MemTrax A game to measure memory and screen for memory impairment, particularly early Alzheimer’s disease

1. MemTraxA game to measure memory and screen for memory impairment, particularly early Alzheimer’s disease J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated), Department of Psychiatry and Behavioral Sciences Senior Research Scientist, Stanford / VA Aging Clinical Research Stanford University and VA Palo Alto Health Care System August 27-28, 2012 Slides at: www.medafile.com(Dr. Ashford’s lectures) MemTrax: www.memtrax.com ; www.memtrax.net ; www.memtrax.org

2. Episodic memory- Retentive memory • Specifically, information that is perceived then retained after distraction • Highly dependent on proper neuronal functioning of the medial temporal lobe of the brain

3. Alzheimer pathology affects regions of the cortex that have a high capacity and responsibility for memory storage Sensory, Perception, Memory systems of cortex – Ashford, Coburn, Fuster, 1998

4. Episodic memory • Disrupted by diseases that affect the medial temporal lobe: • Hypoxia • Ischemia (including vascular dementia), • Hypoglycemia, • Thiamine deficiency, • Alzheimer’s disease (AD), • which devastates this area early in it course

5. Dementia Definition • Multiple Cognitive Deficits: • Memory dysfunction • especially new learning, a prominent early symptom • At least one additional cognitive deficit • aphasia, apraxia, agnosia, or executive dysfunction • Cognitive Disturbances: • Sufficiently severe to cause impairment of occupational or social functioning and • Must represent a decline from a previous level of functioning

7. Discrete regions of the cerebral cortex are selectively affected by Alzheimer pathology Brun & Englund, 1986

8. Braak & Braak, 1991; Braak et al., 2006

9. Correlation analysis between brain perfusion (SPECT) and dementia severity (transformed from the MMSE) (Ashford et al., 2000). This finding is consistent with observations using numerous other modalities, e.g, PET Correlation Proportion of cortical area

10. Cholinergic Changes in AD - 1976 • The most prominent neurotransmitter abnormalities in AD are cholinergic • Reduced activity of choline acetyltransferase (synthesis of acetylcholine)1 • Reduced number of cholinergic neurons in late AD (particularly in basal forebrain)2 • Selective loss of nicotinic receptor subtypes in hippocampus and cortex1,3 1. Bartus RT et al. Science. 1982;217:408-414. 2. Whitehouse PJ et al. Science. 1982;215:1237-1239. 3. Guan ZZ et al. J Neurochem. 2000;74:237-243.

11. Cholineric Hypothesis of AD • Anti-muscarinic agents cause memory impairment – similar to AD • Cholinergic agents improve memory function • Acetyl-cholinesterase is decreased in the AD brain • 1976 – 3 studies show decreased choline-acetyltransferase in AD brain • 1981 - Loss of cholinergic neurons in nucleus basalis of Meynert in AD • Cholinergic agents considered for treatment – lecithin, agonists • Cholinesterase inhibitors (AChE ) considered for treatment of AD • 1st double blind study - physostigmine - Ashford et al., 1981 • 1st successful treatment of AD - physostigmine - Thal et al., 1983 • 4 AChEI medications subsequently approved by FDA for treating AD • AChEIs presumably increases acetylcholine at synapses • Improvement in cognition (? 6-12 months better) • Improvement in function (ADLs, variable) • Improvement in behavior (? basal ganglia) • Loss of nicotinic brain receptors is biggest chemical change in AD brain • Slowing of disease course • Treatment delays nursing home placement • There is loss of benefit with delay of treatment • May treat disease process, not just symptoms

12. Problems with the Cholinergic Hypothesis • Many cholinergic neurons throughout brain, spinal cord, but only discrete groups of ACh neurons are affected in AD • Numerous other neurotransmitter systems are affected in AD • Cholinergic agents are only modestly effective in treating AD, slowing progression • No clear relationship between acetylcholine and microscopic neuropathological features

13. Specific groups of cholinergic, serotonergic, and noradrenergic that project to the cortex, and glutamatergic and somatostatinergic GABA neurons of discrete cortical regions are selectively affected in Alzheimer’s disease Most affected) by AD -memory-write signal • Cortex • - Glutamate neurons • - highly affected by AD • - detail memory • - Rx: memantine • GABA neurons • - Somatostatinergic • neurons affected by AD • – memory modulation Rx: cholinesterase inhibitors (not affected by AD - movement) (Affected by AD -operant conditioning) (Affected by AD early - Classical conditioning)

15. Anti-amyloid therapies • No clear benefit from any therapies • Flurbiprofen – hi-price failure • Anti-bodies (do remove amyloid plaque) • Some question of relation to APOE genotype • Multi-billion dollar investments • All studies of anti-Abeta rx have failed!!! • Possible relationship to statins, NSAIDs • No therapeutic benefit shown, so why would starting earlier have benefit??

16. Neuropil Thread Pathology, which Occurs in Dendrites, is Composed of Hyperphosphorylated TAU Protein and mabe Linked Back to Intact Neuronal Cell Bodies Through Intact Dendrites, though the Neuropil Threads Appear to be able to Break the Dendrites, presumably Amputating all Distal Synapses Shown on the next slides is a view which reflects observations from a double labeling (with PHF-1 and MAP-2) analysis of neurons in the cortex affected by Alzheimer’s disease (Ashford et al., 1998).

17. Double-immunolabeling of posterior cingulate neurons for: • PHF-1 (brown stain) and • MAP2 (pink-purple stain) • A to L are from AD cases. • J is stained only for MAP2. • M is from a nondemented elderly. • See: http://www.medafile.com/jwa/JWA98npt.pdf

18. Progression of tau hyperphosphorylation to neuropil threads and neurofibrillary tangles Ashford et al., 1998, J Neuropathol Exp Neurol.57:972

19. intracellular extra cellular APP – formed during learning - XS in Downs Lipid raft Formed by cholesterol -Transported by ApoE (from macroglia) Iceland mutation APP-673 – no AD Stimulated by acetylcholine through muscarinic receptor Pathway to build new synapses Pathway to remove old synapses NEXIN Stimulates new synapse growth Amyloid –beta: ? Free-radical generator ? To destroy old synapses Turn-over – 8 hours Clearance – IDE, APOE AICD Favored when lipid raft too thick JW Ashford, MD PhD, 2012

20. Alzheimer Neuroplasticity Cascade Hypothesis • Genetic Factors – all related to APP • SNPs - related to APP/beta (strongest factors, but rare) • APOE genotype – related to APP management (most common) • APP 50% excess – Down Syndrome • APP cleavage control (neuroplasticity – APP switch) • Alpha stimulation failure (chemical causes, inadequate stimulation) • Beta degradation over-activity (caused by stress, excess new information) • AICD - APP-intracellular domain • Stimulates tau-hyperphosphorylation causing synapse retraction, forgetting • Gamma secretase modulation prevents AD (NSAIDs, statins) • Excess AICD causes Tau hyperphosphorylation – pTau, poor synapse formation • Poor synapse formation leads to memory failure • Excess pTau causes Paired helical filament (PHF) formation • PHF aggregation leads to Neuropil Thread formation • Neuropil threads cause dendritic amputation, breakage • Dendritic amputation causes massive synapse loss and dementia • Neuropil threads migrate back to cell body to cause tangles

21. Memory tests relevant to Alzheimer’s disease Memory Tests (examples of commonly used tests for assessing memory possibly related to dementia, see Larrabee & Curtiss, 1995): California Verbal Learning Test Hopkins Verbal Learning Test Buschke Selective Reminding Test Fuld Object Learning Test Rey Auditory Verbal Learning Test Benton Visual Retention Test Paired Associate Learning Brief Visuospatial Memory Test Rey-Osterreith Complex Figure (delayed recall) Wechsler Memory Scale Visual Paired Associates (with delayed test) Verbal Paired Associates (with delayed test) Paragraph recall

22. Computerized Cognitive/Memory Tests CANS-MCI - Alzheimer’s Screen Inc. - www.alzheimersscreen.com Hill, Emory - emory.hill@comcast.net Cognosis - Cantab www.cantab.com Cognitive Drug Research - CDR - www.cdr.org (Goring-on-Thames, UK) Wesnes, Keith - enquiries@cdr.org.uk Cognitive Screening Test – CST www.headminder.com CNS Vital Signs - www.cnsvs.com Boyd, Alan (CNS vital signs, NC, USA) - aboyd@cnsvs.com Cognometer - www.cognitivelabs.com Addicott, Michael Cognitive Labs - - Michael@cognitivelabs.com Cogstate - www.cogstate.com (Australia) Bick, Peter - PBick@cogstate.com Cognistat - www.cognistat.com Cognisyst - www.cognisyst.com (Durham, NC) Green, Paul; Allen, Lyle - research@cognisyst.com Cog Screen - www.cogscreen.com Kay, Gary - gkay@tidalwave.net CogTest - www.cogtest.com Sharma, Tonmoy - info@cogtest.com IntegNeuro Paul et al., 2005 Medical Care Corporation - www.mccare.com Shankle, William Rodman - rshankle@mccare.com - see on-line test: www.mccare.com/content/mcis/mcis_overview.html Medical Decision Logic, Inc Tien, Allen - allen@mdlogix.com Memtrax www.memtrax.com /.net /.org Ashford, J. Wesson - washford@medafile.com MicroCog Elwood, 2001 Powell, DH; Kaplan, EF, Whitla D, Weintraub S, Catlin R, Funkenstein HH NetMet - www.netneuromet.com Crooks, Thomas - info@netneuromet.com Neurotrax - www.neurotrax.com (MindStreams) Simon, Ely - info@neurotrax.com

23. Issues for Memory Screening Current testing for memory problems is based on having a tester sit in front of a subject for a prolonged period of time and administer unpleasant tests Testing must be Inexpensive (minimal need for administrator) Fun (so people will return for frequent testing) More precise, reliable, and valid To improve sensitivity To improve specificity

24. Need for Mass Screening Alzheimer’s disease, dementia, and memory problems are difficult to detect when they are mild about 90% missed early about 25% are still missed late There are important accommodations and interventions that should be made when there are cognitive impairments (like needing glasses or having driving restrictions if you have vision problems)

25. MemTrax Memory Screening Presentation of complex pictures (that are easily remembered normally) are useful for detecting memory difficulties Picture memory can be tested by computer, internet Continuous Recognition Testing (CRT) needs standardization for population use Picture memory is less affected by education Other types of stimuli – e.g., faces, figures, written words – symbolic vs. abstract – can be used Audiences can be shown slide presentations

26. MemTraxMemory GAME 50 pictures will be shown (usually there are 10 practice pictures that will be shown first, not now). When you see a picture for the first time, look at it carefully and try to remember it. If you recognize a picture that you have seen before, then respond as quickly as possible (tap space-bar) 1

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43. MEMTRAX Memory Test - answers 116 subjects – mostly elderly normals, some young, some dementia patients False positive errors (false recognition) – 33(64);6(58);47(27)—4,18,23,34(1);1,2,8(0) False negative errors (failure to recognize) – 35(33);27(20);5(16)—32(4);24(3);45(3)

44. The relationship between discriminability (d′) and age on the audience-based continuous recognition test of memory for 868 individuals with all information available Ashford, Gere, Bayley, Journal of Alzheimer’s Disease, 2011

45. The relationship between discriminability performance (d′) and age in 868 individuals on the continuous recognition test of memory- Showing Standard Errors of the Mean Ashford, Gere, Bayley, JAD, 2011

46. The relationship between discriminability performance (d′) and age in 868 individuals on the continuous recognition test of memory – Showing Standard Deviations Ashford, Gere, Bayley, JAD, 2011

47. The relationship between discriminability index (d′) and education in 868 individuals on the continuous recognition test of memory Ashford, Gere, Bayley, JAD, 2011

48. WEB-based ScreeningOn-line Testing Same test paradigm as Audience Screening Testing can be faster – 1-2 minutes for 50 images Many different variations of the test can be given Other aspects of cognition can be tested Test can be repeated frequently to decrease variance Test can be taken over time to detect changes Improved anonymity to protect private information

49. Screening Tests Available On-Line www.memtrax.com (clinical) www.memtrax.net (games) www.memtrax.org (research www.medafile.com (information) Slides at: www.medafile.com For further information, contact: Wes Ashford: washford@medafile.com