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Early Diagnosis of
Dementia
Does it really matter?
Monica K. Crane, MD
Associate Director, Director of Research
Cole Neuroscience Center
Assistant Professor of Medicine, UTMCK
10/03/12
Disclosure Statement of
Financial Interest
I, Monica Crane, MD……
DO have a financial interest/arrangement or
affiliation with one or more organizations that
could be perceived as a real or apparent
conflict of interest in the context of the subject
of this presentation.
My presentation has been peer reviewed by
ETSU, and has been found to be balanced,
evidence based, and free of commercial bias.
Potential Conflict of Interest
Disclosure
Those Relationships Are With:
Eisai/Pfizer Pharmaceuticals
Forest Pharmaceuticals
Novartis Pharmaceuticals
1
Objectives
Background
–Normal Aging
–Protective factors and risk factors
• Early diagnosis of Alzheimer’s
Disease
• Clinical criteria
• Why does it matter?
• Dementia subtypes
• Treatment
Normal Aging
• Intelligence: stable or 
• Visuospatial: mild 
• Attention: stable or mild • Executive function: mild
(reasoning, cognitive flexibility,
problem solving)
• Language: stable
• Memory: mild 
• Speed: always 
– Slowing of thought and action
is the most reliable aging
change!
AD risk factors
Fixed Risk Factors
Modifiable Risk Factors
•
•
•
•
• Lack of exercise
• Smoking
• High blood pressure and
heart disease
• High cholesterol
• Poorly controlled diabetes
• Low education
Age
Family history
Genetics
Mild Cognitive
Impairment (MCI)
2
What were the old Alzheimer’s
disease research criteria?
Auguste Deter, first diagnosed AD
patient, 1906.
• Old criteria: DSM-IV NINCDSADRA criteria validated against
neuropathological gold standards
• VERY POOR specificity (23-88%)
• Old definitions had good detection
of a dementia syndrome (65-96%)
but it was often NOT AD
• There are over 20 common
dementia subtypes and 50+
other rare dementia subtypes
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
Text Revision. Washington, DC: American Psychiatric Press; 2000:157.
Newly Proposed Criteria for probable AD
• Significant abnormality in episodic
memory for ≥ 6 months & at least ONE
objective biomarker:
– Medial temporal and medial/posterior parietal lobe
atrophy
– Abnormal CSF* (95% sensitive, only 29% specific)
• Low amyloid B1-42 concentrations
• Increased total tau and phospho-tau
– FDG-PET scan: AD pattern
– Florbetapir F18 (Amyvid)-PET scan: positive
– Genetics (PSEN1, PSEN2, APP, trisomy 21)
Dickerson. Advances in quantitative magnetic resonance imaging-based biomarkers for Alzheimer disease. Alzheimer's Research & Therapy 2010; 2:21
Meyer et al. Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People. Arch Neurol 2010;67:949-956.
Medial temporal lobe
atrophy
Normal
Alzheimer’s
T1 MRI coronal view
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Limbic System:
Hippocampus
• Stores new memories
or “working memory”
• NEW finding: important
in our ability to envision
the future and replay
events that were never
experienced
• Important in planning
and imagination
Foster DJ, Wilson MA. Nature 2006;440:680-683.
Foster DJ, Knierim JJ. Curr Opinion Neurobiol 2012:22:294-300.
Q: What is happening to
the brain in Alzheimer’s
disease?
A: You would see
hallmark
neuropathologic lesions:
plaques, tangles with
brain atrophy and loss
of neurons and
synapses.
(Extracellular deposits
Abnormal intraneuronal fibrillar material
Florbetapir (Amyvid) binds to amyloid aggregates
(β-amyloid neuritic plaque) in the brain
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• F-florbetapir-PET scan
(Neurology doi: 10.1212/WNL.0b013e3182661f74).
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Why diagnosis early?
1. Early diagnosis Alzheimer's allows prompt treatment
of reversible symptoms (such as other comorbid
illnesses exacerbating the impairment).
2. Alzheimer’s is not curable but is treatable.
3. Early diagnosis gives a patient and their family more
time to arm themselves with knowledge about the
disease and the best way to live with the disease.
Knowledge is empowering.
4. Early diagnosis and treatment can prevent
hospitalization and save health care dollars!
Why should I tell you and your
family about the diagnosis?
1. Early diagnosis will help you and your family
understand why you are having symptoms.
2. Early diagnosis gives you more time to make
big life decisions: financial planning, power of
attorney, living wills.
3. Early diagnosis maximizes your safety and
safety of your family.
Early diagnosis allows treatments for AD that
help slow its progression.
The big challenge for clinicians… there
are many dementia types other than AD
5
Dementia Prevalence
(% of each type seen in US)
• Alzheimer’s Disease ~ 50-80%
• Vascular dementia ~ 5-10%
• Dementia with Lewy Bodies &
Parkinson’s disease dementia ~10%
• Frontotemporal Dementias ~10%
Heterogeneity of dementia
• Alzheimer’s Disease
– Posterior cortical atrophy
– Progressive aphasia
– Amnestic variant
• Vascular dementia
– Large vessel (stroke)
– Small vessel disease/ subcortical
– CADISIL, CAA
• Parkinson’s disease dementia and related disorders
– Parkinson’s disease dementia and Lewy Body Dementia
– Multiple System Atrophy
• Frontotemporal Dementia disorders
– Behavioral variant FTD
– Corticobasal degeneration and Progressive supranuclear palsy
– Primary Progressive Aphasia and Semantic dementia
• Motor neuron diseases
VASCULAR DEMENTIA
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Vascular dementia
• Large vessel
disease
(post-stroke)
• Small vessel disease
– Executive function problems
– Gait disorder
– Depressive symptoms
– Emotional lability
– Memory problems
Cerebrovascular disease and “vascular depression”
Striato-pallido-thalamo cortical pathways
disrupted by vascular lesions.
Alexopoulos GS et al. "Vascular depression" hypothesis. Arch Gen Psych 1997;54:915-922.
Lewy Body Dementia
• Degeneration of an
area in the brain stem
called the substantia
nigra similar to
Parkinson's disease
• Degeneration of
cortical areas of the
brain similar to AD
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Dementia with Lewy Bodies (DLB)
versus dementia in Parkinsons
disease (PDD)
•
.
• LBD is a an umbrella term for
two related clinical diagnoses:
DLB and PDD
• Patients with dementia before
or within 1 year of Parkinson's
symptoms are diagnosed with
DLB.
•
People who have an existing
diagnosis of Parkinson's for ≥ 1
year diagnosed w PDD.
Lewy bodies are the pathophysiological
characteristic of the disease
Clinical Features of Lewy Body
Dementia
•
•
•
•
•
•
•
•
Fluctuating cognition
Memory loss
Hallucinations
Symptoms that resemble Parkinson’s disease
Gait changes
Autonomic dysfunction
Depression
Poor reaction to dopamine agonists and/or
antipsychotic drugs (Positive response to
cholinesterase inhibitors, memantine)
Frontotemporal
dementias
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“Dementia That's Neither
Alzheimer's Nor Easy”
Normal
Alzheimer's
FTD
FDG-PET images of metabolic activity: healthy controls,
AD, and FTD. Scale red (high FDG uptake)-yellowgreen-blue (low FDG uptake).
Photo Credit: Dr. Janet Miller, Dr. Suzanna Lee, MGH/ Harvard, Radiology Rounds April 2006
FTD Prevalence
FTD: Alzheimer’s disease (AD) ratio is 1:1 in
those aged 45-65.
Ratnavalli et al, Neurology 2002.
FTD is more common that AD below age 60.
Knopman et al, Neurology 2004.
FTD spectrum comprises near 15% or more
of the total FTD dementia cases.
Boxer AL, Miller BL. Alzheimer Dis Assoc Disord. 2005.
Frontotemporal dementia subtypes
• Behavior variant (bvFTD): 60% of FTD cases
• Semantic dementia (SD)
• Progressive nonfluent aphasia (PNFA)
• Progressive Supranuclear Palsy (PSP)
• Corticobasal degeneration (CBD)
• FTD with motor neuron disease (FTD-MND)
• ALS/CTE (Chronic Traumatic Encephalopathy)
Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc
Disord. 2005;19 S1:S3-6
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>50% of FTD subtypes misdiagnosed as
primary psychiatric disease
Woolley et al. J Clin Psychiatry. 201; 72(2): 126–133.
Figure. % of patients initially misdiagnosed prior to ND diagnosis
FTD International Research Criteria
1. Early behavioral disinhibition
2. Early apathy or loss of
motivation
3. Loss of emotional recognition,
sympathy, empathy
4. Perseverative, compulsive,
ritualistic behavior
5. Hyperorality/ dietary change
6. FTD neuropsych profile
7. Frontal and/or anterior temporal
atrophy on MRI or other
radiologic findings
8. Presence of a known mutation
Brain 2011: 134; 2456–2477
Mendez and Perryman, 2002;
Mendez et al., 2007;
Rascovsky et al., 2007a; Piguet
et al., 2009), the International
Behavioural Variant FTD
Criteria Consortium (FTDC)
revised guidelines for the
diagnosis of bvFTD.
Frontotemporal lobar degeneration (FTLD) =
Neuropathology of clinical FTD
Pick’s is a FTLD (pathology) not FTD (syndrome)
From: LM Shaw LM, Korecka M, Clark CM, Lee VMY, Troganowski. Biomarkers of neurodeneration for diagnosis and monitoring
therapeutics Nature Reviews Drug Discovery. 2007;6:295-303.
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FTD damages 3 major networks:
Dorosolateral prefrontal cortex (DLPFC)
Anterior cingulate cortex (ACC)
Orbitofrontal cortex (OFC)
Seelar H, Rohrer LD, Pijnenburg YAL, Fox NC, can Swieten JC. Clinical, genetic and pathological
heterogeneity of frontotemporal dementia: A review. J Neurol Neurosurg Psychiatry 2010.
Nonpharmacologic AD prevention
Good physical health = Great
aging brain
 Regular physical exercise
 Positive emotions
 Positive relationships
 Limiting chronic stress
“Memory and the Aging Brain.” Steven W. Anderson, PhD
Thomas J. Grabowski, Jr. MD The University of Iowa. June 2003
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Exercise protects the brain!!
• Aerobic exercise
training increases
brain volume in aging
humans
Pereira AC, et al. An in vivo correlate of exercise-induces
neurogenesis in the adult dentate gyrus. PNAS. 2007; 104:56385643
Lautenschlager NT et al. Effect of physical activity on cognitive
function in older adults at risk for Alzheimer’s disease. JAMA,
2008;300:1077-1079.
Colcombe SJ et al. Aerobic exercise training increases brain volume
in aging humans. J Gerontol A Bio Sci Med SCi 2006;61:1166-1170.
Kramer AF et al. Exercise, cognition and the aging brain. J Appl
Physiol 2006;101:1237-1242.
FDA-approved Medications for
Alzheimer’s Disease
Cholinesterase inhibitors (ChEIs)
ChEIs prevent the enzyme destruction of
the neurotransmitter acetylcholine (Ach)
– Acetylcholine declines in AD; loss of cholinergic input to the
cortex from the basal forebrain.
–Donepezil:
• selective acetylcholinesterase inhibitor
–Rivastigimine & Galatamine:
• Inhibitor of acetylcholinesterase & butyrylcholinesterase.
Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. Alzheimer’s disease and senile dementia: loss of
cholinergic neurons in the basal forebrain. Science 1982;215:1237-1239. (Zarate et al 2007; Muhonen et al 2008, Dodel et
al 2008; Maeng et al 2007; Ferguson et al 2007)
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Memantine (Noncompetitive glutamate Nmethyl-D-aspartate (NMDA)-receptor blocker)
– FDA approved for moderate-severe AD.
– Blocks the NMDA receptor calcium channels,
inhibiting the sustained, low-level influx of excitatory
calcium (Ca2+) ions into postsynaptic glutamatergic
neurons.
– May have a neuroprotective effect by preventing the
negative consequences of persistent activation of
the neuron..
Source: Atri A, et al. Long-term Course and Effectiveness of Combination Therapy in
Alzheimer’s Disease. Alzheimer Dis Assoc Disord. 2008;22:209-221.
Investigational
drugs and vitamin
therapies
NEGATIVE THERAPIES
DRUG
MECHANISM OF ACTION
AN1792 Vaccine
Abeta immunotherapy
Tramiprosate alzhemed - homotaurine
Abeta aggregation inhibitor
Latrepiridine (Dimebon)
Mitochondrial stabilizer – originally antihistamine
Tarenflurbil (Flurizan)
Gamma-secretase modulator
Semagacestat
Gamma-secretase inhibitor
Simvastatin
Possible membrane lipid modifier
Docosahexaenoic acid (DHA)
Possible membrane lipid modifier or
antioxidant
B12, B6 , Folic Acid, Vitamin E, Omega-3
fatty acids, Ginko Biloba
Multiple theories, negative longitunidal
studies
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Statins:
• Elective statin use studied to see if it reduced AD
progression
– Hyperlipidemia promotes Aβ production and deposition in
animal models of AD and cholesterol reduction reduce Aβ
deposition.
• Large clinical trials show no efficacy in delaying
progression but NO increased AD risk.
• Feb 2012: FDA warned that statins could cause
“reversible memory loss.”
• The evidence: USE statins for patients with heart or
cerebrovascular disease (regardless of AD status)
Sano M et al. A randomized, double-blind placebo controlled trial of simvastation to treat AD. Neurology 2011;77:556-563.
Siegel GJ et al. Statin therapy is associated with reduced neuropathologic changes of AD. Neurology 2008;71:383
Amarenco P, Labreuche J.Lipid management in the prevention of stroke: review and updated meta-analysis of statins for
stroke prevention.Lancet Neurology 2009;8:453 – 463.
Vitamins  versus
diet/ lifestyle 
• Vitamin E
– No difference between placebo.
– High doses increase stroke risk.
– Increased relative risk of prostate cancer in
men.
• Homocysteine lowering therapy (B-vitamins), Folic
Acid B6, B12 – no benefit with supplements
– The vitamins lower the homocysteine level but little
else.
– B12 and folic acid supplementation did not have any
statistically significant effect.
Miller ER 3rd et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann
Intern Med. 2005;142:37-46.
Ford et al. Vitamins B12, B6, and folic acid for cognition in older men Neurology 2010;75 :1540-1547.
Vitamins  versus
diet/ lifestyle 
• DHA 
– Docosahexaenoic acid is an omega3 polyunsturated
fatty acid found in fish.
– component of synaptic plasma membranes & affects
rate of signal transduction ?neuroprotective.
– NEGATIVE RCTs: no effect with supplementation.
• Gingko biloba 
– marketed as a supplement that prevents or delays
cognitive decline.
– VERY LARGE RCT were negative.
– A numerically greater number of subjects treated with
gingko developed dementia as compared to placebo.
Quinn JF et al. JAMA 2010;304:1903-1911.
DeKosky ST et al. JAMA. 2008;300:2253-2262.
Snitz BE et al. JAMA. 2009;302:2663-2670.
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Insulin Resistance and AD
• Risk factor for AD: Type II diabetes
– Impaired nsulin signaling in AD, contributing to the
neurodegenerative process.
• Exendin-4 (or Exenatide)
– Phase II trials: testing the effects of novel enzymeresistant analogues of the insulin-releasing incretin
hormone, glucagon-like peptide 1 (GLP-1).
• Intranasal Insulin
– Delayed memory was improved in the MCI group
receiving 20 IU of insulin (P < .05). Among insulintreated participants, no improvement in biomarkers.
Craft S, Baker LD, Montine TJ, et al Arch Neurol. 2011;Sept 12.
Caffeine may decrease level of beta-amyloid
in AD transgenic mice
• AD mice received the equivalent
of 5 cups coffee/day for 2 months
• End result: caffeinated AD mice
performed as well as normal mice
• Caffeinated mice brains showed
~50% reduction in beta amyloid
• Researchers suggested that
caffeine suppresses inflammatory
changes in the brain that lead to
an overabundance of beta
amyloid.
Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice; Gary W
Arendash, Takashi Mori, Chuanhai Cao, Malgorzata Mamcarz, Melissa Runfeldt, Alexander Dickson, Kavon Rezai-Zadeh, Jun Tan,
Bruce A Citron, Xiaoyang Lin, Valentina Echeverria, and Huntington Potter; J Alzheimer's Disease, 2009:17:3.
2. Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice; Chuanhai Cao, John R
Cirrito, Xiaoyang Lin, Lilly Wang, Deborah K Verges, Alexander Dickson, Malgorzata Mamcarz, Chi Zhang, Takashi Mori, Gary W
Arendash David M Holzman and Huntington Potter; J Alzheimer's Disease 2009; 17:3
Supplements vs. food
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Understanding and treating
dementa remains one of the
greatest challenges facing all
levels of health care.
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