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Journal of Alzheimer’s Disease 45 (2015) 947–958 DOI 10.3233/JAD-141947 IOS Press

Olfactory Cortex Degeneration in Alzheimer’s Disease and Mild Cognitive Impairment Megha M. Vasavadaa,1 , Jianli Wanga , Paul J. Eslingera,b,c , David J. Gille , Xiaoyu Suna , Prasanna Karunanayakaa and Qing X. Yanga,d,∗ a Department

of Radiology, Pennsylvania State University College of Medicine, Hershey, PA, USA of Neurology, Pennsylvania State University College of Medicine, Hershey, PA, USA c Department of Neural & Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA d Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, PA, USA e Unity Rehabilitation and Neurology at Ridgeway, Rochester, NY, USA b Department

Handling Associate Editor: Kuncheng Li

Accepted 8 January 2015

Abstract. Background: Olfactory deficits are prevalent in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). These symptoms precede clinical onset of cognitive and memory deficits and coincide with AD pathology preferentially in the central olfactory structures, suggesting a potential biomarker for AD early detection and progression. Objective: Therefore, we tested the hypothesis that structural degeneration of the primary olfactory cortex (POC) could be detected in AD as well as in MCI patients and would be correlated with olfactory functional magnetic resonance imaging (fMRI) alterations, reflecting loss of olfactory cortex activity. Methods: Total structural volumes and fMRI activation volumes of the POC and hippocampus were measured along with olfactory and cognitive behavioral tests in 27 cognitively normal (CN), 21 MCI, and 15 AD subjects. Results: Prominent atrophy in the POC and hippocampus was found in both AD and MCI subjects and correlated with behavioral measurements. While behavioral and volumetric measurements showed a gradual decline from CN to MCI to AD, olfactory activation volume in the POC and hippocampus showed a steeper decline in the MCI group compared to corresponding tissue volume, resembling the AD group. Conclusions: Decline in olfactory activity was correlated with the AD structural degeneration in the POC. A more prominent olfactory activity deficit than that of behavioral and tissue volume measurements was shown in the MCI stage. Olfactory fMRI may thus provide an earlier and more sensitive measure of functional neurodegeneration in AD and MCI patients. Keywords: Alzheimer’s disease, functional MRI, mild cognitive impairment, MRI, olfaction

INTRODUCTION 1 Present address: Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA. ∗ Correspondence to: Qing X. Yang, PhD, 500 University Drive, H066, Department of Radiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. Tel.: +1 717 531 6069; Fax: +1 717 531 8486; E-mail: [email protected]

Standardized behavioral tests have demonstrated that olfactory deficits begin in the early stages of Alzheimer’s disease (AD) [1–3]. These include odor detection threshold, identification, and memory deficits [4–9]. Longitudinal studies have indicated that

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disease progression is significantly correlated with olfactory impairment [2, 3] after consideration of aging effects [10]. Mild cognitive impairment (MCI) patients who convert to AD at an annual rate of 15% also present with prominent olfactory dysfunction [11, 12]. Therefore, olfactory deficits have the potential to be a biomarker of early stage and preclinical AD [13]. Postmortem studies have provided a neuropathological basis for the observed olfactory deficits [13, 14]. Classic AD pathology (amyloid-␤ plaques and neurofibrillary tangles) has been shown to be distributed preferentially in olfactory-related structures when compared with visual, auditory, and somatosensory brain areas [14–19]. Olfactory structures include the olfactory bulb and tract, anterior olfactory nucleus, piriform cortex, entorhinal cortex, amygdala, and periamygdaloid cortex. Furthermore, the pathology in these olfactory structures in the inferior medial temporal region has been shown to be present in the earliest stages of the disease [20]. Clinical diagnosis of AD requires comprehensive evaluation that spans interview and medical history, brain imaging, blood chemistries, clinical exam, and neuropsychological evaluation. Neuroimaging currently serves primarily to rule out other diseases although many studies have shown potential for more than differential diagnosis. Meta-analyses of more than 50 voxel-based morphometry studies have confirmed that significant atrophy occurs in the medial temporal lobe in MCI and AD patients [21, 22]. This technique has detected hippocampal atrophy in AD patients with a mean volume loss between 20% and 52% [23–29]. More recently, Marigliano et al. reported olfactory testing and hippocampal volume loss as easily detectable features for preclinical AD based on a preliminary longitudinal study examining 18 amnestic MCI patients [30]. They observed that olfactory deficits associated with hippocampal volume loss in all subjects who converted to AD. In contrast, there are limited studies on atrophy of the central olfactory structures despite known prominent olfactory deficits in early AD patients [31, 32]. Specifically, there are no studies investigating the atrophy of the primary olfactory cortex and the relationship between the atrophy and olfactory functional activation even though olfactory regions are the first to be affected by AD pathology [13–19]. Establishing a quantitative relationship between the functional activity decline and the corresponding pathological changes in brain structures for the specific function is of great importance for developing imaging biomarkers. Previously, functional activation deficits

in the central olfactory structures have been detected using olfactory functional magnetic resonance imaging (fMRI) in AD patients [33, 34]. Therefore, olfactory deficits in early AD provide a unique opportunity to investigate such specific brain structure-to-function relationships in vivo. Thus, we hypothesized that: 1) atrophy can be detected in the primary olfactory cortex (POC) of MCI and AD patients; and 2) olfactory fMRI activation is correlated to the POC atrophy. To test our hypothesis, we conducted concurrent measurements of olfactory fMRI and tissue volume of the POC, and examined correlations with behavioral assessments. Olfactory activity and volume of the hippocampus were also measured to examine specificity. MATERIALS AND METHODS Study cohort Sixty-four subjects were enrolled in this study: 27 normal controls (CN), 21 MCI (Clinical Dementia Rating Scale (CDR) of 0.5), and 16 AD (CDR of 0.5 or 1) (Table 1). No significant age, gender, or education differences were detected amongst the groups. One AD subject was dropped from data analysis due to excessive head movement during the functional scan leaving a total of sixty-three subjects and 15 AD subjects as listed in Table 1. Pennsylvania State University College of Medicine Institutional Review Board approved the study, and subjects provided written consent prior to participation. Subjects were screened for other neurologic and psychiatric conditions; including checking for complications specific to Table 1 Demographic and behavioral data of the study cohort

Male/Female Age (year) Educational level (year) UPSIT MMSE CVLT-II DRS-2

CN (n = 27)

MCI (n = 21)

AD (n = 15)

12/15 69.5 ± 10.4 16.0 ± 1.7

10/11 73.2 ± 9.0 14.6 ± 2.9

5/10 71.9 ± 11.9 14.3 ± 3.0

34.0 ± 4.2 28.5 ± 1.5 62.6 ± 13.1 13.3 ± 1.6

24.2 ± 8.6∗ 26.5 ± 1.9 47.3 ± 12.7∗ 9.6 ± 3.2∗

15.5 ± 8.4∗,† 18.9 ± 5.4∗,† 21.3 ± 14.1∗,† 3.9 ± 2.5∗,†

CN, cognitively normal controls; MCI, mild cognitive impaired; AD, Alzheimer’s disease; UPSIT, University of Pennsylvania Smell Identification Test; MMSE, Mini-Mental State Examination; CVLTII, California Verbal Learning Test-Short Form Version 2; DRS-2, Dementia Rating Scale 2. Mean ± standard deviation is reported. ∗ p < 0.05, ANOVA when compared to CN. † p < 0.05, ANOVA when compared to MCI.

M.M. Vasavada et al. / Olfactory Cortex Degeneration in AD and MCI

olfactory dysfunction (e.g., head trauma, viral infection, allergies) and for contraindications to MRI (e.g., not-MRI-safe metal implants). AD and MCI subjects underwent comprehensive evaluation and were diagnosed by a board certified neurologist in accordance with NINCDS-ADRDA criteria [35] and Peterson criteria [36], respectively. Fourteen AD subjects and 12 MCI subjects were being treated with a cholinesterase inhibitor and/or memantine. Behavioral tests All participants were administered the University of Pennsylvania Smell Identification Test (UPSIT, Sensonics, Inc., Haddon Heights, NJ, USA) to assess olfactory function, and neurocognitive examinations, which included the Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale-2 (DRS-2), and California Verbal Learning Test-Second Edition Short Form (CVLT-II). Olfactory stimulation paradigm The olfactory paradigm was executed using a programmable olfactometer (Emerging Tech Trans, LLC, Hershey, PA, USA) to deliver odorants to subject’s nostrils accurately without any optical, acoustic, thermal, or tactile cues to the subject. The olfactometer delivered 6 L/min of constant airflow at room temperature bilaterally to the subjects’ nostrils. The olfactory paradigm and MRI image acquisition were synchronized using optical triggers from the MRI scanner. The stimulus was lavender oil (Givaudan Flavors Corporation, East Hanover, NJ, USA) diluted in 1,2-

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propanediol (Sigma, St. Louis, MO, USA). Lavender is an effective, pleasant, and familiar olfactory stimulant with minimal propensity to stimulate the trigeminal system [37]. Four concentrations of lavender were used (Fig. 1) based upon a previous study on young controls [38]. By increasing the concentration during the paradigm the habituation effects were offset and stable activations within the POC and hippocampus were obtained. The odor was presented for 6 s separated by 30 s of odorless air. The presentation order was from weakest to strongest concentration with three presentations of each concentration before moving onto the subsequent higher concentration, which has been shown to be effective in reducing the habituation effect [38]. The olfactory fMRI paradigm also included a visual component and a motor response. The visual component included the words “Rest” and “Smell?”. When the word “Smell?” appeared on the screen the subject was asked to respond “yes” or “no” depending on whether they smelled the lavender odor or not using the button presses in each hand. When “Rest” was displayed on the screen, the subject was asked to just rest and continue paying attention to the screen. The word “Smell?” was displayed for 6 s and was paired with either constant odorless air or with lavender odor while the word “Rest” was displayed for 12 s and paired with only odorless air. Periods with “Rest” and odorless air were used as the baseline condition. The odorless air was kept constant throughout the olfactory paradigm so that the subject could not detect changes in airflow when odor was delivered. Respiration patterns during the execution of fMRI paradigm were monitored and recorded via a chest belt. Respiration was monitored to confirm the subject was awake throughout the paradigm.

Fig. 1. The olfactory fMRI paradigm. Four concentrations of lavender were presented. Each concentration was presented three times before the next higher concentration was presented in a stepwise fashion. Odor presentation started with the weakest concentration and ended with the strong concentration. The visual cue was a display of the words “Smell?” and “Rest” on an LCD screen. When “Smell?” appeared on the screen the subject provided responses using a button press device in each hand, left hand if no smell and right hand if they smelled the stimulus.

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Imaging protocol The imaging data were collected on a 3.0 T MRI system (Magnetom Trio, Siemens Medical Solutions, Erlangen, Germany) with an 8-channel head coil. Functional MRI utilizing the blood oxygen level dependent (BOLD) signal was used to evaluate brain functional activities during odor stimulation. A T2 ∗ -weighted echo planar imaging sequence was used to acquire functional data with slices = 34, slice thickness = 4 mm, field of view (FOV) = 230 × 230, acquisition matrix = 80 × 80, echo time (TE) = 30 ms, repetition time (TR) = 2000 ms, flip angle (FA) = 90º, acceleration factor = 2, and acquisition time (TA) = 7 min 56 s with 234 repetitions. For structural assessment of the POC and hippocampus, T1 -weighted images with 1 mm isotropic resolution were acquired with MPRAGE method: TE = 2.98 ms, TR = 2300 ms, inversion time (IT) = 900 ms, FA = 9º, FOV = 256 mm × 256 mm × 160 mm, acquisition matrix = 256 × 256 × 160, acceleration factor = 2, and TA = 6 min 21 s. fMRI data processing and voxel-based analysis Statistical Parametric Mapping (SPM8, Wellcome Trust Centre for Neuroimaging, University College London, UK) was used to analyze all imaging data. The first 10 images were discarded to remove initial transit signal fluctuations. The following standardized procedure was used to preprocess the fMRI data: 1) spatial realignment within the session to remove any minor head movements (movement

Olfactory cortex degeneration in Alzheimer's disease and mild cognitive impairment.

Olfactory deficits are prevalent in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). These symptoms precede clinical onset ...
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