Running Head: THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 1 The Assessment of Spatial and Non spatial Search Strategies: Using a Human Analog to the Morris Water Task to Assess Spatial and Non spatial Search Strategies Among Healthy Young Adults, Healthy Adults, Those with Amnestic Mild Cognitive Impairment, and T hose with Terra Mills The University of Florida
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 2 Abstract Spatial learning and memory involves the learning of locations within environments. Spatial learning and memory problems are often an initial sign of neurodegenerative processes, particularly in (AD). However, this domain is rarely asse ssed in routine neuropsychological evaluations. The Morris Water Task is used to test spatial learning in animals, and identifying strategies used to complete the task can provide useful information. Using a human analog to the Morris Water Task, we develo ped a novel and reliable protocol to identify spatial versus non spatial search strategies. Participants included: young healthy adults, older healthy adults, amnestic mild cognitive impairment (aMCI), and AD. A bootstrapped ANOVA and planned contrasts sh owed significant differences between younger and all other groups (p<.001) but not between aMCI and AD (p=.072) or between healthy older and the cognitively impaired groups (p=.155) on a composite performance variable. There were significant differences i n spatial strategy use between younger and all other groups (p<.001) but not between aMCI and AD (p=.833) or between healthy older and the cognitively impaired groups (p=.108). The proportion of spatial strategies used gave significant information to the p redictive model for performance over and above that provided by group membership (F change (1, 55 ) = 6.230, p<.05). Results were consistent with the hypothesis that young adults would have better performance and use spatial strategies more often; however, t he lack of significant differences between the other groups was unexpected. This may indicate a general overall decline in spatial memory that occurs with age and does not change significantly with neurodegenerative disease
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 3 Introduction Disease Pathology and senile plaques in the brain ( Braak & Braak 1991 ). The tangles are formed by tau protein fibers and the plaques are formed by be t a amyloid proite in fragments (Sperling, et al., 2011) The plaques and tangles disrupt synaptic connections among neurons in the brain, and cognitive functioning typically declines. The damage from AD starts in the medial temporal lobe (hipp o campus largely affected), and then advance s to the frontal, temporal, and parietal association cortices and limbic regions as the disease progresses eventually affecting activities of daily living ( Sperling, et al., 2011) Most people develop some plaques and tangles as they age; howe ver, those with AD develop far more and memory and cognitive function is affected Public Health Burden age, AD will become a widespread concern in the US, and, indeed, the world AD is the sixth leading cause of death in the United As a large percentage of the population ages, health care expenditure for AD is projected to increase from the current $200 billion to ne Association, 2012). Included with this will be a 500% increase in medicaid and medicare spending. Researchers in the medical field are now working to identify risk factors for AD and to identify those who mi ght be at risk. The hopes are that early medical intervention for those identified could slow or prevent the eventual de v leopment of AD therefore, decreasing the future health care expenditure s. Slowing the effects of AD would reduce health care costs by
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 4 preventing AD would not only save money when it comes to health care expenditure, but it would also save liv es and improve the health of the US population Amnestic Mild Cognitive Impairment Mild cognitive impairment can be experienced by people in their daily lives; however, the changes are not severe enough to interfere with idependent functioning. Amnestic mild cognitive impairment (aMCI) is a type of mild cognitive impairment that primarily affects memory (Fischer, et al., 2007) Because the cognitive changes are not severe enough to disable the affected person in everyday life, they do not meet the diagnos tic criteria for dementia. Those with aMCI have an increased risk of eventually developing AD but not all people with aMCI will convert to AD or even decline over time ( Fischer, et al., 2007; Tabert, et al., 2006) AMCI is believed to result from brain changes occuring in the early stages of AD or other forms of dem entia. Current research looks to predict outcomes of aMCI and to understand the underlying brain changes associated with its pathology Spa tia l Navigation Spatial learning and memory is a type of episodic memory characterized by the learning of locations within environments or object location associations ( Dickerson & Eichenbaum, 2010) In order for spat ial learning and navigation to occur, visual, auditory, and tactile input is perceived in the medial temporal lobe ( Moser, Kropff, & Moser, 2008 ) The identification and encoding of objects in an environment occurs in a network of connections involving the entorhinal cortex, hippocampus in the medial temporal lobe, among the first regions to be affected by AD pathology. Therefore, spatial memory, l earning, and navigation is one of the earliest noted symptoms of AD. Measures that detect deficits in this area of the brain could be
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 5 useful in detecting preclinical AD and those at risk of developing AD. Getting lost and spa tial disorientation can be seen by patients or their family members as an early marker of AD. The Virtual Morris Water Maze The Morris Water Maze (MWM) was originally used to study rodents and their ability to navigate to a n escape platform partly submerged in a circular pool with opaque water. In this task, animals display the ability to use distal environmental cues in the MWM environment to develop a spatial map of the environment. Over trials, they can use these cues to locate the escape platform more ef ficiently Healthy animals have no difficulties in finding the platform multiple times and remembering its location. However, animals with hippocampal lesions appear to be impaired in the spatial mapping demand, having difficulties in locating the platform more efficiently over time (Moffat & Resnick, 2002) Transgenic mice that express genes implicated in AD, develop aspects of the neuropathology of AD, and develop some of the cognitive impairments common in the disease (Eriksen & Janus, 2007) also show impairments in learning and memory on the Morris water maze Adaptations of the MWM have been developed for humans, and they have replicated findings from animal studies. The task is used in a virtual form for obvious logistical reasons, and because virtual presentation makes it easier to better control the environment and to cue environmental manipulations (Moffat, 2009) Performance in the virtual environment has be en shown to correlate with real life route learning and spatial memory in healthy adults, older adults, and those in different stages of AD (King, 2010) Studies have show n that older adults have more difficulties when performing the task compared to young er adults incuding using longer path lengths and difficulty creating a map of the environment at the concl u sion of the task ( King, 2010). The Computer Generated Arena (CG Arena) has proved to be a reliable virtual
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 6 MWM task that mimics all key features of t he MWM paradigm (rectangualar room with distal platform that provides escape and ends each trial) while precisely measuring dimensions of performance shown to be sen sitive to age related change, temporal lobe hippocampal damage TBI, and other neurological conditions (Thomas, Laurence, Luczak, & Jacobs, 1999). The CG Arena is a first person rendering of the MWM environment which the participant navigates with a joystick. Several acquisition trials take place in which the participant attempts to find a stationary hidden platform beginning at sev eral compass points located along the wall. On the time spent navigating in the proximal quadrant of the circular arena is measures. The CG Arena program pro vides a full rendering of the path each participant take to the platform on each of the acquisition When placed in the MWM environment, rodents adopt a number of strategies for finding the platform, some based on spatial cues (e.g., local searching in the quadrant containing the platform) and some nonspatial in nature (e.g., hugging the wall, or swimming at a constant distance from the wall until the platform is encountered). Spatial strategies seem to be most vulnerable to neurodegenerative changes, having been tested in the CRND8 mouse model of amyloidosis (Janus, 2004). The current study evaluated the use of spatial and nonspatial strategies for finding the hidden platform, using a classification scheme for describing the qualitative nature of search paths based on Janus (2004) and sought to determine whether a transition from normal aging to mild cognitive impairment to degenerative dementia stra tegies.
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 7 As a preliminary step toward this investigation, we developed a reliable and easily trainable rating protocol that is applicable to both human and animal behavior that enables each search path to be classified as spatial vs. nonspatial. It is hop ed that evaluation of specific search strategies would have the potential to be sensitive to early abnormalities in the medial temporal lobe spatial learning and memory system as a possible early behavioral indicator of AD pathology. Method The participant s for the study were recruited from two main sources. Some (N=16 ) were patients of the UF Cognitive and Memory Disorders program who underwent interdisciplinary evaluation of cognitive complaints consisting of neurological and laboratory examination, hig h resolution MRI, and comprehensive neuropsychological examination. All data was discussed at the weekly Dementia Con s ensus Conference at Shands Hospital where a consensus diagnosis disease were contacted and invited to participate. The current investigation enrolled 9 aMCI participants and 7 participants with Alzhei Additional healthy participants were recruited from the community as part of a previous study (King, 2010), and consisted of 22 younger (average age 22.83) and 27 older (average age 75.78) adults. Table 1 contains key participant demograph ics. Each participant signed an informed con se nt agreement after the study was thouroughly explained to them. The CG Arena was presented on a desktop/laptop computer attached to a joystic adjacent to their dominant hand. After a standard practice session in which they familiarized themselves with the CG Arena environment, participants underwent eight acquisition trials and a final probe trial. The computer software recorded their search paths and they were later reviewed and categorized by multiple quali fied individuals. W e developed a novel and reliable protocol to identify spatial versus non spatial search strategies. In addition, a
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 8 composite CG Arena performance score was calculated by separately z transforming (a) the number of target acquisitions, ( b) the average path length, and (c) the percent of time spent in the target quadrant during the probe trial and then averaging these three z scores. Results The final 0.784, p < .001, which indicates substantial agreement among raters A 1000 sample bootstrapped ANOVA showed that there were no significant differences between groups based on education [F(4,70)=0.293, p=.882, although, as expected, the young healthy group was significantly younger than all other groups [F(4,70)=181.377, p<.001, all post hoc tests significant at p<.001 with Bonferroni p=.403), there were significantly more non African American raci al/ethnic minorities among the A 1 way (Group) 1000 sample bootstrap ped ANOVA showed a significant group difference in the percentage of trials displaying a spatial strategy, F (3, 56)=27.489, p<. 001 Planned contrasts showed significant differences between younger and all other groups (p<.001) but not between aMCI and AD (p=.833) or between healthy older and the cognitively impaired groups (p=.108). Figures 1 4 depict trial by trial use of spatial and nonspatial strategies in Healthy Younger (Fig. 1), Healthy Older (Fig 2), aMCI (Fig. 3), and AD (Fig. 4) participants. Contr olling for psychomotor speed, there was also a group difference in the compos ite Arena performance score, F(4, 52)=10.554, p<.001 Table 2 provides means and standard deviations of each of the constiuent variables and the composite score for each of the groups. Planne d c ontrasts showed significant differences between younger and a ll other groups (p<.001) but not between aMCI and AD (p=.072) or between healthy older and the cognitively impaired groups (p=.155). Using bootstrapped hierarchical regressions, p s y chomotor speed was not a significant predictor when included with Group to
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 9 predict Arena performance. However, proportion of spatial strategies used did give new and significant information to the predictive model for performance over and above that provided by group membership ( R 2 change=.067, F (1, 55)=6.230, p<.05) and was part of a significant overall model (F(2, 54)=19.438, p < .001) that explained 39.7% of the variance in Arena performance. Conclusion Results suggested that young adults ha d better performance and use d spatial strategies more often than all other groups in navigating to a hidden platform in a virtual MWM. The lack of difference between healthy elders, aMCI, and AD participants was unexpected. This may indicate a general overall decline in spatial memory that occurs with age and doe s not further change significantly with neurodegenerative processes. For this study, it was hoped that CG Arena performance would be detectably different in the aMCI group than in the healthy elder group as a sign of preclinical decline in spatial memory f unction at a point in which the patient would not meet diagnostic criteria for dementia. To be useful, behavioral biomarkers such as CG Arena performance or search path data should detect incipient decline or risk in persons prior to the development of AD symptoms or pathology. The fact that planned contrasts failed to discriminate between healthy elders and the two clinical groups raises some doubt with respect to the effectiveness of the CG Arena in this regard. Strengths of the study were (a) the relia ble protocol with training documents that could be shared between researchers to classify both human and animal behavior and (b) the well classified group s based on comprehensive clinical evaluations including neurological exam, laboratory workup, high res olution neuroimaging, and neuropsychological examination. A weakness of the study was the small sample size. More differences might have been determined between the groups of healthy young adult, healthy adults, those with aMCI, and
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 10 those with AD is a larg er sample size was used. An increased sample size in future research would increase the power to detect significant differences between the groups.
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 11 Table 1 Participant Demographics Healthy younger Healthy older aMCI AD N 23 27 9 7 Age Mean(SD) 22.83 (2.25) 75.78 (7.55) 67.89 (8.25) 73.57 (11.18) Gender (% female) 60.87% 60.71% 77.78% 85.71% Race (% Caucasian) 73.91% 100% 88.89% 85.71% Education Mean years(SD) 15.26 (1.42) 15.51 (2.95) 15.44 (2.56) 14.43 (2.30)
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 12 Table 2 Arena Performance Healthy younger Healthy older aMCI AD Composite Mean Z score (SD) .28 ( .14 ) .15 ( .33 ) .09 ( .31 ) .5 ( .32 ) Target acquisitions Mean(SD) 6(0) 3.48(1.7) 4.6(1.34) 3.25(1.26) Average path length Mean(SD) 117.7(40.28) 396.08(157.42) 385.87(224.9) 432.42(134.79) % time probe Mean(SD) 82.92 ( 10.89 ) 45.45 (2 3 46 ) 33.2 ( 19.68 ) 13.61 ( 15.27 )
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 13 0 10 20 30 40 50 60 70 80 90 100 T1 T2 T3 T4 T5 T6 T7 T8 T9 Percent Trial Younger Adults Non-spatial Spatial Figure 1 : Proportion of spatial (dark gray) and nonspatial (light gray) strategies used on each acquisition trial (T1 T8) and the probe trial (T9) in the Younger Adult Group
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 14 0 10 20 30 40 50 60 70 80 90 100 T1 T2 T3 T4 T5 T6 T7 T8 T9 Percent Trial Older Adults Non-spatial Spatial Figure 2: Proportion of spatial (dark gray) and nonspatial (light gray) strategies used on each acquisition trial (T1 T8) and the probe trial (T9) in the Older Adult Group
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 15 0 10 20 30 40 50 60 70 80 90 100 T1 T2 T3 T4 T5 T6 T7 T8 T9 Percent Trial aMCI Non-spatial Spatial Figure 3: Proportion of spatial (dark gray) and nonspatial (light gray) strategies used on each acquisition trial (T1 T8) and the probe trial (T9) in the aMCI Group
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 16 0 10 20 30 40 50 60 70 80 90 100 T1 T2 T3 T4 T5 T6 T7 T8 T9 Percent Trial AD Non-spatial Spatial Figure 4 : Proportion of spatial (dark gray) and nonspatial (light gray) strategies used on each acquisition trial (T1 T8) and the probe trial (T9) in the AD Group
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 17 References Alzheimer's Association (2010). Changing the trajectory of Alzheimer's disease: A national imperative Chicago, IL. Braak, H., & Braak, E. (1991). Neuropathological stageing of Alzheimer related changes. Acta Neuropathol, 82 (4), 239 259. Dickerson, B. C., & Eichenbaum, H. (2010). The episodic memory system: neurocircuitry and disorders. Neuropsychopharmacology, 35 (1), 86 104. Eriksen, J. L., & Janus, C. G. (2007). Plaques, tangles, and memory loss in mouse models of neurodegeneration. Behav Genet, 37 (1), 79 100. Fischer, P., Jungwirth, S., Zehetmayer, S., Weissgram, S., Hoenigschnabl, S., Gelpi, E., et al. (2007). Conv ersion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology, 68 (4), 288 291. Janus, C. (2004). Search strategies used by APP transgenic mice during navigation in the Morris water maze. Learn Mem, 11(3), 337 346. King, E. G. (2010). Age differences and spatial navigation in novel virtual and real world environments. Unpublished doctoral dissertation, University of Florida, Gainesville, Florida. Moffat, S. D. (2009). Aging and spatial navigation: what do we know and where do we go? Neuropsychol Rev, 19 (4), 478 489. Moffat, S. D., & Resnick, S. M. (2002). Effects of age on virtual environment place navigation and allocentric cognitive mapping. Behav Neurosci, 116 (5), 851 859. Moser, E. I., Kropff, E., & Moser, M. B. ( 2008). Place cells, grid cells, and the brain's spatial representation system. Annu Rev Neurosci, 31 69 89.
THE ASSESSMENT OF SPA T IAL AND NON SPA T IAL SEARCH STRATEGIES 18 Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., et al. (2011). Toward defining the preclinical stages of Al zheimer's disease: recommendations from the National Institute on Aging Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement, 7 (3), 280 292. Tabert, M. H., Manly, J. J., Liu, X., Pelton, G. H., Rosenblum, S., Jacobs, M., et al. (2006). Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive impairment. Arch Gen Psychiatry, 63 (8), 916 924. Thomas, K.G., L aurance, H.E., Luczak, S.E. & Jacobs, W.J. (1999). Age related changes in a human cognitive mapping system: data from a computer generated environment. Cyberpsychol Behav, 2(6) 545 566.