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

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MemTraxA 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

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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

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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
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Episodic 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

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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

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Discrete regions of the cerebral cortex are
selectively affected by Alzheimer pathology
Brun Englund, 1986
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Braak Braak, 1991 Braak et al., 2006
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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
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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. 1982217408-414.
2. Whitehouse PJ et al. Science.
19822151237-1239. 3. Guan ZZ et al. J
Neurochem. 200074237-243.
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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

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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

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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 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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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??

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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 Alzheimers disease (Ashford et al.,
1998).
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• 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

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Progression of tau hyperphosphorylation to
neuropil threads and neurofibrillary tangles
Ashford et al., 1998, J Neuropathol Exp
Neurol.57972
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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 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
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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

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Memory 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

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Computerized 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

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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

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Need 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)

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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

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MemTraxMemory GAME
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• 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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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)
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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 Alzheimers
Disease, 2011
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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
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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
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The relationship between discriminability index
(d') and education in 868 individuals on the
continuous recognition test of memory
Ashford, Gere, Bayley, JAD, 2011
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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

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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_at_medafile.com