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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
• PrevalenceofthemostcommonneurodegeneraJvedemenJas• Lewy-bodydisease
• Parkinson’sdisease&DemenJawithLewybodies• ThefrontotemporallobardegeneraJons• NeurodegeneraJonsofaging
• HippocampalsclerosisandLATE• IsdemenJaoneormulJplediseases?• ChronictraumaJcencephalopathy
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
• PrevalenceofthemostcommonneurodegeneraJvedemenJas• Lewy-bodydisease
• Parkinson’sdisease&DemenJawithLewybodies• ThefrontotemporallobardegeneraJons• NeurodegeneraJonsofaging
• HippocampalsclerosisandLATE• IsdemenJaoneormulJplediseases?• ChronictraumaJcencephalopathy
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
3 types frontotemporal dementia
Behavioral variant Language variants
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
3 types frontotemporal dementia
Behavioral variant Language variants
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)
3 types frontotemporal dementia
Behavioral variant Language variants
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
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
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-TDP43 (55% of FTLD) TypeA TypeB
TypeC
TypeD
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-FUS: the FUS-opathies (<5% of FTLD)
Mackenzie et al. Brain 2008;131:1282–1293
AtypicalFTLDwithveryearlyageatonset
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
Overview
• PrevalenceofthemostcommonneurodegeneraJvedemenJas• Lewy-bodydisease
• Parkinson’sdisease&DemenJawithLewybodies• ThefrontotemporallobardegeneraJons• NeurodegeneraJonsofaging
• HippocampalsclerosisandLATE• IsdemenJaoneormulJplediseases?• ChronictraumaJcencephalopathy
Neurodegenera:on of aging
Limbic-predominantage-relatedTDP-43
encephalopathy(LATE)
25%ofcasesindemenJaautopsyseries
Nelsonetal.Brain04/30/2019
Overview
• PrevalenceofthemostcommonneurodegeneraJvedemenJas• Lewy-bodydisease
• Parkinson’sdisease&DemenJawithLewybodies• ThefrontotemporallobardegeneraJons• NeurodegeneraJonsofaging
• HippocampalsclerosisandLATE• IsdemenJaoneormulJplediseases?• ChronictraumaJcencephalopathy
Neuropathologicallesionsintheveryold:resultsfromalargeBrazilianautopsystudy
Suemotoetal.BrainPathology2019
Nelsonetal.Brain04/30/2019
Overview
• PrevalenceofthemostcommonneurodegeneraJvedemenJas• Lewy-bodydisease
• Parkinson’sdisease&DemenJawithLewybodies• ThefrontotemporallobardegeneraJons• NeurodegeneraJonsofaging
• HippocampalsclerosisandLATE• IsdemenJaoneormulJplediseases?• ChronictraumaJcencephalopathy
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