Olfactory Dysfunction Correlates with Amyloid-β Burden in an Alzheimer's Disease Mouse Model (original) (raw)
Related papers
2020
Background: Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although the causes of damage have been proposed in every olfactory system including olfactory epithelium, olfactory bulb and olfactory cortex, the main causes of AD- related hyposmia are largely unknown. Methods: We here focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also histologically confirmed the pathological changes in three-month-old 5xFAD mouse models which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of anatomical plane. Results: We observed the odorant group, which 5xFAD mouse could not detect, also neither did physiologically activate the OSNs that propagate to the ventral olfactory bulb. Interestingly, the amount of accumulated ...
Amyloid Beta Inhibits Olfactory Bulb Activity and the Ability to Smell
Early olfactory dysfunction has been consistently reported in both Alzheimer's disease (AD) and in transgenic mice that reproduce some features of this disease. In AD transgenic mice, alteration in olfaction has been associated with increased levels of soluble amyloid beta protein (Aβ) as well as with alterations in the oscillatory network activity recorded in the olfactory bulb (OB) and in the piriform cortex. However, since AD is a multifactorial disease and transgenic mice suffer a variety of adaptive changes, it is still unknown if soluble Aβ, by itself, is responsible for OB dysfunction both at electrophysiological and behavioral levels. Thus, here we tested whether or not Aβ directly affects OB network activity in vitro in slices obtained from mice and rats and if it affects olfactory ability in these rodents. Our results show that Aβ decreases, in a concentration-and time-dependent manner, the network activity of OB slices at clinically relevant concentrations (low nM) and in a reversible manner. Moreover, we found that intrabulbar injection of Aβ decreases the olfactory ability of rodents two weeks after application, an effect that is not related to alterations in motor performance or motivation to seek food and that correlates with the presence of Aβ deposits. Our results indicate that Aβ disrupts, at clinically relevant concentrations, the network activity of the OB in vitro and can trigger a disruption in olfaction. These findings open the possibility of exploring the cellular mechanisms involved in early pathological AD as an approach to reduce or halt its progress.
Functional representation of olfactory impairment in early Alzheimer's disease
Journal of Alzheimer's disease : JAD, 2010
We used [18F]fluorodeoxyglucose (FDG) PET analysis to determine performance in different olfactory domains of patients with early AD compared to cognitively healthy subjects, and to map the functional metabolic representation of olfactory impairment in the patient sample. A cohort of patients with early AD (n=24), consisting of 6 subjects with incipient AD and 18 subjects with mild AD, and a control group of 28 age-matched non-demented individuals were assembled. Patients and controls were tested for olfactory performance using the "Sniffin' Sticks" test battery [odor identification (ID), discrimination (DIS) and threshold (THR)], while patients additionally underwent resting state FDG-PET. Voxel-wise PET results in the patients were correlated with olfaction scores using the general linear model in SPM5. Patients with early AD showed significantly reduced function in all three olfactory subdomains compared to controls. After controlling for effects due to patients'...
Olfactory Impairment in Presymptomatic Alzheimer's Disease
Annals of The New York Academy of Sciences, 2009
Alzheimer's disease (AD) impairs olfaction, but it is uncertain how early this occurs in the disease process and whether the effect can be accounted for by other behavioral or genetic markers of the disease. We administered the Brief Smell Identification Test (BSIT) to 471 older people without dementia or cognitive impairment who then completed annual clinical evaluations and brain autopsy at death. BSIT score was associated with more rapid decline in episodic memory and with increased risk of developing incident mild cognitive impairment (MCI), even after controlling for baseline level of episodic memory and possession of an apolipoprotein E ɛ4 allele. In 34 people who died without evidence of cognitive impairment, lower BSIT score was associated with higher level of AD pathology, even after controlling for ɛ4 and for level of episodic memory function when olfaction was assessed. These analyses suggest that among older people without clinical manifestations of AD or MCI, olfactory dysfunction is related to both the level of AD pathology in the brain and the risk of subsequently developing prodromal symptoms of the disease, and that these associations persist after accounting for the effects of other recognized behavioral and genetic markers of the disease.
Journal of Alzheimer's Disease, 2022
Background:Olfactory dysfunction is one of the earliest signs of Alzheimer’s Disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia.Objective:To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members.Methods:We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 [5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging.Results:Worse olfactory identification performance was associated with greater age in mutation carriers (r=−0.52 p=0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r=0.55, p=0.024), CERAD delayed recall (r= 0.63, p=0.007) and greater cortical amyloid-β (r= −0.53, p=0.042) and tau pathology burden (entorhinal: r= −0.59, p= 0.016; inferior temporal: r= −0.52, p= 0.038).Conclusions:Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.
A brief olfactory test for Alzheimer's disease
Journal of the Neurological Sciences, 2013
Background-The early diagnosis of Alzheimer's disease (AD) may help reduce disability, enhance quality of life, and aid clinical trials. Portions of olfactory cortex are the initial sites of AD pathology and patients with AD often have more degeneration of their left than right hemisphere. Since the olfactory epithelium projects mainly to the ipsilateral olfactory cortex, patients with AD may demonstrate an asymmetrical (left greater than right) decrement of odor detection sensitivity. This retrospective, case-control study assessed a quick olfactory test that may help diagnose AD. Methods-Participants with probable AD (N=18), mild cognitive impairment (MCI, N=24), other causes of dementia (OD, N=26) and matched controls (OC, N=26) were tested, with closed eyes, for their ability to detect an odor, one nostril at a time. A container of 14g of peanut butter was opened, held medially at the bottom of a 30 cm ruler, and moved up 1cm at a time during the participants' exhale. Upon odor detection, the distance between the subject's nostril and container was measured. Results-The mean odor detection distance of AD patients' left nostril (5.1 cm), and not their right (17.4 cm), was significantly less (F(3,90) = 22.28, p < 0.0001) than the other groups. The mean, standard error, and 95% Confidence Interval of the L R nostril odor detection difference (cm) for AD was −12.4 ±0.
Assessing Olfactory Learning and Memory in the 5XFAD Mouse Model of Alzheimer’s Disease
2012
Using an operant-olfactometer, the long term learning and memory, executive function, olfactory sensitivity, and working memory of the 5XFAD mouse model of Alzheimer's disease was assessed. Six month old male and female 5XFAD and wildtype mice were tested. No deficits were found on an olfactory discrimination task or a reversal learning task. Female and transgenic mice performed better than male and wildtype mice on the higher odour concentrations, but not the lower concentrations, of the sensitivity task, suggesting differences in learning rate or maximum performance on the task, but not olfactory detection. This study demonstrated for the first time that mice are able to learn an olfactory delayed matching to sample task with delays up to 30 seconds long. Female mice showed higher levels of performance on the matching to sample task than male mice, indicative of better working memory.
The olfactory system is vital mechanism for our survival to interact with the environment, influencing not only on odor detection but also on nutrition, social behavior and well-being. Current findings suggest that before the onset of any cognitive decline reflecting early sing of dementia, dysfunction in the areas processing olfactory information is present at the early stages of Alzheimer’s disease (AD). Behavioral test including thresholds, odor identification, recognition memory tasks are the most common types of odor measurement. However, recent neuroimaging techniques using measures of brain response, including Olfactory Event Related Potentials (OERPs) suggested the potential for detection of AD at the early preclinical stage. The importance of olfactory event related potentials and their relation with AD appear to be very promising. Keywords: Olfactory Event Related Potentials (OERPs), Alzheimer’s disease, Age, Olfaction, Apolipoprotein E