DEMENTIA AND ALZHEIMER'S DISEASE
From Innovations in the Assessment of Neurocognitive and Neurobehavioral Disorders, presented by the University of
California, San Diego, School of Medicine
David P. Salmon, PhD, Professor in Residence, Department of Neurosciences, University of California, San Diego,
School of Medicine
Educational Objectives
The goal of this program is to improve management of dementia and Alzheimer’s disease (AD). After hearing
and assimilating this program, the clinician will be better able to:
 | 1. Explain to patients and families that dementia is a syndrome, not a disease, and treatment varies with the
underlying causes of dementia.
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| 2. Enumerate the key pathologic characteristics of AD.
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| 3. Differentiate mild cognitive impairment from AD.
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| 4. Describe some of the biomarkers currently available to help diagnose the underlying cause of dementia.
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| 5. Discuss the current state of research into the treatment of dementia and AD.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, Dr. Salmon and the
planning committee reported nothing to disclose.
Acknowledgements
Dr. Salmon was recorded at Innovations in the Assessment of Neurocognitive and Neurobehavioral Disorders, held April
3-6, 2008, in San Diego, CA, and sponsored by the University of California, San Diego, School of Medicine. The Audio-Digest
Foundation thanks Dr. Salmon and UCSD for their cooperation in the production of this program.
| Introduction: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) defines dementia as intellectual
decline “of sufficient severity to interfere with occupational or social performance or both”; memory and
at least one other cognitive ability (eg, reasoning, language, visuospatial skills, calculation) must be impaired; state
of awareness must be normal (ie, not delirious); behavioral symptoms (eg, depression, delusions, hallucinations)
may be present; causes of dementia include Alzheimer’s disease (AD), stroke, Parkinson’s disease, traumatic brain
injury, neurodegenerative disease, and multiple causes; AD most frequent cause (55% of cases)
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| Pathology of AD: key pathology comprises plaques composed of dense amyloid and interneuronal neurofibrillary
tangles, which in turn are composed of tau protein, which must be identified on brain biopsy or autopsy; other pathology
includes brain atrophy and loss of neurons; although development of pathology heterogeneous, usually begins
in mediotemporal lobe structures, then spreads to other association cortices, particularly those in temporal
lobes, inferior parietal and temporal junction, and frontal lobes; eventually spreads to all association cortices, sparing
primary sensory and primary motor cortices; cognitive abilities affected by AD include learning and memory,
attention and executive function, language and semantic memory, and visuospatial and constructional abilities
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| Mild cognitive impairment (MCI): preclinical stage of AD; characterized by mild loss of memory and normal
function in activities of daily living; not all patients with MCI progress to AD; those who do progress develop mild,
moderate, and severe AD over time
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| Biomarkers for AD: under development (none considered definitive); imaging—magnetic resonance imaging
(MRI) can detect regional or whole-brain atrophy; functional MRI (fMRI), positron emission tomography (PET),
and single photon emission computed tomography (SPECT) can assess brain function; biochemical tests—can detect
amyloid- β peptides 1 to 42 (A β1-42 ) and tau and phosphorylated tau (P-tau) protein in cerebrospinal fluid
(CSF); magnetic resonance spectroscopy can detect biochemical changes; test to detect A β1-42 in plasma
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| Biochemical changes in AD: oxidative damage; inflammation; synaptic damage and synaptic loss; some can be
detected by above methods; MRI scans taken at intervals can be compared to determine extent and rate of loss of
brain tissue; SPECT and PET with fluoro-2-deoxy-D-glucose (FDG-PET) look for decreased glucose use in brain;
Pittsburgh Compound B (PIB, 11 C-PIB, 11 C-6-OH-benzothiazole) used with PET shows location and density of amyloid
plaques; neurochemical changes or neurotransmitter deficits—large decrease in acetylcholine; smaller decreases in
norepinephrine, somatostatin, and glutamate
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| Approaches to treating AD: can be directed at symptoms or at modifying disease progression; target causal factors
with antiamyloid agents; decrease or prevent neuron damage with antioxidants, anti-inflammatory agents, estrogen,
and nerve growth factors; target neurotransmitter changes with cholinesterase inhibitors or memantine;
target behavioral changes with antidepressants and/or neuroleptics; target social issues involving patient and caregiver
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| Alzheimer’s Disease Assessment Scale (ADAS): most commonly used outcome measure in medication trials for
AD; evaluates severity of cognitive and noncognitive behavioral dysfunction (higher the score, worse the disease);
cognitive component (ADAS-Cog) objectively tests learning, memory, comprehension, constructional praxis, naming,
ideational praxis, orientation, and recognition memory; examiner rates language, comprehension, word finding, and
memory; good test-retest reliability and interrater reliability; limitations—no assessment of attention to task; no detailed
assessment of executive function; no delayed recall (although some drug trials have added delayed recall measures)
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| Cholinesterase inhibitors: most active area of investigation; cholinesterase breaks down acetylcholine, which is
decreased in AD; in theory, if cholinesterase inhibited, acetylcholine will not break down as fast, and cognition
should be improved; medications studied include tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon),
and galantamine (Razadyne); “bottom line from these trials is that cholinesterase inhibitors do seem to improve
or stabilize cognitive test performance and overall global impression of how the patient is doing; they can also
improve or stabilize function and activities of daily living and some behaviors”; however, effects temporary, usually
lasting ≈12 mo (although large-scale meta-analysis suggests 24-mo benefit for some agents); cholinesterase
inhibitors do not alter underlying neurodegeneration, and downhill course of disease continues
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| Rivastigmine transdermal system (Exelon patch): hypothesized advantages include sustained blood levels, fewer
side effects, and greater efficacy; 24-wk double-blind trial in people with AD compared rivastigmine patch, rivastigmine
pill, and placebo; those utilizing either form of rivastigmine showed less cognitive decline than those
taking placebo; differences modest but significant
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| Dimebolin (Dimebon): developed as antihistamine but also found to inhibit cholinesterase, suggesting it may protect
neurons at level of mitochondria; initial Russian studies showed small but significant improvement over placebo;
trials now going on worldwide
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| Phenserine: dual mode of action inhibits cholinesterase and decreases formation of A β1-42 ; compared to donepezil
and placebo in 12-mo trial of 20 patients with mild AD, phenserine showed modest but significant improvement
over placebo; larger trials needed
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| Trials in patients with MCI: done with cholinesterase inhibitors to see if they can modify progression to AD; in trial
of donepezil or vitamin E, no group differences in probability of progression over 36 mo on primary or secondary
outcome measures; “there was a hint” that donepezil was protective in first 12 mo, but not sustained
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| Nerve growth factor gene therapy: phase 1 (ie, safety) trial to assess ex vivo nerve growth factor gene therapy in
8 patients with mild AD; autologous skin fibroblasts genetically modified to express nerve growth factor neurosurgically
implanted in basal forebrain; hypothesis that nerve growth factor would prevent cholinergic neuron degeneration
in basal forebrain, stimulate cholinergic function, and improve overall cognition and brain function; when
tested, few months after cells implanted, they began producing nerve growth factor and started rescuing cholinergic
cells; after 3 to 6 mo, rate of decline on ADAS-Cog seemed to slow by ≈36% (“an intriguing result”); also FDG-
PET indicated widespread increases in brain metabolism; based on these results, dose-finding trial now under way,
to be followed by larger trial comparing sham surgery to treatment
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| Disease-modifying treatment: widely thought that amyloid may be initiating factor in AD; therefore, therapeutic
targets include blocking its buildup or enhancing its removal; amyloid comes from precursor protein that penetrates
cell membrane after being cut by secretase; A β normally cut so it is 1 to 40 amino acids long (Aâ1-40 ), in which
form enzymes break it down and microglia clear it from brain; if cleaved incorrectly, Aâ1-42 formed, which aggregates
and cannot be broken down or cleared; secretase inhibition—in safety trial, secretase inhibitors resulted in no
adverse events, but also produced no changes in cognition; phase 3 (efficacy) trial may be in future; prevention of
aggregation—in trials, tramiprosate (Alzhemed) found to decrease amyloid level in CSF of humans, but did not
show clear benefit on clinical or imaging measures of progression of AD
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| Immunization trial: double-blind placebo-controlled trial of immunization with aggregated human A β1-42 ; speculated
that patients would develop own antibodies that would clear A β1-42 out of brain; trial had to be stopped after 3
injections because some patients developed encephalitis (unclear whether encephalitis due to A β1-42 or to vector);
however, “it looked like [immunization] was having a small but positive effect”; studies now under way to determine
cause of encephalitis; if vector, new vector will be sought
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| Potential protective factors: identified in epidemiologic surveys
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| Nonsteroidal anti-inflammatory drugs (NSAIDs): all trials negative
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| Antioxidants (selegiline and vitamin E): primary end point institutionalization or death; secondary end points
scores on cognitive tests; results showed primary end points delayed slightly, but no effect on cognition; however,
these trials done in patients who already had AD; primary prevention trial needed to see whether earlier treatment
with antioxidants would be more effective in preventing development of AD
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| Homocysteine: elevated homocysteine levels associated with increased risk for stroke and, in several studies, with
increased risk of developing AD; homocysteine levels can be lowered by supplemental B vitamins (B12 plus B6
plus folate); large multicenter trial conducted in patients with mild to moderate AD to determine whether lowering
homocysteine levels improved cognition; homocysteine levels successfully lowered, but no differences between
treated group and placebo group on ADAS-Cog; subgroup analysis raised possibility of benefit in patients
with very mild AD
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| Ongoing and planned clinical trials: simvastatin; R-flurbiprofen (NSAID); docosahexaenoic acid (DHA)
(omega-3 fatty acid); receptor for advanced glycation end products (RAGE; inhibitor that binds amyloid fibrils); intravenous
immunoglobulin (IV Ig; A β1-42 antibody); bapineuzumab (monoclonal antibody to A β1-42 )
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| What cognitive tests are used in addition to ADAS-Cog? Varies from study to study; several studies used Rey Auditory
Verbal Learning Test (RAVLT)
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| What is speaker’s reaction to Donepezil (Aricept) and memantine (Namenda) being handed out indiscriminately by
neurologists and primary care physicians to patients who complain of memory loss without trying to determine
type of dementia patient has? difficult to know what to tell patients and families; memantine only approved for
moderate to severe levels of dementia, but also being given to those with mild levels; fortunately, both drugs have
relatively mild side effects, but unclear that they will have any benefit on cognition
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| What is role of memantine? blocks glutamatergic receptors; perhaps reduces cytotoxicity, resulting in less neuron
death
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| When to start treatment? trials under way in which treatment being initiated when patient has MCI, but primary
prevention trials must be very large and last for long time (expense of such trials enormous)
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| Is there any data on augmenting memantine with rivastigmine transdermal system (patch) in moderate dementia?
speaker not aware of any data on such combinations, but one school of thought suggests combination treatments
may be necessary
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| How do volumetric changes in hippocampus compare across diagnoses? speaker proposes that “the hippocampus
must be particularly sensitive to just about everything” because studies on such diverse diagnoses as schizophrenia,
bipolar disorder, and posttraumatic stress disorder also show hippocampal volume changes
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| Are nutritional treatments being studied? in large trial, ginkgo biloba had small but significant effect, but not much
different from effect expected with donepezil; tramiprosate (nutriceutical) showed no benefit; trials with DHA
underway
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| What to do after patient has been on medications for some time? unknown; some suggest that when taken off medication,
patients’ cognition may drop below level of those on placebo; in trials, not clear that any harm would be
done by discontinuing medication, but cognition goes back to placebo level
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| What is speaker’s reaction to pharmaceutical companies advertising these drugs directly to public? so far, medication
trials have showed only modest benefits, but pharmaceutical companies create demand for these medications
through advertising
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| What is role of mental and physical activity in onset of dementia and AD? epidemiologic studies suggest benefit to
mental and physical activity in protecting against onset of dementia or AD; controlled efficacy trials being
planned
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| What role do genetic factors play? autosomal dominant form of AD rare (<5% of cases of AD), but some research
being done to see if progression to AD could be stopped at genetic level
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Suggested Reading
Behl P et al: The effect of cholinesterase inhibitors on decline in multiple functional domains in Alzheimer’s disease:
a two-year observational study in the Sunnybrook dementia cohort. Int Psychogeriatr July 8:1, 2008 [Epub ahead of
print]; Burns A et al: Defining treatment response to donepezil in Alzheimer’s disease: responder analysis of patient-
level data from randomized, placebo-controlled studies. Drugs Aging 25:707, 2008; Chiu CC et al: The effects of
omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: A preliminary randomized,
double-blind, placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry 32:1538, 2008; Doody RS et al:
Dimebon Investigators. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients
with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet
372:207, 2008; Emre M et al: Pooled analyses on cognitive effects of memantine in patients with moderate to severe
Alzheimer’s disease. J Alzheimers Dis 14:193, 2008; Ferris SH et al: Alzheimer’s Disease Cooperative Study Group.
ADCS Prevention Instrument Project: overview and initial results. Alzheimer Dis Assoc Disord 20(Suppl 3):S109, 2006;
Gilman S et al: AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with
AD in an interrupted trial. Neurology 64:1553, 2005; Heckemann RA et al: Automatic volumetry on MR brain images
can support diagnostic decision making. BMC Med Imaging 8:9, 2008; Jack CR Jr et al: Members of the Alzheimer’s
Disease Cooperative Study (ADCS). Longitudinal MRI findings from the vitamin E and donepezil treatment
study for MCI. Neurobiol Aging 29:1285, 2008; Klein J: Phenserine. Expert Opin Investig Drugs 16:1087, 2007; Lee
ST et al: Panax ginseng enhances cognitive performance in Alzheimer Disease. Alzheimer Dis Assoc Disord Jun 17,
2008 [Epub ahead of print]; Petersen RC et al: Alzheimer’s Disease Cooperative Study Group. Vitamin E and donepezil
for the treatment of mild cognitive impairment. N Engl J Med 352:2379, 2005; Petersen RC: Mild cognitive impairment
or questionable dementia? Arch Neurol 57:643,2000; Petersen RC: Aging, mild cognitive impairment, and
Alzheimer’s disease. Neurol Clin 18:789, 2000; Petersen RC: Mild cognitive impairment: transition between aging
and Alzheimer’s disease. Neurologia 15:93, 2000; Sugaya K et al: Practical issues in stem cell therapy for Alzheimer’s
disease. Curr Alzheimer Res 4:370, 2007; Tuszynski MH et al: A phase 1 clinical trial of nerve growth factor
gene therapy for Alzheimer disease. Nat Med 11:551, 2005; Tuszynski MH et al: Growth factor gene therapy for
Alzheimer disease. Neurosurg Focus 13:e5, 2002; Wouters H et al: Revising the ADAS-cog for a more accurate assessment
of cognitive impairment. Alzheimer Dis Assoc Disord Jun 17, 2008 [Epub ahead of print].
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