8/7/2019 DLB and Atypical Parkinson Syndromes

1/19

AtypicalParkinson-Syndromes

ThomasGasser

NeurologischeKlinikundHertie-InstitutfrklinischeHirnforschung

UniversittTbingen

Lewy-bodyParkinsonsdisease

withandwithoutdementia(PD,PDD,DLB)

goodandsustainedL-Doparesponse

otherParkinsoniansyndromes

L-Dopa-responsevariable

Differentialdiagnosis ofParkinsoniansyndromes

8/7/2019 DLB and Atypical Parkinson Syndromes

2/19

DementiainParkinsonsdisease

LewyPathologie

Contiuum:-PD-PDwithlatedementia

-DLB

DementiainParkinsonsdisease

DementiawithLewy-bodies

Secondmostcommonformofdegeenrative

dementia

Dementiawith

Frontaldysfunctionvisual-spatialdysfunction

fluctuatingattention

Hallucinations

Dementiawithin1yearofparkinsonism

8/7/2019 DLB and Atypical Parkinson Syndromes

3/19

DLB

CorticalLewy-bodies

And

Lewy-neurites

Ransmayeretal.,

Nervenarzt2002

ContinuumofPDandDLB

80%ofpatientswithPDdevelopdementiaafter

10years

SevereSNCAmutations(A53T,triplications)

oftenhaveearlydementia,corticalLewy

pathology

MilderSNCAmutations(duplications)haveless

dementia

8/7/2019 DLB and Atypical Parkinson Syndromes

4/19

AtypicalParkinson-Syndromes

Neurodegenerativediseases

Multiplesystemsatrophy(MSA)

Progressivesupranuclearpalsy(PSP)

Corticobasaldegeneration(CBD)Others

DruginducedPS

ToxicPS

PSduetostrukturalbrainlesions

Parkinson-Syndromes

Parkinson`sdisease75%

Sporadic90%

Familial10%

AtypicalParkinson-Syndromes25%

Multiplesystematrophy

ProgressiveSupranuklereBlickparese

CorticobasalDegenerationSymptomaticParkinson-Syndromes

vascularParkinson-Syndrome

Normalpressurehydrocephalus

8/7/2019 DLB and Atypical Parkinson Syndromes

5/19

Multiplesystematrophy(MSA)

AutonomicfailureParkinsonsyndromeCerebellardysfunctionPoorL-doparesponse

11C-Racloprid

MSAredflags

Wenningetal.,MovDisord2003

8/7/2019 DLB and Atypical Parkinson Syndromes

6/19

MSAneuropathology

5678

Parkinsonism

Essentialtremor

B:Swedish-American A:Swedish

1

234

9

1011

MSA?Onset71,Rapidprogression

PoorL-dopa-response

Severeorthostatichypotension

DLB-likeOnset35

Dopa-responsiveparkinsonism

Dementia

SNCA

duplicationSNCA

triplication

AB

8/7/2019 DLB and Atypical Parkinson Syndromes

7/19

Analysisof384topSNPsfromPD-associationstudy

SNCA

AssociationstudyinMSA

Scholzetal.,2009

Heterozygousriskallelecarriers

=1.3[95%CI:1.13.4]

homozygousriskallelecarriers

=6.2[95%CI:3.4-11.2]

Reminder:ParkinsonGWAS

SNCAMAPT

Bonferronithreshold

463,187SNPsin1,713cases&3,978controls

8/7/2019 DLB and Atypical Parkinson Syndromes

8/19

MaincriteriasporadicParkinson-

SyndromeSupranuclearverticalgaze palsy

Additionalcriteriaposturalinstabilitydysphagiaaxialrigiditysubcorticaldementia

ProgressiveSupranuclearPalsy

ProgressiveSupranuclearPalsy

Verticalgazepalsy

blepharospams

8/7/2019 DLB and Atypical Parkinson Syndromes

9/19

ImagingPSP

PSP

Mikrotubule-

associated

ProteinTau(MAPTau)

8/7/2019 DLB and Atypical Parkinson Syndromes

10/19

usuallyprominentparkinsonismProgressivesupranuclearpalsyCorticobasaldegeneration

occasionallyprominentparkinsonismFrontotemporaldementiawithparkinsonismlinkedtochromosome17

usuallyprominentdementiaAlzheimersdiseasePickdisease

TauopathiesMicrotubuleassociatedproteinTau,MAPTau

8/7/2019 DLB and Atypical Parkinson Syndromes

11/19

Tauopathies

4Repeat-Tau3Repeat-Tau

pairedhelicalfilaments

Alzheimerdisease

straightfilaments

PSP

Pickbodies

Picksdisease

twistedribbons

FrontotemporalDementia

Tau-PolymorphisminPSP

Exon9Exon10

Exon9Exon10

Exon9Exon10

Exon9Exon10

100%

50%

A0 A0

controlsPSP

Conrad,1997

CA-Repeat

A0-Allele

8/7/2019 DLB and Atypical Parkinson Syndromes

12/19

Tau-H1-HaplotypbeiPSP

Exon9Exon10 Exon8Exon11

Exon9Exon10 Exon8Exon11

A0

H1

H2

Bakeretal.,1999

PSPKontrollen

H1/H187%62%

H1/H212%31%

H2/H20%6%

8/7/2019 DLB and Atypical Parkinson Syndromes

13/19

Parkinsonsyndromemarkedasymmetry

corticalsensorylossalienhandsigndementia

Corticobasaldegeneration

UnilateralekortikaleAtrophiederPerizentralregion

(Nachweisbarkeitin>50%derFlle)

CortikobasalDegeneration(CBD)

8/7/2019 DLB and Atypical Parkinson Syndromes

14/19

CortikobasalDegeneration(CBD)

FragileXTremorAtaxiaSyndrome(FXTAS)

8/7/2019 DLB and Atypical Parkinson Syndromes

15/19

FMR1-Gene

5-UTR

Normal

(5-39)

Grayzone

(40-55)

Pre-mutation

(55-200)

CGG-RepeatFullmutation

(>200)

Fragile-X

Mentalretardation

Fragile-X

Tremorataxia

Syndrome

FXTAS

FragileXTremorAtaxiaSyndrome(FXTAS)

(Mostly)inmaleFragileXpremutationcarriers

Symptoms:

mixedtremor(resting/intention/postural)

Ataxia

Parkinsonism

mildcognitiveimpairment

Neuropathology:eosinophilic,intranuclearinclusionsin

neuronsandastrocytes

ElevatedFMR1mRNAlevels,butreducedFMRPlevels

8/7/2019 DLB and Atypical Parkinson Syndromes

16/19

FragileXTremorAtaxiaSyndrome(FXTAS)

Premutationcarrierfrequency

~1/800males

PenetranceofFXTAS

~30%

EstimatedprevalenceofFXTAS

1/3000males

FXTASisacommoncauseof

lateonsetataxia/tremor/parkinsonism

FragileXTremorAtaxiaSyndrome(FXTAS)

?

Prmutation,60repeats

Prmutation,200repeats

Mutation400repeats

8/7/2019 DLB and Atypical Parkinson Syndromes

17/19

LeitsymptomeExtrapyramidale

Bewegungsstrung

Bilateralitt

FrontaleGangstrung

(Gang-Apraxie)bei

geringerfeinmotorischerBehinderungderHnde

Demenz

Hypertonus/Diabetes

KeineL-Dopa-Response

cMRTbeiSAE(SubkortikalearteriosklerotischeEnzephalopathie)

8/7/2019 DLB and Atypical Parkinson Syndromes

18/19

LeitsymptomeFrontaleGangstrung(Gang-Apraxie)beigeringerfeinmotorischerStrungderHnde

DemenzBlasenfunktionsstrung

OftrascheProgression

TransienteklinischeBesserungnachLP

KeineL-Dopa-Response

MRTbeiNormaldruck-Hydrozephalus(NPH)

Video

8/7/2019 DLB and Atypical Parkinson Syndromes

19/19

Drug-InducedParkinsonism

Crucialtoruleout,sincemostcasesarereversible

Carefulmedicationhistorylistdrugnames

Commonoffendingdrugtypes

Antipsychotics

haloperidol,chlorpromazine,thioridizine,perphenazine

risperidone,olanzapine

Antiemeticsmetoclopramide,prochlorperazine

Dopaminedepletorsmethyldopa,reserpine,tetrabenazine

Combinationdrugse.g.,Triavil(amitriptyline,perphenazine)

Treatment:Stopoffendingmedication

www.wemove.org