1. Speed of processing, the missing measure in early detection of MCI? Ruth O’Hara March 13 th 2001 Yogesh Shah

2. MCI Introduction Early detection Speed of processing Study Conclusions

3. 2001 and beyond $100 Billion/year Delay 2 years – 2 million less AD Delay 6 months – $ 6 billion/year

4. Early Detection Detection of preclinical cognitive deficits is important for identifying those at risk for Alzheimer’s Neuropsychological measures may not be sufficiently sensitive to preclinical cognitive impairment

5. Normal Speed of Processing Decline

6. Millisecond Difference “… the speed of memory performance may be the first aspect of the memory system to decline as the system begins to fail.” Int’l Jnl Ger Psychiatry, Vol. 10: 199-206 (’95) “… traditional tests for dementia were relatively ineffective for identifying its early forms. The only effective assessment… is one that measures both speed & accuracy.” Int Psychogeriatr, 1996;8(3):397-411

7. Millisecond Difference “…research suggests that speed of performance may reflect the efficiency of mental processes.” Nature Neuroscience 2000; 3:509-515 “… speed scores identify impairments that would otherwise be missed using traditional measures. …speed scores on measures of attention & memory… identify patients with MCI”. Research & Practice In Alzheimer’s Disease, Vol. 3, 2000

8. Millisecond Difference A few 100ms in processing speed may spell the difference between healthy & “unhealthy” brain

9. Slower Reaction Time on Memory Tasks is Associated with Presence of the Apolipoprotein E4 allele: A Brief Report Ruth O’Hara, Ph.D.,1 Barbara Sommer, M.D., 1 Helena C. Kraemer, Ph.D., 1 Jerome Yesavage, M.D., 1,2 Joy Taylor, Ph.D., 1,2 Kevin Morgan, B.A., 1 and Greer Murphy, M.D., Ph.D. 1 1 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA 2 VA Palo Alto Health Care System, Palo Alto, CA Info@cogcare.com

10. Reaction Time The ability of a computerized battery of neurocognitive tests (Cognometer) to differentiate between the cognitive performance of subjects with and without the  4 allele.

11. Abstract Detection of preclinical cognitive deficits is important for identifying those at risk for Alzheimer’s disease, but available neuropsychological measures may not be sufficiently sensitive to preclinical cognitive impairment, particularly in high functioning, younger older adults. Utilizing a battery of computerized cognitive tests designed to provide a more sensitive measure of age-related cognitive performance, we compared the performance of 10 older adults with the AD risk-factor Apolipoprotein e4 allele with 17 older adults without the e4 allele. This battery includes measures of attention, sensory-motor, visuospatial, working memory (executive) and delayed memory function, which incorporate reaction time components that reflect information-processing speed. The e4 group was significantly slower in performing all delayed memory and specific working memory tasks, although no significant differences were observed between the groups with respect to accuracy on almost all these measures. This suggests that reaction time performance on such memory and working memory measures might be able to detect subtle cognitive deficits, particularly in younger, older adults.

12. Abstract The  4 group was significantly slower in performing all delayed memory and specific working memory tasks, although no significant differences were observed between the groups with respect to accuracy.

13. Abstract Reaction time performance on memory measures might be able to detect subtle memory deficits, particularly in younger, older adults

14. Method 10 older adults with Apolipoprotein  4 allele with 17 older adults without the  4 allele AGE- 74.6 EDU- 16.2 MMSE-26

15. Stanford Apolipoprotein E4 allele Cognometer Study Mean Reaction Times in Milliseconds E4(n=10)NON-E4(n=17)P Value Physical Reflexes344.9 (77.5)303.2 (47.1).09 Perceptual Reflexes 482.5 (102.2)401.6 (77.9).03 Running Memory1161.6 (174.8)929.5 (154.5).001 *Working Memory Speed 3168.7 (1489.5)2021.4 (693.9).01 Working Memory Capacity 1788.9 (620.7)1256.7 (272.7).001 Delayed Memory1562.9 (309.0)1096.5 (220.7).001 Immediate Memo1730.9 (414.7)1151.7 (282.1).001 *Executive decision-making, “set switching” task

16. Individuals with the Apolipoprotein E4 allele Exhibit Significantly Slower Reaction Times on Cognometer Tests

17. Reaction Time-conclusion Individuals with the  4 allele have greater difficulty with the information processing involved in executive and memory functions

18. Reaction Time-conclusion Reaction time performance on memory measures might be able to detect subtle memory deficits, particularly in younger, older adults

19. Current issues -MCI… Is there a frontal, executive deficit in MCI? Are standard neuro-psych instruments sensitive to working memory deficits? Can reaction time measures be meaningful outcome in anti-dementia drug trials?

21. MCI – is there also a frontal, executive deficit? ADCS* – “patients with MCI perform worse on memory measures…. But equal to healthy people in other cognitive areas.” Stanford ApoE4 study (et al)** suggests working memory processing speed may also be a meaningful MCI measure. * Alzheimer’s Disease Cooperative Study **“speed scores on measures of attention & memory… identify patients with MCI”; Research & Practice In Alzheimer’s Disease, Vol. 3, 2000

22. “…experience with cholinesterase inhibitors shows that other outcome measures may be more sensitive to drug effects… reaction time measures can be meaningful outcome measures in anti-dementia drug trials.” Lancet, Vol. 356, December 16, 2000; Dr. Jeffrey Cummings, Dept. of Neurology, UCLA