Current Update on Alzheimer’s
Disease
Nancy Isenberg, MD, MPH
Kristoffer Rhoads
Virginia Mason Medical Center
Neurosciences Institute
October 5th 2012
“Should we begin to think of lifelong control of Aβ metabolism in the
same way that we now think of lifelong control of cholesterol
metabolism? The lesson of the DIAN study and of the study on the
protective APP mutation is that reduction of the risk of late-life dementia
requires a long-term and possibly lifelong effort.” S. Gandy MD
N Engl J Med 2012, Nature 2012
Increased Life Expectancy and
Epidemic of Alzheimer’s
•
•
10,000 Americans reach 65 each day
Present day life expectancy 78 years (vs. 47 years in
1900)
•
Age is single greatest risk factor for Alzheimer’s disease
•
80 million Baby Boomers (born 1946-1964)
Dementia, Healthcare &
Economic Burden
In 2000, dementia was the third most costly health
condition, with annual cost estimated $100
billion (in 1997 US prices), $172 Billion in 2010
Davis, J, Hsiung, GY, Lui-Ambrose, T. Br. J of Sports Med, May 2011, Bateman et al. NEJM 2012
$604 Billion worldwide in 2010 Wimo & Price 2010
Dementia is associated with significant increases
in post-op and hospital delirium, falls and rapid
readmission rates Ibid.
CURRENT AREAS OF FOCUS FOR PATIENT SAFETY AND CARE WITHIN
VIRGINIA MASON MEDICAL CENTER
Dementia, Healthcare &
Economic Burden
• Annual combined cost to treat type 2
•
•
diabetes, heart disease, hypertension and
stroke $238 billion/year.
7/8 (83%) of American workers are obese
or have a chronic condition resulting in >
$1 trillion each year of lost economic
activity and productivity
For every $1 invested in effective
prevention and public health initiatives,
$5.60 is saved
RWJ Public Health Portfolio 2011
Integrate physical activity every day in every way
Market what matters for a healthy life
Make healthy foods and beverages available everywhere
Activate employers and health care professionals
Strengthen schools as the heart of health
Outline
• History
• Pathology
• Genetics and Other Risk Factors
• Clinical History and Diagnostic Work Up
• Neuroimaging
• Management & Treatment
• Future Considerations
History
•
•
•
•
1906 Alois Alzheimer presented case:
confused, psychotic 51 year-old
woman who progressed rapidly until
death 4 years later. Her autopsied
brain tissue showed waxy protein
fragments/twisted fibers that define
disease
1910 Emile Kraepelin described
Alzheimer’s disease as presenile
dementia in 8th edition of his Textbook
of Psychiatry
1968 Same plaques and tangles
cause “senility”
1984,1986 Beta amyloid, Tau protein
discovered as suspects in AD
neurodegenerative cascade
History
•
•
•
•
1993 APOE-4 gene identified
as risk for Alzheimer’s
disease
2004 Pittsburgh Compound B
engineered
2011 NIA updates criteria &
guidelines for diagnosis of
Alzheimer’s to include
preclinical stage
2012 May 15th NIH unveils
Alzheimer’s Prevention Trial
-Crenezumab in
preclinical AD (La Bobera)
-Nasal Insulin in MCI and AD
Obama admin. allocated $500 million for
in Alzheimer’s disease in fiscal yr. 2012
Pathology
•
•
•
Amyloid accumulation,
synaptic dysfunction,
neuronal loss all lead to
cortical atrophy
Note: sulcal widening,
gyral atrophy, thinning of
cortical ribbon and
ventricular enlargement.
Involvement is initially in
entorhinal cortex
spreading transsynaptically to
hippocampus
PLoS1, Lui et al 2012
(A) Neuritic plaques, stained with anti-Aβ42 antibodies
(B) Neurofibrillary Tau Tangles, stained with paired helical filament τ antibody.
Vandenberghe R , Tournoy 2005;81:343-352
Pathology & Palliation
• With the progressive degeneration of AD, cell
•
loss in the nucleus basalis of Meynert in the
basal forebrain has been observed. This nucleus
is the principle producer of acetylcholine to the
brain and led to the development of
cholinesterase inhibitors for treatment of AD
Other deficiencies have also been reported with
dopamine, norepinephrine, and serotonin in
postmortem analysis
Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging and the
Alzheimer’s Association workgroup Alz & Dementia 2011
NEJM 2012
The new Alzheimer’s disease
criteria
• Preclinical AD
-AD pathology in COGNITIVELY NORMAL
INDIVIDUALS
• Mild Cognitive Impairment (MCI) due to AD
-AD pathology in patients with amnestic
symptoms and impairments
• AD dementia
-Dementia with AD pathology
Risk Reduction Opportunity
Alzheimers Dement. 2011 May;7(3):280-92. Epub 2011 Apr
Genetics
• Alzheimer’s disease is the most common
•
•
progressive neurodegenerative disorder
Genetics are the second greatest risk
factor after age
Approximately 75% of cases of AD are
mixed (combination of genetic, epigenetic
and environmental) and 25% of cases are
familial
Arch Gen Psychiatry 2009
Genetics
• In familial AD, 95-99% of cases are late onset
•
•
(after 60-65 years), 1-5% are early onset (before
60) with cases as early as 30s reported
For early onset AD, 60% of cases are familial
and 40% sporadic
3 genes identified with early onset familial AD:
• APP on chromo 21 (10-15% of cases)
• Presenilin 1 (PSEN1) on chromo 14 (70% of
cases)
• Presenilin 2 (PSEN2) on chromo 1 (less than
5%)
Genetics
• Apolipoprotein E 4 is genetically linked to late
•
•
onset familial and sporadic AD. It has genedose effect on increasing risk and lowering age
of onset
Heterozygotes for ε4 allele (25 % population)
have lifetime risk of 30 % by 85
Homozygotes for ε4 allele (2% of population)
have lifetime risk of 60 % by 85
Genetics
•
•
•
•
Genome-wide association studies (GWAS) have
identified other genes that modulate risk of late-onset AD
including CR1, CLU, BIN1, PICALM, SORL1, GAB4,
MS4A4/MS4A6E, CD2AP, CD33, EPHA1, HLA-DRB1/5
and ABCA7, though the relative contribution is modest
Genetic testing is available for APP, PSEN1, PSEN2 and
APOE alleles
APOE2 is protective
C9ORF72 hexanucleotide GGGGCC repeat expansion
accounts for 40% familial ALS and 30% familial FTD (&
fewer sporadic cases) found in some patients with
Alzheimer’s disease, likely atypical presentation FTD
Majounie et al. 2012
Epigenetics
•
•
•
Aging and Alzheimer’s disease are associated with
epigentic dysregulation at various levels including DNA
methylation and histone modifications
Pharmacological inhibition of DNA methylation in
hippocampus after learning task impairs memory
consolidation in mouse model of AD Day & Sweatt, 2011
Promotion of histone acetylation improves learning in
mouse model of AD, and increases learning related gene
expression, suggesting epigenetic regulation of learning
and memory in health and disease Pelag et al., 2010
N AT U R E | V O L 4 8 3 | 8 M A R C H 2 0 1 2
Tao Porchon Lynch, 93 year old yoga master
Epigenetics in action…
Multifactorial Basis of Alzheimer’s Disease Pathogenesis
Alzheimer’s disease (AD) is likely to be caused by copathogenic interactions among multiple factors, including APP/Ab, apoE4,
tau, a-synuclein, TDP-43, aging, and various comorbidities.
Huang & Mucke, 2012
Risk Factors for Dementia
•
Related Health Conditions
•
Smoking
•
Alcohol
•
Sitting disease-Sedentary life style
•
•
Depression
Sleep apnea
•
Delirium
•
Hospitalization/Sepsis
•
Head Injury
•
Low level of education
Synergy
•
Type 2 Diabetes
•
Obesity
•
High blood pressure
•
Hyperlipidemia
•
Cerebrovascular risk
Environmental Risk Reduction
Barnes & Yaffe 2011
Military Exposure as Risk
Factors for AD
• Traumatic brain injury
- Odds ratio 4-6
- 1/3 retired football players with MCI, risk
for CTE
• Post traumatic stress disorder
• Others
- Gulf War Illness
- Smoking
Proposed Mechanisms
of Risk
• Earlier onset of amyloid/tau deposition
• Acceleration of amyloid/tau deposition
• Reduction of brain reserve independent of
amyloid/tau
• Combination of above factors
• Current DOD study to examine the effects of
TBI/PTSD on AD biomarkers in humans
Dementia
• Clinical Presentation:
A syndrome of acquired
impairment of two or more cognitive domains
sufficient to affect daily life
• Etiology:
Any disorder causing progressive
dysfunction to brain systems involved in
cognition
Clinical Presentation of AD
• Slowly progressive and significant decline
• Memory impairment
• One or more of following:
 Aphasia
 Apraxia
 Agnosia
 Disturbance of executive function
Which impair personal, social, occupational
functioning
DSM IV
Clinical history
Mild
• Insidious episodic memory reflecting early hippocampal
involvement- “tip of the tongue” “I can see his face…”
• Visuospatial dysfunction reflecting parietal lobe and posterior cingulate
injury “can’t find my car”
Moderate
• Neuropsychiatric and behavioral symptoms (e.g. disinhibition, apathy,
agitation, anxiety, depression, delusions, paranoia) can be seen in up to
80% of AD, usually in moderate to severe stages; these are leading
cause for nursing home placement
• Reduplication paramnesias are common
Severe
• Frontal lobe involvement manifest with unmasking of primitive reflexes
(positive Gabellar tap , hand grasp reflex, gegenhalten, palmomental
reflex)
• Pyramidal and extrapyramidal signs
• Seizures in 20% during late stage
• Late stage dysphagia contributing factor leading to death with
pneumonia
Alzheimer
variants
• Logopenic Progressive Aphasia• Slowed, non-fluent speech and poor comprehension
of complex language.
Early involvement of left posterior temporal cortex
and parietal lobule.
• Posterior Cortical Atrophy (Benson’s syndrome)
visual variant AD
• Balint’s syndrome, prosopagnosia, alexia, agraphia
Bilateral parietal and temporal involvement
Mild Cognitive Impairment (MCI)
• Individuals who develop a degenerative
•
dementia go through a transitional state of
milder cognitive impairment (MCI) without
significant functional impact
Clinical Heterogeneity of MCI
• Amnestic MCI
• Multiple domains MCI
• Single non-memory domain MCI
Mild Cognitive Impairment
• Amnestic MCI ~10% /year convert to
•
Alzheimer’s disease
Multiple Domain MCI
 Alzheimer’s disease
 Vascular Dementia/Mixed (VCI)
 Normal aging
• Single non-memory domain MCI
 Frontotemporal Dementia
 Lewy Body Dementia
 Alzhiemers Dementia
Model of Vascular Cognitive Impairment
Heart Disease
Diabetes
Difficulty managing
medications
and following
treatment plans
Problems with planning,
sequencing and problem
solving
Missing medications
Difficulty adopting health
behaviors
Poor illness control
White matter changes
Disrupted frontal lobe function
Office Assessment
• Careful history from family member or
•
•
other well informed source
Quantified assessment of cognitive
function
Neurological exam
Screening: MMSE
•
•
30 items, 6 domains, 5-10 minutes
Standard cutoff of 23-24
•
•
•
•
•
Sensitivity = 66-73%
Specificity = 87-92%
Positive Predictive Value= 58-67%
Misclassification rate = 15%
Age and education effects/norms
•
•
Sensitivity = 92%
Specificity = 96%
Screening: MMSE
•
Improved validity in combination
•
Clock drawing
• Depends on scoring system
• Sensitivity = .92 (MCI = .75)
•
Several other measures as good, if not better
•
Short Blessed Memory Test & Animals (Kilada et al., 2005)
• 5-item recall and animal naming
•
Mini-Cog (Borsen et al., 2000)
• 3-item recall and clock
•
Especially true for MCI
Cognitive screening
• Mini-Cog : 3-word recall (0-3 points) +
•
•
clock drawing ( 0 or 2 points). Takes 2-4
minutes. Overall accuracy at detecting
mild cognitive impairment = 83%
Will rule in 13 of 20 possible patients
Will rule out 18 of 20 healthy patients
Am J Geriatr Psychiatry. 2010 Sep;18(9):759-82.
Screening and case finding tools for the detection of dementia.
Part I: evidence-based meta-analysis of multidomain tests.
Functional Assessment –FAQ
Tests functional limitations/changes rather than
cognitive
• Sensitivity and specificity comparable to the
MMSE
• Rating functional abilities over past 4 weeks
– Not applicable
– Normal
– Some difficulty but does by self
– Needs assistance
– Dependent
Pfeffer RI, et al. J Gerontol 37:323-329:1982
Screening: Montreal Cognitive
Assessment (MoCA)
Screening: MoCA
• Better sensitivity (cutoff =26, slightly lower
in community setting)
 MCI
• MMSE =18%
• MoCA = 90%
 AD
• MMSE = 78%
• MoCA = 100%.
• Specificity
– MMSE = 100%
– MoCA = 87%
http://www.guideline.gov/content.aspx?id=34444
US Department of Health & Human Services, Jan 2012
Prevention Programs
RWJ Public Health Portfolio 2011
Cognitive Screening
• Better diagnostic aids are needed
 In primary care settings, <50% of patients with
dementia are diagnosed
Mattson, et al. JAMA; 302(4):385-393.
Lopponen M, et al. Age Ageing 2003;32(6):606-612.
HYBRID (2MIN.) SKINNY MOCHA
PROSPECTIVELY COLLECTING SENSITIVITY DATA
Mixed Dementia
• Mixed AD and VaD




Most frequent form of mixed dementia
28% in dementia clinics
>50% in community samples
Periventricular lesions in 90% of AD cases
• Other Mixed Dementias
 31% with Lewy Body and VaD
Langa et al. JAMA, 2004
Laboratory Assessment
• Blood




CBC, chemistry, TSH
B12, folate, Vitamin D
Syphilis serology
Genetic, perhaps & only with counseling
• CSF
•
 Ab, tau
Imaging
 Structural imaging, including volumetric studies
 SPECT, PET FDG, Amyvid
• Neuropsychology
Neuroimaging
•
•
•
•
•
•
•
•
MRI is the most sensitive and robust measure of rate of change in
AD, MCI and healthy controls
- Hippocampus, ventricles, comparable
- Brain atrophy commonly used as an
outcome measure in AD clinical trials
MRI Volumetric analysis
[F18]flouro-deoxyglucose (FDG)–PET
SPECT
Diffusion Tensor Imaging
Pittsburgh compound B (PiB)-PET
Florbetapir (Amyvid) imaging (FDA approved in April 2012) DOES
NOT ESTABLISH Dx. of AD
~15% of patients with dementia are difficult to diagnose
• Need specialized training to read Amyvid studies for sensitivity 92%
and specificity 95%
MRI Volumetric Analysis
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
MRI Volumetric Analysis
• Validated, FDA approved, quantitative
•
analysis MR research tool developed by
the Martinos Center for Biomedical
Imaging Group at Mass General and MIT
Alzheimer's Disease Neuroimaging
Initiative (ADNI, a multicenter 5 year
longitudinal biomarker study of blood,
CSF, MRI, PET for diagnosis and clinical
trials of 821 adults ages 55-90 (200
control, 400 MCI, 200 AD)
http://www.adni-info.org/
MRI Volumetric Analysis
• Significant difference in hippocampal
•
•
volumes(HV) between control, MCI, and
AD
MCI HV average 86% of normal control
HV
AD HV average 78% of normal control HV
MRI Volumetric Analysis
• Automated mapping of hippocampal
•
atrophy in 1-yr repeat MRI data from 490
subjects with AD, MCI and controls.
Annual HV loss rates:
Neuroimage. 2009




Normal 0.7% / yr
MCI 3.1% / yr
AD 5.6% / yr
Converters from MCI--> AD, rates similar to
AD
Mixed Dementia
FDG-PET Normal vs AD
Amyvid Imaging
Treatment
•
•
•
Key driver of the cost of Alzheimer's disease is the severity of the
disease, so disease stabalization & prevention are a potential
sources of cost savings
Drug therapies that can limit increases in behavioral problems
and cognitive and functional impairment, and postpone
institutionalization (without an increase in longevity) may serve to
reduce the economic & social burden on Alzheimer's disease
patients & families. CNS drugs 2010
FDA approved medications for symptomatic treatment of AD:
 Cholinesterase inhibitors: donepezil, galantamine, and rivastigmine
• Approved for mild to moderate AD with indication for severe AD given to
donepezil
 Noncompetitive NMDA receptor antagonist: memantine
• Approved for moderate to severe AD
Doody et al. Neurology. 2001;56(9):1154-1166
Treatment
• These drugs have been shown in multiple
•
studies to demonstrate modest effects for 2-5
years on measures of cognition, ADLs, global
function compared to placebo
+/- benefit seen in moderate to severe AD for
combination of two classes
Dement Giatr Cogn Disord 2007;24(1):20-27;
NEJM 2012, BMC Neurol 2011
Part of advertisement for donepezil 23 mg aimed at doctors.
Schwartz L M , Woloshin S BMJ 2012;344:bmj.e1086
©2012 by British Medical Journal Publishing Group
Treatment
Donepezil
Galantamine
Rivastigimine
(oral)
Rivastigmine
(patch)
Memantine
Mechanism of
action
Cholinesterase
inhibitor
Cholinesterase
inhibitor
Cholinesterase
inhibitor
Cholinesterase
inhibitor
NMDA receptor
antagonist
Dose
(beginning and
max)
5mg PO qday
to 23 mg PO
qday
4mg PO BID to
12 mg PO BID,
24mg ER daily
1.5mg q day to
6.0 mg PO
qday
Transdermal
4.6mg q 24hours
to 9.5mg
q24hours
5mg PO qday to
10mg PO BID
Absorption
affected by
food
No
Yes
Yes
No
No
Serum half life
(hours)
70-80
5-7
2-8
3-4
60-80
Side effects
N/V, diarrhea,
muscle
cramps,
weight loss,
vivid dreams
N/V, diarrhea,
weight loss,
dizziness
N/V, diarrhea,
weight loss,
dizziness
Possibly less GI
side effects
Dizziness, confusion
Treatment
•
•
Despite the slight variations in the mode of action of the
three cholinesterase inhibitors --no evidence of any
differences between them with respect to efficacy. The
evidence from one large trial shows fewer adverse
events associated with donepezil compared with
rivastigmine
The addition of memantine to the treatment of AD with
cholinesterase inhibition significantly altered the treated
history of AD by extending time to nursing home
admission
Lopez, O L et al. J Neurol Neurosurg Psychiatry 2009;80:600-607, Cochrane May 2012
Figure 3. Long-term effects of the concomitant use of memantine with cholinesterase
inhibition in AD.
O’Brien J T et al. J Psychopharmacol 2010;25:997-1019
Copyright © by British Association for Psychopharmacology
Treatment
• Aerobic and strength training
• Multi-disciplinary Team approach
• Cognitive Training and De-escalation strategies
• Family referral to available resources such as
•
•
Alzheimer Association and support groups in the
area
Discussion of advance directives, durable power
of attorney, POLST form
Address Caregiver stress
Driving with Dementia
• Crash involvement triples at age 80
•
•
•
•
•
•
(trend starts at 74, but not as high as teens)
Fatality rates are higher due to fragility,
13x higher at age 80 than at ages 30-59
MVA= 23% of accidental deaths
They are a risk to themselves, not the population
1.5M elders with dementia drive
No proven office tools for predicting safety
Road testing is not cost effective
•
Driving with Dementia
American Academy Neurology 2010 Practice
Parameter:… “clinicians should reassess dementia
severity and appropriateness of continued
driving every 6 months.”
Small prospective studies correlating office cognitive
assessment with road tests:
•
•
4 of 7 with Alzheimer’s failed their 2nd test @ 6
mos
Worsening survival curve in drivers w/ AD, even
at 6 mos post initial assessment with mild
dementia
Driving with Dementia
• Clock drawing
• MMSE
• Benton Line orientation
• Trail making test
• Driver Scanning test
2009 Meta-analysis, Mathias & Lucas, Intl Psychogenetics
CORRELATE WITH POOR
PERFORMANCE IN DRIVING
SIMULATOR…
BUT
THERE ARE NO
ESTABLISHED CUTOFFS
FOR PASS/FAIL
Driving with Dementia
COCHRANE, 2009: Driving assessment for maintaining
mobility and safety in drivers with dementia.
• Studies evaluating driving skills in
•
•
dementia are fraught with methodologic
difficulty
Office based tests correlate grossly with
driver test failure- real or simulated
There is no clear cutoff point in office tests
to differentiate the driver most at risk
Driving with Dementia
Practical approach?:Use office tests as a referral
trigger for more detailed evaluation
• Psychometric testing by psychologist
• OT eval (Trail making, Driver scanning,
•
•
reaction time tests), behind the wheel or
simulator
Negotiate a solution with him/her and
family
Recommend a driving skills test at DOL,
report if necessary
Guide to Medicare Covered
Preventive Visits
Hospitalization for an acute medical problem is
associated with significant cognitive decline in
elderly patients
.
Ehlenbach, W. J. et al. JAMA 2010;303:763-770
Risk factors for delirium
•
•
•
Non-modifiable
Age
•
» Dementia
Chronic illness
» Depression
•
Severity of illness on
admission
•
•
• ETOH
•
Modifiable
Sepsis/ metabolic
derangements (the
underlying disease)
Sedatives/ analgesics,
other meds
Sleep deprivation
Prolonged mechanical
ventilation
Prolonged restraint use
•
•
•
Early identification of dementia, a
vital component of Delirium
Prevention
Develop an effective, reliable pathway at Virginia Mason
for annual screening for dementia, in all persons 65 &
older, as well as those with vascular &/or metabolic risk
50 & older
To work with Dr. Rhoads to develop a streamlined,
sensitive Virginia Mason tool to compare to MoCA
To develop a team approach for risk reduction program
at Virginia Mason with focus on modifiable lifestyle and
dietary factors
Treatment & Prevention: Healthy
Aging
•
•
•
•
•
Cardiovascular & metabolic
health
Aerobic Activity levels
Engagement
Mood
Prevention of hospitalization &
delirium
Where do we STRESS?
• 2007 estimates for “neurosoftware” are
•
•
$225 million (evidence?!)
>50% of adults take a supplement to total
$23 billion/year
We DO form new brain cells in adulthood
despite a century of being told it’s
impossible
HEALTH PROMOTION, PREVENTION &
RISK REDUCTION:
Hypertension/Diabetes/Obesity
•
•
Higher midlife BP predicts cognitive decline, increases dementia
risk
Multiple domains of cognitive impairment
 Attention
 Learning & memory
 Perceptual skills
•
•
•
•
Decreased cerebral blood flow/metabolism
1.2 - 1.5 x more rapid decline vs. controls
Alzheimer’s disease TYPE 3 DIABETES
Rate of global decline over 10 years is significantly faster for
those obese in midlife Neurology 2012
Prevention and Interventions:
Move the Brain
• Sedentary community-dwelling adults (age 60 – 79)
• Intervention (6 months)
•
 Aerobic
 Stretching/toning
Aerobic ex group increased gray and white matter
 Prefrontal
 Temporal
Mice benefit too
Neuroimage. 2012 Apr 12;61(4):1206-1212. [Epub ahead of print]
Prevention and Interventions:
Exercise Dosage
• Meta-Analysis of 18 RCT of aerobic fitness
training in ages 55 - 80
 Greatest effects:
•
•
•
•
Combined aerobic + strengthening
Longer duration (>30 min.)
Executive function
Ages 60 - 70 benefitted the most
The Time × Group interaction was significant (P < 0.001) for both left and right Hipp.
PNAS 2011
Association between APOE status and exercise engagement for the mean cortical binding
potential (MCBP)
Head, D. et al. Arch Neurol 2012;0:archneurol.2011.845v1-8.
Copyright restrictions may apply.
Prevention and Interventions:
Exercise Recommendations
• 30+ minutes of moderate physical activity at least
5 days per week (60-70% of max heart for age)
• 20+ minutes of vigorous physical activity at least 3
days per week (70-80% of max heart for age)
• Can be done in 10 minute bouts (Instant Recess)
• More complex movement = more complex
synaptic connections with thicker myelin
Cardiovascular fitness
• Improved organ blood flow, induction of
•
antioxidant pathways, and enhanced
angiogenesis and vascular regeneration
with cardiovascular exercise, better
glucose regulation
Enhanced neuronal and also vascular
plasticity
• VM Move the Brain Campaign
Prevention and Interventions: Diet
•
Antioxidants
•
Vitamin E
•
Vitamin C
•
Coenzyme Q10
•
Lipoic Acid
•
Flavonoids
•
•
Resveratrol
•
•
Green tea, red wine, berries, cocoa
Red grapes, red wine,
Carotenoids
•
Carrots, yams, squash
•
COLORS OF THE RAINBOW
Prevention and Interventions
•
•
Alcohol
•
1-2 drinks a day for men; 1 for women
•
Red wine
•
Grape seed extract
•
Pomegranate juice
Once impairments are present:
•
Minimal if any alcohol use
•
Vitamin D replacement >40
•
Smoking CESSATION
Marine Omega-3 & Dementia
Study links RBC DHA and EPA levels in dementia-free
Framingham Study participants (n 1,575; 854 women, age 67
9 years) to performance on cognitive tests and to volumetric
brain MRI, with serial adjustments for age, sex, and education
Lower RBC DHA levels are associated with smaller brain
volumes and a “vascular” pattern of cognitive impairment even
in persons free of clinical dementia. Neurology 2012
Caregiver Burden in Dementia
Int. J of Ger. Psy. 2012
Future Considerations
•
•
•
Better diagnostic aids are needed
 In primary care settings, <50% of patients with
dementia are diagnosed
 Can Virginia Mason screen everyone 65 & older
annually, and those >50 with vascular & metabolic
risk? MoCA
CSF and Serum Biomarkers for preclinical AD
Reduced CSF β-amyloid1-42, elevated CSF total
tau & phosphorylated tau are diagnostic of AD and
predictive of incipient AD in MCI patients
Mattson, et al. JAMA; 302(4):385-393.
Lopponen M, et al. Age Ageing 2003;32(6):606-612.
Future Considerations
•
•
•
•
•
Bapineuzumab: humanized monoclonal antibody
against Aβ. However, initial studies found rare
cases of vasogenic cerebral edema
Solanezumab, a humanized anti-Aβ monoclonal
antibody directed against the midregion of the Aβ
peptide, was shown to neutralize soluble Aβ
species, now in phase III trials.
Crenezumab trial just beginning with preclinical
AD in Columbia
BMS-708163 : γ-secretase inhibitor in phase II
Etazolate: neurotrophic α-secretase (nonamyloidogenic) pathway activator in phase II
What’s good for the Heart is
good for the Brain
Thank You for Your Attention
Questions?
True enjoyment comes from activity of the mind and exercise of the
body; the two are ever united.
- Alexander von Humboldt
It is exercise alone that supports the spirits, and keeps the mind in
vigor.
-Marcus Tullius Cicero