1. MemTrax A 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: (Dr. Ashford’s lectures)
MemTrax: ; ;

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
The associated decline of cognitive function in AD with decreased cholinergic neurotransmission in the cortex, hippocampus, and amygdala is the basis for what is known as the cholinergic hypothesis of AD
1. Bartus RT et al. Science. 1982;217:
2. Whitehouse PJ et al. Science. 1982;215:
3. Guan ZZ et al. J Neurochem. 2000;74:

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
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:

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

19. Stimulated by acetylcholine through muscarinic receptor
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. - Hill, Emory -
Cognosis - Cantab
Cognitive Drug Research - CDR (Goring-on-Thames, UK) Wesnes, Keith -
Cognitive Screening Test – CST
CNS Vital Signs Boyd, Alan (CNS vital signs, NC, USA) -
Cognometer Addicott, Michael Cognitive Labs - -
Cogstate (Australia) Bick, Peter -
Cognistat -
Cognisyst (Durham, NC) Green, Paul; Allen, Lyle -
Cog Screen Kay, Gary -
CogTest Sharma, Tonmoy -
IntegNeuro Paul et al., 2005
Medical Care Corporation Shankle, William Rodman see on-line test:
Medical Decision Logic, Inc Tien, Allen -
Memtrax /.net /.org Ashford, J. Wesson -
MicroCog Elwood, 2001
Powell, DH; Kaplan, EF, Whitla D, Weintraub S, Catlin R, Funkenstein HH
NetMet Crooks, Thomas -
Neurotrax - (MindStreams) Simon, Ely -

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. MemTrax Memory GAME 1
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)

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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
The relationship between discriminability (d′) and age on the audience-based continuous recognition test of memory. Each data point represents the recognition score of an individual participant expressed as a discriminability index d′. One individual whose score was unusually poor (d’ = -2.64) was removed from the plot.
Ashford, Gere, Bayley, Journal of Alzheimer’s Disease, 2011 44

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
The relationship between discriminability performance (d′) and age in 868 individuals on the continuous recognition test of memory. Numbers inside the bars indicate the group n. The bars show the mean discriminability score for each age group and brackets show SEM.
Ashford, Gere, Bayley, JAD, 2011 45

46. The relationship between discriminability performance (d′) and age in 868 individuals on the continuous recognition test of memory – Showing Standard Deviations
The relationship between discriminability performance (d′) and age in 868 individuals on the continuous recognition test of memory. Numbers inside the bars indicate the group n. The bars show the mean discriminability score for each age group and brackets show one standard deviation on either side of the mean.
Ashford, Gere, Bayley, JAD, 2011 46

47. The relationship between discriminability index (d′) and education in 868 individuals on the continuous recognition test of memory
Numbers inside the bars indicate the group n. The bars show the mean discriminability score for each age group and brackets show SEM.
Ashford, Gere, Bayley, JAD, 2011 47

48. WEB-based Screening On-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
(clinical)
(games)
(research
(information)
Slides at:
For further information, contact:
Wes Ashford: