Download Session 209 Presentation - Alzheimer`s Association

3/6/2017
Predicting Clinical Outcome in
Dementia
With Lewy Bodies
Jonathan Graff-Radford, MD
Assistant Professor of Neurology
Mayo Clinic, Rochester
Meeting Name Here
And Date Here
Disclosure
Relevant Financial Relationship(s)
• None
Off Label Usage
• Acetylcholinesterase inhibitors
Outline
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History of Dementia with Lewy Bodies (DLB)
Overview of DLB
Neuroimaging
Pathology
Review the importance of coexisting
Alzheimer’s pathology in DLB
• Identify hippocampal volumes as a predictor of
treatment response and survival in DLB
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1 Year of Cognitive Impairment,
Balance Difficulty, Visual Hallucinations
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Exam – moderate parkinsonism
SMS 27/38
Hypersomnia, +autonomic features
Commenced on Donepezil
Markedly improved after 4 weeks, SMS 35/38
Parkinsonism remained
Improvement sustained at age 68
History
Dementia with Lewy Bodies (DLB)
• 1912 – Fritz Jakob Heinrich Lewy (1885–1950)
described the cellular inclusions that are characteristic
of Parkinson disease
• 1919 – Konstantin Nikolaevich Tretiakoff (1892–1956)
named them after Lewy (‘corps de Lewy’, or Lewy
bodies)
• 1961 – H. Okazaki first reported Lewy bodies in
cerebral cortex in patients with dementia
Okazaki et al: J Neuropathol Exp
Neurol,1961
History
Dementia with Lewy Bodies (DLB)
• Concept of DLB began in 1961,
when Okazaki published two cases
• Both were diagnosed with
dementia
and died shortly thereafter with
severe extrapyramidal rigidity
• Autopsy showed Lewy body
pathology in the cerebral cortex
Okazaki et al: J Neuropathol Exp
Neurol,1961
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History
Dementia with Lewy Bodies (DLB)
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Little published over next 20 years, almost all in Japan,
who adopted the term diffuse Lewy body disease
1990 – Hansen reported that 36% of patients diagnosed of AD had Lewy
bodies at autopsy “the Lewy body variant of AD”
1996 – DLB characterized (1st Consensus conference), McKeith et al,
Neurology, 1996
1997 – a missense mutation in α-synuclein gene was shown to cause a
dominantly inherited form of PD with Lewy pathology
1997 – Lewy bodies and Lewy neurites from cases of idiopathic PD were
shown to be immunoreactive for α-synuclein
Hansen L et al:Neurology 40:1; 1990.
Polymeropoulos M et al: Science 276, 2045;
1997)
Overview
Dementia with Lewy Bodies (DLB)
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Now considered the primary cause of dementia in up to
20% of patients (2nd behind AD)
Incidence of 112 per 100,000 person-years in people
aged 65 years and older
Overview
Dementia with Lewy Bodies (DLB)
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60-70% male
APOE e4 was more frequent in DLB compared to controls
Less frequent when DLB was compared with AD
Reflect the mixed synuclein/AD pathology seen in
most DLB cases?
APOE4 actually more common in pure synucleinopathies
Tsuang D et al: JAMA Neurology, 2013
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Prognosis
Dementia with Lewy Bodies (DLB)
Compared with Alzheimer disease,
patients with DLB
• Have faster cognitive decline
• Have a shorter survival
• Are admitted to nursing homes
2 years earlier
Time to death based on
best estimate of onset (years)
Olichney JM et al: Neurology, 1998; Rongve
A et al: J of Geriatric Psychiatry, 2013
Williams et al: Neurology, 2006
Criteria
Dementia with Lewy Bodies (DLB)
Symptom/Sign
Dementia
Manifestation
Frequency (%)
Attention, visual spatial
> memory
100
Core Features
Fluctuations
Visual hallucinations
Parkinsonism
REM sleep behavior disorder
Altered levels of attention
60
Recurrent, fully formed
50-75
Action > rest tremor
75
Act out dreams
79
Mckeith et al: Neurology, 2006
Fluctuations
Dementia with Lewy Bodies (DLB)
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Fluctuating cognition with marked variations in
attention and alertness
Fluctuation occurs in 50-75%
At Mayo, 63% of DLB patients,12% of AD patients and
0.5% of normals
Positive predictive value of 83% for the
clinical diagnosis of DLB
Ferman TJ et al: Neurology, 2004
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Fluctuations
Dementia with Lewy Bodies (DLB)
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Mayo fluctuations scale (19 questions)
4 questions distinguish DLB from AD
– Drowsiness and lethargy all the time
– Daytime sleep of 2 or more hours (before 7 pm)
– Staring into space for long periods
– Times when the patient’s flow of ideas seem
disorganized not logical
No differences between AD and DLB when directly asked if patient
fluctuates
Ferman TJ et al: Neurology, 2004
Fluctuations
Dementia with Lewy Bodies (DLB)
100
80
60
%
40
20
0
0
1 or 2
3 or 4
Fluctuations composite score
Ferman TJ et al: Neurology, 2004
Hallucinations
Dementia with Lewy Bodies (DLB)
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Hallucinations (fully formed)
– Occur in 63% of autopsy-confirmed cases
– 20% of those with AD without any α-synuclein
– Hallucinations within the first 5 years of dementia, the odds were 4–5
times greater for autopsy-confirmed LBD
Ferman TJ et al: Parkinsonism & Related
Disorders, 2013
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Parkinsonism
Dementia with Lewy Bodies (DLB)
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Parkinsonism is common in community
– 50% of those 85 and older
Half of DLB cases have parkinsonism at presentation
Compared to Parkinsons disease less resting tremor and myoclonus,
greater symmetry and worse response to levodopa
REM Sleep Behavior Disorder
Dementia with Lewy Bodies (DLB)
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Increased the odds by 6-fold of autopsy-confirmed DLB
172 path confirmed RBD cases
– LBD(n=138)
– MSA (n=19)
– AD (n=6)
– PSP(n=2)
Present in 79% of DLB
Boeve BF, Silber MH, Ferman TJ, et al:
Neurology, 1998; Nelson PT et al: J Neurol
257:359; 2010
Boeve BF: Sleep Med 14(8):754, Aug 2013
REM Sleep Behavior Disorder
Dementia with Lewy Bodies (DLB)
Core question on recurrent
dream enactment behavior
yielded a sensitivity of 98%
and specificity of 74% for the
diagnosis of RBD
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Criteria
Dementia with Lewy Bodies (DLB)
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NACC data from 31 expert academic centers
Sensitivity of DLB clinical diagnoses was 32%
Need to improve ability to diagnose DLB
Nelson PT et al: J Neurol 257:359; 2010
Criteria
Dementia with Lewy Bodies (DLB)
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81% of DLB patients who receive neuroleptics
have adverse reaction
50% severe neuroleptic sensitivity
– Sudden onset of sedation, confusion, rigidity
– Smaller group have NMS like reactions
Not dose dependent
Three-fold increase in mortality
Radiology MRI
Dementia with Lewy Bodies (DLB)
Magnetic Resonance Imaging (MRI)
Normal
DLB
AD
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Radiology FDG PET
Dementia with Lewy Bodies (DLB)
DLB
Normal
AD
Radiology FDG PET
Dementia with Lewy Bodies (DLB)
Cingulate Island Sign
DLB
AD
Radiology DaT Scan
Dementia with Lewy Bodies (DLB)
Ioflupane binds presynaptically to
the dopamine transporter
receptors (DaT)
DLB
Normal
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Radiology Amyloid PET
Dementia with Lewy Bodies (DLB)
Pathology
Dementia with Lewy Bodies (DLB)
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The pathological hallmark of AD is deposition of Aβ in plaques and tau
protein in neurofibrillary tangles
DLB is characterized by the deposits of α-synuclein protein
Majority DLB patients have coexistent AD pathology
Probable DLB cases (n=40)
Braak Stage I,II
Braak Stage III, IV
Braak Stage V,VI
N=8
N=22
N=10
Braak H et al: J Neuropathol Exp Neurol
70(11):960, 2011.
Fujishiro H et al: J Neuropathol Exp Neurol,
2008
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Imaging Predictors of Cholinesterase
Inhibitor Response In DLB
• In DLB, hippocampal atrophy is associated with
AD neurofibrillary tangle pathology
• Both DLB and AD are frequently treated with
cholinesterase inhibitors
• Earlier and greater loss of cholinergic neurons in the
nucleus basalis in DLB
• DLB patients with greater cholingergic loss but
intact hippocampus may respond better to
cholinesterase inhibitors
Imaging Predictors of Cholinesterase
Inhibitor Response in DLB
Objective
• To determine whether imaging markers of AD
pathology such as hippocampal atrophy and
PiB PET are associated with treatment
response to cholinesterase inhibitors in DLB
Imaging Predictors of Cholinesterase
Inhibitor Response in DLB
Methods
• Retrospective analysis on consecutive treatment-naive
DLB patients (n=54)
• Patients subsequently received cholinesterase inhibitors
and underwent MRI with volumetry
• Response assessed from baseline and follow-up
Mattis Dementia Rating Scale
• Subjects were divided into three groups
(reliable improvement, stable, or reliable decline) using
DRS reliable change indices previously published
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Imaging Predictors of Cholinesterase
Inhibitor Response in DLB
DLB patients with reliable cognitive improvement had larger hippocampal
Hippocampal volumes
(% TIV)
volumes than those that declined (P = 0.02) or remained stable (P = 0.04)
0.6
0.5
0.4
0.3
Reliable
decline
Stable
Reliable
improvement
Graff-Radford et al: Brain, 2012
Imaging Predictors of Cholinesterase
Inhibitor Response in DLB
Summary
• Acetylcholinesterase inhibitor treatment response in
DLB patients is associated with the imaging markers of
AD pathology
• DLB patients cognitively improve on
acetylcholinesterase inhibitor treatment if they do not
have imaging evidence
of coexisting AD
Prognosis
Association with Hippocampal Volumes?
• Medial temporal atrophy is seen in a
proportion of
DLB subjects
– Hippocampal atrophy is associated with
Alzheimer's disease-related neurofibrillary tangle
pathology
Burton EJ et al: Brain, 2009; Barber et al:
Neurology, 1999
Kantarci et al: Neurology, 2012
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Objective
• Investigate whether hippocampal volumes can
predict survival in patients with probable DLB
• Could hippocampal volume be a prognostic
marker?
Methods
Patient Selection
Patients
DLB determined
by 3rd Consortium
criteria (2005)
167 consecutive patients with probable DLB
who had antemortem MRI
If the patient was diagnosed prior to
the implementation of these criteria,
their charts were retrospectively verified
to meet criteria
McKeith et al: Neurology, 2005
Methods
Hippocampal volumes
determined from MRI
using automated
techniques
Cognitive, demographic,
and genetic markers
obtained at the time
of imaging
Followed patients for
time to death
Analyzed pathology
findings in 54 patients
who underwent
autopsy
McKeith et al: Neurology, 2005
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Methods
Neuroimaging
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Hippocampal volumes determined via MRI at 1.5 or 3 Tesla
1.5 Tesla
Spoiled gradient recalled
acquisition (SPGR)
3 Tesla
Magnetization prepared rapid
gradient echo (MPRAGE)
acquisition
• Volume data analysis was performed by
Volumes from 1.5 Tesla
• Hippocampal volume –
were converted to
FreeSurfer version 5.3
3 Tesla
• Total intracranial volume –
Statistical parametric mapping algorithm (SPM12)
McKeith et al: Neurology, 2005
Methods
Statistical Analysis
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Linear regression models predicting hippocampal volumes using age at
MRI and total intracranial volume
– The residuals from these models were used as predictors
in the Cox proportional hazards models for survival
from age at onset
• Actual residuals
• Residuals trichotomized
– Low – 0-33.33%
– Medium – 33.33-66.67%
– High – 66.67-100%
Results
Characteristics of DLB Subjects at Time of Imaging (N=167)
Males (%)
134 (80)
ε4 carriers (%)
79 (49)
Cognitive impairment onset age
68 (63, 74)
MRI age
72 (67, 76)
Education
DRS
MMSE
Parkinsonism
14 (12, 16)
125 (112, 133)
24 (21, 27)
121 (87)
Median (IQR) reported for the continuous variables and counts (%) for the categorical
variables
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Results
In univariate analysis, the following were associated with
shorter survival
Age at onset of
cognitive impairment
Presence of at least 1
APOE4 allele
Hazard ratio 1.06
95% CI 1.03-1.08
P<0.0001
Hazard ratio 1.55
95% CI 1.07-2.24
P=0.02
Results
Hazard Ratios and P-Values for Hippocampal Volume
Hippocampal volume
HR (95% CI)
P
Low to High (continuous)
1.28 (1.04-1.58)
0.022
Medium vs. High
1.62 (1.02-2.58)
0.043
Low vs. High
1.79 (1.14-2.83)
0.012
Medium/Low vs. High
1.71 (1.14-2.55)
0.009
• Pearson correlation
among age at onset
and age at MRI
was 0.96
• Did not have age at
onset and age at MRI in
the same model
APOE4 was not related to survival in any of the models
after including hippocampal volume
• True even when comparing medium/low
hippocampal volume to high hippocampal volume
• P=0.075; the hazard ratio was 1.41 (95% CI 0.97-2.04)
Results
Pathology
DLB Likelihood
High
34 (63%)
Intermediate
15 (28%)
Low/None
4 (9%)
All without LBDs pathology had AD pathology
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Results
Predicted Survival for Subjects With Onset of
Cognitive Symptoms at Different Ages
Age at onset 60
Age at onset 68
Age at onset 75
APOE4-, High
hippocampal volume
Group
12.68 (10.63-17.70)
10.63 (8.66-14.54)
8.77 (7.48-12.71)
APOE4+, High
hippocampal volume
11.04 (8.77-15.00)
8.89 (7.56-12.36)
7.74 (6.82-10.76)
APOE4-, Medium/Low
hippocampal volume
9.65 (8.10-13.70)
8.10 (7.34-11.08)
7.34 (6.52-9.45)
APOE4+, Medium/Low
hippocampal volume
8.56 (7.44-11.70)
7.38 (6.74-9.29)
6.74 (6.21-7.84)
Results
Predicted Survival for Subjects With Onset of
Cognitive Symptoms at Different Ages
Survival probability
1.0
Age 68
APOE-; High HV
APOE+; High HV
APOE-; Med/low HV
APOE+; Med/low HV
Survival (years)
APOE4High HV
10.63 (8.66-14.54)
0.6
APOE4+
High HV
8.89 (7.56-12.36)
0.4
APOE4Med/Low HV
8.10 (7.34-11.08)
0.2
APOE4+
Med/Low HV
7.38 (6.74-9.29)
0.8
0.0
0
5
10
15
20
Survival time (years)
Discussion
DLB patients with larger hippocampal volumes
survived longer compared to those with
smaller hippocampal volumes
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Discussion
3 year shorter predicted survival
• Low hippocampal volume + APOE4 compared with preserved
hippocampal volume and absence of APOE4
• Onset of symptoms at age 68
Discussion
• In DLB patients, hippocampal atrophy is associated with AD
neurofibrillary tangle pathology
• Findings are similar to the results of an
autopsy based study
– AD burden associated with shorter survival in
12 path confirmed DLB patients
• Hippocampal volume and APOE4 are likely not the
only two factors that influence survival in DLB
Kantarci et al: Neurology, 2012; Wakisaka Y
et al: Acta Neuropath, 2003
Williams et al: Neurology, 2006; Burton EJ
et al: Brain, 2009
Discussion
• Others have shown that parkinsonism is
an important factor for survival
• DLB patients with rapidly progressive dementia
may have no other coexisting pathology
Kantarci et al: Neurology, 2012; Wakisaka Y
et al: Acta Neuropath, 2003
Williams et al: Neurology, 2006; Burton EJ
et al: Brain, 2009
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Conclusion
• Among patients with clinically diagnosed DLB,
those with neuroimaging evidence of hippocampal atrophy have
shorter survival and better response
to treatment
• These findings may be used to give patients and caregivers a more
accurate prognosis
Kantarci et al: Neurology, 2012; Wakisaka Y
et al: Acta Neuropath, 2003
Williams et al: Neurology, 2006; Burton EJ
et al: Brain, 2009
Thank You!
Co-Investigators
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Timothy G. Lesnick
Bradley F. Boeve
Scott A. Przybelski
David T. Jones
Matthew L. Senjem
Jeffrey L. Gunter
Lidia Sarro
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Tanis J. Ferman
David S. Knopman
Melissa E. Murray
Dennis W. Dickson
Clifford R. Jack, Jr.
Ronald C. Petersen
Kejal Kantarci
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Study Funding
• Study Funding: NIH [R01 AG040042, R01
AG11378, P50 AG16574, U01 AG06786, C06
RR018898]
• Mangurian Foundation
• The Elsie and Marvin Dekelboum Family
Foundation
• The Robert H. and Clarice Smith and Abigail Van
Buren Alzheimers Disease Research Program
References
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Alzheimer disease. Neurology 2006;67:1935-1941
2. Burton EJ et al. Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and
vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain 2009.
3. Rongve A, Vossius C, Nore S, Testad I, Aarsland D. Time until nursing home admission in people with mild dementia:
comparison of dementia with Lewy bodies and Alzheimer's dementia. International journal of geriatric psychiatry 2013
4. Olichney JM, Galasko D, Salmon DP, et al. Cognitive decline is faster in Lewy body variant than in Alzheimer's disease.
Neurology 1998;51:351-357
5. Josephs KA, Ahlskog JE, Parisi JE, et al. Rapidly progressive neurodegenerative dementias. Arch Neurol 2009;66:201-207
6. Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, O'Brien JT. Medial temporal lobe atrophy on MRI in dementia with
Lewy bodies. Neurology 1999;52:1153-1158.
7. Kantarci K, Dickson DW, Vemuri P, et al. Ante mortem Hippocampal Atrophy Predicts Presence of Alzheimer’s Disease
Pathology in Pathologically Proven Lewy Body Disease. Neurology 2012
8. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB
Consortium. Neurology 2005;65:1863-1872
9. Raman MR, Preboske GM, Przybelski SA, et al. Antemortem MRI findings associated with microinfarcts at autopsy. Neurology
2014;82:1951-1958
10. Wakisaka Y, Furuta A, Tanizaki Y, Kiyohara Y, Iida M, Iwaki T. Age-associated prevalence and risk factors of Lewy body
pathology in a general population: the Hisayama study. Acta Neuropathol 2003;106:374-382.
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