Beyond Alzheimer’s disease: overview of other major forms of … · 2019. 5. 7. · • Spared...

Beyond Alzheimer’s disease: overview of other major forms

of neurodegenera:ve demen:a SalvatoreSpina,MD,PhD

AssistantProfessorofNeurologyMemoryandAgingCenter

UCSF

Disclosure

•  Ireceiveresearchsupportfrom•  NIHK08AG052648•  TauConsorJum•  BluefieldConsorJumforFrontotemporalDemenJaResearch•  Chan-ZuckerbergIniJaJve

•  IhavenoconflictsofinterestrelatedtothispresentaJon

Overview

• PrevalenceofthemostcommonneurodegeneraJvedemenJas• Lewy-bodydisease

• Parkinson’sdisease&DemenJawithLewybodies• ThefrontotemporallobardegeneraJons• NeurodegeneraJonsofaging

• HippocampalsclerosisandLATE• IsdemenJaoneormulJplediseases?• ChronictraumaJcencephalopathy

Prevalence of Alzheimer’s disease

Totalprevalence 1800/100,000

<65yo 72

Age65-74 288

Age75-84 792

>85yo 666

Prevalence of neurodegenera:ve demen:as

Alzheimer'sdisease66%

VasculardemenJa23%

LewyBodyDisease7%

FrontotemporalDemenJas

3% Other1%

Overview




Lewy body disease – alpha-synucleinopathy •  Parkinson’sdisease

•  ResJngtremor•  Rigidity•  Bradykinesia•  Posturalinstability•  Asymmetriconset•  ResponsivenesstoL-DOPA

•  Prevalence:•  41/100.000atage40-49•  1900/100.000>80years

•  PDdemenJa•  30-40%ofallPDcases•  80%ager20-yearsduraJon

•  DemenJawithLewybodies•  AhenJon/execuJveandvisuospaJaldeficit

•  CogniJvefluctuaJons•  VisualhallucinaJons•  REM-sleepbehaviordisorder•  Parkinsonism

•  Prevalence:7%ofallcasesofdemenJa

Other common symptoms of LBD • SymptomsofautonomicdysfuncJon(consJpaJon,sweaJngabnormaliJes,sexualdysfuncJon,etc.)

• Decreasedsenseofsmell• SeborrheicdermaJJs• Anxiety/depression• Hypophonia• Decreasedfacialexpression• Delusionalthinking

Substan:a nigra degenera:on

Lewybodies

alpha-synucleinimmunohistochemistry

Overview




Frontotemporal Lobar Degeneration (FTLD)

• Neurodegenerative process characterized by predominant neuronal loss and gliosis (atrophy) of the frontal and temporal lobes of the brain

Arnold Pick

§ …. circumscribed lobar (frontotemporal) atrophy ….

Pick A. Prager Med Wochenschr

1892;17:165-167

Alzheimer A. Z ges Neurol Psychiat 1911;4:356-385

Alois Alzheimer defines Pick’s disease

§  …. absence of plaques, presence of round-shaped neurofibrillary tangles (Pick bodies), and swollen neurons ….

•  Commoncausepre-seniledemenJa•  1:1withAD45–64years(Ratnavalli2002)•  MorecommonthanAD<60years

(Knopman2004)•  Commoninelderly?

•  3%prevalence80–90(2003Skoog)

Pathologicalen6ty Prevalence

Alzheimer’sDisease 1800/100,000

<65yo 72

Age65-74 288

Age75-84 792

>85yo 666

PDD-LBD ~800

FrontotemporaldemenJas 15-50

Prevalence of neurodegenera:ve demen:as

3 types frontotemporal dementia

Behavioral variant Language variants

Semantic variant

Non-fluent variant

R L

R L R L

Interna:onal Research Criteria for Behavioral Variant FTD

1.  Early (2-3 yrs) behavioral disinhibition 2.  Early (2-3 yrs) apathy or inertia 3.  Early (2-3 yrs) loss of emotional reactivity/sympathy and

empathy 4.  Perseverative, stereotyped or compulsive/ritualistic behavior 5.  Hyperorality and dietary changes 6.  FTD neuropsychological profile 7.  Frontal or anterior temporal atrophy on MRI 8.  Presence of known mutation

Rascovskyetal.Brain2011

Regions Involved in Emo:on

Insula AnteriorCingulate Amygdala

Emo:onal Deficits in FTD

• Lack of concern for loved one’s illness • Cruelty to children, animals elderly • Lack of concern when others are sad • Rude comments to others • Lose respect for intrapersonal space • “Disgusting” behaviors • Diminished response to pain

Behavioral Variant FTD



Semantic variant

Non-fluent variant

R L

R L R L

Primary Progressive Aphasia (PPA)

= Non-fluent CBD, PSP (tau) = Logopenic – AD (AB42, tau)

= Semantic dementia FTD (TDP-43)

Mesulam et al. Ann Neurol. 2001

Gorno-Tempini ML et al. Ann Neurol. 2004

L Insula

R Insula Orbital Frontal

Anterior Cingulate

Orbital Frontal

L Amygdala R Amygdala

Left Right

Seman:c Demen:a vs Controls

Rosen et al. Brain 2002;125:2286-2295

Seman:c variant PPA (svPPA) leP-temporal pole degenera:on

•  ImpairedconfrontaJonnaming•  Lossofwordmeaning(moresevereforlowfrequencywords)•  Impairedobjectknowledge(moresevereforlowfrequencyitems)•  Surfacedyslexia(regularizaJonofirregularphoneJcwords)

•  Colonel,knight,yacht,etc.•  SparedrepeJJon•  Sparedgrammar• Ogenhyper-verbal,fluentaphasia

Animals Become Prototypical

Seman:c demen:a

Right-temporal pole degenera:on Behavioral variant FTD with addi:onal peculiar features

• Lossofknowledgeoffamousfaces• increasedinteresttowardsword-searchgames• Extremelyrigidandstereotypicbehavior• Ogencold,disJnct,anJ-socialpersonality• Hyper-religiosity



Semantic variant

Non-fluent variant

R L

R L R L

Nonfluent variant PPA (nfvPPA) leP posterior frontoinsular atrophy

• AgrammaJsm

• Efforqul,halJngspeechwithsounderrorsanddistorJons

• Impairedcomprehensionofcomplexsentences• Sparedsinglewordcomprehension• Sparedobjectknowledge

NonfluentvariantPPA(nfvPPA)



Semantic variant

Non-fluent variant

R L

R L R L

3 more types of frontotemporal demen:a…

• FTDwithmotorneurondisease(FTD-MND)• Progressivesupranuclearpalsysyndrome(PSP-S)• CorJcobasalsyndrome(CBS)

FTDwithmotorneurondisease(FTD-MND)

• Amyotrophiclateralsclerosis(ALS)•  10%ofFTDpaJentsdevelopALS• MostALSpaJentsdevelopcogniJveimpairment

• ProgressivemuscleweaknessanddegeneraJonleadingtodeathwithin3yearsonaverage

Progressive supranuclear palsy syndrome (PSP-S) Richardson’s syndrome

•  Earlyfalls•  EyemovementabnormaliJes• Axialrigidity• ParkinsonianfeaturesnotresponsivetoL-DOPA

•  ExecuJvedysfuncJon•  Increasedimpulsivity• Disruptedsleeppahern

Cor:cobasal syndrome (CBS)

• Asymmetriclimbrigidity,dystonia,myoclonus

• Oralorlimbapraxia• CorJcalsensorydeficits

•  astereognosis•  agraphesthesia

• Alien-limbphenomenon

Frontotemporal lobar degeneration (FTLD)

FTLD-tau FTLD-TDP*

Pick’s 3R tau

CBD 4R tau

PSP 4R tau

FTDP-17 MAPT

Other CTE, AGD, MST

FTLD-FUS FTLD-3 CHMP2b

Type C Type D VCP

Type B (C9orf72) (TARDP?)

aFTLD-U

NIFID ??? (FUS)

BIBD Type A (PGRN)

(C9orf72)

Type U (C9orf72)

svPPA nfvPPA PSPS CBS FTD-MND bvFTD

*Mackenzie harmonized scheme, 2011

Alzheimer’s Disease

FTLD-tau: the tauopathies (40% of FTLD)

Pick’sdisease Progressivesupranuclearpalsy

CorJcobasaldegeneraJon

Pickbodies Tugedastrocyte AstrocyJcplaque


FTLD-tau FTLD-TDP*

Pick’s 3R tau

CBD 4R tau

PSP 4R tau

FTDP-17 MAPT

Other CTE, AGD, MST


Type C Type D VCP


aFTLD-U

NIFID ??? (FUS)

BIBD Type A (PGRN)

(C9orf72)

Type U (C9orf72)




FTLD-TDP43 (55% of FTLD) TypeA TypeB

TypeC

TypeD


FTLD-tau FTLD-TDP*

Pick’s 3R tau

CBD 4R tau

PSP 4R tau

FTDP-17 MAPT

Other CTE, AGD, MST


Type C Type D VCP


aFTLD-U

NIFID ??? (FUS)

BIBD Type A (PGRN)

(C9orf72)

Type U (C9orf72)




FTLD-FUS: the FUS-opathies (<5% of FTLD)

Mackenzie et al. Brain 2008;131:1282–1293

AtypicalFTLDwithveryearlyageatonset


FTLD-tau FTLD-TDP*

Pick’s 3R tau

CBD 4R tau

PSP 4R tau

FTDP-17 MAPT

Other CTE, AGD, MST


Type C Type D VCP


aFTLD-U

NIFID ??? (FUS)

BIBD Type A (PGRN)

(C9orf72)

Type U (C9orf72)




Overview




Neurodegenera:on of aging

Limbic-predominantage-relatedTDP-43

encephalopathy(LATE)

25%ofcasesindemenJaautopsyseries

Nelsonetal.Brain04/30/2019

Overview




Neuropathologicallesionsintheveryold:resultsfromalargeBrazilianautopsystudy

Suemotoetal.BrainPathology2019

Nelsonetal.Brain04/30/2019

Overview




McKeeetal.BrainPathology2015

ChronictraumaJcencephalopathy

Chronic trauma:c encephalopathy •  99%autopsyprevalenceamongNFLplayers

• mulJplerepeatedheadtrauma/concussionsishighestriskfactor•  canpresentasabehavioralsyndrome

•  irritability•  explosiveaggressivebehavior•  depressionleadingtosuicide

•  canmanifestasalate-onsetamnesJcsyndromeindisJnguishablefromAlzheimer’sdisease

• Prevalenceispossibly1/3insubjectwithsignificanth/ocontactsportparJcipaJonandvirtuallyabsentinsubjectwithnocontactsporthistoryregardlessofh/osingleheadtrauma

Take home messages • Alzheimer’sdiseaseisthemostcommonbutnottheonlycauseofdemenJathroughoutthelifespan

•  FrontotemporaldemenJasareascommonasADinsubjectsaged65andmorecommonthanADinpeopleyoungerthan60-yearold

• DemenJaisveryunlikelycausedbyasinglepathologicprocess• CoexistenceofmulJplepathologiesistherule,andtheirnumberincreaseswithage

•  ThelikelihoodofdevelopingcogniJvesymptomsisdirectlyassociatedwiththenumberofdifferentdiseasestogetheraffecJngthesamebrain

• ChronictraumaJcencephalopathyisanewlyrecognizedcauseofcogniJveimpairment.Itsimpactishighinsubjectswithh/ocontactsportsbutlikelyminimalinsubjectswithnoh/orepeatedheadtrauma

Acknowledgments Seeley Lab Bill Seeley Jesse Brown Celica Cosme Mackenzie Hepker Jersey Deng Stephanie Gaus Ji-Hye Hwang Alex Lee Norbert Lee Alissa Nana Sarat Vatsavajai

UCSF Memory & Aging Center Adam Boxer Joel Kramer Bruce Miller Howard Rosen Virginia Sturm

UCSF Brain Bank Lea Grinberg Eric Huang

UCSF Epidemiology & Biostatistics John Kornak

GE Global Research Dan Meyer Alberto Santamaria-Pang

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