CAS’s Basic Technology

CAS technology is non-invasive and non-intrusive; the only direct contact with the patient is through their manipulation of a one handed steering wheel with a knob called a manipulandum. The patient sits in front of a computer screen and watches the automated presentation of computer generated displays that highlight various locations on the screen. The patient moves the manipulandum to indicate the highlighted location.

We continually change the strength of the highlighting perceptual signal by mixing that signal, designed to activate a particular cortical area, with a type of noise that impedes that activation. We continually monitor the patient’s accuracy in their ability to indicate the highlighted location on the computer screen.

The continual monitoring of the patients’ indication of the perceived stimulus allows us to assess the information processing capacity of the cortical area responsible for function in the selected stimulus domain. In effect, CAS technology is testing cortical circuits by inserting a signal and monitoring the response.

Importantly, the CAS approach to testing makes it independent of the patient’s language capabilities, and cultural, ethnic, educational, or socioeconomic background. Moreover, the testing environment does not effect results.

The Clinical Origins of CAS

CAS originated in the coherence of three types of experience: direct care of patients with late-life cognitive decline, the literature on cognitive aging and Alzheimer’s disease, and ongoing basic and clinical scientific research.

Alois Alzheimer recognized the diverse focal onset and multi-focal progression of late-life cognitive decline (Alzheimer et al., 1995). Most of the symptoms of the disease that now bears his name reflect posterior hemispheric dysfunction. We often recognize these patients by their readily verifiable, and symptomatically prominent, verbal memory disorder. Just as often they present after becoming lost in familiar settings, having trouble recognizing objects, or having increasingly limiting language disorders. (Cummings, 2000)

CAS’s Links to AD Neuropathology

The distribution of the neuropathological markers of Alzheimer’s disease is consistent with its diverse clinical presentations. Two widely recognized forms begin in either mesial temporal areas or in posterior cortical areas. In either case, AD neuropathology spreads to involve both regions and eventually invades most of the cortical and sub-cortical cerebral hemispheres (Brun and Englund, 1981). This diversity of symptoms and progression poses a tremendous problem for early detection and clinical management.



Lessons from Cellular Neurophysiology

The cellular neurophysiology of posterior association cortex, explored in non-human primates, reveals several relevant aspects of cortical neuronal information processing:

• Specialized analysis of particular signals
• Disruption by particular patterns of noise
• Modulation by high-level cognitive factors

Together, these findings suggested that cortical function can be assessed by presenting stimuli that are designed to activate specific neuronal populations. Those stimuli can be inter-mixed with signals that are randomized in the target domain and varied to define signal/noise sensitivity in that domain. (Duffy et al., 2005)

Early Results from CAS Technology

Initially, CAS’s cognitive psychophysics focused on characterizing the role of posterior cortical information processing impairments in the syndrome of spatial disorientation in AD. This work tested the hypothesis that spatial disorientation in AD reflects focal deficits in posterior cortical analysis of optic flow, the patterned visual motion that guides our self-movement during ambulatory and vehicular transit. Studies of young and older adult subjects and AD patients revealed selective impairments in the ability of the AD patients to discern the simulated heading direction in an optic flow field, the critical visual cue needed to judge the direction of self-movement.

Further analysis revealed that AD patients can be classified in to two symptom sub-types: Some AD patients show tremendous impairments of visual motion processing, whereas other AD patients show visual motion processing capacities much like those seen in neuropsychologically healthy older adults. These findings indicated that cognitive psychophysics can not only detect selective impairments, but quantify the severity of those impairments within diagnostic groups (O'Brien et al., 2001).

Linking CAS to the Real World Deficits

The spatial disorientation of many early AD patients (~40%) is debilitating because it forces them to give-up driving and independent living. CAS addresses this limiting symptom complex with a specialized virtual reality navigational test battery. This system first presents a virtual excursion through an architectural environment and then presents a short battery of tests about that environment and the excursion route.


This testing system has been shown to detect navigational impairment in both cognitive aging and AD with a close correlation with real-world navigational impairment. Age-related declines in navigational performance are evident in comparisons of young (YNC), older normal controls (ONC), mild cognitive impairment (MCI), and AD patients. (Cushman et al., 2008)

Linking CAS to Cortical Function

To assess links between impaired optic flow perception and cortical pathophysiology we developed a new type of scalp recorded visual evoked potential using the same types of optic flow stimuli used in CAS’s cognitive psychophysics tests. These studies revealed that AD patients show substantially decreased posterior cortical N200 evoked responses to optic flow, suggesting a focal processing impairment as detected in CAS testing.



The close relationship between CAS psychophysics, cortical neurophysiology, and real world behavioral issues in AD is illustrated by a model that links all three. In this analysis, the results of real world navigational testing was predicted by a multiple linear regression model that included CAS psychophysical test results and optic flow evoked potentials that were obtained in older adults and AD patients.

The stepwise regression analysis independently selected three variables from the many measures included in the data set. The selected variables were optic flow psychophysical threshold scores, optic flow evoked potential amplitudes, and visual contrast sensitivity. Together, these variables predicted navigational test scores with an R2 = .95; the analysis also identified two AD group outlier subjects who performed more poorly then predicted by these variables. (Kavcic et al., 2006)

Summary

CASscan is a new technology for the in-office, automated detection of cognitive impairment. In 15 minutes of testing, this technology yields quantitative cerebral function profiles shown to be related to the real-world impairments and cortical pathophysiology of AD. The physician receives a report immediately after testing and is able to integrate that information into further diagnostic and therapeutic planning.

Reference List

Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat 8:429-431.

Brun A, Englund E (1981) Regional pattern of degeneration in alzheimer's disease: neuronal loss and histopathological grading. Histopathology 5:549-564.

Cummings JL (2000) Cognitive and behavioral heterogeneity in Alzheimer's disease: seeking the neurobiological basis. Neurobiol Aging 21:845-861.

Cushman LA, Stein K, Duffy CJ (2008) Detecting navigational deficits in cognitive aging and Alzheimer disease using virtual reality. Neurology 71:888-895.

Duffy CJ, Page WK, Froehler MT (2005) Posterior cortical processing of self-movement cues: MSTd's role in Papez's circuit for navigation and orientation. In: Head Direction Cells and the Neural Mechanisms of Spatial Orientation (Taube JS, Wiener SI, eds), pp -480. Cambridge: MIT Press.

Kavcic V, Fernandez R, Logan DJ, Duffy CJ (2006) Neurophysiological and perceptual correlates of navigational impairment in Alzheimer's disease. Brain 129:736-746.

O'Brien HL, Tetewsky S, Avery LM, Cushman LA, Makous W, Duffy CJ (2001) Visual mechanisms of spatial disorientation in alzheimer's disease. Cerebral Cortex 11:1083-1092.