UPDATE IN DEMENTIA

Jody Corey-Bloom, MD, PhD

University of California, San Diego
La Jolla, CA

Disclosures
Principal Investigator on numerous clinical trials for
dementia; support from various pharmaceutical
organizations including

Elan
TEVA
SIENA
PRANA

Differential Diagnosis of Dementia

Other dementias
Frontal lobe dementia
CBS, PSP, Others
Vascular dementias
DLB
Parkinsons
disease
AD and DLB

Vascular
dementias and
AD

AD
5% 10%

5% 7% 8%

65%

Small GW et al. JAMA 1997; American Psychiatric Association.

Am J Psychiatry 1997; Morris JC. Clin Geriatr Med 1994
3

Alzheimer disease in the US (2010-2050)

estimated using the 2010 census
Hebert et al, 2013
US mortality,
education, and new
US Census Bureau
estimates of current
and future population
Projection: 13.8
million, with 7.0 million
aged 85 years or
older, by 2050

Pathologic features and biomarkers for AD

Structure:

MRI

whole brain atrophy

regional atrophy

Function:

FMRI
PET/SPECT

Brain atrophy and

neuron loss

activation
glucose use

Biochemistry:

A42
tau, P-tau

CSF

Amyloid
plaques

MR Spectroscopy
PET Amyloid (PiB, F-PiB)
Plasma A

NFTs

Biochemical changes: oxidative damage, inflammation, synaptic damage

Earlier treatment intervention: increased attention to

the continuum from normal aging to AD and
recognition of a transitional zone

Normal aging
Symptoms
DX

M
C
I

NHP

+
AD

death

What is Mild Cognitive Impairment?

Transitional state
Affects ~ 15% of older adults
Increasing prevalence with age
Subtypes
Amnestic MCI: memory impairment with minimal to no
other cognitive loss
Everyday function largely preserved
Often progressive; some stabilize; some improve
May be prodromal to AD or other specific dementias

MCI: Clinical Outcome

convert to probable AD at an increased rate
Normal elderly

1-2% per yr

MCI

10-15% per yr

AD
AD

Hypothetical progression of neurodegeneration and

cognitive dysfunction from normal to MCI to AD

Trojanowski et al, 2010

Hypothetical depiction of biomarker changes during

the progression of AD
revision of the temporal order of biomarker abnormalities
1. CSF A depletion
and cortical
amyloid
deposition
2. Tau-mediated
synaptic and
neuronal injury=
substrate for
hippocampal and
cortical atrophy
Aisen et al, 2011
2011 by Lippincott Williams & Wilkins

10

New Diagnostic Guidelines for MCI

Albert et al, 2011

core clinical criteria for use by healthcare providers

without access to advanced imaging or CSF analysis
research criteria for research settings, including trials
incorporate the use of imaging and CSF biomarkers
criteria for MCI due to AD has four levels of certainty,
depending on presence and nature of biomarker findings
11

Diagnosis-Independent Alzheimer Disease

Biomarker Signature in Cognitively Normal
Elderly People De Meyer et al, 2010

novel method of analysis correctly classified 90% of AD

unexpected presence of the AD signature in more than 1/3 of
NC suggests that AD pathology is active and detectable earlier
than envisioned
12

Amyloid Cascade Hypothesis

Wan et al, 2009

13

PET in vivo imaging of fibrillar amyloid

(A) plaques
Most validated marker is PiB--first
labeled with 11C but current efforts
with 18F-labelled tracers
florbetapir (AV-45) Amyvin just
approved by FDA
Increased cortical PIB closely
reflects distribution of A fibrillar
plaques
Less useful for progression

Doraiswamy et al, 2012

+PIB in 10-30% of NC (poor

specificity or early harbinger?)
14

PET in vivo imaging of fibrillar amyloid (A)

plaques: Florbetapir F18 Scan
Negative Florbetapir Scan

Positive Florbetapir Scan

indicates sparse to no
NPs
is inconsistent with a
neuropathological
diagnosis of AD at the
time of image acquisition
reduces the likelihood that
a patient's cognitive
impairment is due to AD

indicates moderate to
frequent amyloid NPs
may be observed in older
people with normal
cognition and in patients
with various neurologic
conditions, including AD.

Positive scan does not establish dx of AD/other cognitive disorder

Scan not useful in predicting dementia or monitoring tx response
15

Amyloid imaging in AD: comparison

of florbetapir and Pittsburgh
compound-B PET Wolk et al, 2012
Correlation between florbetapir-F18 and PiB-C11 SUVRs in the
composite cortical ROI

14 NC;
12 AD

R=0.60

16

New Diagnostic Guidelines for AD

McKhann et al, 2011

flexible enough to be used by both general healthcare

providers and specialized investigators
criteria for all-cause dementia and for AD dementia
Retained framework of probable AD; redefined possible
AD in a more focused manner
Biomarker evidence integrated into the diagnostic
formulations for probable and possible AD
17

Treatment of AD

23
(23
mg
mg)

23 mg tab

(patch)

Patch, incl
13.3 mg

DOMINO: Donepezil and Memantine

for Moderate-to-Severe AD
Howard et al, 2012

N=295, 52 weeks, UK: continue

donepezil, discontinue donepezil,
discontinue donepezil and start
memantine, or continue donepezil
and start memantine
continuing donepezil (compared
with discontinuing); starting
memantine when donepezil stopped --associated with better scores
adding memantine while continuing
donepezil was not better than
continuing donepezil alone

Vellas et al, 2012

Long-term use of standardised ginkgo biloba

extract for the prevention of Alzheimers disease
(GuidAge): a randomized placebo-controlled trial.
Ginkgo biloba 120 mg BID vs placebo for incident AD in elderly
patients (n=2854) with memory complaints in France over 2 yrs:
Year
1

Ginkgo

Placebo

RRR

0.7%

1.0%

28%
RRI

1.7%

1.0%

65%

Dodel et al, 2013

IVIG for treatment of mild-to-moderate Alzheimer

disease: a phase 2, randomized, double-blind,
placebo-controlled, dose-finding trial
IVIG contains naturally occurring antibodies against
amyloid and has been postulated to remove cerebral
amyloid through a peripheral sink mechanism
Two small open label studies have suggested that IVIG
can stabilize AD
First published trial of intravenous immunoglobulin, n=58
Most primary and secondary outcomes were negative
Small study; probably underpowered; but echoes the
largely negative immunotherapy results (unpublished to
date) of bapineuzumab and solanezumab in AD

Safety and Tolerability of the -Secretase

Inhibitor Avagacestat in a Phase 2 Study of
Mild to Moderate Alzheimer Disease
Coric et al, 2012
Randomized, double-blind, placebo-controlled,
24-week phase 2 study
N=209; Avagacestat25, 50, 100, or 125 mg po qd
Discontinuation rates for the 25-mg and 50-mg doses of
avagacestat were comparable with placebo
100-mg and 125-mg dose arms were poorly tolerated
(skin, GI) with trends for cognitive worsening
study establishes an acceptable safety and tolerability
dose range for future avagacestat studies in AD.

Recent Failed Clinical Trials in AD

Anti-amyloid
Semagacestat: gamma secretase inhibitor
Flurizan (Tarenflurbil)
Alzhemed (Tramiprosate)
AN1792, Bapineuzumab Phase II
Bapineuzumab Phase III Program
Nicotinic Agonist
AZD3480 (Ispronicline)
Lipitor (Atorvastatin)
Zocor (Simvastatin)
Avandia (Rosiglitazone)

Alzheimers Prevention Trials at a Glance

Trial

Participants

Treatment

Outcomes

API: AD
Prevention
Initiative

300 Columbians
incl 100 PSEN1

Crenezumab 1: cognitive;
(Genentech) 2: biomarkers

DIAN:
240 EOAD
3 antiInitial: identify
Dominantly
family members amyloid tx
tx candidate;
Inherited AD
incl 60 mutations TBD
f/u: study
Network
effects
gantenerumab, solanezumab, beta-secretase
I
A4: AntiAmyloid Tx of
Asymptomatic
AD

1500 healthy
seniors incl 500
with amyloid+
scans

1 antiamyloid tx
TBD

1: cognitive;
2: biomarkers

Dementia with Lewy Bodies (DLB)

Second most common dementia in the elderly
10-15% of dementia cases at autopsy
Widely inclusive--spectrum of disorders in which LBs
likely play a causal role in the development of dementia

- Pts with PD who become demented (PDD)

- Demented pts with neocortical LBs and AD changes (LBV)
- Demented pts with diffuse neocortical LB path (DLBD)

3rd Report of the DLB Consortium: revised criteria

(2005)

CENTRAL FEATURE

Dementia
Relative sparing of memory
Attention, executive function, V-S

CORE FEATURES
1=possible DLB
2=probable DLB

Fluctuations in attention
Recurrent, well-formed VH
Parkinsonism

REM Sleep Behavior Disorder

Severe neuroleptic sensitivity
Abnormal SPECT DAT scan or MIBG myocardial
scintigraphy

Repeated falls, syncope, transient LOC, severe ANS

dysfunction, systematized delusions, auditory or other
sensory hallucinations, depression, preservation of
MTL on CT/MRI, occipital hypoperfusion on
SPECT/PET

SUGGESTIVE FEATURES

SUPPORTIVE FEATURES

Pentagon copying is more impaired in DLB

Ala et al, 2001

3rd Report of the DLB Consortium: revised criteria (2005)

CENTRAL FEATURE

Dementia
attention, executive function, V-S

CORE FEATURES
1=possible DLB
2=probable DLB

Fluctuations in attention
Recurrent, well-formed VH
Parkinsonism

SUGGESTIVE FEATURES

SUPPORTIVE FEATURES

REM Sleep Behavior Disorder

Severe neuroleptic sensitivity
Abnormal SPECT DAT scan or MIBG myocardial
scintigraphy

Repeated falls, syncope, transient LOC, severe

ANS dysfunction, systematized delusions,
auditory or other sensory hallucinations,
depression, preservation of MTL on CT/MRI,
occipital hypoperfusion on SPECT/PET

Core features of DLB

Fluctuation

Visual
hallucinations

Parkinsonism

Greatest difficulty in clinical practice

Variation in attentional
performance/arousal
Recurrent, complex; early
Association with reduced occipital
uptake in visual cortex
Axial tendency; greater postural
instability, gait difficulty
Resting tremor less common
Limited evidence regarding levodopa
responsiveness

Third Report of the DLB Consortium: revised criteria (2005)

CENTRAL
FEATURE
CORE
FEATURES
SUGGESTIVE
FEATURES

SUPPORTIVE
FEATURES

Dementia
attention, executive function, V-S

Fluctuations in attention
Recurrent, well-formed VH
Parkinsonism

REM Sleep Behavior Disorder

Severe neuroleptic sensitivity
Abnormal SPECT DAT scan or MIBG
myocardial scintigraphy
Repeated falls, syncope, transient LOC, severe
ANS dysfunction, auditory or other sensory
hallucinations, depression, preservation of MTL on
CT/MRI, occipital hypoperfusion on SPECT/PET

REM Sleep Behavior Disorder (RBD)

act out their dreams
Mov Disord 2001 Jul;16(4):622-30 Association of REM
sleep behavior disorder and neurodegenerative disease
may reflect an underlying synucleinopathy BOEVE et al.

Likelihood of having REM sleep behavior

disorder?

N=360

DLB

PD

56%

vs

AD
2%

P<0.01

Differentiating DLB from AD using a SPECT dopaminergic

presynaptic ligand 123I-FP-CIT
marker for pre-synaptic neuronal degeneration
Walker et al, 2002; McKeith et al, 2007)

NC

PD

AD

DLB

In vivo assessment of vesicular monoamine

transporter type 2 (VMAT2) in DLB and AD
([18F]AV-133) tissue ratio (RT) PET images
NC

DLB

PD

AD
Lower VMAT2
densities; i.e.
reductions of
dopaminergic
nigrostriatal afferents
in patients with DLB

Villmagne et al, 2011

Copyright restrictions may apply.

Myocardial scintigraphty: Heart to mediastinum

uptake ratio of [123I]MIBG in AD and DLB
Quantification of postganglionic sympathetic cardiac innervation

Yoshita et al, 2001

Third Report of the DLB Consortium: revised criteria (2005)

CENTRAL
CORE
FEATURES

SUGGESTIVE
FEATURES

SUPPORTIVE
FEATURES

Dementia
attention, executive function, V-S
Fluctuations in attention
Recurrent, well-formed VH
Parkinsonism
REM Sleep Behavior Disorder
Severe neuroleptic sensitivity
Abnormal SPECT DAT scan or MIBG myocardial
scintigraphy

Repeated falls, syncope, transient LOC,

severe ANS dysfunction, systematized
delusions, auditory or other sensory
hallucinations, depression, preservation of
Medial Temporal Lobe on CT/MRI, occipital
hypoperfusion on SPECT/PET

Medial temporal lobe (MTA) atrophy

absence of MTA and other
cortical atrophy in DLB vs AD
(Whitwell et al, 2007)

absence of MTA: 100% specificity for separating age- and

severity-matched DLB from AD (Barber et al, 1999)

Parieto-occipital
hypometabolism on PET
Klein et al, 2010

Dementia with Lewy

Bodies
Occipital hypoperfusion on
SPECT

Kemp et al, 2007

Alpha-synuclein in the CSF

Differentiates Synucleinopathies
From Alzheimer Disease.
Tateno et al, 2012
significantly lower SNCA
SNCA helps in the
differentiation of
synucleinopathies
(DLB, PD, and MSA)
from AD.
CSF SNCA levels did
not significantly differ
among the 3
synucleinopathies

Treatment of DLB
generally parallels
that for AD: ChEI,
Memantine
levodopa may be less
effective in treating
motor impairments
Traditional
neuroleptics and
other dopamine
blockers such as
metoclopramide
probably best
avoided

McKeith,
2000,
Lancet

Rivastigmine: NPI

Aarsland,
2009

Memantine: CGIC

Emre et al, 2010

Memantine for patients with Parkinson's disease dementia or
dementia with Lewy bodies: a randomized, double-blind,
placebo-controlled trial
199 pts with PDD or DLB; 80% completed the trial
Memantine 10 mg BID or placebo for 24 weeks
DLB pts who received memantine showed greater
improvement on the ADCS-CGIC and NPI; no significant
differences for PDD
No significant differences for cognition, ADCS-ADL, or
caregiver burden for either group

Donepezil for dementia with

Lewy bodies: A randomized,
placebo-controlled trial
Mori et al, 2012
Randomized, d-b, p-c
phase II trial, 48 centers in
Japan, n=140, 12 wks
3, 5, or 10 mg
MMSE, NPI, Zarit
Caregiver Burden
Interview, CIBIC-plus
Donepezil at 5 and
10mg/day produced
significant cognitive,
behavioral, and global
improvements

Mean change from baseline

on the MMSE

Frontotemporal Dementias
5-10% of dementias
Common cause of dementias < age 60
+FH in up to 40%
-commonest mutations are MAPT
and progranulin (PGRN)
Umbrella term for heterogeneous group of clinical disorders
behavioral variant FTD (bvFTD)
BEHAVIOR
progressive nonfluent aphasia (PNFA)
LANGUAGE
semantic dementia (SD)
Frontotemporal lobar degeneration (FTLD) reserved by
some for spectrum of FTD-related pathologies

Frontotemporal Dementia

BEHAVIORAL VARIANT FTD (bvFTD)

Behavioral

Changes in behavior and personality;

apathy, submissiveness, social
withdrawal; disinhibition, compulsions
Dietary change

Cognitive

Frontal/executive dysfunction,
perseverations
Diminished word output

Neurologic

*MND, PSP, CBS

Imaging

Bilateral frontal and/or anterior

temporal lobe abnormality

Frontotemporal Dementia

BEHAVIORAL VARIANT FTD (bvFTD)

Frontotemporal Dementia

PROGRESSIVE NONFLUENT APHASIA (PNFA)

Behavioral Less common

Cognitive

Effortful language output, diminished verbal

fluency; loss of grammar; motor speech
deficits (pronunciation, stuttering, speech
apraxia)
Executive and working memory dysfunction

Neurologic Motor features of PSP, CBS

Imaging

Left perisylvian atrophy

Left frontal opercular atrophy in PNFA

Sapolsky et al, 2011

Caselli
and Jack,
1992

Frontotemporal Lobar Degeneration

SEMANTIC DEMENTIA
Behavioral

Cognitive

Imaging

Mental rigidity, compulsions

Coldness, emotional withdrawal,
depression
Progressive loss of knowledge about
words and objects; fluent, empty speech
with loss of word meaning
Difficulty naming and recognizing words,
idiosyncratic word usage, semantic
paraphasias
Asymmetric; predominantly affecting
dominant (left) anterior temporal lobe

MRI: Semantic Dementia

Frontotemporal Dementia
Frontotemporal Dementia (Neary, 1998; McKhann, 2001)
bvFTD
PNFA
SD
Increasing recognition of other features and syndromes
that can occur in the setting of FTD
Progressive supranuclear palsy syndrome (PSP-S)
Corticobasal syndrome (CBS)
Motor neuron disease (MND)

Frontotemporal Dementia
PSP-S

Akinesia, rigidity, vertical supranuclear gaze

palsy, early falls; apathy

CBS

Asymmetric akinesia and rigidity, limb

apraxia/alien limb, myoclonus; nonfluent
speech

MND

Bulbar symptoms (dysarthria, dysphagia);

weakness, spasticity, hyperactive reflexes,
clonus, fasciculations that may precede,
coincide or follow; especially bvFTD; rapid
progression to death in 2 years

Frontotemporal Lobar Degeneration Classification

3 distinct neuropathologic categories (inclusions)
40%

50%

10%
FUS

TAR DNA-BP

ALS

Fused in Sarcoma

ALS

Josephs, 2008

FTD Syndromes and Pathology

Leyton & Hodges, 2010

Statistical parametric map of significant cerebral blood flow

differences between patients with FTLD and AD
Yellow=significantly reduced perfusion in AD compared with FTLD; blue=significantly
reduced perfusion in FTLD compared with AD

Hu et al, 2010

De Souza et al, 2011

Cerebrospinal fluid biomarkers in the

differential diagnosis of Alzheimer's
disease from other cortical dementias
N=164
P-Tau/A42 ratio was
the best biomarker for
distinguishing AD
from FTD and SD,
with a sensitivity of
91.7% and 98.3%,
respectively, and a
specificity of 92.6%
and 84.2%,
respectively

Bibl et al, 2011

CSF Tau, p-Tau 181 and Amyloid-

38/40/42 in Frontotemporal Dementias
and Primary Progressive Aphasias

differential expression
in FTD (n=25), PPA
(n=12), AD (n=25) and
NC (n=20)

High CSF p-tau ; low A42 /

A40 and A42 /A38 for AD
CSF A38 was reduced in
FTD as compared to others
(including PPA)
CSF tau and p-tau levels
were elevated in PPA as
compared to FTD

FTD: Treatment Advances

SSRIs, trazodone
drugs that modify serotonin have the strongest
biological rationale
Antipsychotics should be used with great caution
Probably best to avoid cholinesterase inhibitors
no cholinergic deficit
Memantine?

Boxer et al, 2013

Memantine in patients with frontotemporal lobar

degeneration: a multicentre, randomized, double-blind,
placebo-controlled trial
randomized, parallel group, double-blind trial of 20 mg
memantine qd vs. placebo for 26 weeks in 81 patients with
FTD (Neary criteria bvFTD or semantic dementia)
Memantine had no effect on either the NPI or CGIC
Memantine was generally well tolerated; however, patients
in the memantine group had more frequent cognitive
adverse events (confusion, memory loss) than those in the
placebo group

VASCULAR DEMENTIA(S)
Heterogeneous: definitions and diagnostic criteria vary
Dementia syndrome(s) accompanied by evidence from
clinical history, neurological examination, and
neuroimaging of cerebrovascular lesions causally
connected to the dementia
Encompasses a variety of clinical presentations and
pathophysiologies
Uncommon as a group; however, some vascular pathology
in about 29-41% of population-based dementia cases
Less than one-third represent pure syndromes
Majority associated with other pathology (often AD)

A Clinico-Pathologicical Study of Heart

and Brain Lesions in Vascular Dementia
Andin et al, 2005
Lund University Hospital (Sweden) Project
1976 - 1995
Autopsy series of 175 clinically diagnosed VaD cases
Only 28% pathologically classified as pure VaD
Remaining 72% showed AD pathology in addition to
a mixture of vascular lesions

Vascular Cognitive Impairment (VCI)

prevalence of cognitive impairment caused by vascular disease
underestimated; recognition of important earlier stage
Bowler, 2005

Notion of risk factors in susceptible host: brain at risk

Copyright 2005 BMJ Publishing Group Ltd.

Vascular Cognitive Impairment (VCI)

Importance of VCI: vascular disease is the largest single
identifiable risk factor for dementia apart from age;
treatable
Non-modifiable Risk Factors
Age, gender
Race, ethnicity
Modifiable Risk Factors
Hypertension, DM
Heart disease (atrial fibrillation)
Cigarettes, heavy alcohol
Lack of criteria
Range of etiologies

Vascular contributions to cognitive impairment and

dementia: a statement for healthcare professionals
from the AHA/ASA Gorelick et al, 2011
importance of construct of VCI
cerebral amyloid angiopathy is emerging as an important
marker of risk for AD and VCI
neuropathology of cognitive impairment in later life is
often a mixture of AD and microvascular brain damage
Neuroimaging is important for defining and detecting VCI
Risk factors for VCI same as risk factors for stroke;
vascular risk factors may also be risk markers for AD
Detection and control of the traditional risk factors for
stroke and cardiovascular disease may be effective in
the prevention of VCI