The neuropeptide neurotensin (NT) has been linked to cardiometabolic disease. Cardiovascular risk factors are being recognized as risk factors for cognitive impairment.
Objective:
To examine the association of the stable precursor of NT, pro-neurotensin/neuromedin N (pro-NT/NMN), with incident cognitive impairment (ICI).
Methods:
We conducted a prospective nested case-control study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. In 2003-2007, REGARDS enrolled 30,239 Black and White adults aged ≥45 years. ICI was identified using a 3-test cognitive battery administered biannually. Baseline pro-NT/NMN was measured by immunoassay in 393 cases of ICI and 490 controls after 3.4 years follow up. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race, age, and sex differences were studied with stratified models and interaction testing.
Results:
Pro-NT/NMN was higher in Black participants and those with hypertension and diabetes. Women with a 4th versus 1st-quartile pro-NT/NMN had 2.28-fold increased odds of ICI (95% CI 1.08–4.78) after adjusting for risk factors and incident stroke. There was no association of higher pro-NT/NMN quartiles with ICI in the overall group or men. There were no race or age differences in associations.
Conclusion:
In this biracial population-based study, elevated systemic pro-NT/NMN was associated with more than doubled risk of ICI in women but not men. Others reported sex-specific associations in women for cardiovascular mortality and diabetes with higher pro-NT/NMN, supporting a role for future research on sex differences in the neurotensinergic system.
CarrawayR, LeemanSE (1973) The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem248, 6854–6861.
2.
ErnstA, HellmichS, BergmannA (2006) Proneurotensin 1-117, a stable neurotensin precursor fragment identified in human circulation. Peptides27, 1787–1793.
3.
OsadchiiOE (2015) Emerging role of neurotensin in regulation of the cardiovascular system. Eur J Pharmacol762, 184–192.
4.
CookeJH, PattersonM, PatelSR, SmithKL, GhateiMA, BloomSR, MurphyKG (2009) Peripheral and central administration of xenin and neurotensin suppress food intake in rodents. Obesity (Silver Spring)17, 1135–1143.
5.
LiJ, SongJ, ZaytsevaYY, LiuY, RychahouP, JiangK, StarrME, KimJT, HarrisJW, YiannikourisFB, KatzWS, NilssonPM, Orho-MelanderM, ChenJ, ZhuH, FahrenholzT, HigashiRM, GaoT, MorrisAJ, CassisLA, FanTW, WeissHL, DobnerPR, MelanderO, JiaJ, EversBM (2016) An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature533, 411–415.
6.
FriryC, FeliciangeliS, RichardF, KitabgiP, RovereC (2002) Production of recombinant large proneurotensin/neuromedin N-derived peptides and characterization of their binding and biological activity. Biochem Biophys Res Commun290, 1161–1168.
7.
BarchettaI, CiminiFA, LeonettiF, CapocciaD, Di CristofanoC, SilecchiaG, Orho-MelanderM, MelanderO, CavalloMG (2018) Increased plasma proneurotensin levels identify NAFLD in adults with and without type 2 diabetes. J Clin Endocrinol Metab103, 2253–2260.
8.
BarchettaI, CiminiFA, CapocciaD, BertocciniL, CeccarelliV, ChiappettaC, LeonettiF, Di CristofanoC, SilecchiaG, Orho-MelanderM, MelanderO, CavalloMG (2018) Neurotensin is a lipid-induced gastrointestinal peptide associated with visceral adipose tissue inflammation in obesity. Nutrients10, 526.
9.
MelanderO, MaiselAS, AlmgrenP, ManjerJ, BeltingM, HedbladB, EngstromG, KilgerU, NilssonP, BergmannA, Orho-MelanderM (2012) Plasma proneurotensin and incidence of diabetes, cardiovascular disease, breast cancer, and mortality. JAMA308, 1469–1475.
10.
FawadA, BergmannA, StruckJ, NilssonPM, Orho-MelanderM, MelanderO (2018) Proneurotensin predicts cardiovascular disease in an elderly population. J Clin Endocrinol Metab103, 1940–1947.
11.
JanuzziJLJr, LyassA, LiuY, GagginH, TrebnickA, MaiselAS, D’AgostinoRBSr, WangTJ, MassaroJ, VasanRS (2016) Circulating proneurotensin concentrations and cardiovascular disease events in the community: The framingham heart study. Arterioscler Thromb Vasc Biol36, 1692–1697.
12.
WetterstenN, CushmanM, HowardVJ, HartmannO, FilippatosG, BeriN, CloptonP, HowardG, SaffordMM, JuddSE, BergmannA, StruckJ, MaiselAS (2018) Usefulness of proneurotensin to predict cardiovascular and all-cause mortality in a united states population (from the reasons for geographic and racial differences in stroke study). Am J Cardiol122, 26–32.
13.
DanielsLB, MaiselAS (2015) Cardiovascular biomarkers and sex: The case for women. Nat Rev Cardiol12, 588–596.
14.
SaverJL, CushmanM (2018) Striving for ideal cardiovascular and brain health: It is never too early or too late. JAMA320, 645–647.
15.
de Toledo Ferraz AlvesTC, FerreiraLK, WajngartenM, BusattoGF (2010) Cardiac disorders as risk factors for Alzheimer’s disease. J Alzheimers Dis20, 749–763.
16.
AbeteP, Della-MorteD, GargiuloG, BasileC, LangellottoA, GaliziaG, TestaG, CanonicoV, BonaduceD, CacciatoreF (2014) Cognitive impairment and cardiovascular diseases in the elderly. A heart-brain continuum hypothesis. Ageing Res Rev18, 41–52.
17.
MuqtadarH, TestaiFD, GorelickPB (2012) The dementia of cardiac disease. Curr Cardiol Rep14, 732–740.
18.
FerreiraLK, Tamashiro-DuranJH, SquarzoniP, DuranFL, AlvesTC, BuchpiguelCA, BusattoGF (2014) The link between cardiovascular risk, Alzheimer’s disease, and mild cognitive impairment: Support from recent functional neuroimaging studies. Braz J Psychiatry36, 344–357.
19.
YeBS, SeoSW, KimJH, KimGH, ChoH, NohY, KimHJ, YoonCW, WooSY, KimSH (2015) Effects of amyloid and vascular markers on cognitive decline in subcortical vascular dementia. Neurology85, 1687–1693.
KalariaRN (2012) Cerebrovascular disease and mechanisms of cognitive impairment: Evidence from clinicopathological studies in humans. Stroke43, 2526–2534.
22.
GillettSR, ThackerEL, LetterAJ, McClureLA, WadleyVG, UnverzagtFW, KisselaBM, KennedyRE, GlasserSP, LevineDA, CushmanM (2015) Correlates of incident cognitive impairment in the reasons for geographic and racial differences in stroke (REGARDS) Study. Clin Neuropsychol29, 466–486.
23.
CushmanM, CallasPW, McClureLA, UnverzagtFW, HowardVJ, GillettSR, ThackerEL, WadleyVG (2016) N-terminal pro-B-type natriuretic peptide and risk of future cognitive impairment in the REGARDS cohort. J Alzheimers Dis54, 497–503.
CipolliniV, TroiliF, GiubileiF (2019) Emerging biomarkers in vascular cognitive impairment and dementia: From pathophysiological pathways to clinical application. Int J Mol Sci20, 2821.
26.
HowardVJ, CushmanM, PulleyL, GomezCR, GoRC, PrineasRJ, GrahamA, MoyCS, HowardG (2005) The reasons for geographic and racial differences in stroke study: Objectives and design. Neuroepidemiology25, 135–143.
27.
CallahanCM, UnverzagtFW, HuiSL, PerkinsAJ, HendrieHC (2002) Six-item screener to identify cognitive impairment among potential subjects for clinical research. Med Care40, 771–781.
28.
MomsJ, HeymanA, MohsR, HughesJ, van BelleG, FillenbaumG, MellitsE, ClarkC (1989) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part I. Clinical and neuropsychological assesment of Alzheimer’s disease. Neurology39, 1159.
29.
RosenWG (1980) Verbal fluency in aging and dementia. J Clin Exp Neuropsychol2, 135–146.
30.
AlexanderKS, ZakaiNA, GillettS, McClureLA, WadleyV, UnverzagtF, CushmanM (2014) ABO blood type, factor VIII, and incident cognitive impairment in the REGARDS cohort. Neurology83, 1271–1276.
31.
HowardG, AndersonR, JohnsonNJ, SorlieP, RussellG, HowardVJ (1997) Evaluation of social status as a contributing factor to the stroke belt region of the United States. Stroke28, 936–940.
32.
WheltonPK, CareyRM, AronowWS, CaseyDEJr, CollinsKJ, Dennison HimmelfarbC, DePalmaSM, GiddingS, JamersonKA, JonesDW, MacLaughlinEJ, MuntnerP, OvbiageleB, SmithSCJr, SpencerCC, StaffordRS, TalerSJ, ThomasRJ, WilliamsKASr., WilliamsonJD, WrightJTJr (2018) 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension71, e13–e115.
33.
CasalePN, DevereuxRB, KligfieldP, EisenbergRR, MillerDH, ChaudharyBS, PhillipsMC (1985) Electrocardiographic detection of left ventricular hypertrophy: Development and prospective validation of improved criteria. J Am Coll Cardiol6, 572–580.
34.
SolimanEZ, HowardG, PrineasRJ, McClureLA, HowardVJ (2010) Calculating Cornell voltage from nonstandard chest electrode recording site in the Reasons for Geographic And Racial Differences in Stroke study. J Electrocardiol43, 209–214.
35.
HowardVJ, KleindorferDO, JuddSE, McClureLA, SaffordMM, RhodesJD, CushmanM, MoyCS, SolimanEZ, KisselaBM, HowardG (2011) Disparities in stroke incidence contributing to disparities in stroke mortality. Ann Neurol69, 619–627.
36.
SaffordMM, BrownTM, MuntnerPM, DurantRW, GlasserS, HalanychJH, ShikanyJM, PrineasRJ, SamdarshiT, BittnerVA (2012) Association of race and sex with risk of incident acute coronary heart disease events. JAMA308, 1768–1774.
37.
TracyR, BovillE, StumpD, LinT, GomolT, CollenD, MannK (1988) Reduction of in vitro artifact during blood collection in TIMI II. Blood78, 376.
38.
KochW, EhrenhaftA, GriesserK, PfeuferA, MüllerJ, SchömigA, KastratiA (2002) TaqMan systems for genotyping of disease-related polymorphisms present in the gene encoding apolipoprotein E. Clin Chem Lab Med40, 1123–1131.
39.
StephensM, SmithNJ, DonnellyP (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet68, 978–989.
40.
D’AgostinoRB, WolfPA, BelangerAJ, KannelWB (1994) Stroke risk profile: Adjustment for antihypertensive medication. The Framingham Study. Stroke25, 40–43.
41.
DupouyS, Viardot-FoucaultV, AlifanoM, SouazeF, Plu-BureauG, ChaouatM, LavaurA, HugolD, GespachC, GompelA, ForgezP (2009) The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression. PLoS One4, e4223.
42.
AlexanderMJ (1993) Estrogen-regulated synthesis of neurotensin in neurosecretory cells of the hypothalamic arcuate nucleus in the female rat. Endocrinology133, 1809–1816.
