Gregory A. Jicha, M.D. Ph.D. Assistant Professor of Neurology. Sanders Brown Center on Aging

Transcription

1 Gregory A. Jicha, M.D. Ph.D. Assistant Professor of Neurology UK Alzheimer s Disease Center Sanders Brown Center on Aging

2 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, with ih 3 to 4 new cases per day in KY alone Kentucky ranks 8 th in state death rates/100,000 population for Alzheimer s lh Kentucky ranks 13 th in state rates for nursing home residents with cognitive impairment

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4 Heart disease per 100K population per 100K population AD Death rates Death rates es per 100K population es per 100K population Neoplasm 55 CVD Death rat Death rat

5 The direct and indirect costs of Alzheimer s and other dementias amount to more than $148 billion annually In 2005, Medicare spent $91 bll billion (compared to $117 billion on the Iraq war) for persons with Alzheimer s and other dementias, projected to increase to $160 billion by 2010 and $189 billion by 2015 Congress spent only $647 million on AD research in 2005

6 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

7 Good Brain Bad Brain

8 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 Absence of other systemic/brain disorders

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

10 Diagnosisi This is easy

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

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25 Heart disease per 100K population per 100K population AD Death rates Death rates es per 100K population es per 100K population Neoplasm 55 CVD Death rat Death rat

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27 Heart disease per 100K population per 100K population AD Death rates Death rates es per 100K population es per 100K population Neoplasm 55 CVD Death rat Death rat

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29 1906 first description of Auguste D. age cholinergic deficit in AD discovered 1984 b amyloid discovered as key component of AD plaques 1986 tau protein discovered as key component of NFT

30 Alzheimer s disease pathology

31 1) APP is a membrane bound glycoprotein gy 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

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33 Amyloid plaques Increasing severity of diseasee NFTs

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35 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 id& tau

36 V subdural hematoma, reversible posterior leukoencephalopathy l h 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)

37 Clinical cause of MCI following Medical evaluation per AAN practice parameter Probable degenerative B12 deficiency thyroid dysfunction vascular NPH SDH

38 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

39 1. Memory loss. 2. Difficulty performing familiar tasks. 3. Problems with language. 4. Disorientation i ti to time and place. 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.

40 3 M 5 M 3 5 M S 1 2 E 1 3 E

41 Wahlund et al, 1999 Psych Res 90(3):

42 Smith et al, Neurology Apr 17;68(16):

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

44 Rowe CC et al., Imaging beta amyloid burden in aging and dementia. Neurology May 15;68(20):

45 POPULATION E2 8% E3 77% AD E2 4% E3 58% E4 15% E4 38% Petersen et al., JAMA 1995;273:

46 No proven serum biomarkers CSF amyloid and tau are commercially available Not proven yet Not covered by most insurance

47 Biomarker Sensitivity Specificity Sample (n) CSF total tau CSF phospho-tau CSF AB CSF AB+tau Blennow K, NeuroRx Apr;1(2): Review

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49 Intervention: Primary Prevention Secondary Prevention Treatment Clinical State Normal Pre- symptomatic AD Mild Cognitive Impairment AD Brain Pathologic State No Disease No Symptoms Early Brain AD Brain Changes Changes No Symptoms Mild Symptoms Moderate to Severe Impairment Disease Progression National Institute on Aging, USA.

50 AD Research: the Search for Causes Epidemiologic Studies Scientists examine characteristics, lifestyles, and disease rates of groups of people to gather clues about possible causes of AD. The NIA is currently funding epidemiologic studies in a variety of different groups. Two of the studies focus on religious communities. Researchers conduct yearly exams of physical and mental status, and studies of donated brains at autopsy. Some early results indicate: Mentally stimulating activity protects the brain in some ways. In early life, higher skills in grammar and density of ideas are associated with protection against AD in late life.

51 Green R & DeKosky S, Neurology Nov 14;67(9 Suppl 3):S2 5.

52 f developing AD Risk of Zandi PP et al, JAMA Nov 6;288(17):

53 Schumaker et al, JAMA Jun 23;291(24):

54 McGeer & McGeer, Neurobiol Aging May;28(5):

55 2,528 subjects 4 year duration NSAIDs actually increased the risk of developing AD ADAPT Research Group, Neurology May 22;68(21):

56 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.

57 Delay (years) Year e of AD U.S. Prevalenc (millio ons) Brookheimer et al. Am J Pub Health ;88:

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59 6 Improve 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. 1998;8: *Stern RG, et al. Am J Psychiatry. 1994;151:

60 *** p < ** p < Holmes: Neurology, Volume 63(2).July 27,

61 Normal function Alzheimer s disease Treated with Memantine

62 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.

63 100% Level of detection TIME Level of Function

64 100% Minimal i improvement seen in most cases Level of detection of Func ction Or here? Level In several years do you want to be here? TIME

65 100% Level of detection Or here? of Func ction Or here? Or here? Level In several years do you want to be here? TIME Or here?

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67 Case 1: yo 3 Forgetful No functional impairment 5 Tests normal Dx: worried well

68 Entorhinal Limbic Cortical Normal MCI Dementia

69 Amyloid plaques Increasing severity of disease NFTs

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72 Case 1: yo 3 More forgetful No functional impairment 5 Memory tests abnormal Dx: MCI

73 Entorhinal Limbic Cortical Normal MCI Dementia

74 Increasing severity of diseasee MCI NFTs Amyloid plaques

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77 Cognitive Continuum Normal Mild Cognitive Impairment Dementia

78 Mini- Logical 10 mental memory 15 state II 8 exam Normal MCI AD 0 Normal MCI AD General cognition Memory Petersen RC et al: Arch Neurol 56: , 1999

79 MCI AD 12%/yr Control AD 1-2%/yr Initial exam Months 50 Initial exam Months Petersen RC et al: Arch Neurol 56: , 308, 1999

80 Neuro imaging with MRI Jack CR. In Mild Cognitive Impairment. Ed. RC Petersen, Oxford University Press 2003

81 MCI: Conversion to Dementia Stable (%) 50 W W < W < Years Jack CR. In Mild Cognitive Impairment. Ed. RC Petersen, Oxford University Press 2003

82 6 Improve 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. 1998;8: *Stern RG, et al. Am J Psychiatry. 1994;151:

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84 Case 1: yo 3 Starting to have trouble with ADLs Multiple cognitive domains abnormal 5 Dx: Early AD

85 Entorhinal Limbic Cortical Normal MCI Dementia

86 Amyloid plaques Increasing severity of diseasee NFTs

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91 *** p < ** p < Holmes: Neurology, Volume 63(2).July 27,

92 Case 1: yo Even basic ADLs affected Severely fragmented cognitive function Prominent behavioral changes Dx: Late stage AD

93 Entorhinal Limbic Cortical Normal MCI Dementia

94 Amyloid plaques Increasing severity of diseasee NFTs

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98 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.

99 Heart disease per 100K population per 100K population AD Death rates Death rates es per 100K population es per 100K population Neoplasm 55 CVD Death rat Death rat

100 Heart disease per 100K population per 100K population AD Death rates Death rates es per 100K population es per 100K population Neoplasm 55 CVD Death rat Death rat

101 You can help us promote normal, healthy, brain aging g for all!