Title: MemTrax A game to measure memory and screen for memory impairment, particularly early Alzheimer
1MemTraxA game to measure memory and screen for
memory impairment, particularly early Alzheimers
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. Ashfords
lectures) - MemTrax www.memtrax.com www.memtrax.net
www.memtrax.org
2Episodic 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
3Alzheimer 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
4Episodic memory
- Disrupted by diseases that affect the medial
temporal lobe - Hypoxia
- Ischemia (including vascular dementia),
- Hypoglycemia,
- Thiamine deficiency,
- Alzheimers disease (AD),
- which devastates this area early in it course
5Dementia 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
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7Discrete regions of the cerebral cortex are
selectively affected by Alzheimer pathology
Brun Englund, 1986
8Braak Braak, 1991 Braak et al., 2006
9Correlation 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
10Cholinergic 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. 1982217408-414.
2. Whitehouse PJ et al. Science.
19822151237-1239. 3. Guan ZZ et al. J
Neurochem. 200074237-243.
11Cholineric 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
12Problems 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
13Specific 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 Alzheimers 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)
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15Anti-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??
16Neuropil 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 Alzheimers 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
18Progression of tau hyperphosphorylation to
neuropil threads and neurofibrillary tangles
Ashford et al., 1998, J Neuropathol Exp
Neurol.57972
19intracellular
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 remove old synapses
Pathway to build new 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
20Alzheimer 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
21Memory tests relevant to Alzheimers 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
22Computerized Cognitive/Memory Tests
- CANS-MCI - Alzheimers Screen Inc. -
www.alzheimersscreen.com Hill, Emory -
emory.hill_at_comcast.net - Cognosis - Cantab www.cantab.com
- Cognitive Drug Research - CDR - www.cdr.org
(Goring-on-Thames, UK) Wesnes, Keith -
enquiries_at_cdr.org.uk - Cognitive Screening Test CST
www.headminder.com - CNS Vital Signs - www.cnsvs.com Boyd, Alan (CNS
vital signs, NC, USA) - aboyd_at_cnsvs.com - Cognometer - www.cognitivelabs.com
Addicott, Michael Cognitive Labs - -
Michael_at_cognitivelabs.com - Cogstate - www.cogstate.com (Australia) Bick,
Peter - PBick_at_cogstate.com - Cognistat - www.cognistat.com
- Cognisyst - www.cognisyst.com (Durham, NC)
Green, Paul Allen, Lyle - research_at_cognisyst.com
- Cog Screen - www.cogscreen.com Kay, Gary -
gkay_at_tidalwave.net - CogTest - www.cogtest.com Sharma, Tonmoy -
info_at_cogtest.com - IntegNeuro Paul et al., 2005
- Medical Care Corporation - www.mccare.com
Shankle, William Rodman - rshankle_at_mccare.com
- see on-line test www.mccare.com/content/mci
s/mcis_overview.html - Medical Decision Logic, Inc Tien, Allen -
allen_at_mdlogix.com - Memtrax www.memtrax.com /.net /.org Ashford, J.
Wesson - washford_at_medafile.com - MicroCog Elwood, 2001
- Powell, DH Kaplan, EF, Whitla D, Weintraub S,
Catlin R, Funkenstein HH - NetMet - www.netneuromet.com Crooks, Thomas -
info_at_netneuromet.com - Neurotrax - www.neurotrax.com (MindStreams)
Simon, Ely - info_at_neurotrax.com
23Issues 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
24Need for Mass Screening
- Alzheimers 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)
25MemTrax 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
26MemTraxMemory 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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43MEMTRAX 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)
44The 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 Alzheimers
Disease, 2011
45The 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
46The 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
47The relationship between discriminability index
(d') and education in 868 individuals on the
continuous recognition test of memory
Ashford, Gere, Bayley, JAD, 2011
48WEB-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
49Screening 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_at_medafile.com