Alzheimer's Disease New 6

8/9/2019 Alzheimer's Disease New 6

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AlzheimerAlzheimers Disease:s Disease:Amyloid Cascades,Amyloid Cascades,

Inflammation and OxidativeInflammation and Oxidative

Stress Creating AgeStress Creating Age--RelatedRelatedNeuroplasticity Failure?Neuroplasticity Failure?

Douglas F. Watt, Ph.D.Douglas F. Watt, Ph.D.

Cambridge City HospitalCambridge City HospitalHarvard Medical SchoolHarvard Medical School


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Dylan Thomas on Aging & DeathDylan Thomas on Aging & Death

Do not go gentle into that goodDo not go gentle into that goodnight,night,Old age should burn and rave atOld age should burn and rave atclose of day;close of day;

Rage, rage against the dying of theRage, rage against the dying of thelight.light.

Though wise men at their end knowThough wise men at their end knowdark is right,dark is right,

Because their words had forked noBecause their words had forked nolightning theylightning theyDo not go gentle into that goodDo not go gentle into that goodnight.night.

Good men, the last wave by, cryingGood men, the last wave by, cryinghow brighthow brightTheir frail deeds might have dancedTheir frail deeds might have dancedin a green bay,in a green bay,

Rage, rage against the dying of theRage, rage against the dying of thelight.light.

Wild men who caught and sangWild men who caught and sangthe sun in flight,the sun in flight,And learn, too late, they grieved itAnd learn, too late, they grieved iton its way,on its way,

Do not go gentle into that goodDo not go gentle into that goodnight.night.

Grave men, near death, who seeGrave men, near death, who seewith blinding sightwith blinding sight

Blind eyes could blaze like meteorsBlind eyes could blaze like meteorsand be gay,and be gay,Rage, rage against the dying of theRage, rage against the dying of thelight.light.

And you, my father, there on theAnd you, my father, there on thesad height,sad height,Curse, bless me now with yourCurse, bless me now with yourfierce tears, I pray.fierce tears, I pray.

Do not go gentle into that goodDo not go gentle into that goodnight.night.Rage, rage against the dying of theRage, rage against the dying of thelight.light.


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Aging is . . . . vastly overAging is . . . . vastly over--rated!rated! Bible states that aging isBible states that aging iswages of sinwages of sin? Colorful but . .? Colorful but . .

Appears to be more theAppears to be more the wages of metabolism andwages of metabolism anddefensedefense(damage to multiple systems from inflammation,(damage to multiple systems from inflammation,

oxidative stress, other products of energy generation).oxidative stress, other products of energy generation). Damage to basic cellular components (DNA, nuclear &Damage to basic cellular components (DNA, nuclear &

mitochondrial), glycation of proteins (sugarmitochondrial), glycation of proteins (sugar--proteinprotein

bonds)bonds) advanced glycation end products (advanced glycation end products (AGEAGE))((e.ge.g deterioration of collagen),deterioration of collagen), junk proteins (amyloid).junk proteins (amyloid).

Major role for inflammation (and INFLAMMajor role for inflammation (and INFLAM OS) . . . weOS) . . . weare slowly eaten from within by own immune systems.are slowly eaten from within by own immune systems.

INFLAM may increase with age (INFLAM may increase with age ( propro--INFLAM cytokines)INFLAM cytokines) Evidence that defenses against OS & regulation ofEvidence that defenses against OS & regulation of

INFLAM decline with ageINFLAM decline with age losing tug of war betweenlosing tug of war between

forces of cellular protection vs cellular degradation.forces of cellular protection vs cellular degradation. Aging process may even accelerate?Aging process may even accelerate?


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Youth is wonderful, and it is aYouth is wonderful, and it is a

shame to waste it on the young!shame to waste it on the young! Most lifestyle choices that decrease CAD and CA alsoMost lifestyle choices that decrease CAD and CA also

decrease AD (fruits/veggies,decrease AD (fruits/veggies, --3, exercise, good quality3, exercise, good qualitysleep,sleep, chronic stresschronic stress),), suggesting convergentsuggesting convergentmechanisms across the diseases of aging (DOA)mechanisms across the diseases of aging (DOA)..

Sleep, exercise andSleep, exercise and --3/3/--6 ratio all decrease tonic6 ratio all decrease tonic

INFLAM. Exercise upregulates antioxidant defenses.INFLAM. Exercise upregulates antioxidant defenses. Calorie restriction (Calorie restriction (~30%~30%)) is gold standard for reducingis gold standard for reducing

both DOA & aging itself, but . . . .both DOA & aging itself, but . . . .

CR a painfully difficult lifestyle modification (


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The Big PictureThe Big Picture (Diseases of Aging/AD)(Diseases of Aging/AD) Aging population, (large demographic group of babyAging population, (large demographic group of baby

boomers), heading into decades of greatest risk.boomers), heading into decades of greatest risk. Prevention effort re: allPrevention effort re: allDOADOA(CA, CAD/MI/CVA, Diabetes,(CA, CAD/MI/CVA, Diabetes,

AD, arthritis) virtually nonexistent (2AD, arthritis) virtually nonexistent (2--4% of health care4% of health caredollar spent on prevention, 75dollar spent on prevention, 75--90% on established DOA).90% on established DOA). Old adage: ounce of prevention is worth a pound of cure,Old adage: ounce of prevention is worth a pound of cure,

but is real ratio > 1 oz to 500 lbs?but is real ratio > 1 oz to 500 lbs? No cure in sight for DOANo cure in sight for DOA

AD shows no sign of decreasing its penetration (doublesAD shows no sign of decreasing its penetration (doublesincidence every five years starting with 60incidence every five years starting with 60--65).65). AD may even increase (explosion of DM & obesity), as CVAD may even increase (explosion of DM & obesity), as CV

disease risk increases AD risk. Comorbidities of INFLAM?disease risk increases AD risk. Comorbidities of INFLAM? No majorNo majordiseasedisease--modifyingmodifyingtreatment yet available, esp.treatment yet available, esp.

if one considers treatment to start only once patient isif one considers treatment to start only once patient isdemented (several new drugs may be such a treatment?).demented (several new drugs may be such a treatment?).

No definitive laboratory measure, although severalNo definitive laboratory measure, although several

available good biomarkers.available good biomarkers.


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Popular Conceptions Re: ADPopular Conceptions Re: AD If someone is becoming forgetful in their old age,If someone is becoming forgetful in their old age,

that is more likely aging rather than AD.that is more likely aging rather than AD.

AD has little to nothing to do w/ diet or lifestyle.AD has little to nothing to do w/ diet or lifestyle. Exercise has no impact on either the generationExercise has no impact on either the generation

or treatment of AD.or treatment of AD.

Genes account for most of AD.Genes account for most of AD. AD is caused by exotic cellular derangements andAD is caused by exotic cellular derangements and

is not related to basic aging processes.is not related to basic aging processes.

AD is largely untreatable. Not much point inAD is largely untreatable. Not much point incholinesterase inhibitors. No other treatments.cholinesterase inhibitors. No other treatments.

AD is an aggressive disease and often causes aAD is an aggressive disease and often causes afairly rapid decline.fairly rapid decline.

EACH OF THESE IS MORE WRONG THAN RIGHT!EACH OF THESE IS MORE WRONG THAN RIGHT!


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SOME BASICS ABOUT ADSOME BASICS ABOUT AD Most common brain disease in US (& possibly globally)Most common brain disease in US (& possibly globally)

A neuropsychiatric epidemic, in context ofA neuropsychiatric epidemic, in context ofgraying ofgraying ofAmerica.America. Frequently quoted statistics (~ 4/5 mil) areFrequently quoted statistics (~ 4/5 mil) areserious underestimation.serious underestimation.

Late Dx contributes to serious underestimation, alongLate Dx contributes to serious underestimation, alongwith overreliance on MMSE, and overestimation of VD.with overreliance on MMSE, and overestimation of VD.

Incidence doubles every five years after age of 60 to 65.Incidence doubles every five years after age of 60 to 65. Suggests etiology of AD is intrinsically linked to brain'sSuggests etiology of AD is intrinsically linked to brain's

aging, and/or responses to aging.aging, and/or responses to aging.

By middle 80By middle 80s, 35s, 35--45% chance of some stage of45% chance of some stage ofAlzheimer's disease, all other factors being equal.Alzheimer's disease, all other factors being equal.

Including earliest prodromal stages (MCI amnesticIncluding earliest prodromal stages (MCI amnestic

subtype), incidence may be significantly greater.subtype), incidence may be significantly greater.


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Hebert LE,Hebert LE, ScherrScherr PA,PA, BieniasBienias JL, Bennett DA, & Evans DAJL, Bennett DA, & Evans DA(2003). Alzheimer disease in the US population. Prevalence(2003). Alzheimer disease in the US population. Prevalence

estimates using the 2000 census. Archestimates using the 2000 census. Arch NeurolNeurol, 60:1119, 60:1119--1122.1122.


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Hebert LE,Hebert LE, ScherrScherr PA,PA, BieniasBienias JL, Bennett DA, & Evans DAJL, Bennett DA, & Evans DA(2003). Alzheimer disease in the US population. Prevalence(2003). Alzheimer disease in the US population. Prevalence

estimates using the 2000 census. Archestimates using the 2000 census. Arch NeurolNeurol 60:111960:1119--1122.1122.


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Hebert LE,Hebert LE, ScherrScherr PA,PA, BieniasBienias JL, Bennett DA, & Evans DA.JL, Bennett DA, & Evans DA.(2003). Alzheimer disease in the US population. Prevalence(2003). Alzheimer disease in the US population. Prevalence

estimates using the 2000 census. Archestimates using the 2000 census. Arch NeurolNeurol, 60:1119, 60:1119--1122.1122.

In 2000, ~ 4.5 million persons with AD in the US population. ByIn 2000, ~ 4.5 million persons with AD in the US population. By 2050, this2050, thisnumber will increase by 3number will increase by 3--fold, to 13.2 million. (These numbers may befold, to 13.2 million. (These numbers may beunderestimations, given late diagnosis and other issues)underestimations, given late diagnosis and other issues)


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Clinical Presentation of AD.Clinical Presentation of AD.

Insidious, virtually invisible, onset of progressivelyInsidious, virtually invisible, onset of progressivelyamnestic cognitive decline. Includes classically,amnestic cognitive decline. Includes classically,but not invariably:but not invariably:

Declining shortDeclining short--term memory (retrieval failures initially,term memory (retrieval failures initially,then deepening storage failure);then deepening storage failure);

Mild attentional and working memory declines,Mild attentional and working memory declines,disruption of cognitive executive functions;disruption of cognitive executive functions;

Dysnomia, verbal fluency & semantic process. declines;Dysnomia, verbal fluency & semantic process. declines;

Declining spatial cognition/spatial relations esp. analytic,Declining spatial cognition/spatial relations esp. analytic,although this tends to appear later in the disease;although this tends to appear later in the disease;

Affective and behavioral comportment declines, withAffective and behavioral comportment declines, withpersonalitypersonalityaffective changes, late onset psychiatricaffective changes, late onset psychiatricdisorders, frequently misdiagnosed asdisorders, frequently misdiagnosed asidiopathicidiopathic..

Other clinical phenotypes besides this. Variability in presentaOther clinical phenotypes besides this. Variability in presentation esp.tion esp.in context of coin context of co--morbid conditions (depression, CV disease, metabolicmorbid conditions (depression, CV disease, metaboliccompromise, other neurologic & medical diseases).compromise, other neurologic & medical diseases).


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The Problem of EarlyThe Problem of Early

Diagnosis: A Search forDiagnosis: A Search for

Better BiomarkersBetter BiomarkersBiomarkers Critical to The Effort to Dx and TreatBiomarkers Critical to The Effort to Dx and Treat

Dx is often way too late (mild to mod dementia)Dx is often way too late (mild to mod dementia)MMSE is totally inadequate as dementia screenMMSE is totally inadequate as dementia screenNeed for simple clinical testsNeed for simple clinical tests priorprior to declineto decline

Disease staging and predictionDisease staging and prediction

Critical to evaluation of early stage RxCritical to evaluation of early stage RxCost effective approachesCost effective approaches


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Early Diagnosis ProblemEarly Diagnosis Problem

MCIMCI

ADAD

TIMETIMEBRA

IN

BRA

IN

HEALT

H

HEALT

H

PrePre--ClinicalClinical

AgeAge

NOTNOT herehere

(where current(where currentRx often starts)Rx often starts)

FromFrom MonyMony de Leon,de Leon,2008 (2008 (AlzAlz Forum)Forum)

Preventative Treatment Clinical TreatmentPreventative Treatment Clinical Treatment


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Need for Early DiagnosisNeed for Early Diagnosis Recent candidates: HC atrophy, CSF protein alterations,Recent candidates: HC atrophy, CSF protein alterations,

changes in rate of ventricular enlargement in aging,changes in rate of ventricular enlargement in aging,regional cortical thinning, SPECT/PET patterns.regional cortical thinning, SPECT/PET patterns.

Current CSF markers:Current CSF markers: total tau,total tau, phosphorylated tau,phosphorylated tau,amyloidamyloid 4242 (( instead ofinstead of!). Spinal taps unpleasant.!). Spinal taps unpleasant.

Most desirable would be serum assays (no spinal tap).Most desirable would be serum assays (no spinal tap).

Five protein biomarker molecular signature recentlyFive protein biomarker molecular signature recentlyshowed 96% total accuracy predicting clinical AD: ILshowed 96% total accuracy predicting clinical AD: IL--11,,ILIL--3, EGF (epidermal growth factor), TNF3, EGF (epidermal growth factor), TNF-- & G& G--CSFCSF(granulocyte colony(granulocyte colony--stimulating factorstimulating factor -- white cells).white cells).

All these are cytokines! Cytokine elevation marksAll these are cytokines! Cytokine elevation markstransition from MCI to mild dementia (suggests ADtransition from MCI to mild dementia (suggests ADbrought on by INFLAM, or ADbrought on by INFLAM, or AD leads toleads to INFLAM, or both).INFLAM, or both).

But this is too late!!! We need biomarkers that defineBut this is too late!!! We need biomarkers that definebeginning of clinical decline!beginning of clinical decline!

E l Bi k AE l Bi k A Li d PETLi d PET


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Early Biomarker AEarly Biomarker A Ligand PET vs.Ligand PET vs.Structural Atrophy Biomarker on MRIStructural Atrophy Biomarker on MRI

P i f Bi k i ADP i f Bi k i AD


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Progression of Biomarkers in ADProgression of Biomarkers in ADAA is identified by CSF Ais identified by CSF A42 or PET amyloid imaging. Tau42 or PET amyloid imaging. Tau--mediated neuronal injury andmediated neuronal injury anddysfunction is identified by CSF tau ordysfunction is identified by CSF tau or fluorodeoxyglucosefluorodeoxyglucose--PET. Brain structure is measured byPET. Brain structure is measured byuse of structural MRI.use of structural MRI. AA==--amyloid. MCI=mild cognitive impairment.amyloid. MCI=mild cognitive impairment.

V i bl Mi ht Shift Bi kV i bl Mi ht Shift Bi k


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Variables Might Shift BiomarkersVariables Might Shift Biomarkers

Current Ability To Assay BiomarkersCurrent Ability To Assay Biomarkers


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Current Ability To Assay BiomarkersCurrent Ability To Assay Biomarkers

Is Missing Critical Components!!Is Missing Critical Components!!

No reliable chemical biomarkers of toxicNo reliable chemical biomarkers of toxic oligomericoligomeric formsformsof solubleof solubleAA or other solubleor other solubleAA or diffuse plaques.or diffuse plaques.

Absence of PETAbsence of PET ligandsligands for density of NFTs is a seriousfor density of NFTs is a seriousgap in both our research and clinical tool set.gap in both our research and clinical tool set.

Absence of accepted biomarker forAbsence of accepted biomarker for microglialmicroglial activationactivation

(imaging CNS inflammation).(imaging CNS inflammation). Absence of biomarker for synaptic function/lossAbsence of biomarker for synaptic function/loss

(appearing to be the most critical biological issue in AD).(appearing to be the most critical biological issue in AD).

Doubtful that virtually any imaging or other biomarker isDoubtful that virtually any imaging or other biomarker islikely to be as revealing as postmortem brain biopsy.likely to be as revealing as postmortem brain biopsy.

However, better biomarkers would offer huge gains toHowever, better biomarkers would offer huge gains toearly diagnosis, early treatment, & gauging effective Rx.early diagnosis, early treatment, & gauging effective Rx.


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Cognitive Screening IssuesCognitive Screening Issues

Identification of early amnestic issues is critical, andIdentification of early amnestic issues is critical, andcannot be done reliably through clinical interviewingcannot be done reliably through clinical interviewing..

Most commonly applied screening instrument (MMSE)Most commonly applied screening instrument (MMSE) Underestimates cognitive deficit seriously (not normed properly)Underestimates cognitive deficit seriously (not normed properly)..

Poor screen for shortPoor screen for short--term memory issues (critical!)term memory issues (critical!)

Poor screen for executive issues (important).Poor screen for executive issues (important).

Poor screen for naming and fluency issues (important).Poor screen for naming and fluency issues (important).

MontrMontral Cognitive Assessment (MoCA): much betteral Cognitive Assessment (MoCA): much better Decent assessment of shortDecent assessment of short--term memory (? delay interval?)term memory (? delay interval?)

Assessment of verbal fluency.Assessment of verbal fluency.

Some assessment of at least a subset of executive functions.Some assessment of at least a subset of executive functions.

Not in widespread use (but improving).Not in widespread use (but improving).

Requires more time than MMSE but returns much better data.Requires more time than MMSE but returns much better data. Requires minimal training (but more than MMSE).Requires minimal training (but more than MMSE).


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Functional Imaging BiomarkerFunctional Imaging Biomarker


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Prediction of future MCIPrediction of future MCI

AccuracyAccuracy

de Leon et al, PNAS, 2001

Functional Imaging BiomarkerFunctional Imaging Biomarker

EC Glucose MetabolismEC Glucose Metabolism44--year advance MCI predictionyear advance MCI prediction

84%84%

Hi t b li t t d liHi t b li t t d li


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AccuracyAccuracy

Mosconi et alMosconi et alNeurobiolNeurobiol. Aging, 2007. Aging, 2007

Hippocampus metabolism: automated samplingHippocampus metabolism: automated sampling

77--years advance prediction of symptomsyears advance prediction of symptoms

Prediction of future MCIPrediction of future MCI

84%84%

ADAD NLNL


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PIBPIB

FDGFDG

ADAD NLNL

Li Rinne de Leon in ress EJNM 2008

Atrophy and MetabolismAtrophy and Metabolism


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NLNL MCIMCI ADAD19931993

19971997 20032003

E EE

Atrophy and MetabolismAtrophy and Metabolism1010--Year decline from NL to AD (de Leon, 2008)Year decline from NL to AD (de Leon, 2008)

NYU 2008

Acc ac fo FDG and PIBAccuracy for FDG and PIB


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AD vs NLAD vs NL MCI vs NLMCI vs NL

PIBPIB --FrontalFrontal

L.L.9696

SS 94 SPSS 94 SP 100100

7575

SS 62 SPSS 62 SP 100100

FDGFDG --HIPPOHIPPO 9292SS 88 SPSS 88 SP 100100

8585SS 85 SPSS 85 SP 8686

Accuracy for FDG and PIBAccuracy for FDG and PIB

FDG

PIB

Li , Rinne, de Leon in press EJNM 2008

PP--tau231 Diagnostic Specificity for ADtau231 Diagnostic Specificity for AD


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Buerger et al Arch Neuro 2002

PP-tau231 Diagnostic Specificity for ADtau231 Diagnostic Specificity for AD

22--Year Longitudinal Performance Of CSF BiomarkersYear Longitudinal Performance Of CSF Biomarkers


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Brys et alBrys et al NeurobiolNeurobiol. Aging 2007. Aging 2007

22 Year Longitudinal Performance Of CSF BiomarkersYear Longitudinal Performance Of CSF Biomarkers

Accuracy: MCI to AD prediction (plus progression?)Accuracy: MCI to AD prediction (plus progression?)

P-tau231 T-tau

A42/40 Isoprostane

BaselineBaseline White barsWhite bars

FollowFollow--upup Dark barsDark bars

83% 83%

74%69%

LongitudinalLongitudinal


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CSF Biomarkers:CSF Biomarkers:


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CSF Biomarkers:CSF Biomarkers:

Which Predict Declines (CDR>0)?Which Predict Declines (CDR>0)?

Fa an et al ArchFa an et al Arch NeurolNeurol 20072007


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Pathological Markers forPathological Markers forAlzheimerAlzheimers Disease:s Disease:

Plaques and TanglesPlaques and Tangles

BetaBeta


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BetaBetaAmyloid:Amyloid:InterInter--cellularcellularjunkjunkproteins (found more inproteins (found more instructures that receivestructures that receiveheavy inputs fromheavy inputs fromcortex). In form ofcortex). In form oflarge oligomers & fibrilslarge oligomers & fibrils(A(A stickysticky & tends to& tends toaggregate). Existsaggregate). Exists asasoligomers inside of cellsoligomers inside of cellsalso. Research hasalso. Research hastended to focus ontended to focus onlarge extracellularlarge extracellularplaques (fibrils) ratherplaques (fibrils) ratherthan small oligomers,than small oligomers,but evidence suggestsbut evidence suggests

that oligomers are morethat oligomers are moredestructive (destructive (synapses)synapses)

Imaging Plaques in AD w/Imaging Plaques in AD w/


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Imaging Plaques in AD w/Imaging Plaques in AD w/

PIBPIBKlunkKlunket al.et al. used PET radioused PET radio--

ligand Pittsburgh Compoundligand Pittsburgh Compound--BB

(PIB), which selectively binds(PIB), which selectively binds

to amyloid plaques. Greatestto amyloid plaques. Greatest

PIB binding in frontal lobes, w/PIB binding in frontal lobes, w/

greatest metabolic defects ingreatest metabolic defects intemporaltemporal--parietal lobes.parietal lobes.

SuggestsSuggests poor correlation ofpoor correlation of

plaque burden w/ symptomsplaque burden w/ symptomsand that other issues (tangleand that other issues (tangle

density) must be considered.density) must be considered.

Amyloid Processing in ADAmyloid Processing in AD


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Amyloid Processing in ADAmyloid Processing in ADAPP proteolysis.APP proteolysis. The amyloidThe amyloid-- ((AA))

peptide derived via proteolysis frompeptide derived via proteolysis fromlarger precursor molecule (amyloidlarger precursor molecule (amyloidprecursor protein (APP 695precursor protein (APP 695770 amino770 aminoacids). APP can undergoacids). APP can undergo proteolyticproteolyticprocessing by 1 of 2 pathways. Mostlyprocessing by 1 of 2 pathways. Mostlyprocessed via aprocessed via a nonamyloidogenicnonamyloidogenicpathway, precludingpathway, precludingAA. First cleavage. First cleavage

mediated bymediated by --secretase, (secretase, (disintegrindisintegrin//metalloproteasesmetalloproteases --ADAM), withinADAM), withinAAdomain, preventing creation ofdomain, preventing creation ofAApeptide. Two fragments released, onepeptide. Two fragments released, onelarger (larger (sAPPsAPP), smaller), smaller carboxycarboxy--terminal fragment (C83). APP notterminal fragment (C83). APP notcleaved by noncleaved by non--amyloidogenicamyloidogenic pathwaypathway

becomes substrate forbecomes substrate for --secretase (secretase (--site APP cleaving enzyme 1; BACE1),site APP cleaving enzyme 1; BACE1),releasingreleasing sAPPsAPP, retaining last 99 amino, retaining last 99 aminoacids of APP (C99) within membrane.acids of APP (C99) within membrane.The first amino acid of C99 is the firstThe first amino acid of C99 is the firstamino acid ofamino acid ofAA. C99 is subsequently. C99 is subsequentlycleaved 38cleaved 3843 amino acids from the43 amino acids from the

amino terminus to releaseamino terminus to release

AA, by, by

--

secretase complex, (presenilin 1/2,secretase complex, (presenilin 1/2,nicastrinnicastrin, anterior pharynx defective, &, anterior pharynx defective, &presenilin enhancer 2). Thispresenilin enhancer 2). This cleavagecleavageproduces Aproduces A1140, &40, &amyloidogenicamyloidogenic

AA1142 at ratio of 10:1. AICD, APP42 at ratio of 10:1. AICD, APPintracellular domain; APHintracellular domain; APH--1, anterior1, anteriorpharynx defective; PEN2, presenilinpharynx defective; PEN2, presenilinenhancer 2.enhancer 2.

Turned on by neuroplasticity challenge, esp. injury, butTurned on by neuroplasticity challenge, esp. injury, but

also from cholinergic and other amine deafferentation.also from cholinergic and other amine deafferentation.

AICD recentl im licated

ll lB i C ll l C


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Basic Cellular CompartmentsBasic Cellular CompartmentsOrganelles:Organelles:(1) nucleolus(1) nucleolus

(2) nucleus(2) nucleus

(3)(3) ribosomesribosomes (litt le(litt le

dots)dots)

(4) vesicle(4) vesicle

(5) rough(5) rough endoendo--

plasmicplasmic reticulumreticulum

(6) Golgi apparatus(6) Golgi apparatus

(7) Cytoskeleton(7) Cytoskeleton

(8) smooth(8) smooth endoendo--

plasmicplasmic reticulumreticulum

(9) m itochondria(9) m itochondria

(10) vacuole(10) vacuole

(11) cytoplasm(11) cytoplasm

(12)(12) lysosomelysosome

(13)(13) centriolescentrioles withinwithin

centrosomecentrosome


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Beta AmyloidBeta Amyloid intracellular,intracellular,not just extranot just extra--cellular.cellular.


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not just extranot just extra cellular.cellular.Relationship between intraRelationship between intra--cellular & extracellular Acellular & extracellular A

pools ispools is poorly understood.poorly understood.Found in many cellularFound in many cellularcompartments, and gainscompartments, and gainsentry to cell via severalentry to cell via several

receptors:receptors: RAGE, lipid,RAGE, lipid,NMDA, and nicotinicNMDA, and nicotinic ..APOE 4 facilitates intake ofAPOE 4 facilitates intake ofAA more than other alleles.more than other alleles.Binding toBinding to RAGERAGE increasesincreasesinflammation. ERABinflammation. ERAB(endoplasmic(endoplasmic--reticulumreticulumassociated binding protein)associated binding protein)combines w/ beta amyloid,combines w/ beta amyloid,

attracting beta amyloid intoattracting beta amyloid intocells.cells. Assembly state ofAssembly state ofAAinside cells critical toinside cells critical to

pathogenic effects, w/ largepathogenic effects, w/ large

oligomers ofoligomers ofAA destructivedestructivere: many cellular functions.re: many cellular functions.

LeFerlaLeFerla et al, NRN, 2007et al, NRN, 2007

Synaptic loss correlates best w/ cognitive decline in AD.Synaptic loss correlates best w/ cognitive decline in AD.


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FROM QUERFORTH & LAFERLA: NormalFROM QUERFORTH & LAFERLA: Normalsynapse shown at top. At bottom, ansynapse shown at top. At bottom, anAlzheimerAlzheimers disease synapses disease synapseshowingshowingpleiotropic effects ofpleiotropic effects of--amyloid peptideamyloid peptide((AA). Rings represent synaptic vesicles.). Rings represent synaptic vesicles.Application/expression ofApplication/expression ofAA, especially, especiallyoligomers, impair synaptic plasticity byoligomers, impair synaptic plasticity byaltering balances between longaltering balances between long--termtermpotentiation (LTP) & longpotentiation (LTP) & long--termtermdepression (LTD) and reducing numbersdepression (LTD) and reducing numbersof dendritic spines. At highof dendritic spines. At highconcentrations, oligomers suppressconcentrations, oligomers suppresssynaptic transmission.synaptic transmission.AA facilitatesfacilitatesendocytosisendocytosis of MNDA and AMPAof MNDA and AMPAreceptors.receptors.AA binds to receptors of p75binds to receptors of p75neurotrophin (p75NTr) and BDNFneurotrophin (p75NTr) and BDNF(receptor is tyrosine kinase B receptor(receptor is tyrosine kinase B receptor[[trkBrtrkBr]), exacerbating already low levels]), exacerbating already low levelsof BDNF and nerve growth factorof BDNF and nerve growth factor(NGF).(NGF).AA impairs nicotinic acetylcholineimpairs nicotinic acetylcholine(ACh) receptor ((ACh) receptor (nAChrnAChr) signaling and) signaling and

release from presynaptic terminal.release from presynaptic terminal.Numbers of hippocampal synapsesNumbers of hippocampal synapsesdecrease in MCI while remainingdecrease in MCI while remainingsynaptic profiles show compensatorysynaptic profiles show compensatoryincreases in size.increases in size.(APP = amyloid precursor protein,(APP = amyloid precursor protein, pCaMKIIpCaMKII

phosphorylated calciumphosphorylated calciumcalmodulincalmodulindependentdependentprotein kinase 2,protein kinase 2, pCREBpCREB phosphorylated cyclic AMPphosphorylated cyclic AMPresponseresponse--elementelement--binding protein,binding protein, trkArtrkAr tyrosinetyrosinekinase A receptor, and VGCC voltagekinase A receptor, and VGCC voltage--gated calciumgated calciumchannel.)channel.)

Molecular Pathways (MAPMolecular Pathways (MAP--K) MediatingK) MediatingC ll l S ( k )


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Response to Cellular Stress (yikes!)Response to Cellular Stress (yikes!)Underlines nonUnderlines non--linear regulatory envelopeslinear regulatory envelopesoperating at deep cellular levels involvedoperating at deep cellular levels involved

in response toin response tobiologicalbiologicalstressors!stressors!

Data supporting primacy of AData supporting primacy of A in AD.in AD.


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Data supporting primacy of App g p y in AD.

Deposition of ADeposition of A in neuropil is sin qua non for Dx of AD.in neuropil is sin qua non for Dx of AD. Mutations of AMutations of APP gene (or secretase) cause early onsetPP gene (or secretase) cause early onset

form of AD (familial AD).form of AD (familial AD).

Mutation alone enough to generate both plaques & tangles.Mutation alone enough to generate both plaques & tangles. Triplication of ATriplication of APP in DownPP in Downs syndrome leads to invariables syndrome leads to invariable

AD in DownAD in Downs at age > middle to late 30s at age > middle to late 30s.s.

Mutations of PS1, PS2 and AMutations of PS1, PS2 and APP (familial AD) all have inPP (familial AD) all have incommon production ofcommon production oflongerlongerforms (Aforms (A--4242.).)

ApoE4 allele promotes aggregation & internalization of AApoE4 allele promotes aggregation & internalization of A..

At least in vitro (? in vivo), long forms of AAt least in vitro (? in vivo), long forms of A neurotoxic,neurotoxic,

promotes apoptosis, phosphorylation of tau (promotes apoptosis, phosphorylation of tau ( NFT).NFT). Transgenic mice overTransgenic mice over--expressing mutations of Aexpressing mutations of APP showPP show

cognitive decline and plaque (but no NFT).cognitive decline and plaque (but no NFT).

Synaptic effects ofSynaptic effects ofAA mediated by small oligomers of Amediated by small oligomers of A4040more than Amore than A42, correlates much better w/ cog42, correlates much better w/ cog dysfxndysfxn..

Neurofibrillary TanglesNeurofibrillary Tangles


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Neurofibrillary TanglesNeurofibrillary TanglesTends to be found early more instructures that send many projectionsto cortex (reticular activating system,basal forebrain, thalamic intralaminar

nuclei, hippocampus). Highly correlatedwith atrophic change & regional brainfailure. Extensive tangling of neocortexonly in middle-late stages.


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Distribution of neurofibrillary tanglesDistribution of neurofibrillary tangles


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Mesulam,2000

Imaging Both Plaques and TanglesImaging Both Plaques and Tangles


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Imaging Both Plaques and TanglesImaging Both Plaques and Tangles

FromFrom ShoghiShoghi--JadidJadid et al.et al.PETPET radioligandradioligand (18(18--

FDDNP), which binds toFDDNP), which binds to

both amyloid plaquesboth amyloid plaques andand

neurofibrillary tangles.neurofibrillary tangles.Greatest 18FDDNPGreatest 18FDDNP

binding in medial temporalbinding in medial temporal

area (amygdala, entorhinalarea (amygdala, entorhinal

cortex & hippocampuscortex & hippocampus

proper). Greater metabolicproper). Greater metabolic

defects, with FDG PET, indefects, with FDG PET, in

laterallateral temporal lobe. Notetemporal lobe. Note

brainstem tagging in AD,brainstem tagging in AD,

suggesting significantsuggesting significant

plaque and/or tangleplaque and/or tangle

burden.burden.

(Holmes, C. et al. (2008) amyloid vaccine

does not slow progression of AD dementia


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does not slow progression of AD dementia

too little too late . . . or wrong idea all together?

Plaques vs. tanglesPlaques vs. tangles Linkage ofLinkage of


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q gq g gg

these markers still not elucidated.these markers still not elucidated. Genetics of AD favor process related toGenetics of AD favor process related toAA .. Neuropsychology of AD favors process related toNeuropsychology of AD favors process related to NFT,NFT, asas

tangling density predicts regional decline/atrophy.tangling density predicts regional decline/atrophy. Beta amyloid pathway, when genetically mutated (FAM AD)Beta amyloid pathway, when genetically mutated (FAM AD)

yields same progressive tangling as sporadic ADyields same progressive tangling as sporadic AD butbut No accepted explanation links spatial & temporal distributionNo accepted explanation links spatial & temporal distribution

of NFT to distribution of Aof NFT to distribution of A. If A. If A NFT, why do regionsNFT, why do regionsw/ highestw/ highestAA not have highest NFT?not have highest NFT?

Recent suggestions:Recent suggestions: intraintra--cellularcellularAA and small oligomersand small oligomersmay drive pathway into NFT. NFT: marker for oxidativemay drive pathway into NFT. NFT: marker for oxidative

stress associated with upregulated stress kinases?stress associated with upregulated stress kinases? Deposition ofDeposition ofAA isis upstreamupstream of tangling & regional failure.of tangling & regional failure. Likely multiple cell pathways interpolated betweenLikely multiple cell pathways interpolated betweenAA &&

NFT. Would stopping progression of NFT stop decline?NFT. Would stopping progression of NFT stop decline? Markers for oxidative stress in CNS appear before eitherMarkers for oxidative stress in CNS appear before either

plaques or tangles. Plaques appear before tangles.plaques or tangles. Plaques appear before tangles.

MesulamMesulams theory linking known risks theory linking known riskf l i i i


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factors to neuroplasticity issues.factors to neuroplasticity issues.

Recent work underlines additional risk factors: hyperRecent work underlines additional risk factors: hyper--

lipidemialipidemia, obesity, serious ischemic change, diabetes,, obesity, serious ischemic change, diabetes,

low education, recurrent depression, ? PTSD.low education, recurrent depression, ? PTSD.

Oxidative Stress & Inflammation:Oxidative Stress & Inflammation:R l ti hi t Pl & T l ?Rel tion hip to Pl q e & T ngle ?


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Relationship to Plaques & Tangles?Relationship to Plaques & Tangles? Roughly 1Roughly 1--2% of absorbed O2% of absorbed O22 forms free radicalsforms free radicals 10101111 perper

cell/daycell/day mostly MITO (mitochondrial).mostly MITO (mitochondrial).

In animal models, OS markersIn animal models, OS markers (lipid OS)(lipid OS) appearappear BEFOREBEFOREAA/NFT./NFT.

Reduced MITO enzymes in AD expose other parts of cell (lackingReduced MITO enzymes in AD expose other parts of cell (lackingprotective mechanisms in MITO) toprotective mechanisms in MITO) to OS (HOS (H22OO22 and ONOO).and ONOO).

Antioxidant defensesAntioxidant defenses (esp.(esp. hemeheme oxygenaseoxygenase) promote tau) promote tauphosphorylation via GSK3phosphorylation via GSK3 PHF & neurofibrillary tangling.PHF & neurofibrillary tangling.

AA accumulates, creating OS extraaccumulates, creating OS extra--cellularlycellularly (via lipid membranes)(via lipid membranes)and intraand intra--cellularlycellularly (via many organelles).(via many organelles).

AA plaques irritate (and even attract) glial cellsplaques irritate (and even attract) glial cells INFLAM and OSINFLAM and OSfrom this, particularly upregulation of profrom this, particularly upregulation of pro--inflammatory cytokines.inflammatory cytokines.

AA plaques contain Feplaques contain Fe++++

(disturbed iron homeostasis)(disturbed iron homeostasis) OS (HOS (H22OO22)) PHF oftenPHF often glycatedglycated, promoting INFLAM, and increasing APP/A, promoting INFLAM, and increasing APP/A.. OSOS

upregulates APP and Aupregulates APP and A via stress kinase pathways (JNK and p38).via stress kinase pathways (JNK and p38).

Conclusions: OS precedesConclusions: OS precedes AA/NFT, but/NFT, but AA increases INFLAM &increases INFLAM &

OSOS vicious circle of OS/INFLAM/NFT driving synaptic loss.vicious circle of OS/INFLAM/NFT driving synaptic loss.

Oxidative Stress, Inflammation, Intra/ExtraOxidative Stress, Inflammation, Intra/ExtraCellular Amyloid Phosphorylation of TauCellular Amyloid Phosphorylation of Tau


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Cellular Amyloid, Phosphorylation of Tau,Cellular Amyloid, Phosphorylation of Tau,

Synaptic Loss and Eventual ApoptosisSynaptic Loss and Eventual Apoptosis

TANGLING &

APOPTOSIS

INFLAM and more OXIDATIVE STRESSINFLAM and more OXIDATIVE STRESS

FENTONFENTON

CHEMISTRYCHEMISTRY

PeroxynitritePeroxynitrite as mediator betweenas mediator between


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plaques and tangles?plaques and tangles? AA deposits stimulate production of NO/superoxidedeposits stimulate production of NO/superoxide

through activating microglia andthrough activating microglia and astrocytesastrocytes..

PeroxynitritePeroxynitrite (from NO + superoxide) upstream effector(from NO + superoxide) upstream effectorfor tau phosphorylation.for tau phosphorylation. In recent study, research group (Zhang et al.) injectedIn recent study, research group (Zhang et al.) injected

SINSIN--1 (1 (peroxynitriteperoxynitrite generator) bilaterally into rat HC.generator) bilaterally into rat HC. Levels of nitrated andLevels of nitrated and hyperphosphorylatedhyperphosphorylated tau markedlytau markedly

increased immediately after drug administration (~ hrs).increased immediately after drug administration (~ hrs). GSKGSK--33 involved ininvolved in peroxynitriteperoxynitrite--induced tau hyperinduced tau hyper--

phosphorylationphosphorylation

. Phosphorylated tau degraded efficiently

. Phosphorylated tau degraded efficientlyby proteasomes, but nitrated tau more resistant.by proteasomes, but nitrated tau more resistant.

However, did not cause cell death, and tau alterationsHowever, did not cause cell death, and tau alterationswere reversed within 48 hrs.were reversed within 48 hrs.

More longMore long--term studies will be necessary (OS long termterm studies will be necessary (OS long termissue).issue).


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IntracellularIntracellular --AmyloidAmyloid driving adriving adestructive cascadedestruct ive cascadePromotes tangles, synapticPromotes tangles, synaptic

CaCa++++ channel dysfunction,channel dysfunction,inhibits proteasomes,inhibits proteasomes,increasesincreases oxidative stress,oxidative stress,decreases mitochondrialdecreases mitochondrialenergy generation. APOE 4energy generation. APOE 4alleleallele pproduction &roduction &uptake ofuptake ofA.A.

How to reduce thisHow to reduce this? In? In

animal models:animal models: DHA,DHA, CHOL, NMDA blockade,CHOL, NMDA blockade,multiple polyphenols (esp.multiple polyphenols (esp.turmeric, resveratrol &turmeric, resveratrol &

EGCG), andEGCG), and homocystine.homocystine.

LeFerla et al, NRN, 2007


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Inflammation andInflammation and

Neuroplasticity: TwoNeuroplasticity: Two

Sides of the AD Equation?Sides of the AD Equation?Cytokines Regulate Neuroplasticity, Sleep and Other CNS FunctionCytokines Regulate Neuroplasticity, Sleep and Other CNS Functionss

ProPro--Inflammatory Cytokines Show UInflammatory Cytokines Show U--Shaped Functional Curve in CognitionShaped Functional Curve in CognitionDepression of Neuroplasticity is Primary Consequence of InflammaDepression of Neuroplasticity is Primary Consequence of Inflammationtion

Current Treatments Have Focused Solely on Neuroplasticity SideCurrent Treatments Have Focused Solely on Neuroplasticity SidePrediction: Future Treatments Will Address InflammationPrediction: Future Treatments Will Address Inflammation

Inflammation in CNS:Inflammation in CNS: DecreasedDecreasedl /Pl ti it /N i & A t i


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Plasticity/Neurogenesis &Plasticity/Neurogenesis &ApoptosisApoptosis Activated microglia actually consume AActivated microglia actually consume A in an antibodyin an antibody--dependentdependent

fashion and organize inflammatory responses. May be mixed bagfashion and organize inflammatory responses. May be mixed bagyields majoryields major in proin pro--INFLAM cytokines.INFLAM cytokines.

Markers for CNS inflammation (glial activation) correlate w/ amyMarkers for CNS inflammation (glial activation) correlate w/ amyloidloiddeposition but precede atrophy/tangling by many years.deposition but precede atrophy/tangling by many years.

AA is potent activator of release of ILis potent activator of release of IL--11, IL, IL--6, TNF6, TNF--, NO and NOS, NO and NOSby glial cells. ILby glial cells. IL--11 also promotes amyloid precursor protein.also promotes amyloid precursor protein.

InterferonInterferon-- promotes above process: suggests basic forpromotes above process: suggests basic for

comorbidity of depression/AD as comorbidities of INFLAM.comorbidity of depression/AD as comorbidities of INFLAM. TNFTNF-- promotes GLU toxicity and Ca++ channel overload,promotes GLU toxicity and Ca++ channel overload,

depresses neuroplasticity. Both TNFdepresses neuroplasticity. Both TNF-- and ILand IL--11 decrease LTP.decrease LTP.

ProPro--INFLAM cytokines depress neurogenesis/stem cells and causeINFLAM cytokines depress neurogenesis/stem cells and cause

overover--selection of apoptosisselection of apoptosis neuroplasticity challenge & failure.neuroplasticity challenge & failure. Serum levels of ILSerum levels of IL--6 & CRP: modestly predictive re: AD.6 & CRP: modestly predictive re: AD.

Why long time lag between plaque, INFLAM markers and cognitiveWhy long time lag between plaque, INFLAM markers and cognitivedecline/tangling? Suggests unknown intermediate variables.decline/tangling? Suggests unknown intermediate variables.

Treatments for tangling in AlzheimerTreatments for tangling in Alzheimerss


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diseasedisease the neglected biomarker?the neglected biomarker? Two processes of tau phosphorylation & synaptic loss in parallelTwo processes of tau phosphorylation & synaptic loss in parallel..

What about aiming at tangling instead of AWhat about aiming at tangling instead of A?? PeroxynitritesPeroxynitrites contribute to high GSK3 activity, increasingcontribute to high GSK3 activity, increasing

phosphorylation of tau (phosphorylation of tau ( PK B/C, inhibitory of GSK3).PK B/C, inhibitory of GSK3). PeroxynitritesPeroxynitrites decrease PKCdecrease PKC--mediated uptake ofmediated uptake ofcholinecholine and AChand ACh

acetyltransferaseacetyltransferase activity, thusactivity, thus cholinergic activity in BF.cholinergic activity in BF. MethyleneMethylene blueblue peroxynitritesperoxynitrites (limiting(limiting superoxidessuperoxides (produces(produces

peroxynitritesperoxynitrites), in turn producing), in turn producing phosphorylation of tau .phosphorylation of tau . GSK3 promotes phosphorylation ofGSK3 promotes phosphorylation ofkinesinkinesin (vesicle(vesiclecargocargo

protein), inhibiting axonal transport, promoting synaptic loss.protein), inhibiting axonal transport, promoting synaptic loss. Most interesting new treatment might be ADMost interesting new treatment might be AD--108, based on108, based on

fragment of ADNP (fragment of ADNP (activity dependent neuroprotective proteinactivity dependent neuroprotective proteinhuge peptide affecting ~ 400 genes).huge peptide affecting ~ 400 genes). This fragment (NAP or ALThis fragment (NAP or AL--108) is anti108) is anti--tangle agent and alsotangle agent and also

appears to be very promoting of neuroplasticity and synapticappears to be very promoting of neuroplasticity and synapticfunction (and thus is antifunction (and thus is anti--AD).AD).


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NAP (fragment of larger neuro-

protective/trophic peptide)


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Cholinergic Issues inCholinergic Issues in


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Cholinergic Issues inCholinergic Issues in

AlzheimerAlzheimers Disease:s Disease:

Therapy Opportunities,Therapy Opportunities,Links to Neuroplasticity ChallengeLinks to Neuroplasticity Challenge

Where is ACh decline in AD:Where is ACh decline in AD:Possible Interactions?


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Possible Interactions?Possible Interactions?

ACh promotesACh promotes (alpha) secretase ((alpha) secretase (sAPPsAPP) which blocks A) which blocks A.. BF ACh tangling is excellent marker for severity of AD.BF ACh tangling is excellent marker for severity of AD. ACh deprivation (from BF tangling) leads to corticalACh deprivation (from BF tangling) leads to cortical

dysfunction and likely neuroplasticity challenge/decrement.dysfunction and likely neuroplasticity challenge/decrement. AA blocks ACh synthesis and ACh neurotransmission in BF.blocks ACh synthesis and ACh neurotransmission in BF. ACh deprivation promotes AACh deprivation promotes A pathway (positive feedback)?pathway (positive feedback)? In PD, exposure to antiIn PD, exposure to anti--ACh drugs predicts AD/AACh drugs predicts AD/A & tangles.& tangles. MM11 receptors preserved in cortex, nicotine receptors and Mreceptors preserved in cortex, nicotine receptors and M22

more affected/pruned out. Muscarinic agonists?more affected/pruned out. Muscarinic agonists? ACh modulates effects of central cytokines, reducing potentialACh modulates effects of central cytokines, reducing potential

for delirium in peripheral infection.for delirium in peripheral infection. ACh deprivation is not primary correlate of STM troubles butACh deprivation is not primary correlate of STM troubles but

may be very relevant to vulnerability to confusional states.may be very relevant to vulnerability to confusional states. Increased ACh tone promotes neuroplasticity and decreasesIncreased ACh tone promotes neuroplasticity and decreases

propro--INFLAM cytokines, while raising ILINFLAM cytokines, while raising IL--4.4. Recent study shows that chronic antiRecent study shows that chronic anti--ACh drugs increase riskACh drugs increase risk

for developing AD, suggesting thatfor developing AD, suggesting that ACh tone is etiologicACh tone is etiologic..

Cholinergic Systems in ADCholinergic Systems in AD


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Possible Interactions Between CholinergicPossible Interactions Between CholinergicDeficit Infection and Synaptic DysfunctionDeficit Infection and Synaptic Dysfunction


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Deficit, Infection and Synaptic DysfunctionDeficit, Infection and Synaptic Dysfunction

Proposed sequence of events in system ic infection:Proposed sequence of events in systemic infection: (A) Peripherally produced pro(A) Peripherally produced pro--inflammatory cytokinesinflammatory cytokines(TNF(TNF ) enter CNS, activate microglia producing inflammatory mediators) enter CNS, activate microglia producing inflammatory mediators affecting neuronal fxn, causing delirium.affecting neuronal fxn, causing delirium.Cholinergic inhibition modulatesCholinergic inhibition modulates microglialmicroglial activation and limits severity and duration of delirium. (B) Inactivation and limits severity and duration of delirium. (B) In somesomesituations, microglia might already be primed, which leads to ovsituations, microglia might already be primed, which leads to overer--activation on new stimuli. If cholinergicactivation on new stimuli. If cholinergicinhibition also fails, due to preinhibition also fails, due to pre--existing neurodegeneration or drugs with anticholinergic effectsexisting neurodegeneration or drugs with anticholinergic effects, inflammation, inflammationcould spin out of control, leading to severe prolonged delirium.could spin out of control, leading to severe prolonged delirium. The green arrows indicate 4 ways in which controlThe green arrows indicate 4 ways in which controlcould be recould be re--established over activated microglia: (1) direct inhibition ofestablished over activated microglia: (1) direct inhibition ofmicroglialmicroglial activation by antiactivation by anti--inflammatoryinflammatorytreatment (treatment (egeg,, minocyclineminocycline); (2) inhibition of effects of cytokines (); (2) inhibition of effects of cytokines (egeg, anti, anti--TNFTNF ); augmentation of inhibitory); augmentation of inhibitorycholinergic control by (3) nicotinecholinergic control by (3) nicotine--receptorreceptor ligandsligands or (4)or (4) cholinomimeticcholinomimetic drugs (drugs (egeg, cholinesterase inhibitors)., cholinesterase inhibitors).

van Gool et. al., 2010


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Treatment of ADTreatment of ADMore than Just ACh RxMore than Just ACh RxAlthough no single Rx isAlthough no single Rx isdiseasedisease--modifying,modifying,

multimulti--agent Rx might be.agent Rx might be.

ACh, NMDA, OmegaACh, NMDA, Omega--3, polyphenols, exercise for now3, polyphenols, exercise for nowTreatments on the Frontier?Treatments on the Frontier?
http://www.ncbi.nlm.nih.gov/pubmed?term=%22M%C3%BCnch%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Carlson%20DA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Engel%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Martins%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Sharman%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Kenklies%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Hager%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Maczurek%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract


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Multimodal treatment approachesMultimodal treatment approaches


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Integrated treatment approach improves cognitive function in demIntegrated treatment approach improves cognitive function in demented andented and

clinically depressed patients.clinically depressed patients.

BraginBragin VV,, ChemodanovaChemodanova MM,, DzhafarovaDzhafarova NN,, BraginBragin II,, CzerniawskiCzerniawski JLJL,, AlievAliev GG..

Stress Relief and Memory Training Center, Brooklyn, New York, USStress Relief and Memory Training Center, Brooklyn, New York, USA.A.

The purpose of this study was to evaluate the efficacy of an intThe purpose of this study was to evaluate the efficacy of an integrative treatment approachegrative treatment approach

on cognitive performance. The study sample comprised 35 medicallon cognitive performance. The study sample comprised 35 medically ill patients (20 male,y ill patients (20 male,

15 female) with an average age of 71.05, who were diagnosed with15 female) with an average age of 71.05, who were diagnosed with mild dementia andmild dementia anddepression. These patients were evaluated at baseline and at sixdepression. These patients were evaluated at baseline and at six, 12, and 24 months of, 12, and 24 months of

treatment, which included antidepressants (treatment, which included antidepressants (sertralinesertraline, citalopram, or, citalopram, orvenlafaxinevenlafaxine XR, aloneXR, alone

or in combination withor in combination withbupropionbupropion XR), cholinesterase inhibitors (XR), cholinesterase inhibitors (donepezildonepezil,, rivastigminerivastigmine

ororgalantaminegalantamine), as well as vitamins and supplements (multivitamins, vitamin E), as well as vitamins and supplements (multivitamins, vitamin E, alpha, alpha--

lipoic acid, omegalipoic acid, omega--3 and coenzyme Q3 and coenzyme Q--10). Patients were encouraged to modify their diet10). Patients were encouraged to modify their dietand lifestyle and perform mild physical exercises.and lifestyle and perform mild physical exercises. RESULTS SHOW THAT THERESULTS SHOW THAT THE

INTEGRATIVE TREATMENT NOT ONLY PREVENTED COGNITIVEINTEGRATIVE TREATMENT NOT ONLY PREVENTED COGNITIVE

DECLINES FOR 24 MONTHS BUT EVEN IMPROVED COGNITION RELATIVEDECLINES FOR 24 MONTHS BUT EVEN IMPROVED COGNITION RELATIVE

TO BASELINE, ESPECIALLY MEMORY ANDTO BASELINE, ESPECIALLY MEMORY AND FRONTAL LOBEFRONTAL LOBE FUNCTIONS.FUNCTIONS.

Impact of Lifestyle VariablesImpact of Lifestyle Variables
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+V%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+V%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+V%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+V%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Chemodanova+M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Chemodanova+M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Chemodanova+M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Chemodanova+M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Dzhafarova+N%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Dzhafarova+N%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Dzhafarova+N%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Dzhafarova+N%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+I%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+I%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+I%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+I%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Czerniawski+JL%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Czerniawski+JL%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Czerniawski+JL%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Czerniawski+JL%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Aliev+G%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Aliev+G%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Aliev+G%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Aliev+G%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Aliev+G%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Czerniawski+JL%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+I%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Dzhafarova+N%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Chemodanova+M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bragin+V%22%5BAuthor%5D


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on Oxidative Stress and INFLAM?on Oxidative Stress and INFLAM? Sleep, exercise and diets high in phytochemicals & OmegaSleep, exercise and diets high in phytochemicals & Omega--3 are3 are

antianti--inflammatory and control OS. High phytochemical diets downinflammatory and control OS. High phytochemical diets downregulate inflammation and oxidative stress via several mechanismregulate inflammation and oxidative stress via several mechanisms.s.

Exercise promotes slow wave sleep (which is antiExercise promotes slow wave sleep (which is anti--inflammatory).inflammatory). Exercise up regulates antioxidant defense mechanisms (adaptiveExercise up regulates antioxidant defense mechanisms (adaptive

response to increased oxidative stress in exercising organism).response to increased oxidative stress in exercising organism). Social comfort decreases stress, and stress promotes inflammatioSocial comfort decreases stress, and stress promotes inflammation.n.

High phytochemical diets also reduce glycation of protein as doeHigh phytochemical diets also reduce glycation of protein as doessexercise. Advanced glycation end products promote inflammation.exercise. Advanced glycation end products promote inflammation. Inflammation itself promotes oxidative stress.Inflammation itself promotes oxidative stress. Oxidative stress damages mitochondrial DNAOxidative stress damages mitochondrial DNA eventual cellulareventual cellular

failure and programmed cell death.failure and programmed cell death. All lifestyle issues thus impinge on biggies of OS, INFLAM, GLYCAll lifestyle issues thus impinge on biggies of OS, INFLAM, GLYCAA

and promote either LT cellular protection or cellular degradatioand promote either LT cellular protection or cellular degradation.n.

How are Modern LifestylesHow are Modern Lifestyles ADAD(& Other Diseases Of Aging)?(& Other Diseases Of Aging)?


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(& Ot e seases O g g)( g g)EVOLUTIONARYEVOLUTIONARY

ENVIRONMENTENVIRONMENT

1)1) Intense aerobic exerciseIntense aerobic exercise

2)2) High phytochemical dietsHigh phytochemical diets

3)3) OmegaOmega--6/Omega6/Omega--3 ratio3 ratiobetween 4:1 to 2:1between 4:1 to 2:1

4)4) Calorie limitations (Calorie limitations (caloriecalorierestrictionrestriction))

5)5) 9+ hours sleep (see #1)9+ hours sleep (see #1)

6)6) Intimate social groupsIntimate social groups

7)7) High stress related toHigh stress related tohomeostatic needshomeostatic needs

CURRENT TECHNOLOGICCURRENT TECHNOLOGIC

ENVIRONMENTENVIRONMENT

1)1) Little aerobic exerciseLittle aerobic exercise

2)2) Low phytochemical dietsLow phytochemical diets

3)3) OmegaOmega--6/Omega6/Omega--3 ratio3 ratiobetween 20:1 to 40:1between 20:1 to 40:1

4)4) Unlimited calories (Unlimited calories (caloriecalorieenhancementenhancement))

5)5) 7 or less hours of sleep7 or less hours of sleep

6)6) Social isolation commonSocial isolation common

7)7) High stress related to socialHigh stress related to socialneeds & other issuesneeds & other issues

Conclusions:Conclusions: We are in an alien environment from the standpoint of our genomeWe are in an alien environment from the standpoint of our genome,,one promoting inflammation, oxidative stress, glycation of proteone promoting inflammation, oxidative stress, glycation of proteins, and longins, and long--termtermbiological failure. Promotion of Diseases of Aging is a primarybiological failure. Promotion of Diseases of Aging is a primary consequence.consequence.

Alzheimer's Disease New 6

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