, NajmiS, HsuP, RoeCM, MorrisJC, BenzingerTL (2015) The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia. Neuroimage Clinical8, 246–252.
22.
de GrootJC, de LeeuwFE, OudkerkM, van GijnJ, HofmanA, JollesJ, BretelerMM (2000) Cerebral white matter lesions and cognitive function: The Rotterdam Scan Study. Ann Neurol47, 145–151.
23.
FolsteinMF, FolsteinSE, McHughPR. “Mini-mental state” (1975) A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
24.
HenryJD, CrawfordJR, PhillipsLH (2004) Verbal fluency performance in dementia of the Alzheimer’s type: A meta-analysis. Neuropsychologia42, 1212–1222.
25.
CerhanJH, IvnikRJ, SmithGE, TangalosEC, PetersenRC, BoeveBF (2002) Diagnostic utility of letter fluency, category fluency, and fluency difference scores in Alzheimer’s disease. Clin Neuropsychol16, 35–42.
26.
DavidJP, FerratE, ParisotJ, NagaH, LakrounS, MenasriaF, SaddedineS, NatellaPA, PaillaudE, FromentinI, Bastuji-GarinS (2016) White matter lesions: Prevalence and clinical phenotype in asymptomatic individuals aged ≥50 years. Dement Geriatr Cogn Disord42, 159–168.
27.
FernandoMS, O’BrienJT, PerryRH, EnglishP, ForsterG, McMeekinW, SladeJY, GolkharA, MatthewsFE, BarberR, KalariaRN, IncePG (2004) Comparison of the pathology of cerebral white matter with post-mortem magnetic resonance imaging (MRI) in the elderly brain. Neuropathol Appl Neurobiol30, 385–395.
28.
KurosuH, YamamotoM, ClarkJD, PastorJV, NandiA, GurnaniP, McGuinnessOP, ChikudaH, YamaguchiM, KawaguchiH, ShimomuraI, TakayamaY, HerzJ, KahnCR, RosenblattKP, Kuro-oM (2005) Suppression of aging in mice by the hormone Klotho. Science309, 1829–1833.
OgawaY, KurosuH, YamamotoM, NandiA, RosenblattKP, GoetzR, EliseenkovaAV, MohammadiM, Kuro-OM (2007) BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci U S A104, 7432–7437.
31.
NakanishiK, NishidaM, HaradaM, OhamaT, KawadaN, MurakamiM, MoriyamaT, Yamauchi-TakiharaK (2015) Klotho-related molecules upregulated by smoking habit in apparently healthy men: A cross-sectional study. Sci Rep5, 14230.
32.
HoriS, MiyakeM, OnishiS, TatsumiY, MorizawaY, NakaiY, AnaiS, TanakaN, FujimotoK (2016) Clinical significance of alpha and beta Klotho in urothelial carcinoma of the bladder. Oncol Rep36, 2117–2125.
33.
KandaE, AiM, OkazakiM, YoshidaM, MaedaY (2016) Association of high-density lipoprotein subclasses with chronic kidney disease progression, atherosclerosis, and Klotho. PLoS One11, e0166459.
34.
LittlejohnsTJ, HenleyWE, LangIA, AnnweilerC, BeauchetO, ChavesPH, FriedL, KestenbaumBR, KullerLH, LangaKM, LopezOL, KosK, SoniM, LlewellynDJ (2014) Vitamin D and the risk of dementia and Alzheimer disease. Neurology83, 920–928.
35.
SaitoY, YamagishiT, NakamuraT, OhyamaY, AizawaH, SugaT, MatsumuraY, MasudaH, KurabayashiM, Kuro-oM, NabeshimaY, NagaiR (1998) Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun248, 324–329.
36.
Kuro-oM, MatsumuraY, AizawaH, KawaguchiH, SugaT, UtsugiT, OhyamaY, KurabayashiM, KanameT, KumeE, IwasakiH, IidaA, Shiraki-IidaT, NishikawaS, NagaiR, NabeshimaYI (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature390, 45–51.
37.
AkimotoT, YoshizawaH, WatanabeY, NumataA, YamazakiT, TakeshimaE, IwazuK, KomadaT, OtaniN, MorishitaY, ItoC, ShiizakiK, AndoY, MutoS, Kuro-oM, KusanoE (2012) Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease. BMC Nephrol13, 155.
38.
HuMC, ShiM, ZhangJ, PastorJ, NakataniT, LanskeB, RazzaqueMS, RosenblattKP, BaumMG, Kuro-oM, MoeOW (2010) Klotho: A novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J24, 3438–3450.
39.
SiahanidouT, GaratziotiM, LazaropoulouC, KourlabaG, PapassotiriouI, KinoT, ImuraA, NabeshimaY, Chrousos (2012) Plasma soluble alpha-klotho protein levels in premature and term neonates: Correlations with growth and metabolic parameters. Eur J Endocrinol167, 433–440.
40.
LauWL, LeafEM, HuMC, TakenoMM, Kuro-oM, MoeOW, GiachelliCM (2012) Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int82, 1261–1270.
MassoA, SanchezA, Gimenez-LlortL, LizcanoJM, CaneteM, GarciaB, Torres-ListaV, PuigM, BoschA, ChillonM (2015) Secreted and transmembrane alphaKlotho isoforms have different spatio-temporal profiles in the brain during aging and Alzheimer’s disease progression. PLoS One10, e0143623.
43.
YoonHE, LimSW, PiaoSG, SongJH, KimJ, YangCW (2012) Statin upregulates the expression of klotho, an anti-aging gene, in experimental cyclosporine nephropathy. Nephron Exp Nephrol120, 123–133.
44.
RubinekT, WolfI, Modan-MosesD (2016) The longevity hormone Klotho is a new player in the interacion of the growth hormone/insulin-like growth factor 1 axis. Pediatr Endocrinol Rev14, 9–18.
45.
PodhornaJ1, KrahnkeT2, ShearM3, HarrisonJE4; Alzheimer’s Disease Neuroimaging Initiative (2016) Alzheimer’s Disease Assessment Scale-Cognitive subscale variants in mild cognitive impairment and mild Alzheimer’s disease: Change over time and the effect of enrichment strategies. Alzheimers Res Ther8, 8.
