41 Dementia Jicha - UK HealthCare CECentralJackCR. In MildCognitive Impairment. Ed. RC Petersen,...

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Gregory A. Jicha, M.D. Ph.D.Assistant Professor of NeurologyUK Alzheimer’s Disease CenterSanders‐Brown Center on Aging

There are now more than 5 million people in the United States living with Alzheimer’s, almost 80,000 here in KY

Every 72 seconds someone develops Alzheimer’s Every 72 seconds, someone develops Alzheimer s, with 3 to 4 new cases per day in KY alone

Kentucky ranks 8th in state death rates/100,000 population for Alzheimer’s

Kentucky ranks 13th in state rates for nursing home residents with cognitive impairment

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Neoplasm CVD

Memory and at least one other cog domain involved

DSM‐IV Criteria

Impaired general cognitive function

Social, educational, occupational function impaired

No medically reversible cause found

Good Brain Bad Brain

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Alzheimer’s disease (NINDS‐ADRDA)

•Dementia by DSM‐III‐R/V criteria

•Deficits in two or more areas of cognition

•Progressive worsening of memory and cognitive dysfunction

•Onset age 40‐90

•Absence of other systemic/brain disorders

Hypertension Hypertension Diagnosis Treatment Adaptation to disease process Prevention of complications End stage of the disease process

Diagnosis This is easy…

DrugTrade NameDiuretics (partial list)Chlorthalidone (G)‐HygrotonHydrochlorothiazide (G)‐Hydrodiuril, Microzide, EsidrixIndapamide‐ LozolMetolazone‐Mykrox, Zaroxolyn

Loop diureticsBumetanide (G)‐ BumexEthacrynic acid‐ EdecrinFurosemide(G)‐ LasixTorsemide‐Demadex

Potassium‐sparing agentsAmiloridehydrochloride (G)‐MidamorSpironolactone (G‐AldactoneTriamterene (G)‐Dyrenium

Adrenergic inhibitorsPeripheral agentsReserpine (G)‐ SerpasilCentral alpha‐agonistsClonidine

Calcium antagonistsNondihydropyridinesDiltiazemhydrochloride‐Cardizem SR, CardizemCD, Dilacor XR, TiazacVerapamil hydrochloride‐ Isoptin SR, Calan SR Verelan, Covera HS

DihydropyridinesAmlodipinebesylate‐NorvascFelodipine‐ PlendilIsradipine‐DynaCirc, DynaCirc CRNicardipine‐ Cardene SRNifedipine‐Procardia XL, Adalat CCNisoldipine‐Sular

ACE inhibitorsBenazepril hydrochloride‐LotensinCaptopril (G)‐ CapotenEnalapril maleate‐ VasotecFosinopril sodium‐MonoprilLisinopril‐Prinivil, ZestrilMoexipril‐ UnivascQuinapril hydrochloride‐AccuprilRamipril‐Altace

ACE inhibitors and diureticsBenazepril hydrochloride and hydrochlorothiazide‐LotensinHCTCaptopril and hydrochlorothiazide‐CapozideEnalapril maleate and hydrochlorothiazide‐VasereticLisinopril and hydrochlorothiazide‐Prinzide, Zestoretic

Angiotensin II receptor antagonists and diurecticsLosartanpotassium and hydrochlorothiazide‐Hyzaar

Calcium antagonists and ACE inhibitorsAmlodipinbesylate and benazepril hydrochloride‐LotrelDiltiazemhydrochloride and enalapril maleate‐TeczemVerapamil hydrochloride (extended release) and trandolapril Tarka‐ Felodipine and enalaprilmaleate‐ Lexxel

Other combinations Triamterene and hydrochloride (G)‐ CatapresGuanabenz acetate (G)‐WytensinGuanfacine hydrochloride (G)‐ TenexMethyldopa (G)‐Aldomet

Alpha‐blockersDoxazosinmesylate‐ CarduraPrazosinhydrochloride (G)‐MinipressTerazosin hydrochloride‐Hytrin

Beta‐blockersAcebutolol‐SectralAtenolol (G)‐ TenorminBetaxolol‐ KerloneBisoprolol fumarate‐ ZebetaCarteolol hydrochloride‐CartrolMetoprolol tartrate (G)‐ LopressorMetoprolol succinate‐ Toprol‐XLNadolol (G)‐ CorgardPenbutolol sulfate‐ LevatolPindolol (G)‐ ViskenPropranolol hydrochloride (G)‐ Inderal, Inderal LATimololmaleate (G)‐ Blocadren

Combined alpha‐ and beta‐blockersCarvedilol‐ CoregLabetalol hydrochloride (G)‐Normodyne, Trandate

Direct vasodilatorsHydralazine hydrochloride (G)‐ApresolineMinoxidil (G)‐ Loniten

Ramipril‐AltaceTrandolapril‐Mavik

Angiotensin II receptor blockersLosartanpotassium‐ CozaarValsartan‐DiovanIrbesartan‐Avapro

(G) indicates generic available.

DrugTrade Name (Combination Drugs) Beta‐adrenergic blockers and diureticsAtenolol and chlorthalidone‐ TenoreticBisoprolol fumarate and hydrochlorothiazide‐ZiacMetoprolol tartrate and hydrochlorothiazide‐LopressorHCTNadololand bendroflumethiazide‐ CorzidePropranolol hydrochloride and hydrochlorothiazide‐ InderidePropranolol hydrochloride and hydrochlorothiazide (extended release)‐ Inderide LATimololmaleate and hydrochlorothiazide‐Timolide

Ot e co b at o s a te e e a dhydrochlorothiazide‐Dyazide, Maxide Spironolactone and hydrochlorothiazideAldactazideAmiloridehydrochloride and hydrochlorothiazideModureticGuanethidinemonosulfate and hydrochlorothiazideEsimilHydralazine hydrochloride and hydrochlorothiazideApresazideMethyldopa and hydrochlorothiazideAldorilReserpine and hydrochlorothiazideHydropresReserpine hydralazine hydrochloride, and hydrochlorothiazideSer‐Ap‐EsClonidine hydrochloride and chlorthalidoneCombipresMethyldopa and chlorothiazideAldochlorReserpine and chlorthalidoneDemi‐RegrotonReserpine and chlorothiazideDiupresPrazosinhydrochloride and polythiazideMinizide

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Neoplasm CVD

1906‐ first description of Auguste D. age 51

1976‐ cholinergic deficit in AD discovered

1984‐ b‐amyloid discovered as key component of AD plaques

1986‐ tau protein discovered as key component of NFT

Alzheimer’s disease pathology

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1)APP is a membrane‐bound glycoprotein that may serve as a growth factor in injury and repair

2)APP is normally cleaved by ‐secretase and ‐secretase, but in AD, ‐secretase is active

3) ‐amyloid is toxic to cells and accumulates in brain tissue as amyloid plaques, a hallmark of the disease

Aggregated AAggregated AAA4242 AmyloidAmyloid plaquesplaques

TauTau

PHFPHF NFTNFT

Nerve cell death & Nerve cell death & Alzheimer’s diseaseAlzheimer’s diseaseOxidative StressOxidative Stress

APPAPP

HyperphosphorylatedHyperphosphorylated tautau

Increasing severi

NFTsAmyloid plaques

ity of disease

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Check for reversible causes of dementia MMSE or other bedside cognitive testing? Imaging studies? Imaging studies? MRI, PET, SPECT, PIB

Genetic testing? ApoE status

Biomarkers? CSF amyloid & tau

V‐subdural hematoma, reversible posterior leukoencephalopathy

I‐Syphilis, HIV, PML T‐trauma, NPH, drugs A‐SLE, Sjogren’s, MS M‐Thyroid, Wernicke’s, Wilson’s, SCD (B12) I‐Vasculitis, Hashimoto’s N‐neoplasm, limbic encephalitis S‐nonconvulsive status (EPC)

Clinical cause of MCI following Medical evaluation per AAN practice parameter

Probable degenerative

B12 deficiency

thyroid dysfunction

vascular

NPH

SDH

Benzodiazepines: valium, ativan NSAIDs: ASA, ibuprofen, indomethacin, naproxen, sulindac Antidepressants: TCAs, SSRIs Anticonvulsants: PHT, VPA, CBZ, PHB Antihypertensives: B‐blockers, Ca‐channel blockersyp , H2 receptor antagonists: cimetidine, ranitidine Antibiotics: Cephalexin, metronidazole, fluoroquinolones Anticholinergics: Benztropine, trihexiphenidyl Antiarrhythmics: disopyramide, quinidine, tocanaide, amiodarone Antiparkinson agents: L‐DOPA, pergolide, bromocriptine Muscle relaxants: Baclofen, cyclobenzaprine, methocarbamol Others: antihistamines/decongestants, digoxin, steroids, narcotics

1. Memory loss. 2. Difficulty performing familiar tasks. 3. Problems with language. 4. Disorientation to time and place.P d d j d 5. Poor or decreased judgment.

6. Problems with abstract thinking. 7. Misplacing things. 8. Changes in mood or behavior. 9. Changes in personality. 10.Loss of initiative.

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MM

121311126

SE

Wahlund et al, 1999 Psych Res 90(3): 193‐199

Shoghi‐Jadid K, et al. Localization of neurofibrillary tangles and beta‐amyloid plaques in the brains of living patients with Alzheimer disease

POPULATION

E2 8%

AD

E2 4%

E3 77%

E4 15%

E3 58%

E4 38%

Petersen et al., JAMA 1995;273:1274‐1278

No proven serum biomarkers

CSF amyloid and tau are commercially available CSF amyloid and tau are commercially available

Not proven yet

May not covered by some insurance

BiomarkerBiomarker SensitivitySensitivity SpecificitySpecificity Sample (n)Sample (n)

CSF total tauCSF total tau 81.481.4 91.591.5 30273027

CSFCSFCSF CSF phosphophospho--tautau 81.381.3 91.291.2 15881588

CSF AB42CSF AB42 85.985.9 88.588.5 12011201

CSF AB+tauCSF AB+tau 89.389.3 90.290.2 11951195

Blennow K, NeuroRx. 2004 Apr;1(2):213‐25. Review

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Drugs used to treat mild to moderate AD symptoms include:

• Aricept (donepezil)

• Exelon (rivastigmine)

• Razadyne (galantamine)

• Namenda (memantine)

• These drugs can help improve some patients’ abilities to carry out activities up to a year or so but they do not stop or reverse

AD Research: the Search for Treatments

out activities up to a year or so, but they do not stop or reverse AD.

Scientists are also studying agents that someday may be useful in preventing AD. For example, they have experimented with a vaccine against AD. Although the first clinical trial was stopped due to side effects in some participants, valuable information was gathered.

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. Pre

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.S. P

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Delay Delay (years)(years)

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19971997 2007200720172017 20272027

20372037 20472047

YearYear

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00

Brookheimer et al. Brookheimer et al. Am J Pub HealthAm J Pub Health. 1998;88:1337. 1998;88:1337--1342.1342.

‐6

0

6

Improve

Rogers SL, Friedhoff, LT. Eur Neuropsychopharmacol. 1998;8:67‐75.*Stern RG, et al. Am J Psychiatry. 1994;151:390‐396.

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Decline in ADAS‐Cog scorebased on the natural history ofuntreated patients with moderateAlzheimer’s disease* Decline

0 6 12

Cumulative Weeks From Baseline of the Double‐blind Study

9862 74 8526 38 5014

Tariot PN. Farlow MR. Grossberg GT. Graham SM. McDonald S. Gergel I. Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 291(3):317‐24, 2004 Jan 21.

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Normal functionNormal function

Alzheimer’s Alzheimer’s diseasedisease

Treated with Treated with MemantineMemantine

n

100%

Level of detection

Leve

l of F

unction

TIME

n

100%

Level of detection

Minimal improvement seen in most cases

Leve

l of F

unction

TIME

In several years do you want to be here?

Or here? n100%

Level of detection

Or here?

Leve

l of F

unction

TIME

In several years do you want to be here?

Or here?

Or here?

Or here?

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Case 1: 1995

72 yo ♂

Forgetful

No functional impairment

Tests normal32

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Tests normal

Dx: “worried well”

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C

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Normal MCI Dementia

Ento

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c

Increasing sever

NFTsAmyloid plaques

rity of disease

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Case 1: 1996

73 yo ♂

More forgetful

No functional impairment

Memory tests abnormal12

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Memory tests abnormal

Dx: MCI

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Normal MCI Dementia

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Increasing severity of dis

MCI

NFTsAmyloid plaques

sease

Cognitive Continuum

NormalNormal

Mild CognitiveMild CognitiveMild CognitiveMild CognitiveImpairmentImpairment

DementiaDementia

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NormalNormal MCIMCI ADAD

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NormalNormal MCIMCI ADAD

Logi

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Logi

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MemoryMemory

Petersen RC et al: Arch Neurol 56:303‐308, 1999

MCI MCI AD 12%/yrAD 12%/yr Control Control AD 1AD 1--2%/yr2%/yr

90

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90

100

Petersen RC et al: Arch Neurol 56:303Petersen RC et al: Arch Neurol 56:303--308, 1999308, 1999

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Initial 12 24 36 48exam Months

Initial 12 24 36 48exam Months

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Neuro‐imaging with MRI

Jack CR. In Mild Cognitive Impairment. Ed. RC Petersen, Oxford University Press 2003

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100

StableStable(%)(%)

W W 00

MCI: Conversion to DementiaMCI: Conversion to Dementia

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25

0 1 2 3 4 5 6

( )( )

YearsYears

--2.5 < W

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Increasing severity of dis

NFTsAmyloid plaques

sease

*** p < 0.0001** p < 0.005

Holmes: Neurology, Volume 63(2).July 27, 2004.214‐219

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0

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0

Case 1: 200481 yo ♂

Even basic ADLs affected

Severely fragmented cognitive function

Prominent behavioral changes

Dx: Late stage AD

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Normal MCI Dementia

Ento

rhin

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Li

mbi

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Increasing severity of disNFTs

Amyloid plaquessease

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Tariot PN. Farlow MR. Grossberg GT. Graham SM. McDonald S. Gergel I. Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 291(3):317‐24, 2004 Jan 21.

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You can You can help us help us promote promote promote promote normal, normal, healthy, healthy, brain brain

aging for aging for all!all!

Targeting Alzheimer’s disease pathology


TauTau

PHFPHF NFTNFT


APPAPP


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DeKosky S, J Am Geriatr Soc. 2003 May;51(5 Suppl Dementia):S314‐20. Review. Gilman S, Neurology. 2005 May 10;64(9):1553‐62.

Masliah E et al, Neurology. 2005 Jan 11;64(1):129‐31. Nichol JA, Nat Med. 2003 Apr;9(4):448‐52.

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RAGE Inhibitor study NIH/NIA/ADCS & Pfizer collaborative

Passive immunization trial Elan/Wyeth pharmaceutical trial

GLAD (gamma‐globulin liquid in Alzheimer’s disease) NIH/NIA/ADCS & Baxter collaborative

Dimebon (mitochondrial pore complex) Medivata & Pfizer collaborative

Rember (novel tau antiaggregant therapy) TauRx pharmaceuticals

S‐Connect (Souvenaid nutritional drink for AD) Danone (that’s German for Dannon, as in yogurt)







1) APP is a membrane‐bound glycoprotein that may serve as a growth factor in injury and repair



TTP488 1mg/KgVehicle

TTP488 reduced amyloid load in brains of 9 month old mice

"Used with the permission of TransTech Pharma and Pfizer, Inc."




‐secretase inhibitor Eli Lilly Inc.






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Maeda J, et al., J Neurosci. 2007 Oct 10;27(41):10957‐68










Relkin N et al., Neurobiol Aging. 2008 Feb 20. [Epub ahead of print]








TauTau

PHFPHF NFTNFT


APPAPP


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Doody et al, Lancet. 2008 Jul 19;372(9634):207‐15.








TauTau

PHFPHF NFTNFT


APPAPP


Asuni et al, J Neurosci. 2007 Aug 22;27(34):9115‐29.







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We can’t win this fight

against AD without you!

41 Dementia Jicha - UK HealthCare CECentralJackCR. In MildCognitive Impairment. Ed. RC Petersen,...

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