The olfactory system is affected early in Alzheimer’s disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI). Olfactory training is effective for improving olfactory and cognitive function by stimulating the olfactory pathway, but its effect on patients with MCI remains unclear.
Objective:
The aim of this randomized, prospective, controlled, blinded study was to assess whether a 4-month period of olfactory training (frequent short-term sniffing various odors) may have an effect on olfactory function, cognitive function, and morphology of medial temporal lobe (MTL) subregions and olfactory bulb in MCI patients.
Methods:
A total of thirty-seven MCI patients were randomly assigned to the training group or a placebo group, which were performed twice a day for 4 months. Olfactory assessments, cognitive tests and magnetic resonance imaging were performed at the baseline and follow-up period.
Results:
After the training, there was an increase in odor discrimination, and increased cortical thickness of bilateral hippocampus (CA23DG and CA1) and mean MTL. Additionally, the change of olfactory score was positively associated with change of volume of olfactory bulb and hippocampus; the change of global cognition was positively associated with change of cortical thickness of hippocampus, entorhinal cortex and mean MTL; the change of cortical thickness of entorhinal cortex was positively associated with change of executive function.
Conclusion:
Olfactory training was associated with an increase in cortical thickness of the hippocampus but not olfactory bulb volume in patients with MCI. Olfactory training may serve as an early intervention of preventing hippocampal atrophy.
ChenB, ZhongX, MaiN, PengQ, WuZ, OuyangC, ZhangW, LiangW, WuY, LiuS, ChenL, NingY (2018) Cognitive impairment and structural abnormalities in late life depression with olfactory identification impairment: An Alzheimer’s disease-like pattern. Int J Neuropsychopharmacol21, 640–648.
9.
ChenB, WangQ, ZhongX, MaiN, ZhangM, ZhouH, HaehnerA, ChenX, WuZ, AuberLA, RaoD, LiuW, ZhengJ, LinL, LiN, ChenS, ChenB, HummelT, NingY (2022) Structural and functional abnormalities of olfactory-related regions in subjective cognitive decline, mild cognitive impairment and Alzheimer’s disease. Int J Neuropsychopharmacol25, 361–374.
10.
DevanandDP, LiuX, TabertMH, PradhabanG, CuasayK, BellK, de LeonMJ, DotyRL, SternY, PeltonGH (2008) Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer’s disease. Biol Psychiatry64, 871–879.
11.
CroyI, SymmankA, SchellongJ, HummelC, GerberJ, JoraschkyP, HummelT (2014) Olfaction as a marker for depression in humans. J Affect Disord160, 80–86.
12.
ChenB, ZhongX, ZhangM, MaiN, WuZ, ChenX, PengQ, ZhouH, WangQ, YangM, ZhangS, AuberLA, CroyI, HummelT, NingY (2021) The additive effect of late-life depression and olfactory dysfunction on the risk of dementia was mediated by hypersynchronization of the hippocampus/fusiform gyrus. Transl Psychiatry11, 172.
13.
HummelT, RissomK, RedenJ, HahnerA, WeidenbecherM, HuttenbrinkKB (2009) Effects of olfactory training in patients with olfactory loss. Laryngoscope119, 496–499.
14.
SorokowskaA, DrechslerE, KarwowskiM, HummelT (2017) Effects of olfactory training: A meta-analysis. Rhinology55, 17–26.
15.
PetersenRC, RobertsRO, KnopmanDS, GedaYE, ChaRH, PankratzVS, BoeveBF, TangalosEG, IvnikRJ, RoccaWA (2010) Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging. Neurology75, 889–897.
16.
HaehnerA, ToschC, WolzM, KlingelhoeferL, FauserM, StorchA, ReichmannH, HummelT (2013) Olfactory training in patients with Parkinson’s disease. PLoS One8, e61680.
17.
Birte-AntinaW, IlonaC, AntjeH, ThomasH (2018) Olfactory training with older people. Int J Geriatr Psychiatry33, 212–220.
18.
HaehnerA, RodewaldA, GerberJC, HummelT (2008) Correlation of olfactory function with changes in the volume of the human olfactory bulb. Arch Otolaryngol Head Neck Surg134, 621–624.
19.
MahmutMK, MuschM, HanP, AbolmaaliN, HummelT (2020) The effect of olfactory training on olfactory bulb volumes in patients with idiopathic olfactory loss. Rhinology58, 410–412.
20.
SeubertJ, FreiherrJ, FrasnelliJ, HummelT, LundströmJN (2013) Orbitofrontal cortex and olfactory bulb volume predict distinct aspects of olfactory performance in healthy subjects. Cereb Cortex23, 2448–2456.
21.
BuschhüterD, SmitkaM, PuschmannS, GerberJC, WittM, AbolmaaliND, HummelT (2008) Correlation between olfactory bulb volume and olfactory function. Neuroimage42, 498–502.
22.
PetersenRC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med256, 183–194.
23.
HummelT, SekingerB, WolfSR, PauliE, KobalG (1997) ‘Sniffin’ sticks’: Olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses22, 39–52.
24.
FolsteinMF, FolsteinSE, McHughPR (1975) “Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
25.
FillenbaumGG, van BelleG, MorrisJC, MohsRC, MirraSS, DavisPC, TariotPN, SilvermanJM, ClarkCM, Welsh-BohmerKA, HeymanA (2008) Consortium to Establish a Registry for Alzheimer’s Disease (CERAD): The first twenty years. Alzheimers Dement4, 96–109.
26.
PrigatanoGP (1978) Wechsler Memory Scale: A selective review of the literature. J Clin Psychol34, 816–832.
27.
GordonNG (1972) The Trail Making Test in neuropsychological diagnosis. J Clin Psychol28, 167–169.
28.
KaplanE, GoodglassH, WeintraubS, SegalO (1983) The Boston naming test. Lea & Febiger, Philadelphia.
29.
PékG, FülöpT, Zs-NagyI (1989) Gerontopsychological studies using NAI (’Nurnberger Alters-Inventar’) on patients with organic psychosyndrome (DSM III, Category 1) treated with centrophenoxine in a double blind, comparative, randomized clinical trial. Arch Gerontol Geriatr9, 17–30.
30.
YousemDM, GeckleRJ, BilkerWB, DotyRL (1998) Olfactory bulb and tract and temporal lobe volumes. Normative data across decades. Ann N Y Acad Sci855, 546–555.
31.
YousemDM, GeckleRJ, DotyRL, BilkerWB (1997) Reproducibility and reliability of volumetric measurements of olfactory eloquent structures. Acad Radiol4, 264–269.
32.
DonixM, BurggrenAC, SuthanaNA, SiddarthP, EkstromAD, KrupaAK, JonesM, Martin-HarrisL, ErcoliLM, MillerKJ, SmallGW, BookheimerSY (2010) Family history of Alzheimer’s disease and hippocampal structure in healthy people. Am J Psychiatry167, 1399–1406.
33.
ZeinehMM, EngelSA, BookheimerSY (2000) Application of cortical unfolding techniques to functional MRI of the human hippocampal region. Neuroimage11, 668–683.
34.
ZeinehMM, EngelSA, ThompsonPM, BookheimerSY (2003) Dynamics of the hippocampus during encoding and retrieval of face-name pairs. Science299, 577–580.
35.
AmaralDG, InsaustiR (1990) Hippocampal formation. The Human Nervous System, Paxinos G, ed. Academic Press, San Diego, pp. 711–755.
36.
ShorvonS (2000) The human hippocampus. Functional anatomy, vascularization and serial sections with MRI. J Anat197 (Pt 3), 513–518.
37.
SahayA, WilsonDA, HenR (2011) Pattern separation: A common function for new neurons in hippocampus and olfactory bulb. Neuron70, 582–588.
38.
LiY, XuJ, LiuY, ZhuJ, LiuN, ZengW, HuangN, RaschMJ, JiangH, GuX, LiX, LuoM, LiC, TengJ, ChenJ, ZengS, LinL, ZhangX (2017) A distinct entorhinal cortex to hippocampal CA1 direct circuit for olfactory associative learning. Nat Neurosci20, 559–570.
39.
Montero-CrespoM, DomínguezM, Alonso-NanclaresL, DefelipeJ, Blazquez-LlorcaL (2020) Three-dimensional analysis of synaptic organization in the hippocampal CA1 field in Alzheimer’s disease. Brain144, 553–573.
40.
PiniL, PievaniM, BocchettaM, AltomareD, BoscoP, CavedoE, GalluzziS, MarizzoniM, FrisoniGB (2016) Brain atrophy in Alzheimer’s disease and aging. Ageing Res Rev30, 25–48.
41.
MankinEA, FriedI (2020) Modulation of human memory by deep brain stimulation of the entorhinal-hippocampal circuitry. Neuron106, 218–235.
42.
SmalheiserNR, LugliG, LenonAL, DavisJM, TorvikVI, LarsonJ (2010) Olfactory discrimination training up-regulates and reorganizes expression of microRNAs in adult mouse hippocampus. ASN Neuro2, e00028.
43.
CookHT, LugliG, LarsonJ, ThimmapuramJ, SmalheiserNR (2011) Mitochondrial small RNAs that are up-regulated in hippocampus during olfactory discrimination training in mice. Mitochondrion11, 994–995.
44.
SmalheiserNR, LugliG, ThimmapuramJ, CookEH, LarsonJ (2011) Endogenous siRNAs and noncoding RNA-derived small RNAs are expressed in adult mouse hippocampus and are up-regulated in olfactory discrimination training. RNA17, 166–181.
45.
KimBY, ParkJY, KimEJ, KimBG, KimSW, KimSW (2019) The neuroplastic effect of olfactory training to the recovery of olfactory system in mouse model. Int Forum Allergy Rhinol9, 715–723.
46.
KimBY, ParkJ, KimE, KimB (2020) Olfactory Ensheathing cells mediate neuroplastic mechanisms after olfactory training in mouse model. Am J Rhinol Allergy34, 217–229.
47.
RochefortC, GheusiG, VincentJD, LledoPM (2002) Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J Neurosci22, 2679–2689.
HeckDH, KozmaR, KayLM (2019) The rhythm of memory: How breathing shapes memory function. J Neurophysiol122, 563–571.
55.
Al AïnS, PouponD, HétuS, MercierN, SteffenerJ, FrasnelliJ (2019) Smell training improves olfactory function and alters brain structure. Neuroimage189, 45–54.
56.
Takehara-NishiuchiK (2014) Entorhinal cortex and consolidated memory. Neurosci Res84, 27–33.
57.
WangX, LiuEJ, LiuQ, LiSH, LiT, ZhouQZ, LiuYC, ZhangH, WangJZ (2020) Tau acetylation in entorhinal cortex induces its chronic hippocampal propagation and cognitive deficits in mice. J Alzheimers Dis77, 241–255.
58.
NegoiasS, PietschK, HummelT (2017) Changes in olfactory bulb volume following lateralized olfactory training. Brain Imaging Behav11, 998–1005.
59.
JobinB, BollerB, FrasnelliJ (2021) Volumetry of olfactory structures in mild cognitive impairment and Alzheimer’s disease: A systematic review and a meta-analysis. Brain Sci11, 1010.
