drwmartinhd_neuroscience410notes

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Neuroscience 410

Huntington Disease - Clinical

March 18, 200

Huntingtons DiseaseHuntingtons DiseaseNeuroscience 410Neuroscience 410

March 20, 2007March 20, 2007

W. R. Wayne Martin, MD, FRCPCW. R. Wayne Martin, MD, FRCPC

Division of NeurologyDivision of Neurology

University of AlbertaUniversity of Alberta

Huntingtons DiseaseHuntingtons Disease

inherited neurodegenerative disorderinherited neurodegenerative disorder autosomal dominantautosomal dominant

age of onset: 35age of onset: 35 -- 45 yr45 yrjuvenile variantjuvenile variant

55--10% of affected individuals10% of affected individuals


motor, cognitive, and behaviouralmotor, cognitive, and behaviouraldysfunctiondysfunction

death 15death 15 -- 20 yr after symptom onset20 yr after symptom onset


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prevalenceprevalence 10 / 100,000 population10 / 100,000 population

about 65 symptomatic patientsabout 65 symptomatic patients

ChoreaChorea

irregular, unpredictable, purposeless,irregular, unpredictable, purposeless,rapid movements that flow randomlyrapid movements that flow randomly

from one bod art to anotherfrom one bod art to another

Huntingtons diseaseHuntingtons disease

Huntingtons DiseaseHuntingtons DiseaseClinical FeaturesClinical Features -- 11

motor dysfunctionmotor dysfunction chorea is usually the earliest signchorea is usually the earliest sign

, ,, ,

progressiveprogressive

motor impersistencemotor impersistence

eye movement abnormalitieseye movement abnormalities

impaired initiation of saccadesimpaired initiation of saccades

slow saccadesslow saccades


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motor dysfunctionmotor dysfunction dystonia and parkinsonismdystonia and parkinsonism

,,

unsteadiness, immobility, dysarthria,unsteadiness, immobility, dysarthria,

dysphagiadysphagia

motor signs eventually appear in allmotor signs eventually appear in all


juvenile onsetjuvenile onset rigidity, dystonia, bradykinesia,rigidity, dystonia, bradykinesia,

seizuresseizures

rapidly progressive dementiarapidly progressive dementia


cognitive impairmentcognitive impairment executive function is thought to beexecutive function is thought to be

cortical deficits absent (aphasia,cortical deficits absent (aphasia,

agnosia, apraxia)agnosia, apraxia)


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cognitive impairmentcognitive impairment some degree of impairment issome degree of impairment is

occasionally minimaloccasionally minimal

rate of progression variesrate of progression varies

considerablyconsiderably


behavioural changesbehavioural changes gradual change in personalitygradual change in personality

--

schizophrenia and other psychoses inschizophrenia and other psychoses in

10%10%

alcohol abuse; high suicide riskalcohol abuse; high suicide risk

Huntingtons DiseaseHuntingtons DiseaseNeurobiologyNeurobiology -- 11

pathologypathology striatal atrophystriatal atrophy

most striking in, but not limited tomost striking in, but not limited to

striatumstriatum

diffuse cortical changes, primarily frontaldiffuse cortical changes, primarily frontal

degree of pathology is related to thedegree of pathology is related to the

duration of symptomatic HDduration of symptomatic HD


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selective neuronal lossselective neuronal loss striatal projection neurons arestriatal projection neurons are

medium spiny neurons (GABA)medium spiny neurons (GABA)

striatal interneurons are sparedstriatal interneurons are spared

SS/NPYSS/NPY

cholinergiccholinergic

Figure 4 Results of the voxel based morphometric analysis of the Huntington's disease patientsubgroups v age matched controls: panels A and B for the criterion motor defic its; panels C and D for thecriterion cognitive deficits. All regions are shown where the corresponding subgroup (n = 12 each) had asignificantly decreased grey matter density in comparison with an age matched group of normal controls

(n = 15 each) at p

Copyright2004 BMJ PublishingGroupLtd.

Kassubek J et al. J Neurol Neurosurg Psychiatry 2004;75:213-220


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Figure 1. Caudate volume and estimated years to onset (YTO) in preclinical subjects

Aylward EH et al. Neurology 2004;63:66-72

Figure 2. Longitudinal change in caudate volume for p reclinical subjects

Aylward EH et al. Neurology 2004;63:66-72

Ciarmiello A et al. J Nucl Med 2006; 47:215-222


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Huntingtons DiseaseHuntingtons DiseaseGeneticsGenetics -- 11

autosomalautosomaldominantdominant

chromosome 4chromosome 4 very lowvery low

spontaneousspontaneousmutation ratemutation rate

Huntingtons DiseaseHuntingtons DiseaseGeneticsGenetics -- 22

D

4

S

1

0

D

4

S

1

8

0

D

4

S

1

2

7

D

4

S

1

8

2

D

4

S

9

5

D

4

S

9

5

Huntingtons Disease Collaborative Research GroupHuntingtons Disease Collaborative Research Group.. AAnovel gene containing a trinucleotide repeat that is expandednovel gene containing a trinucleotide repeat that is expandedand unstable on Huntingtons disease chromosomesand unstable on Huntingtons disease chromosomes.. CellCell1993;72:9711993;72:971--983983

HD (IT15)(CAG) n

GPRK2L ADD1

cen tel

Human IT15 GeneHuman IT15 Gene

CAG

Normal

-

(CAG) 40 -240

Huntingtons Disease


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Huntingtons DiseaseHuntingtons DiseaseCAG Repeat NumberCAG Repeat Number -- 11

< 27 normal

27-35 mutable normal

36-39 reduced penetrance> 39 HD phenotype

Crauford D, et al. J Med Genet 1993;30:1008-1011


t(yr)

CAG Repeat Length

AgeofOnse

Andrew SE, et al. Nature Genetics 1993;4:398-403


50

60

70

80

CAG Repeat Length

Years

Nature Genetics Reviews

35 40 45 50 55 60 65

0

10

20

30

40

ge o onset

Rate of Progression


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Huntingtons DiseaseHuntingtons DiseaseDiagnosisDiagnosis

CAG repeat analysisCAG repeat analysis determine the presence of the genedetermine the presence of the gene

diagnosis of symptomatic HD isdiagnosis of symptomatic HD isbased on the clinical featuresbased on the clinical features

supportive counselling is crucial before,supportive counselling is crucial before,during, and after DNA testing,during, and after DNA testing,

re ardless of whether or not the atientre ardless of whether or not the atient

is symptomaticis symptomatic

IT15IT15

universal expression in multiple

tissues

new class of protein important to

huntingtin

3144 amino acids, m.w. = 348 kDa

no evidence of regional selectivity in

brain

neurons and glia


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huntingtinhuntingtin

transgenic mouse modelstransgenic mouse models significantly reduced levels associated withsignificantly reduced levels associated with

aberrant brain development and perinatalaberrant brain development and perinatal

lethalitylethality

normal levels, even of mutant huntingtin, isnormal levels, even of mutant huntingtin, is

associated with normal brain developmentassociated with normal brain development

critical role in neurogenesiscritical role in neurogenesis

Huntingtons DiseaseHuntingtons DiseaseCellular MechanismsCellular Mechanisms

huntingtinhuntingtin -- normally localized innormally localized incytoplasmcytoplasm

-- huntingtin and ubiquitinhuntingtin and ubiquitin

associated nuclear membraneassociated nuclear membrane

changeschanges

precedes phenotypic changesprecedes phenotypic changes

(transgenic mice)(transgenic mice)

Huntingtons DiseaseHuntingtons DiseaseCellular MechanismsCellular Mechanisms

translocation of mutant huntingtintranslocation of mutant huntingtinfrom cytoplasm to nucleus mayfrom cytoplasm to nucleus may

represent the dominant gain ofrepresent the dominant gain of

functionfunction


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Huntingtons DiseaseHuntingtons DiseasePathophysiologyPathophysiology

animal modelsanimal models intrastriatal kainic acidintrastriatal kainic acid

, ., .

1976;263:5171976;263:517--519519

Coyle JT, Schwarcz R. NatureCoyle JT, Schwarcz R. Nature

1976;263:2441976;263:244--246246

intrastriatal quinolinic acidintrastriatal quinolinic acid

Beal F and othersBeal F and others

Huntingtons DiseaseHuntingtons DiseasePathophysiologyPathophysiology

excitotoxic hypothesisexcitotoxic hypothesis intrastriatal injection of excitotoxic aminointrastriatal injection of excitotoxic amino

acids mimics the characteristic pathologyacids mimics the characteristic pathology

of HDof HD

toxicity can be prevented by NMDAtoxicity can be prevented by NMDA

antagonistsantagonists

butbut acute striatal lesion is unlike the slowacute striatal lesion is unlike the slow

insidious cell loss associated withinsidious cell loss associated with

neurodegenerative diseaseneurodegenerative disease

Huntingtons DiseaseHuntingtons DiseaseWeak Excitotoxic HypothesisWeak Excitotoxic Hypothesis

Impaired mitochondrial energy metabolism

Neuronal sensitivity to

endogenous glutamate

Gradual loss of neurons

(final mechanism = excitotoxicity)


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Weak Excitotoxic HypothesisWeak Excitotoxic Hypothesis

33--NPANPA inhibits succinate dehydrogenase andinhibits succinate dehydrogenase and

associated with striatal pathologyassociated with striatal pathology

similar to HDsimilar to HD

blocked by NMDA antagonistsblocked by NMDA antagonists


CurrentCurrent TreatmentTreatment

symptomaticsymptomatic

Huntingtons DiseaseHuntingtons DiseaseExperimental TreatmentExperimental Treatment

goalgoal to delay or prevent the onset ofto delay or prevent the onset of

individualindividual


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postulated mechanismspostulated mechanisms excitotoxicityexcitotoxicity

Ca+2

CORTICO-STRIATAL NEURON

GLUTAMATE

RELEASE

NMDA GLY

P

PC

lamotrigine

riluzole

NMDA GLY

P

PC


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APV, APH

CPP

CGS 19755

Kynurenic

acid

HAA 966

NMDA GLY

P

PC

remacemide

PCP

ketamine

MK801

DX / DM

Electron Transport ChainElectron Transport Chain

Succinate

O2

Complex I

Complex II

Ubiquinone

Coenzyme Q10

Cytochrome CNADH

Complex III Complex IV

CARECARE -- HDHD(Co(Co--enzyme Qenzyme Q1010 and Remacemide inand Remacemide in

HD)HD)

multimulti--centre, placebocentre, placebo--controlled,controlled,randomized, prospective trialrandomized, prospective trial

2 x 2 factorial design2 x 2 factorial design

347 patients with symptomatic HD347 patients with symptomatic HD 30 month follow30 month follow--up, using validated clinicalup, using validated clinical

rating scales (UHDRS)rating scales (UHDRS)

Huntington Study Group; NIH fundedHuntington Study Group; NIH funded


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CARECARE -- HDHD(Co(Co--enzyme Qenzyme Q1010 and Remacemide inand Remacemide in

HD)HD) endend--point =point =total functional capacitytotal functional capacity

The Huntington Study Group.The Huntington Study Group. A ran dom ized, p laceb oA ran dom ized, p laceb o--

controlled trial of coenzyme Qcontrolled trial of coenzyme Q1010 and remacemide inand remacemide in

Huntingtons diseaseHuntingtons disease. Neurolog y 2001; 57:397. Neurolog y 2001; 57:397--404404

(600 mg/d)


2CARE2CARE

1010


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minocyclineminocycline caspase n oncaspase n on

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