DEMENS MED LEWYLEGEMER OG PARKINSON DEMENS

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1 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

2 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 Name Surname 08/08/2018 2

3 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 Name Surname 08/08/2018 3

4 Relationship between DLB and PD dementia-the «Lewy body dementias» Clinical symptoms Dementia Lewy bodies Plaques Halliday & McCann 2009

5 Cum Survival Spectrum of cognitive impairment in PD Severity of impairment: continuum of decline MMSE score in 226 PD, prevalence sample Time to declince: wide variation Non-linear decline: Survival Function Time to dementia: 1,0 Survival Function Censored 0,8 0,6 0,4 0,2 Name Surname 08/08/ ,0 0,00 10,00 20,00 30,00 davonset

6 Frequency of dementia in PD Point-prevalence: 25-30% Cumulative prevalence 80% % PD Controls Pollock13 Snow14 Okada15 Sutcliffe16 Mutch17 Martilla18 Wang19 Wallin 19b Melcon20 Wang21 Mayeux22 Tison23 Aarsland24 All studies combined 10 0 Baseline 4-yr 8-yr* The Sydney Study. Hely et al. 2008

7 How common is PD-MCI? Study N %MCI Cohort Pai et al Clinic Foltynie et al Community/Incidence Muslimovic et al Clinic(early PD) Hoops et al Clinic Aarsland Community/Incidence Mamikonyan et al % Clinic MCI in de-novo PD Reference N PD/NCl Selection Age Cutoff Definition impaired Reid et al /50 Hospital 63 2 SD Dem 17% Impaired Muslimovic /70 Hospital SD 3/17 PD: 24% Foltynie /no Incidence SD 1/3 36% Aarsland /175 Incidence /3 PD: 18.9% Elgh /30 Community /5 domains 30% Yarnall Incidence MDS 42.5%

8 DLB: Clinical criteria Dementia 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 Executive/visuospatial Core featues Cognitive fluctuations Visual hallucinations Parkinsonism Suggestive features Positive DaTSCAN Neuroleptic hypersensitivity -Dementia occurring in the context of PD, i.e. > 1 yr between onset of parkinsonism and dementia, is PDD REM sleen behavioral disorder Supportive features: severe, early autonomic dysfuction, depression, preserved medtial temporal lobe McKeith et al. 2005

9 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

10 survival Rate of decline on MMSE in DLB and AD- The Dementia study in Western Norway-DemVest event: CDR=3 or death probad probdlb years Rongve et al. BMJ Open (In press) Name Surname 08/08/

11 Higher costs and shorter time to nursing home admission in DLB than AD Rongve et al Vossius et al. 2014

12 Risk factors for DLB and dementia in PD Hyposmia Idiopathic RBD MCI (Non-amnestic) Isolated visual hallucinations LBD Delirium-tendency Idiopathic PD Primary autonomic dysfunction

13 RBD: Prodrome for PD and for DLB: Median time to disease: 7.5y DLB: 29 PD: 22 MSA: 2 MCI: 12 PLOS One 2014 Name Surname 08/08/

14 Do DLB patients have diffuse LBD? Prospective clinic-pathologic validation study first 50 Newcastle cases Primary clinical dx Pathol dx DLB n=29 AD n=15 VaD n=5 PSP n=1 Prob DLB n= Poss DLB n= Prob AD n= Poss AD n= VaD n= Clinical dx DLB: Sens 0.83; Spec 0.95 McKeith et al. Neurology Mar 14;54(5):

15 The role of amyloid pathology for dementia in PD and DLB Pathological evidence CSF evidence Imaging evidence Name Surname 08/08/

16 Memory z-score CSF abeta42 and cognition in PD Memory and ab42 Ab42 predicts cognitive declin Ab42 and motor type Alves et al. JNNP 2010; 2012 Siderowf. Neurology 2010

17 myloid imaging 1) Only 15% of PDMCI have abnormally high PIB-binding 2) PIB-binding correlates with cognition: Gomperts et al 2008, 2012 Petrou et al Neurology 2012

18 CSF ved DLB: AD profil hyppig; predikerer raskere progresjon CSF AD profile* is common in DLB (46%) * tau/aβ42 >0.52 (Duits 2014). N=168 Steenoven I et al. Subm Abdelnour et al Subm Name Surname 08/08/

19 Genetics and PDD / DLB Increased risk: APOE e4 GBA SCNA Tau H1 haplotype? Reduced risk: APOE e2 LRRK2 Name Surname 08/08/

20 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

21 Sensitivity: 78% Specificity: 90% PPV: 82.4% NPV: 87.5% EU/US approval for the diagnosis of probable DLB Lancet Neurol 2007

22 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

23 Drug-treatment of DLB and PDD Cholinesterase inhibitors (memantine?) Hallucinations: atypical antipsychotics? ChEI?? Pimavanserin??, 5HT6-antagonists??? Parkinsonism: LDOPA? Depression: SSRI?? RBD: clonazepam ( ); melatonin; CHEI? Delicate balance between effect and side-effects

24 Anti-dementia drugs: CGIC-Meta-analysis Wang et al JNNP 2015

25 DLB/PDD: Management in clinical practice Challenges Many different symptoms Treating one symptom may worsen another High risk for side-effects Robust evidence lacking Strategy Discuss with patient/family which symptoms to target Treatment should be tightly monitored

26 Conclusions/summary Dementia is a common complication in PD DLB is common, likely 15-20% of dementia PDD/DLB: Severe prognosis, characteristic clinical presentation, similar mechanisms Clinical criteria and biomarkers can help (Dat scan) Management of PDD and DLB is similar Overall measures; Information and guidance Cholinesterase inhibitors: Good evidence Antipsychotic: Clozapine in PD, no evidence in DLB

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