What is Alzheimer`s Disease?

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Transcript What is Alzheimer`s Disease?

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: www.medafile.com (Dr. Ashford’s lectures)
MemTrax: www.memtrax.com ; www.memtrax.net ; www.memtrax.org
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
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
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
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
Discrete regions of the cerebral cortex are
selectively affected by Alzheimer pathology
Brun & Englund, 1986
Braak & Braak, 1991; Braak et al., 2006
Correlation analysis
between brain perfusion
(SPECT) and
dementia severity
(transformed from the
(Ashford et al., 2000).
This finding is consistent
with observations using
numerous other
modalities, e.g, PET
Proportion of cortical area
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.
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
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
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
- Glutamate neurons
- highly affected by AD
- detail memory
- Rx: memantine
- GABA neurons
- Somatostatinergic
neurons affected by AD
– memory modulation
(not affected by AD - movement)
(Affected by AD early
- Classical conditioning)
(Affected by AD
-operant conditioning)
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??
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 MAP2) analysis of neurons in the cortex
affected by Alzheimer’s disease
(Ashford et al., 1998).
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
M is from a nondemented
Progression of tau hyperphosphorylation to neuropil threads and neurofibrillary tangles
Ashford et al., 1998, J Neuropathol Exp Neurol.57:972
extra cellular
APP – formed
during learning
- XS in Downs
Stimulated by acetylcholine
through muscarinic
Pathway to build new synapses
Stimulates new
synapse growth
JW Ashford, MD PhD, 2012
Iceland mutation
APP-673 – no AD
Lipid raft
Formed by cholesterol
-Transported by ApoE
(from macroglia)
Pathway to remove old synapses
Amyloid –beta:
? Free-radical generator
? To destroy old synapses
Turn-over – 8 hours
Clearance – IDE, APOE
Favored when
lipid raft too thick
Alzheimer Neuroplasticity Cascade
Genetic Factors – all related to APP
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
SNPs - related to APP/beta (strongest factors, but rare)
APOE genotype – related to APP management (most common)
APP 50% excess – Down Syndrome
Stimulates tau-hyperphosphorylation causing synapse retraction, forgetting
Gamma secretase modulation prevents AD (NSAIDs, statins)
Excess AICD causes Tau hyperphosphorylation – pTau, poor synapse
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
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
Computerized Cognitive/Memory Tests
CANS-MCI - Alzheimer’s Screen Inc. - www.alzheimersscreen.com Hill, Emory - [email protected]
Cognosis - Cantab www.cantab.com
Cognitive Drug Research - CDR - www.cdr.org (Goring-on-Thames, UK) Wesnes, Keith [email protected]
Cognitive Screening Test – CST
CNS Vital Signs - www.cnsvs.com
Boyd, Alan (CNS vital signs, NC, USA) - [email protected]
Cognometer www.cognitivelabs.com
Addicott, Michael Cognitive Labs - [email protected]
Cogstate www.cogstate.com
(Australia) Bick, Peter - [email protected]
Cognistat www.cognistat.com
Cognisyst www.cognisyst.com (Durham, NC) Green, Paul; Allen, Lyle - [email protected]
Cog Screen www.cogscreen.com
Kay, Gary - [email protected]
CogTest www.cogtest.com
Sharma, Tonmoy - [email protected]
Paul et al., 2005
Medical Care Corporation - www.mccare.com
Shankle, William Rodman [email protected]
- see on-line test: www.mccare.com/content/mcis/mcis_overview.html
Medical Decision Logic, Inc
Tien, Allen - [email protected]
www.memtrax.com /.net /.org
Ashford, J. Wesson - [email protected]
Elwood, 2001
Powell, DH; Kaplan, EF, Whitla D, Weintraub S, Catlin R, Funkenstein HH
NetMet www.netneuromet.com
Crooks, Thomas - [email protected]
Neurotrax www.neurotrax.com (MindStreams)
Simon, Ely - [email protected]
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
Need for Mass Screening
• Alzheimer’s disease, dementia, and memory
problems are difficult to detect when they are
– 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)
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
Memory 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)
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)
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
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
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
The relationship between discriminability index (d′) and
education in 868 individuals on the continuous recognition
test of memory
Ashford, Gere, Bayley, JAD, 2011
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
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: [email protected]