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Eye Blink Rate as a biological marker of Mild Cognitive Impairment
INTPSY-10704; No of Pages 5 International Journal of Psychophysiology xxx (2013) xxx–xxx
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Eye Blink Rate as a biological marker of Mild Cognitive Impairment☆ Aristea Ladas a, Christos Frantzidis b, Panagiotis Bamidis b, Ana B. Vivas a,⁎ a b
Psychology Dept., The University of Sheffield International Faculty, City College, and South East European Research Center, SEERC, Thessaloniki, Greece Dept of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece
a r t i c l e
i n f o
Article history: Received 15 October 2012 Received in revised form 1 July 2013 Accepted 25 July 2013 Available online xxxx Keywords: Eye Blink Rate MCI Biological marker Dopamine
a b s t r a c t We investigated the relationship between dopamine activity (DA), as measured by Eye Blink Rate (EBR), and cognitive function in old adults with Mild Cognitive Impairment (MCI) and healthy controls. Research has been inconclusive so far about the factors responsible for the transition from MCI to dementia. However, some studies suggest that cortical hyperexcitability in very early stages of pathological aging may progressively lead to cell death, and thus to Alzheimer's disease. Hence, we speculated that a dysfunction of DA activity, as measured by EBR, may characterize people with MCI, and account for their poor cognitive function. Thirty three (33) healthy and thirty six (36) old adults with MCI (Mean age = 67.52 y.o.) participated in this study. The EBR was recorded under resting conditions, using two gold skin electrodes above and below the left eye. Cognitive function was assessed with a battery of neuropsychological tests. Participants with MCI showed significantly higher EBR than the healthy controls. Also, EBR was negatively related to scores on the Montreal Cognitive Assessment test (MoCA) test. We propose that abnormally increased dopamine activity, as indexed by relatively high EBR, may be partially responsible for the neurotransmitter imbalance in the central nervous system of people with MCI, and the overall impaired cognitive performance. In addition, this finding suggests that an abnormally high EBR may be a potential biomarker of the transition from healthy aging to dementia. © 2013 Published by Elsevier B.V.
1. Introduction The extension of the life span observed during the last decades has led to a dramatic increase of the number of people suffering from dementia (World Health Organization, WHO, 2003). Currently, there are 5.4 million dementia patients, only in the EU (Ferri et al., 2005). Prognosis of dementia prevalence is even more dramatic, according to international-scale studies (Alzheimer's Disease International, 2010; WHO, 2003), reaching the level of a global epidemic in the upcoming years (Brookmeyer et al., 2007). As Alzheimer's dementia (AD) still remains untreated, detecting dementia in very early stages, with the goal of preventing or delaying the illness, has now become a public health priority (for reviews see Arnáiz and Almkvist, 2003; Burns and Zaudig, 2002). Efforts to identify individuals who may later develop dementia have focused on the progression from healthy age-related cognitive decline to pathological aging. Mild Cognitive Impairment (MCI) thus is considered an intermediate stage between normal and pathological aging, as a substantial ☆ This research was supported by the LLM Project (CIP-ICT-PSP-2008-2-238904) of the ICT Policy Support Programme as part of the Competitiveness and Innovation Framework Programme by the European Commission. ⁎ Corresponding author at: Psychology Department, The University of Sheffield International Faculty, City College, Thessaloniki, 24 Proxenou Koromila, 546 22 Thessaloniki, Greece. Tel.: +30 2310 253 477. E-mail address: [email protected] (A.B. Vivas).
percentage of people diagnosed with MCI converts later to dementia of the Alzheimer's type (Arnáiz and Almkvist, 2003). Consequently, an outstanding issue is to find factors that may predict which MCI patients will later convert to dementia (Rinne and Någren, 2010). In the past, the belief that amnesic MCI (i.e. MCI with impairments solely in memory and no other cognitive domains) is the pre-stage of AD, used to prevail. However, other evidence now suggests that impairments of processes others than memory, such as learning, attention and executive functions, may also predict progression to AD (for reviews see Arnáiz and Almkvist, 2003; Morris et al., 2001). Early detection (e.g., at the MCI stage) of cognitive impairments in clinical settings is mostly carried out with neuropsychological assessment. Neuropsychological tools may reliably screen for very early dementia symptoms, however only if they are properly interpreted by the clinician (Arnáiz and Almkvist, 2003). This calls for the need to identify other, more objective, markers of central nervous system function, which in combination with the neuropsychological evaluation, could lead to more robust recognition of AD in a prodromal stage. Although functional magnetic resonance imaging (fMRI) (Bäckman et al., 1999; Wagner, 2000) and Transcranial Magnetic Stimulation (TMS) (for a review see Pennisi et al., 2011) have been extensively used for this purpose, they are costly and highly sophisticated technologies. This deters hospitals, let alone AD associations, from utilizing these techniques to detect MCI individuals at-risk for AD. The aim of the present paper is to introduce a cost-effective, simple and reliable marker of CNS function
0167-8760/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
Please cite this article as: Ladas, A., et al., Eye Blink Rate as a biological marker of Mild Cognitive Impairment, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
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A. Ladas et al. / International Journal of Psychophysiology xxx (2013) xxx–xxx
which, in combination to neuropsychological assessment, could essentially compose a screening mechanism that may lead to a more valid detection of cognitive impairment prior to Alzheimer's disease (AD), that is MCI. The suggested herein (bio)marker is the Eye Blink Rate (EBR). EBR is a non-invasive, reliable and easily quantifiable measure of brain central dopamine activity (DA) (Karson, 1983; Mackert et al., 1991; Shukla, 1985; Taylor et al., 1999). How is dopamine related to early dementia symptoms? According to Braak and colleagues, in the very first stages of Alzheimer's disease, neurofibrillary pathology is firstly observed in the entorhinal cortex, and progresses to the hippocampus, which is then spread to the rest of the limbic system and thereafter to other cortical regions (Braak and Braak, 1997; Braak et al., 2005; Delacourt et al., 1999). Given the crucial role of the entorhirnal cortex and the hippocampus in episodic memory (Woodard et al., 2009; Burianova et al., 2010; Coward, 2010), it is not surprising that in the very early stages of AD, such as the preclinical stage of MCI, specifically episodic memory is impaired (Winblad et al., 2004; Dudas et al.2005; Ahmed et al., 2008a, b; Kalpouzos et al., 2009; Leyhe et al., 2009; Fayed et al., 2010). Importantly, dopamine is one of the main neurotransmitters in the hippocampus and the limbic system (e.g. mesolimbic and mesocortical dopamine pathways). Thus, one could expect that individuals with MCI should also show DA deficits, as previously suggested (Albert et al., 2011; Nagaraja and Sivaramakrishnan, 2001). This argument is supported by recent studies that suggest a DA dysfunction at the core of Alzheimer's dementia. Neurodegeneration, which contributes to the progression from healthy aging to MCI, and then to dementia (Pennisi et al., 2011), has been partly attributed to the anomalous cortical hyperexcitability observed at early stages of pathological aging. Specifically, dopamine seems to modulate cortical cholinergic release, which is typically impaired in AD patients (Martorana et al., 2009). In line with this, administration of L-dopa in AD patients, similar to the effects of acetylcholinesterase inhibitors typically administered in such cases, may reduce this anomalous cortical hyperexcitability, as balance in the function of neurotransmitters seems to be restored after the precursor of dopamine is administered (Martorana et al., 2008; for a review see Martorana, Esposito and Koch, 2010). Cortical hyperexcitability, which eventually leads to cell death (Martorana, Esposito and Koch, 2010) is primarily observed in the primary motor (M1) and premotor cortex, and DA seems to play a key role in this process particularly in M1 (Hosp et al., 2011; for a review see Pennisi et al., 2011). Dopamine is also directly related to several cognitive functions such as episodic memory, learning and executive functions (for a review see Bäckman et al, 2006), which are considered to be neuropsychological predictors of conversion from MCI to AD (Arnáiz and Almkvist, 2003). Therefore, alterations in the dopaminergic system observed in AD may contribute significantly to the progressive cognitive decline in pathological aging (for a review see Martorana et al., 2010). In this piece of work, we aimed at investigating DA activity in MCI, and its relationship to cognitive functions, by using a non-invasive marker, EBR. We expect that the group of MCI will have significantly lower EBR than the healthy controls. Also, we expect that EBR will be correlated with general cognitive functions, such as attention, and memory. 2. Method 2.1. Participants Thirty-six adults (23 females and 13 males) diagnosed with MCI, and 33 healthy controls (23 females and 6 males) participated in the study. Participants in the MCI were assessed according to the Petersen criteria (Petersen and Morris, 2005; for a review see Petersen et al., 2001). The Mini Mental State Examination (MMSE; Folstein, Folstein and McHugh, 1975) was used as a basic screening tool for MCI, but this
was complemented with the Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005) to increase sensitivity of diagnosis and classification (Nazem et al., 2009). Both groups were matched in age and years of education (see Table 1 for demographics and clinical characteristics). Exclusion criteria for both groups were: i) use of medication that could interfere with the function of the central nervous system and/or eyelid kinetics; ii) a score of 9 or above (for women) and 6 or above (for men) in the Instrumental Activities of Daily Living (IADL; Lawton and Brody, 1969); iii) a history of neurologic and/or psychiatric disorders other than MCI; iv) a score of 5 or above in the Geriatric Depression Scale (GDS short version; Sheikh and Yesavage, 1986); v) a history of substance abuse including alcohol and nicotine; and vi) severe mobility, hearing or vision problems which would impede participation in the study. The exclusion criteria were assessed via a detailed clinical interview of the participant and the caregiver (if applicable). All participants provided a signed informed consent of participation, after being fully informed on the study. The study was approved by the local Bioethics Committee. All participants were recruited from the Greek Association of Alzheimer's Disease and Related Disorders, as well as local day care centers via posters and oral presentations. This study was part of the screening process for the Long Lasting Memories (LLM) Project funded by the European Commission (ICT-CIP-PSP scheme) (see Bamidis et al., 2011; www.longlastingmemories.eu). 2.2. Material 2.2.1. Neuropsychological measures To assess cognitive status, we employed the MMSE and the MoCA tests. The MMSE, is the most widely used measure of global cognition especially in the geriatric population (Schultz-Larsen et al., 2007). It assesses functions such as orientation to space and time, visuospatial skills, praxis, attention and working memory as well as short-term memory, registration and language (for a review see Brayne, 1998). Since there is some controversy about the sensitivity of the MMSE to differentiate healthy individuals from individuals with MCI (Nazem et al., 2009; for a review see Tombaugh and McIntyre, 1992; Wind et al., 1997; Yochim et al., 2008), we used this assessment tool in combination with the MoCA. The MoCA was designed as a brief cognitive screening tool that assesses short-term memory, visuospatial abilities, several aspects of executive function, working memory, attention (sustained and executive), language and orientation to time and space. It covers more cognitive domains than the MMSE, and it is thought to be more sensitive to Mild Cognitive Impairment than the MMSE itself (Aggarwal and Kean, 2010). In addition, the following neuropsychological tests were employed to obtain specific measures of memory and executive attention; the Digit Span Backward task (Wechsler, 1981) and the Trail Making Test (part B) (Reitan and Wolfson, 1995), respectively. 2.2.2. Neurophysiological measure — EOG protocol Horizontal (electrodes lateral to the external canthi) and vertical (electrodes above and below the left eye) gold skin electrodes were Table 1 Demographic variables for study participants. Variables
Healthy
MCI
Age (years) Mean SD Range
67.48 6.14 56–81
67.56 7.28 57–85
Education (years)a Mean SD Range
9.43 4.23 6–16
8.23 5.13 6–17
a
SD = standard deviation. a Independent t-test: all N 0.05.
Please cite this article as: Ladas, A., et al., Eye Blink Rate as a biological marker of Mild Cognitive Impairment, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
A. Ladas et al. / International Journal of Psychophysiology xxx (2013) xxx–xxx
used for the electro-oculogram, according to past research (Colzato, van den Wildenberg and Hommel, 2008). The EBR was recorded for 6 min under resting conditions with eyes open. The data were derived from the two electrodes placed above and below the left eye.
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MMSE and the MoCA scores, r(67) = .466, p b .0001, and negative relation between the MoCA and the TMT B scores, r(67) = − .435, p b 0001, showing that better performance on the MoCA was associated with better (i.e. faster) performance on the TMT B (see Table 3). No other correlations reached statistical significance.
2.3. Procedure 4. Discussion Each participant was invited to an appointment, at the facilities of the Greek Association for Alzheimer's Disease and Related Disorders. While sitting in a quiet room, a psychologist fully explained the LLM study. Then, time was given for any clarification questions. All tests took place on the same day between 9 a.m. and 5 p.m., as research has shown that there are no diurnal variations in EBR in old adults (De Padova et al., 2009). The EOG recording was part of an electroencephalogram (EEG) testing procedure. The EBR was measured in the beginning of the EEG procedure, prior to the initiation of the EEG protocol. The order of the neurocognitive tests was counterbalanced across participants. Finally, participants were instructed to take a break between tests if needed. 2.4. Analyses The Matlab software was used to extract EBRs from the EOG recordings. We used a semi-automated algorithm, with the raw EOG signal as input to the algorithm. The EOGs were filtered to eliminate high-frequency noise that contaminated the data. Then a threshold parameter was set, indicating blink onset. An eye blink was defined as a sharp high amplitude wave of 100 V, of 500 ms, as in Colzato et al. (2009). The number of blinks, as well as, the blink rate were automatically computed and visually inspected and reconfirmed. Independent t-tests were used to see whether the cognitive state groups differ in mean EBR and/or test scores. To test for a relationship between EBR and cognitive performance we conducted Pearson correlations in the overall sample and adopted a stricter significance level (p = .01) to address the issue of multiple comparisons. 3. Results Means and standard deviations for both cognitive state groups (MCI, and healthy controls) are presented in Table 2. Results showed that the MCI group had significantly higher EBR than the Healthy controls group, t(67) = 2.146, p = .035, and significantly worse performance in the TMT B test than the Healthy controls, t(67) = 3.491, p = .001. However, there were no significant differences between the two groups on the Digit Span Backwards task. In addition, EBR scores were significantly negatively correlated with MoCA scores, r(67) = −.323, p = .007. That is, higher EBR were associated with worse overall cognitive performance as measured by the MoCA. There was also a significant positive correlation between the Table 2 Means and standard deviations (SD) for all dependent variables per cognitive state group. Variables
Healthy
MCI
EBR Mean SD
20.24 13.24
27.60 15.09
MoCA Mean SD
26.58 1.56
23.72 2.76
TMT B Mean SD
128.76 74.26
200.53 94.28
4.33 1.19
4.94 2.35
Digit span back. Mean SD
In the present study we employed a non-invasive biological measure, EBR, to investigate DA activity in MCI and its relationship to cognitive performance. This is the first study to report that adults with MCI have significantly higher EBR than healthy controls. Also adults with MCI performed significantly worse than healthy controls on the Trial Making Test (Part B), a test that it is thought to measure executive attention, among other functions (Reitan and Wolfson, 1995). Finally EBR scores were significantly associated with MoCA scores, that is the higher the EBR the worse the performance on the MoCA. To our knowledge this is the first time that EBR is measured specifically in an MCI group. However, there are very few studies in the literature investigating the validity of EBR as a biological marker of DA activity in healthy elderly people (Bentivoglio et al., 1997; Chen et al., 2003; De Padova et al., 2009; Karson, 1983; Karson et al., 1981, 1982; Sun et al., 1997). The mean age of individuals across these studies is 65.22 years old (SD = 11.2), which is very close to the mean age of the participants in this study (67.52). Most importantly, the mean EBR of all the samples in these published studies is 20.27 blinks/min, which is almost identical to the mean EBR (20.24 blinks/min) of the group of healthy controls in our study. Thus we can safely conclude that the MCI group has abnormally high EBR, and not the opposite (that the group of healthy controls has lower EBR than expected). The finding of abnormally high EBR in the group of MCI suggests an excess of DA activity in the central nervous system. It is not clear what the exact neural mechanisms are (e.g., location) that mediate the relationship between EBR and DA activity but animal studies support the role of D2 receptors in this relationship (Karson, 1983; Lawrence and Redmond, 1991; although see Van der Post et al., 2004 for a negative finding). Hence, administration of D2 receptor agonists and antagonists produces an increase and decrease in EBR, respectively. One more study has also suggested that the relationship between EBR and DA activity may be mediated by D1 receptors (Elsworth et al., 1991). Thus one plausible hypothesis is that the higher EBR observed in our sample of MCI participants may be due to abnormally high activity of DA receptors, although this needs to be confirmed by further studies. The finding of abnormally increased dopamine activity in participants with MCI is in contradiction with previous studies reporting a decline of dopamine activity with aging (Volkow et al., 1998), and loss of dopamine receptor activity in AD (Kemppainen et al., 2003), however it may fit well with the hypothesis of a overall neurotransmitter imbalance in the very early stages of AD. According to this hypothesis, a dysfunction of the cholinergic and dopaminergic systems is at the core of the cortical hyperexcitability observed in early stages of AD (for a review see Martorana et al., 2010). DA and Acetylcholine (Ach) do have a complex functional relationship though, and the exact mechanisms underlying the DA modulation of cholinergic activity have not been fully revealed yet. For instance, it has been proposed that while D1 receptors exert a Table 3 Inter-correlations for measures of Eye Blink Rate, MMSE, MoCA, TMT B and Digit Span Backwards task. Note the negative correlation between MoCA scores and EBR and MoCA and TMT B scores and the positive correlations between MMSE and MoCA scores. Pearson's r EBR MMSE MoCA TMT B
MMSE
MoCA
TMT B
Digit span back.
−.149
−.323⁎ .466⁎
.171 −.128 −.435⁎
.245 .105 −.192 −.060
⁎ p b 0.01.
Please cite this article as: Ladas, A., et al., Eye Blink Rate as a biological marker of Mild Cognitive Impairment, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
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positive modulation of cortical cholinergic activity; D2 receptors negatively modulate Ach release in the prefrontal cortex (Brooks et al., 2007). Thus, it is possible that abnormally increased D2 receptor activity could add to cholinergic dysfunction in MCI, leading to cortical hyperexcitability and overall impaired cognitive performance. An alternative hypothesis may be that the finding of abnormally increased EBR in the MCI group, results from dopamine receptor upregulation due to early compensatory mechanisms. Similarly, other studies have reported hyperactivation in the prefrontal cortex and hippocampus of individuals with MCI, relative to healthy controls, as a result of early compensatory mechanisms (see for instance, Clément and Belleville, 2010). However, our study is not able to discriminate among these two hypotheses. As we predicted, EBR was also significantly correlated to MoCA scores: higher EBR was related to worse overall cognitive status. The finding of a significant relationship between MoCA scores and EBR, and not between MMSS and EBR, is in agreement with the higher sensitivity of the former to detect MCI (Nasreddine et al., 2005; Nazem et al., 2009; Sweet et al., 2011). We believe that the same hypothesis put forward to explain the finding of higher EBR in the MCI group, can also account for the relationship between EBR and MoCA scores. That is, higher DA function (higher EBR), and thus greater neurotransmitter imbalance, would result in worse overall cognitive performance in this group. This may account as well for the worse performance in executive attention (Trial Making test, Part B) observed in the MCI group as compared to the healthy control group (see Table 2). However, TMT part B scores were not correlated with mean EBR. This is an unexpected finding, since TMT-B is considered to be a measure of executive functions that have been linked to DA activity (for a review see Bäckman et al, 2006). Thus we were expecting to find a correlation between performance on TMT-B and EBR scores. An explanation for the present finding may be that DA activity and cognitive performance do not have a linear relationship. The predominant theory is that DA has a positive effect on cognitive function, particularly on functions that depend on the frontal lobe such as executive and motor functions. In support to this theory, many studies have reported worse performance on cognitive tests associated to reductions in DA activity as part of aging (Bäckman et al., 2000; Volkow et al., 1998). Also, administration of DA agonists improves cognitive performance in tasks of dual coding, reaction time, immediate and delayed recall (Schuck et al., 2002) and working memory (Luciana and Collins, 1997; Luciana et al., 1998) in young adults. However, studies done mostly with rats suggest that there may be an inverted “U” relationship between DA activity and cognitive performance: excessive as well as insufficient DA activity impairs cognitive function. For instance, it has been shown that high doses of D1 receptor agonists impair performance in working memory tasks, which are dependent on prefrontal lobe function as it is the case for the TMT-B, in rats (Zahrt et al., 1997). Our results fit well with this hypothesis. We found that participants with MCI have abnormally high EBR, which suggests excessive DA receptor activity. In addition, the MCI group had worse cognitive performance in the TMT-B than the group of healthy adults. Thus, in line with the inverted “U” shaped hypothesis, excessive DA receptor activity (abnormally high EBR) appears to have impaired performance in the MCI group. However, our study admittedly possesses certain limitations. For example, there has been no care for a differentiation between subtypes of MCI herein, although other studies have distinguished two main subtypes of MCI; these are amnesic and nonamnesic subtypes. In addition, we did not employ a second independent and more direct measure of DA activity in order to achieve a further confirmation on the exact mechanisms underlying the increased EBR in the MCI group. Thus, future studies need to be conducted to replicate this novel finding, but furthermore, test whether increased EBR is a neurobiological marker of all subtypes of MCI or not.
To sum up, this is the first study to investigate the likely role of EBR as a (potential) biological marker of DA activity, in the central nervous system, in adults with MCI. Our results show that EBRs are abnormally high, and thus support EBR as a valid index of neurotransmitters imbalance in early stages of dementia. EBR scores also correlate with scores in the MoCA test, which is a sensitive tool to detect MCI. This finding further strengthens the validity of EBR as a biological marker of pathological cognitive decline. Finally, it is crucial to carry out longitudinal studies to test whether EBR is a significant factor to predict progression from MCI to dementia. Conflict of interest All authors declare that they have no conflict of interest. References Ahmed, S., Arnold, R., Thompson, S.A., Graham, K.S., Hodges, J.R., 2008a. Names of objects, faces and buildings in mild cognitive impairment. Cortex 44, 746–752. 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Please cite this article as: Ladas, A., et al., Eye Blink Rate as a biological marker of Mild Cognitive Impairment, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
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Contents lists available at ScienceDirect
International Journal of Psychophysiology journal homepage: www.elsevier.com/locate/ijpsycho
Eye Blink Rate as a biological marker of Mild Cognitive Impairment☆ Aristea Ladas a, Christos Frantzidis b, Panagiotis Bamidis b, Ana B. Vivas a,⁎ a b
Psychology Dept., The University of Sheffield International Faculty, City College, and South East European Research Center, SEERC, Thessaloniki, Greece Dept of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece
a r t i c l e
i n f o
Article history: Received 15 October 2012 Received in revised form 1 July 2013 Accepted 25 July 2013 Available online xxxx Keywords: Eye Blink Rate MCI Biological marker Dopamine
a b s t r a c t We investigated the relationship between dopamine activity (DA), as measured by Eye Blink Rate (EBR), and cognitive function in old adults with Mild Cognitive Impairment (MCI) and healthy controls. Research has been inconclusive so far about the factors responsible for the transition from MCI to dementia. However, some studies suggest that cortical hyperexcitability in very early stages of pathological aging may progressively lead to cell death, and thus to Alzheimer's disease. Hence, we speculated that a dysfunction of DA activity, as measured by EBR, may characterize people with MCI, and account for their poor cognitive function. Thirty three (33) healthy and thirty six (36) old adults with MCI (Mean age = 67.52 y.o.) participated in this study. The EBR was recorded under resting conditions, using two gold skin electrodes above and below the left eye. Cognitive function was assessed with a battery of neuropsychological tests. Participants with MCI showed significantly higher EBR than the healthy controls. Also, EBR was negatively related to scores on the Montreal Cognitive Assessment test (MoCA) test. We propose that abnormally increased dopamine activity, as indexed by relatively high EBR, may be partially responsible for the neurotransmitter imbalance in the central nervous system of people with MCI, and the overall impaired cognitive performance. In addition, this finding suggests that an abnormally high EBR may be a potential biomarker of the transition from healthy aging to dementia. © 2013 Published by Elsevier B.V.
1. Introduction The extension of the life span observed during the last decades has led to a dramatic increase of the number of people suffering from dementia (World Health Organization, WHO, 2003). Currently, there are 5.4 million dementia patients, only in the EU (Ferri et al., 2005). Prognosis of dementia prevalence is even more dramatic, according to international-scale studies (Alzheimer's Disease International, 2010; WHO, 2003), reaching the level of a global epidemic in the upcoming years (Brookmeyer et al., 2007). As Alzheimer's dementia (AD) still remains untreated, detecting dementia in very early stages, with the goal of preventing or delaying the illness, has now become a public health priority (for reviews see Arnáiz and Almkvist, 2003; Burns and Zaudig, 2002). Efforts to identify individuals who may later develop dementia have focused on the progression from healthy age-related cognitive decline to pathological aging. Mild Cognitive Impairment (MCI) thus is considered an intermediate stage between normal and pathological aging, as a substantial ☆ This research was supported by the LLM Project (CIP-ICT-PSP-2008-2-238904) of the ICT Policy Support Programme as part of the Competitiveness and Innovation Framework Programme by the European Commission. ⁎ Corresponding author at: Psychology Department, The University of Sheffield International Faculty, City College, Thessaloniki, 24 Proxenou Koromila, 546 22 Thessaloniki, Greece. Tel.: +30 2310 253 477. E-mail address: [email protected] (A.B. Vivas).
percentage of people diagnosed with MCI converts later to dementia of the Alzheimer's type (Arnáiz and Almkvist, 2003). Consequently, an outstanding issue is to find factors that may predict which MCI patients will later convert to dementia (Rinne and Någren, 2010). In the past, the belief that amnesic MCI (i.e. MCI with impairments solely in memory and no other cognitive domains) is the pre-stage of AD, used to prevail. However, other evidence now suggests that impairments of processes others than memory, such as learning, attention and executive functions, may also predict progression to AD (for reviews see Arnáiz and Almkvist, 2003; Morris et al., 2001). Early detection (e.g., at the MCI stage) of cognitive impairments in clinical settings is mostly carried out with neuropsychological assessment. Neuropsychological tools may reliably screen for very early dementia symptoms, however only if they are properly interpreted by the clinician (Arnáiz and Almkvist, 2003). This calls for the need to identify other, more objective, markers of central nervous system function, which in combination with the neuropsychological evaluation, could lead to more robust recognition of AD in a prodromal stage. Although functional magnetic resonance imaging (fMRI) (Bäckman et al., 1999; Wagner, 2000) and Transcranial Magnetic Stimulation (TMS) (for a review see Pennisi et al., 2011) have been extensively used for this purpose, they are costly and highly sophisticated technologies. This deters hospitals, let alone AD associations, from utilizing these techniques to detect MCI individuals at-risk for AD. The aim of the present paper is to introduce a cost-effective, simple and reliable marker of CNS function
0167-8760/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
Please cite this article as: Ladas, A., et al., Eye Blink Rate as a biological marker of Mild Cognitive Impairment, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
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which, in combination to neuropsychological assessment, could essentially compose a screening mechanism that may lead to a more valid detection of cognitive impairment prior to Alzheimer's disease (AD), that is MCI. The suggested herein (bio)marker is the Eye Blink Rate (EBR). EBR is a non-invasive, reliable and easily quantifiable measure of brain central dopamine activity (DA) (Karson, 1983; Mackert et al., 1991; Shukla, 1985; Taylor et al., 1999). How is dopamine related to early dementia symptoms? According to Braak and colleagues, in the very first stages of Alzheimer's disease, neurofibrillary pathology is firstly observed in the entorhinal cortex, and progresses to the hippocampus, which is then spread to the rest of the limbic system and thereafter to other cortical regions (Braak and Braak, 1997; Braak et al., 2005; Delacourt et al., 1999). Given the crucial role of the entorhirnal cortex and the hippocampus in episodic memory (Woodard et al., 2009; Burianova et al., 2010; Coward, 2010), it is not surprising that in the very early stages of AD, such as the preclinical stage of MCI, specifically episodic memory is impaired (Winblad et al., 2004; Dudas et al.2005; Ahmed et al., 2008a, b; Kalpouzos et al., 2009; Leyhe et al., 2009; Fayed et al., 2010). Importantly, dopamine is one of the main neurotransmitters in the hippocampus and the limbic system (e.g. mesolimbic and mesocortical dopamine pathways). Thus, one could expect that individuals with MCI should also show DA deficits, as previously suggested (Albert et al., 2011; Nagaraja and Sivaramakrishnan, 2001). This argument is supported by recent studies that suggest a DA dysfunction at the core of Alzheimer's dementia. Neurodegeneration, which contributes to the progression from healthy aging to MCI, and then to dementia (Pennisi et al., 2011), has been partly attributed to the anomalous cortical hyperexcitability observed at early stages of pathological aging. Specifically, dopamine seems to modulate cortical cholinergic release, which is typically impaired in AD patients (Martorana et al., 2009). In line with this, administration of L-dopa in AD patients, similar to the effects of acetylcholinesterase inhibitors typically administered in such cases, may reduce this anomalous cortical hyperexcitability, as balance in the function of neurotransmitters seems to be restored after the precursor of dopamine is administered (Martorana et al., 2008; for a review see Martorana, Esposito and Koch, 2010). Cortical hyperexcitability, which eventually leads to cell death (Martorana, Esposito and Koch, 2010) is primarily observed in the primary motor (M1) and premotor cortex, and DA seems to play a key role in this process particularly in M1 (Hosp et al., 2011; for a review see Pennisi et al., 2011). Dopamine is also directly related to several cognitive functions such as episodic memory, learning and executive functions (for a review see Bäckman et al, 2006), which are considered to be neuropsychological predictors of conversion from MCI to AD (Arnáiz and Almkvist, 2003). Therefore, alterations in the dopaminergic system observed in AD may contribute significantly to the progressive cognitive decline in pathological aging (for a review see Martorana et al., 2010). In this piece of work, we aimed at investigating DA activity in MCI, and its relationship to cognitive functions, by using a non-invasive marker, EBR. We expect that the group of MCI will have significantly lower EBR than the healthy controls. Also, we expect that EBR will be correlated with general cognitive functions, such as attention, and memory. 2. Method 2.1. Participants Thirty-six adults (23 females and 13 males) diagnosed with MCI, and 33 healthy controls (23 females and 6 males) participated in the study. Participants in the MCI were assessed according to the Petersen criteria (Petersen and Morris, 2005; for a review see Petersen et al., 2001). The Mini Mental State Examination (MMSE; Folstein, Folstein and McHugh, 1975) was used as a basic screening tool for MCI, but this
was complemented with the Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005) to increase sensitivity of diagnosis and classification (Nazem et al., 2009). Both groups were matched in age and years of education (see Table 1 for demographics and clinical characteristics). Exclusion criteria for both groups were: i) use of medication that could interfere with the function of the central nervous system and/or eyelid kinetics; ii) a score of 9 or above (for women) and 6 or above (for men) in the Instrumental Activities of Daily Living (IADL; Lawton and Brody, 1969); iii) a history of neurologic and/or psychiatric disorders other than MCI; iv) a score of 5 or above in the Geriatric Depression Scale (GDS short version; Sheikh and Yesavage, 1986); v) a history of substance abuse including alcohol and nicotine; and vi) severe mobility, hearing or vision problems which would impede participation in the study. The exclusion criteria were assessed via a detailed clinical interview of the participant and the caregiver (if applicable). All participants provided a signed informed consent of participation, after being fully informed on the study. The study was approved by the local Bioethics Committee. All participants were recruited from the Greek Association of Alzheimer's Disease and Related Disorders, as well as local day care centers via posters and oral presentations. This study was part of the screening process for the Long Lasting Memories (LLM) Project funded by the European Commission (ICT-CIP-PSP scheme) (see Bamidis et al., 2011; www.longlastingmemories.eu). 2.2. Material 2.2.1. Neuropsychological measures To assess cognitive status, we employed the MMSE and the MoCA tests. The MMSE, is the most widely used measure of global cognition especially in the geriatric population (Schultz-Larsen et al., 2007). It assesses functions such as orientation to space and time, visuospatial skills, praxis, attention and working memory as well as short-term memory, registration and language (for a review see Brayne, 1998). Since there is some controversy about the sensitivity of the MMSE to differentiate healthy individuals from individuals with MCI (Nazem et al., 2009; for a review see Tombaugh and McIntyre, 1992; Wind et al., 1997; Yochim et al., 2008), we used this assessment tool in combination with the MoCA. The MoCA was designed as a brief cognitive screening tool that assesses short-term memory, visuospatial abilities, several aspects of executive function, working memory, attention (sustained and executive), language and orientation to time and space. It covers more cognitive domains than the MMSE, and it is thought to be more sensitive to Mild Cognitive Impairment than the MMSE itself (Aggarwal and Kean, 2010). In addition, the following neuropsychological tests were employed to obtain specific measures of memory and executive attention; the Digit Span Backward task (Wechsler, 1981) and the Trail Making Test (part B) (Reitan and Wolfson, 1995), respectively. 2.2.2. Neurophysiological measure — EOG protocol Horizontal (electrodes lateral to the external canthi) and vertical (electrodes above and below the left eye) gold skin electrodes were Table 1 Demographic variables for study participants. Variables
Healthy
MCI
Age (years) Mean SD Range
67.48 6.14 56–81
67.56 7.28 57–85
Education (years)a Mean SD Range
9.43 4.23 6–16
8.23 5.13 6–17
a
SD = standard deviation. a Independent t-test: all N 0.05.
Please cite this article as: Ladas, A., et al., Eye Blink Rate as a biological marker of Mild Cognitive Impairment, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
A. Ladas et al. / International Journal of Psychophysiology xxx (2013) xxx–xxx
used for the electro-oculogram, according to past research (Colzato, van den Wildenberg and Hommel, 2008). The EBR was recorded for 6 min under resting conditions with eyes open. The data were derived from the two electrodes placed above and below the left eye.
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MMSE and the MoCA scores, r(67) = .466, p b .0001, and negative relation between the MoCA and the TMT B scores, r(67) = − .435, p b 0001, showing that better performance on the MoCA was associated with better (i.e. faster) performance on the TMT B (see Table 3). No other correlations reached statistical significance.
2.3. Procedure 4. Discussion Each participant was invited to an appointment, at the facilities of the Greek Association for Alzheimer's Disease and Related Disorders. While sitting in a quiet room, a psychologist fully explained the LLM study. Then, time was given for any clarification questions. All tests took place on the same day between 9 a.m. and 5 p.m., as research has shown that there are no diurnal variations in EBR in old adults (De Padova et al., 2009). The EOG recording was part of an electroencephalogram (EEG) testing procedure. The EBR was measured in the beginning of the EEG procedure, prior to the initiation of the EEG protocol. The order of the neurocognitive tests was counterbalanced across participants. Finally, participants were instructed to take a break between tests if needed. 2.4. Analyses The Matlab software was used to extract EBRs from the EOG recordings. We used a semi-automated algorithm, with the raw EOG signal as input to the algorithm. The EOGs were filtered to eliminate high-frequency noise that contaminated the data. Then a threshold parameter was set, indicating blink onset. An eye blink was defined as a sharp high amplitude wave of 100 V, of 500 ms, as in Colzato et al. (2009). The number of blinks, as well as, the blink rate were automatically computed and visually inspected and reconfirmed. Independent t-tests were used to see whether the cognitive state groups differ in mean EBR and/or test scores. To test for a relationship between EBR and cognitive performance we conducted Pearson correlations in the overall sample and adopted a stricter significance level (p = .01) to address the issue of multiple comparisons. 3. Results Means and standard deviations for both cognitive state groups (MCI, and healthy controls) are presented in Table 2. Results showed that the MCI group had significantly higher EBR than the Healthy controls group, t(67) = 2.146, p = .035, and significantly worse performance in the TMT B test than the Healthy controls, t(67) = 3.491, p = .001. However, there were no significant differences between the two groups on the Digit Span Backwards task. In addition, EBR scores were significantly negatively correlated with MoCA scores, r(67) = −.323, p = .007. That is, higher EBR were associated with worse overall cognitive performance as measured by the MoCA. There was also a significant positive correlation between the Table 2 Means and standard deviations (SD) for all dependent variables per cognitive state group. Variables
Healthy
MCI
EBR Mean SD
20.24 13.24
27.60 15.09
MoCA Mean SD
26.58 1.56
23.72 2.76
TMT B Mean SD
128.76 74.26
200.53 94.28
4.33 1.19
4.94 2.35
Digit span back. Mean SD
In the present study we employed a non-invasive biological measure, EBR, to investigate DA activity in MCI and its relationship to cognitive performance. This is the first study to report that adults with MCI have significantly higher EBR than healthy controls. Also adults with MCI performed significantly worse than healthy controls on the Trial Making Test (Part B), a test that it is thought to measure executive attention, among other functions (Reitan and Wolfson, 1995). Finally EBR scores were significantly associated with MoCA scores, that is the higher the EBR the worse the performance on the MoCA. To our knowledge this is the first time that EBR is measured specifically in an MCI group. However, there are very few studies in the literature investigating the validity of EBR as a biological marker of DA activity in healthy elderly people (Bentivoglio et al., 1997; Chen et al., 2003; De Padova et al., 2009; Karson, 1983; Karson et al., 1981, 1982; Sun et al., 1997). The mean age of individuals across these studies is 65.22 years old (SD = 11.2), which is very close to the mean age of the participants in this study (67.52). Most importantly, the mean EBR of all the samples in these published studies is 20.27 blinks/min, which is almost identical to the mean EBR (20.24 blinks/min) of the group of healthy controls in our study. Thus we can safely conclude that the MCI group has abnormally high EBR, and not the opposite (that the group of healthy controls has lower EBR than expected). The finding of abnormally high EBR in the group of MCI suggests an excess of DA activity in the central nervous system. It is not clear what the exact neural mechanisms are (e.g., location) that mediate the relationship between EBR and DA activity but animal studies support the role of D2 receptors in this relationship (Karson, 1983; Lawrence and Redmond, 1991; although see Van der Post et al., 2004 for a negative finding). Hence, administration of D2 receptor agonists and antagonists produces an increase and decrease in EBR, respectively. One more study has also suggested that the relationship between EBR and DA activity may be mediated by D1 receptors (Elsworth et al., 1991). Thus one plausible hypothesis is that the higher EBR observed in our sample of MCI participants may be due to abnormally high activity of DA receptors, although this needs to be confirmed by further studies. The finding of abnormally increased dopamine activity in participants with MCI is in contradiction with previous studies reporting a decline of dopamine activity with aging (Volkow et al., 1998), and loss of dopamine receptor activity in AD (Kemppainen et al., 2003), however it may fit well with the hypothesis of a overall neurotransmitter imbalance in the very early stages of AD. According to this hypothesis, a dysfunction of the cholinergic and dopaminergic systems is at the core of the cortical hyperexcitability observed in early stages of AD (for a review see Martorana et al., 2010). DA and Acetylcholine (Ach) do have a complex functional relationship though, and the exact mechanisms underlying the DA modulation of cholinergic activity have not been fully revealed yet. For instance, it has been proposed that while D1 receptors exert a Table 3 Inter-correlations for measures of Eye Blink Rate, MMSE, MoCA, TMT B and Digit Span Backwards task. Note the negative correlation between MoCA scores and EBR and MoCA and TMT B scores and the positive correlations between MMSE and MoCA scores. Pearson's r EBR MMSE MoCA TMT B
MMSE
MoCA
TMT B
Digit span back.
−.149
−.323⁎ .466⁎
.171 −.128 −.435⁎
.245 .105 −.192 −.060
⁎ p b 0.01.
Please cite this article as: Ladas, A., et al., Eye Blink Rate as a biological marker of Mild Cognitive Impairment, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010
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positive modulation of cortical cholinergic activity; D2 receptors negatively modulate Ach release in the prefrontal cortex (Brooks et al., 2007). Thus, it is possible that abnormally increased D2 receptor activity could add to cholinergic dysfunction in MCI, leading to cortical hyperexcitability and overall impaired cognitive performance. An alternative hypothesis may be that the finding of abnormally increased EBR in the MCI group, results from dopamine receptor upregulation due to early compensatory mechanisms. Similarly, other studies have reported hyperactivation in the prefrontal cortex and hippocampus of individuals with MCI, relative to healthy controls, as a result of early compensatory mechanisms (see for instance, Clément and Belleville, 2010). However, our study is not able to discriminate among these two hypotheses. As we predicted, EBR was also significantly correlated to MoCA scores: higher EBR was related to worse overall cognitive status. The finding of a significant relationship between MoCA scores and EBR, and not between MMSS and EBR, is in agreement with the higher sensitivity of the former to detect MCI (Nasreddine et al., 2005; Nazem et al., 2009; Sweet et al., 2011). We believe that the same hypothesis put forward to explain the finding of higher EBR in the MCI group, can also account for the relationship between EBR and MoCA scores. That is, higher DA function (higher EBR), and thus greater neurotransmitter imbalance, would result in worse overall cognitive performance in this group. This may account as well for the worse performance in executive attention (Trial Making test, Part B) observed in the MCI group as compared to the healthy control group (see Table 2). However, TMT part B scores were not correlated with mean EBR. This is an unexpected finding, since TMT-B is considered to be a measure of executive functions that have been linked to DA activity (for a review see Bäckman et al, 2006). Thus we were expecting to find a correlation between performance on TMT-B and EBR scores. An explanation for the present finding may be that DA activity and cognitive performance do not have a linear relationship. The predominant theory is that DA has a positive effect on cognitive function, particularly on functions that depend on the frontal lobe such as executive and motor functions. In support to this theory, many studies have reported worse performance on cognitive tests associated to reductions in DA activity as part of aging (Bäckman et al., 2000; Volkow et al., 1998). Also, administration of DA agonists improves cognitive performance in tasks of dual coding, reaction time, immediate and delayed recall (Schuck et al., 2002) and working memory (Luciana and Collins, 1997; Luciana et al., 1998) in young adults. However, studies done mostly with rats suggest that there may be an inverted “U” relationship between DA activity and cognitive performance: excessive as well as insufficient DA activity impairs cognitive function. For instance, it has been shown that high doses of D1 receptor agonists impair performance in working memory tasks, which are dependent on prefrontal lobe function as it is the case for the TMT-B, in rats (Zahrt et al., 1997). Our results fit well with this hypothesis. We found that participants with MCI have abnormally high EBR, which suggests excessive DA receptor activity. In addition, the MCI group had worse cognitive performance in the TMT-B than the group of healthy adults. Thus, in line with the inverted “U” shaped hypothesis, excessive DA receptor activity (abnormally high EBR) appears to have impaired performance in the MCI group. However, our study admittedly possesses certain limitations. For example, there has been no care for a differentiation between subtypes of MCI herein, although other studies have distinguished two main subtypes of MCI; these are amnesic and nonamnesic subtypes. In addition, we did not employ a second independent and more direct measure of DA activity in order to achieve a further confirmation on the exact mechanisms underlying the increased EBR in the MCI group. Thus, future studies need to be conducted to replicate this novel finding, but furthermore, test whether increased EBR is a neurobiological marker of all subtypes of MCI or not.
To sum up, this is the first study to investigate the likely role of EBR as a (potential) biological marker of DA activity, in the central nervous system, in adults with MCI. Our results show that EBRs are abnormally high, and thus support EBR as a valid index of neurotransmitters imbalance in early stages of dementia. EBR scores also correlate with scores in the MoCA test, which is a sensitive tool to detect MCI. This finding further strengthens the validity of EBR as a biological marker of pathological cognitive decline. Finally, it is crucial to carry out longitudinal studies to test whether EBR is a significant factor to predict progression from MCI to dementia. Conflict of interest All authors declare that they have no conflict of interest. References Ahmed, S., Arnold, R., Thompson, S.A., Graham, K.S., Hodges, J.R., 2008a. Names of objects, faces and buildings in mild cognitive impairment. Cortex 44, 746–752. 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Please cite this article as: Ladas, A., et al., Eye Blink Rate as a biological marker of Mild Cognitive Impairment, International Journal of Psychophysiology (2013), http://dx.doi.org/10.1016/j.ijpsycho.2013.07.010