5/5/2010. Good Brain. Bad Brain

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1 Gregory A. Jicha, M.D. Ph.D. Assistant Professor of Neurology UK Alzheimer s Disease Center Sanders Brown Center on Aging There are now more than million people in the United States living with Alzheimer s, almost 8, here in KY Every 72 seconds, someone develops Alzheimer s s, with to 4 new cases per day in KY alone Kentucky ranks 8 th in state death rates/, population for Alzheimer s Kentucky ranks th in state rates for nursing home residents with cognitive impairment Deat th rates per K population AD Deat th rates per K population Heart disease Death rates per K population Neoplasm Death rates per K population CVD DSM IV Criteria Memory and at least one other cog domain involved Impaired general cognitive function Social, educational, occupational function impaired No medically reversible cause found Good Brain Bad Brain

2 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 4 9 Absence of other systemic/brain disorders Hypertension Diagnosis Treatment Adaptation to disease process Prevention of complications End stage of the disease process Diagnosis This is easy Drug Trade Name Diuretics (partial list) Calcium antagonists ACE inhibitors and diuretics Chlorthalidone (G) Hygroton Nondihydropyridines Benazepril hydrochloride and hydrochlorothiazide Hydrochlorothiazide (G) Hydrodiuril, Diltiazem hydrochloride Cardizem SR, Cardizem Lotensin HCT Microzide, Esidrix CD, Dilacor XR, Tiazac Captopril and hydrochlorothiazide Capozide Indapamide Lozol Verapamil hydrochloride Isoptin SR, Calan SR Enalapril maleate and hydrochlorothiazide Metolazone Mykrox, Zaroxolyn Verelan, Covera HS Vaseretic Lisinopril and hydrochlorothiazide Prinzide, Loop diuretics Dihydropyridines Zestoretic Bumetanide (G) Bumex Amlodipine besylate Norvasc Ethacrynic acid Edecrin Felodipine Plendil Furosemide(G) Lasix Isradipine DynaCirc, DynaCirc CR Angiotensin II receptor antagonists and Torsemide Demadex Nicardipine Cardene SR diurectics Nifedipine Procardia XL, Adalat CC Losartan potassium and hydrochlorothiazide Nisoldipine Sular Hyzaar Potassium sparing agents Amiloride hydrochloride (G) Midamor Calcium antagonists and ACE inhibitors Spironolactone (G Aldactone ACE inhibitors Amlodipinbesylate and benazepril hydrochloride Triamterene (G) Dyrenium Benazepril hydrochloride Lotensin Lotrel Captopril (G) Capoten Diltiazem hydrochloride and enalapril maleate Enalapril maleate Vasotec Teczem Adrenergic inhibitors Fosinoprilsodium Monopril Verapamil hydrochloride (extended release) and Peripheral agents Lisinopril Prinivil, Zestril trandolapril Tarka Felodipine and enalapril Reserpine (G) Serpasil Moexipril Univasc maleate Lexxel Central alpha agonists Clonidine Quinapril hydrochloride Accupril Other combinations Triamterene and hydrochloride (G) Catapres Ramipril Altace o e ea Guanabenz acetate (G) Wytensin Trandolapril Mavik hydrochlorothiazide Dyazide, Maxide Spironolactone and hydrochlorothiazide Guanfacine hydrochloride (G) Tenex Aldactazide Methyldopa (G) Aldomet Angiotensin II receptor blockers Amiloride hydrochloride and hydrochlorothiazide Alpha blockers Losartan potassium Cozaar Moduretic Doxazosinmesylate Cardura Valsartan Diovan Guanethidine monosulfate and Prazosinhydrochloride (G) Minipress Irbesartan Avapro hydrochlorothiazide Esimil Terazosin hydrochloride Hytrin Hydralazine hydrochloride and hydrochlorothiazide Apresazide Beta blockers (G) indicates generic available. Methyldopa and hydrochlorothiazide Acebutolol Sectral Aldoril Atenolol (G) Tenormin Reserpine and hydrochlorothiazide Betaxolol Kerlone Drug Hydropres Bisoprololfumarate Zebeta Trade Name (Combination Drugs) Reserpine hydralazine hydrochloride, and Carteolol hydrochloride Cartrol Beta adrenergic blockers and diuretics hydrochlorothiazide Metoprolol tartrate (G) Lopressor Atenolol and chlorthalidone Tenoretic Ser Ap Es Metoprolol succinate Toprol XL Bisoprololfumarate and hydrochlorothiazide Ziac Clonidine hydrochloride and chlorthalidone Nadolol(G) Corgard Metoprolol tartrate and hydrochlorothiazide Combipres Penbutololsulfate Levatol LopressorHCT Methyldopa and chlorothiazide Pindolol(G) Visken Nadololand bendroflumethiazide Corzide Aldochlor Propranolol hydrochloride (G) Inderal, Propranolol hydrochloride and Reserpine and chlorthalidone Inderal LA hydrochlorothiazide Inderide Demi Regroton Timolol maleate (G) Blocadren Propranolol hydrochloride and hydrochlorothiazide Reserpine and chlorothiazide (extended release) Inderide LA Diupres Combined alpha and beta blockers Timolol maleate and hydrochlorothiazide Timolide Prazosinhydrochloride and polythiazide Carvedilol Coreg Minizide Labetalol hydrochloride (G) Normodyne, Trandate Direct vasodilators Hydralazine hydrochloride (G) Apresoline Minoxidil (G) Loniten 2

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4 Deat th rates per K population AD Deat th rates per K population Heart disease Death rates per K population Neoplasm Death rates per K population CVD 96 first description of Auguste D. age 976 cholinergic deficit in AD discovered 984 b amyloid discovered as key component of AD plaques 986 tau protein discovered as key component of NFT Alzheimer s disease pathology 4

5 ) 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 ) amyloid is toxic to cells and accumulates in brain tissue as amyloid plaques, a hallmark of the disease A 42 Aggregated A A Amyloid plaques APP Oxidative Stress Nerve cell death & Alzheimer s disease Tau Hyperphosphorylated tau Increasing severiity of disease NFTs PHF NFT Amyloid plaques

6 Check for reversible causes of dementia MMSE or other bedside cognitive testing? 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 (B2) 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 B2 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 blockers 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. Memory loss. 2. Difficulty performing familiar tasks.. Problems with language. 4. Disorientation to time and place.. Poor or decreased d judgment. 6. Problems with abstract thinking. 7. Misplacing things. 8. Changes in mood or behavior. 9. Changes in personality..loss of initiative. 6

7 M M S E 2 26 Wahlund et al, 999 Psych Res 9(): 9 99 POPULATION E2 8% E 77% E4 % AD E2 4% E 8% E4 8% Shoghi Jadid K, et al. Localization of neurofibrillary tangles and betaamyloid plaques in the brains of living patients with Alzheimer disease Petersen et al., JAMA 99;27: No proven serum biomarkers CSF amyloid and tau are commercially available Not proven yet May not covered by some insurance Biomarker Sensitivity Specificity Sample (n) CSF total tau CSF phospho-tau CSF AB CSF AB+tau Blennow K, NeuroRx. 24 Apr;(2):2 2. Review 7

8 AD Research: the Search for Treatments 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. 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. 6 Improve Delay (years) Year alence of AD U.S. Preva (millions) 6 Decline in ADAS Cog score based on the natural history of 2 untreated patients with moderate Alzheimer s disease* Cumulative Weeks From Baseline of the Double blind Study Decline 98 Brookheimer et al. Am J Pub Health.. 998;88: Rogers SL, Friedhoff, LT. Eur Neuropsychopharmacol. 998;8:67 7. *Stern RG, et al. Am J Psychiatry. 994;:9 96. 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. 29():7 24, 24 Jan 2. 8

9 Normal function % Alzheimer s disease Treated with Memantine Level of detection Level of Function n TIME % Minimal improvement seen in most cases % Level of detection Level of detection Or here? Level of Function n In several years do you want to be here? TIME Or here? Level of Function n In several years do you want to be here? TIME Or here? Or here? Or here? Case : yo Forgetful No functional impairment Tests normal Dx: worried well 2 9

10 Cortical Entorhinal Limbic NFTs Increasing sever rity of disease Amyloid plaques Normal MCI Dementia Case : yo More forgetful No functional impairment Cortical Memory tests abnormal Dx: MCI 2 28 Entorhinal Limbic Normal MCI Dementia

11 MCI Increasing severity of dis sease NFTs Amyloid plaques Cognitive Continuum Normal Mild Cognitive Impairment Dementia al state exam Mini-menta 2 2 memory II Logical MCI AD 2%/yr Control AD -2%/yr Normal MCI AD General cognition Normal MCI Memory AD Initial exam Months Initial exam Months Petersen RC et al: Arch Neurol 6: 8, 999 Petersen RC et al: Arch Neurol 6:-8, 8, 999

12 Neuro imaging with MRI MCI: Conversion to Dementia Stable (%) 7 W Jack CR. In Mild Cognitive Impairment. Ed. RC Petersen, Oxford University Press 2 2 W < W < Years Jack CR. In Mild Cognitive Impairment. Ed. RC Petersen, Oxford University Press 2 6 Improve 6 2 Decline in ADAS Cog score based on the natural history of untreated patients with moderate Alzheimer s disease* Decline Cumulative Weeks From Baseline of the Double blind Study Rogers SL, Friedhoff, LT. Eur Neuropsychopharmacol. 998;8:67 7. *Stern RG, et al. Am J Psychiatry. 994;:9 96. Case : yo Starting to have trouble with ADLs Multiple cognitive domains abnormal Cortical Dx: Early AD 2 22 Entorhinal Limbic Normal MCI Dementia 2

13 Increasing severity of dis sease NFTs Amyloid plaques *** p <. ** p <. Holmes: Neurology, Volume 6(2).July 27,

14 Case : 24 8 yo Even basic ADLs affected Severely fragmented cognitive function Prominent behavioral changes Dx: Late stage AD Cortical 4 Entorhinal Limbic Normal MCI Dementia Increasing severity of dis sease NFTs Amyloid plaques 4

15 Deat th rates per K population AD Deat th rates per K population Heart disease 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. 29():7 24, 24 Jan 2. Death rates per K population Neoplasm Death rates per K population CVD Death rates per K population Deat th rates per K population AD Neoplasm Deat th rates per K population Death rates per K population Heart disease CVD You can help us promote normal, healthy, brain aging for all! Targeting Alzheimer s disease pathology A42 Aggregated A Amyloid plaques APP Tau Oxidative Stress Nerve cell death & Alzheimer s disease Hyperphosphorylated tau PHF NFT

16 DeKosky S, J Am Geriatr Soc. 2 May;( Suppl Dementia):S4 2. Review. Gilman S, Neurology. 2 May ;64(9): 62. Masliah E et al, Neurology. 2 Jan ;64():29. Nichol JA, Nat Med. 2 Apr;9(4):

17 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) 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) TTP488 reduced amyloid load in brains of 9 month old mice Vehicle TTP488 mg/kg ) 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 ) amyloid is toxic to cells and accumulates in brain tissue as amyloid plaques, a hallmark of the disease "Used with the permission of TransTech Pharma and Pfizer, Inc." 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 secretase inhibitor Eli Lilly Inc. Dimebon (mitochondrial pore complex) Medivata & Pfizer collaborative Rember (novel tau antiaggregant therapy) TauRx pharmaceuticals ) 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 ) amyloid is toxic to cells and accumulates in brain tissue as amyloid plaques, a hallmark of the disease 7

18 Maeda J, et al., J Neurosci. 27 Oct ;27(4):97 68 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) ) 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 ) amyloid is toxic to cells and accumulates in brain tissue as amyloid plaques, a hallmark of the disease Relkin N et al., Neurobiol Aging. 28 Feb 2. [Epub ahead of print] 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) A42 Aggregated A Amyloid plaques APP Tau Oxidative Stress Hyperphosphorylated tau PHF NFT Nerve cell death & Alzheimer s disease 8

19 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) Doody et al, Lancet. 28 Jul 9;72(964):27. A42 Aggregated A Amyloid plaques APP Tau Oxidative Stress Nerve cell death & Alzheimer s disease Hyperphosphorylated tau PHF NFT Asuni et al, J Neurosci. 27 Aug 22;27(4):9 29. 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) 9

20 We can t win this fight against AD without you! 2