Neuroanatomy and Pathology of Sporadic Alzheimer's Disease

168 Pages·2015·7.42 MB·English

by  Heiko Braak

Advances in Anatomy, Embryology and Cell Biology
Heiko Braak
Kelly Del Tredici
Neuroanatomy
and Pathology
of Sporadic
Alzheimer's
Disease
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Advances in Anatomy,
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Heiko Braak (cid:129) Kelly Del Tredici
Neuroanatomy and
Pathology of
Sporadic Alzheimer’s
Disease
With 48 figures
HeikoBraak
KellyDelTredici
Zentrumf.Biomed.ForschungAG
KlinischeNeuroanatomie/AbteilungNeurologie
Universita¨tUlm
Ulm
Germany
ISSN0301-5556 ISSN2192-7065(electronic)
ISBN978-3-319-12678-4 ISBN978-3-319-12679-1(eBook)
DOI10.1007/978-3-319-12679-1
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.
Preface
Thedownsideofthecurrenttendencytoprolongedlifeexpectancyindeveloped
countriesistheincreaseindiseasesassociatedwithadvancedage,especiallythose
involving the central nervous system (CNS). Foremost among these is sporadic
Alzheimer’s disease (AD) which leads to dementia (Brookmeyer et al. 2007; Qiu
etal.2009;Reitzetal.2011;MayeuxandStern2012).Nevertheless,today,despite
alleffortsonnumerousfronts,nocausalordisease-modifyingtherapyisavailable
(Doody et al. 2014; Salloway et al. 2014). AD is a neurological disorder of the
humanCNS.Thepathological lesions associated withtheADprocessrequire an
unusually long period of time to evolve, but, in the final analysis, they result in
clinicallyrecognizableimpairmentofhigherbrainfunctions.
This book is written for a readership that is to some extent familiar with the
anatomyofthehumannervoussystemandisinterestedinthechangesitunder-
goes during the AD process. As in the previously published book on sporadic
Parkinson’sdiseasefromthesameSpringerseries(BraakandDelTredici2009),
thepresenteffortapproachesandinterpretsthepathologicalprocessinADchiefly
fromaneuroanatomicalperspective.However,wewanttomakethetextreadable
fornon-experts,interaliabyincludingthroughoutitbothintroductoryandmore
detailedexplanationspertainingtoimportantanatomicalrelationshipsthatfacili-
tateunderstandingthematerialbutthatarenotavailableinstandardtextbooksor
onlycursorilyexplainedtherein,e.g.,theanatomyoftheentorhinalregion.
Clinically, AD only occurs in humans, and the hallmark lesions underlying the
diseaseprocesspredominantlyarefoundinthehumanCNS.Thus,therearenotruly
adequateanimalmodelsforAD(RapoportandNelson2011),althoughtheimplica-
tions of this reality are largely overlooked in much current research. For the past
25 years, an amyloidocentric understanding of AD research has largely ignored
opposing data and arguments, thereby leaving aside important questions that still
requireanswers(Maaroufetal.2010).Theauthorsfocusonfundamentalaspectsof
the AD process as a whole with the intention of encouraging alternatives to the
Ab-centeredunderstandingofAD.
As indicated by itstitle, thisbook deals mainly with morphologically recogniz-
able deviations from the normal anatomical condition of the human CNS. The
vii
viii Preface
AD-associated pathology is illustrated from its beginnings (sometimes even in
childhood) until its final form that is reached late in life. The AD process com-
mences much earlier than the clinically recognizable phase of the disorder and its
timeline includes an unusually extended non-symptomatic phase. The further the
pendulumswingsawayfromthesymptomaticfinalstagestowardstheearlypathol-
ogy, the more obvious the lesions become, although from a standpoint of severity
theyaremoreunremarkableand,thus,frequentlyoverlookedduringroutineneuro-
pathological assessment. For this reason, we decided to deal with the hallmark
lesionsinearlyphasesoftheADprocessinconsiderabledetail.Clinicallymanifest
casesofAD,ontheotherhand,displayextensivedisease-associatedlesionsthat,as
arule,areaccompaniedbynon-AD-relatedpathologies,includingvascularchanges
andconcomitantneurodegenerativedisorders.
For a constitutive introduction to the morphology of AD, one of the authors
(HB)owesaspecialdebtofgratitudetoanAmericancolleague,ThomasL.Kemper,
MD (Department of Anatomy and Neurobiology, Boston University School of
Medicine), who also conveyed to him the fascination with the idea that AD is a
disorderthatadherestotheconditionsofhumanneuroanatomy.Theauthorsthank
theGoetheUniversityFrankfurt(TheBraakCollection).Theyarealsothankfulfor
valuable comments provided by Khalid Iqbal, PhD (New York State Institute for
Basic Research in Developmental Disabilities) and Michel Goedert, MD (MRC
LaboratoryofMolecularBiology,UniversityofCambridge).Theywishtoexpress
their appreciation to Horst-Werner Korf, MD (Dr. Senckenbergische Anatomie,
Goethe University, Frankfurt) for the invitation to prepare this book, Albert
C. Ludolph, MD (Department of Neurology, University of Ulm) for support and
helpful discussions, and Ms. Anne Clauss from Springer (Heidelberg) for careful
editingofthetext.TheyalsoaregratefultoJu¨rgenBohl,MD(formerlyDepartment
ofNeuropathology,UniversityofMainz)forongoingsupport,Ms.SimoneFelden-
gut (Tables, silver staining, immunocytochemistry), Ms. Siegrid Baumann,
Ms. Gabriele Ehmke, Ms. Julia Straub (immunocytochemistry), Mr. Hans-Ju¨rgen
Steudt(OlympusGermany,Stuttgart)fortechnicalassistance,andMr.DavidEwert
(DepartmentofNeurology,UniversityofUlm)forthemanyhoursspentpreparing
andhelpingtodesigntheillustrations.Inviewofthebreadthofthesubjectmatter,it
wasnecessarytoweighthebibliographyinfavorofmorerecentoriginalstudiesand
reviews. In other words, it was not the authors’ intention to supply an exhaustive
surveyofallofthepertinentliteraturefromtheADfield.
Funding for this work was made possible, in part, by the German Research
Council (Deutsche Forschungsgemeinschaft, DFG) Grant number TR 1000/1-1
andtheRobertA.PritzkerPrizefromtheMichaelJ.FoxFoundationforParkinson’s
DiseaseResearch.
This book is dedicated in gratitude to the memories of Eva Braak ({2000),
WilliamR.Markesbery({2011),andIngeGrundke-Iqbal({2012).
Ulm,Germany HeikoBraak
13September2014 KellyDelTredici
Contents
1 Prologue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1 SporadicADIsaProteinopathyLinkedtotheDevelopmentof
IntraneuronalInclusionsofAbnormalTauProteinWhich,
inLaterPhases,AreAccompaniedbytheFormationof
ExtracellularPlaque-LikeDepositsofAmyloid-bProtein. . . . . 3
2.2 SomeNeuronalTypesExhibitaParticularInclinationtothe
PathologicalProcessWhileOthersShowaConsiderable
ResistanceToIt. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.3 ConsistentChangesintheRegionalDistributionPatternof
IntraneuronalInclusionsMakeaStagingProcedure
Possible. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3 BasicOrganizationofNon-thalamicNucleiwithDiffuseCortical
Projections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4 MicrotubulesandtheProteinTau. . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5 EarlyPresymptomaticStages. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.1 Stagea:TheAppearanceofAbnormalTauinAxonsofCoeruleus
ProjectionNeurons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.2 Stagesbandc:PretangleandTangleMaterialDevelopsinthe
SomatodendriticCompartmentsofCoeruleusNeuronsand
SimilarLesionsAppearinAdditionalBrainstemNucleiwith
Diffuse
CorticalProjections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.3 SurvivalofInvolvedNeurons,LossofNeuronalFunction,and
DegradationofRemnantsAftertheDeathofInvolved
Neurons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
ix