DEMENS MED LEWYLEGEMER OG PARKINSON DEMENS
Dag Årsland
Regionalt senter for eldremedisin og samhndling (SEAM), Stavanger
Dept of Old age psychiatry, Institute of Psychiatry, Psychology and
Neuroscience, King’s College London
Overview
▪ Cognitive impairment in PD: Spectrum of severity and timing
▪ PDD and DLB: Classification issues
▪ Prodromal syndrome of DLB?
▪ Mechanisms (atrophy, amyloid, genetic)
▪ Biomarkers
▪ Management
08/08/2018
Name Surname 2
Key clinical challenges:
▪ Diagnose cognitive impairment and dementia in PD
▪ Distinguish DLB from Alzheimer’s disease
▪ Management of DLB and PDD
▪ Less important: Distinguish PDD from DLB
08/08/2018
Name Surname 3
Relationship between DLB and
PD dementia-the «Lewy body dementias»
Plaques
Lewy bodies
Halliday & McCann 2009
Clinical symptoms
Dementia
Spectrum of cognitive impairment in PD
▪ Severity of impairment:
continuum of decline
▪ Time to declince:
wide variation
08/08/2018
Name Surname 5
0,00 10,00 20,00 30,00
davonset 0,0
0,2 0,4 0,6 0,8 1,0
Cum Survival
Survival Function Censored
Survival Function
MMSE score in 226 PD, prevalence sample
Non-linear decline:
Time to dementia:
Frequency of dementia in PD
▪ Point-prevalence: 25-30%
0 10 20 30 40 50 60
Pollock13 Snow14
Okada15 Sutcliffe16
Mutch17 Martilla18
Wang19 Wallin 19b
Melcon20 Wang21
Mayeux22 Tison23
Aarsland24
All studies combined
%
0 10 20 30 40 50 60 70 80
Baseline 4-yr 8-yr*
PD Controls
The Sydney Study. Hely et al. 2008 Cumulative prevalence 80%
Study N %MCI Cohort
Pai et al 2001 102 38.2 Clinic
Foltynie et al 2004 146 30.1 Community/Incidence Muslimovic et al 2005 115 23.5 Clinic(early PD)
Hoops et al 2009 115 17.4 Clinic
Aarsland 2009 196 18.9 Community/Incidence
Mamikonyan et al 2009 106 29.2% Clinic
Reference N PD/NCl Selection Age Cut- off
Definition impaired
Impaired
Reid et al 1996 91/50 Hospital 63 2 SD “Dem” 17%
Muslimovic 05 115/70 Hospital 66.2 2 SD 3/17 PD: 24%
Foltynie 2004 159/no Incidence 70.6 1 SD 1/3 36%
Aarsland 2008 196/175 Incidence 67.6 1.5 1/3 PD: 18.9%
Elgh 2009 88/30 Community 68 1.5 1/5 domains 30%
Yarnall 2014 219 Incidence 66 1.5 MDS 42.5%
How common is PD-MCI?
MCI in de-novo PD
DLB: Clinical criteria
▪ Dementia
Executive/visuospatial
▪ Core featues
Cognitive fluctuations
Visual hallucinations
Parkinsonism
▪ Suggestive features
Positive DaTSCAN
Neuroleptic hypersensitivity
REM sleen behavioral disorder
▪ Supportive features:
▪ severe, early autonomic dysfuction, depression, preserved medtial temporal lobe
McKeith et al. 2005
Pathological Lewy-body type:
-Brain-stem predominant -Limbic (transitional)
-Diffuse neocortical DLB or PDD? The 1-year rule:
-Dementia occurring before or concurrently with parkinsonism is DLB
-Dementia occurring in the context of PD, i.e. > 1 yr
between onset of parkinsonism and dementia, is PDD
How common is DLB?
DemVest: 16% of dementia have probable DLB
N=150 39% male Age 75.8
Aarsland, Rongve, et al. Dem Geriatr Cogn Disord 2008
Rate of decline on MMSE in DLB and AD-
The Dementia study in Western Norway-DemVest
08/08/2018
Name Surname 10
0 2 4 6 8
0.00.20.40.60.81.0
event: CDR=3 or death
years
survival
probAD probDLB
Rongve et al. BMJ Open (In press)
Higher costs and shorter time to nursing home admission in DLB than AD
Rongve et al. 2014
Vossius et al. 2014
”LBD”
Idiopathic RBD
Idiopathic PD
Primary autonomic dysfunction
Isolated visual hallucinations
Risk factors for DLB and dementia in PD
MCI
(Non-amnestic)
Delirium-tendency
Hyposmia
08/08/2018
Name Surname 13
Median time to disease: 7.5y DLB: 29
PD: 22 MSA: 2 MCI: 12
PLOS One 2014
RBD: Prodrome for PD and for DLB:
Do DLB patients have diffuse LBD?
Prospective clinic-pathologic validation study first 50 Newcastle cases
McKeith et al. Neurology. 2000 Mar 14;54(5):1050-8.
Pathol dx Primary clinical
dx
DLB n=29 AD n=15 VaD n=5 PSP n=1
Prob DLB n=25 24 1 0 0
Poss DLB n=1 0 0 0 1
Prob AD n=9 0 7 2 0
Poss AD n=10 3 6 1 0
VaD n=5 2 1 2 0
Clinical dx DLB: Sens 0.83; Spec 0.95
The role of amyloid pathology for dementia in PD and DLB
▪ Pathological evidence
▪ CSF evidence
▪ Imaging evidence
08/08/2018
Name Surname 15
CSF abeta42 and cognition in PD
Alves et al. JNNP 2010; 2012
Siderowf. Neurology 2010
Memory and ab42
Ab42 and motor type
Ab42 predicts cognitive decline
Mem ory z- scor e
Amyloid imaging
Gomperts et al 2008, 2012 Petrou et al Neurology 2012
1) Only 15% of PDMCI have abnormally high PIB-binding
2) PIB-binding correlates with cognition:
CSF ved DLB: AD profil hyppig;
predikerer raskere progresjon
08/08/2018
Name Surname 18
CSF AD profile* is common in DLB (46%)
Steenoven I et al. Subm
* tau/aβ42 >0.52 (Duits 2014). N=168
Abdelnour et al Subm
Genetics and PDD / DLB
▪ Increased risk:
APOE e4
GBA
SCNA
Tau H1 haplotype?
▪ Reduced risk:
APOE e2
LRRK2
08/08/2018
Name Surname 19
DLB-Diagnostic biomarkers:
▪ β-cit SPECT/PET:
DAT red. i
putamen/kaudatus
▪ SPECT/FDG-PET:
occipital hypoactivity
▪ Myocardial scintigraphy
▪ MRI/CT: less MTA
▪ EEG: slow-wave
▪ CSV: reduced Ab42
and alphasyn, normal
tau
Lancet Neurol 2007
Sensitivity: 78%
Specificity: 90%
PPV: 82.4%
NPV: 87.5%
EU/US approval for the
diagnosis of probable DLB
Treatment of DLB and PDD:
▪ Exclude other diseases /Causes
▪ Diagnose DLB (history, medical status, psychiatric/cognitive status, biomarkers)
▪ Overall measures:
General information
Coping strategies for VH
Stockings for orthostasis
▪ Drug treatment
Drug-treatment of DLB and PDD
▪ Cholinesterase inhibitors (memantine?)
▪ Hallucinations: atypical antipsychotics? ChEI??
Pimavanserin??, 5HT6-antagonists???
▪ Parkinsonism: LDOPA?
▪ Depression: SSRI??
▪ RBD: clonazepam (0.25-0.5); melatonin; CHEI?
▪ Delicate balance between effect and side-effects
Anti-dementia drugs: CGIC-Meta-analysis
Wang et al JNNP 2015
